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Sample records for nf-kb expression ameliorates

  1. Astragalus polysaccharides suppress ICAM-1 and VCAM-1 expression in TNF-α-treated human vascular endothelial cells by blocking NF-KB activation

    Institute of Scientific and Technical Information of China (English)

    Yu-ping ZHU; Tao SHEN; Ya-jun LIN; Bei-dong CHEN; Yang RUAN; Yuan CAO; Yue QIAO

    2013-01-01

    Aim:To investigate the effects ofAstragalus polysaccharides (APS) on tumor necrosis factor (TNF)-α-induced inflammatory reactions in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanisms.Methods:HUVECs were treated with TNF-α for 24 h.The amounts of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1) were determined with Western blotting.HUVEC viability and apoptosis were detected using cell viability assay and Hoechst staining,respectively.Reactive oxygen species (ROS) production was measured by DHE staining.Monocyte and HUVEC adhesion assay was used to detect endothelial cell adhesive function.NF-KB activation was detected with immunofluorescence.Results:TNF-α (1-80 ng/mL) caused dose-and time-dependent increases of ICAM-1 and VCAM-1 expression in HUVECs,accompanied by significant augmentation of IKB phosphorylation and NF-KB translocation into the nuclei.Pretreatment with APS (10 and 50 μg/mL)significantly attenuated TNFα-induced upregulation of ICAM-1,VCAM-1,and NF-KB translocation.Moreover,APS significantly reduced apoptosis,ROS generation and adhesion function damage in TNF-α-treated HUVECs.Conclusion:APS suppresses TNFα-induced adhesion molecule expression by blocking NF-KB signaling and inhibiting ROS generation in HUVECs.The results suggest that APS may be used to treat and prevent endothelial cell injury-related diseases.

  2. The expressions of NF-kb and TGFb-1 on odontoblast-like cells of human dental pulp injected with propolis extracts

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    Ira Widjiastuti

    2014-03-01

    Full Text Available Background: Propolis is known to have beneficial effects, namely anti- bacterial, anti-viral, anti-inflammatory, antioxidant, and immunomodulatory. Propolis extracts with anti-inflammatory properties are expected to be useful in treating inflamed pulp tissue with a diagnosis of reversible pulpitis. The inflammation of pulp tissue is caused by bacteria, namely Lactobacillus acidophilus. This research used odontoblast like cells derived from pulp tissue of human third molars. Odontoblast like cells exposed to Lactobacillus achidophilus were used as a model of proinflammatory cytokine signaling. This research examined the effects of propolis extracts on odontoblast like cells exposed to Lactobacillus acidophilus. Purpose: This research was aimed to determine the effectiveness of propolis extracts on the activities of odontoblast-like cells exposed to Lactobacillus acidophillus by measuring the expressions of NFkb and TGF- b1. Methods: First, pulp odontoblast cultures were derived from human dental pulp tissues of impacted third molars removed by using digestion method. Next, odontoblast-like cells exposed to inactive Lactobacillus acidophilus bacteria were given propolis extract. Finally, the activities of odontoblast-like cells were monitored by measuring the expressions of NF-kb and TGFb-1 with immunocytochemistry technique. Results: A decline NF-kb expression and on increase of TGFb-1 expression on odontoblast like cells exposed to inactive Lactobacillus acidophilus. Conclusion: Propolis extracts inhibit the expression of NF-kb, and increase the expression of TGF-b1 in pulp odontoblast-like cells exposed to inactive Lactobacillus acidophillus.Latar belakang: Propolis dilaporkan mempunyai efek menguntungkan yaitu bersifat anti bakteri, anti virus, anti inflamasi, anti oksidan, dan imunomodulator. Ekstrak propolis dengan sifat anti inflamasi diharapkan bermanfaat untuk mengobati jaringan pulpa yang mengalami inflamasi dengan diagnosis pulpitis

  3. A Role for the NF-kb/Rel Transcription Factors in Human Breast Cancer

    Science.gov (United States)

    1998-07-01

    cell system. We initiated our studies using the human fibrosar- coma cell line HT1080 , which is relatively resistant to killing by TNF (4... fibrosarcoma cell line . This cell line was chosen since it is highly resistant to killing by TNF. Expression of IKBOC blocks NF-KB nuclear translocation...To potentially block the activation of NF-KB in response to TNF stimulation, we established an HT1080 cell line (HT1080I) expressing a

  4. Quercetin and Vitamin C Mitigate Cobalt Chloride-Induced Hypertension through Reduction in Oxidative Stress and Nuclear Factor Kappa Beta (NF-Kb) Expression in Experimental Rat Model.

    Science.gov (United States)

    Ajibade, Temitayo Olabisi; Oyagbemi, Ademola Adetokunbo; Omobowale, Temidayo Olutayo; Asenuga, Ebunoluwa Racheal; Adigun, Kabirat Oluwaseun

    2017-02-01

    The objective of the present work was to evaluate the toxic effects of cobalt chloride, a potent oxidative stress-inducing chemical, at 650 ppm in rats and the protective effect of quercetin and/or vitamin C against the cobalt chloride-induced toxicity. Thirty rats were randomly selected, and assigned to one of five groups: control, cobalt chloride, cobalt chloride + quercetin, cobalt chloride + vitamin C and cobalt chloride + quercetin + vitamin C. The exposure of rats to cobalt chloride led to a significant increase (p cobalt chloride on MDA, H2O2 and NO, more potently than with either of the two antioxidants, and increased the antioxidant defence system. Further, treatment of rats with quercetin and vitamin C in combination resulted in significant (p cobalt chloride alone. Immunohistochemical studies revealed a greater expression of nuclear factor kappa beta (NF-kB) in the cobalt chloride group compared with the control- and antioxidants-treated rats. The results of this study suggest a protective role for quercetin and vitamin C in the amelioration of the toxic mechanisms leading to cobalt chloride-induced hypertension and its associated cardiac and renal complications in rats.

  5. Bcl-2、NF-KB在腮腺腺样囊性癌中的表达及临床意义%Expression and clinical significance of Bcl-2、NF-KB in adenoid cystic carcinoma of the parotid gland

    Institute of Scientific and Technical Information of China (English)

    张新华; 南欣荣

    2013-01-01

    目的:探讨Bcl-2和NF-KB在腮腺腺样囊性癌中的表达及意义.方法:应用免疫组化SP法检侧49例腮腺腺样囊性癌和20例正常腮腺组织中Bcl-2和NF-KB的表达情况,统计学分析采用x2检验,P<0.05判断为具有显著性差异.结果:Bcl-2和NF-KB的表达强度显著高于正常腮腺组织(P<0.05),Bcl-2、NF-KB的表达与病理无关(P>0.05),与TNM分期有关,Bcl-2和NF-KB两者存在正相关性(P<0.05,Kappa=0.387).结论:在腮腺腺样囊性癌的发生、发展过程中NF-KB通过上调Bcl-2的表达发挥作用.%Objective To explore the expression and Clinical Significance of Bcl-2,NF-KB in in Adenoid Cystic Carcinoma of the Parotid Gland.Methods Detected the expression of Bcl-2,NF-KB gene protein in 49 cases of adenoid cystic carcinoma of parotid gland was block embedded tissue in Immunohistochemistry SP method,20 cases of normal parotid tissue as control.Using x2 test,the statistically significant difference is defined as P<0.05.Results The total expression rate of Bcl-2 and NF-KB in adenoid cystic carcinoma group are significantly higher than the normal parotid group (P<0.05),the expression of different pathological typing of Bcl-2 and NF-KB are no differences (P > 0.05),the expression of clinical TNM stage of Bcl-2 and NF-KB are differences (P<0.05).There is positive correlation between Bcl-2 and NF-KB (P<0.05 kappa=0.387).Conclusion NF-KB plays a important role by up-regulating the expression of Bcl-2 in the occurrence and development process of adenoid cystic carcinoma of parotid gland.

  6. Combination of Aloe vera and xenograft induction on decreasing of NF-kb of tooth extraction socket preservation in Cavia cobaya

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    Utari Kresnoadi

    2014-03-01

    Full Text Available Background: Tooth extraction can naturally cause inflammation triggering osteoclast proliferation and alveolar bone resorption. Preservation of the tooth extraction sockets is needed for patients in order to reduce alveolar bone resorption risks. Aloe vera is known to have anthraquinones components, namely Aloin, Aloe emedin, and barbaloin, considered as anti-inflammation. Therefore, to overcome the inflammation, the role of NF-kb is very significant to decrease nuclear factor kappa b (NF-kb. As a result, inflammation risks will be decreased. Purpose: The study was aimed to determine the induction effect of combination of Aloe vera and XCB into tooth extraction sockets to reduce inflammation by reducing NF-kb expression, osteoclasts and osteoblasts. Methods: Forty-eight Cavia cobaya were divided into eight groups, each group consisted of six animals. The mandibular incisors of those Cavia cobaya were extracted and induced with either PEG, XCB, Aloe vera, or the combination of Aloe vera + XCB. Those animals were sacrificed on day 7 and day 30 after the extraction. Then immunohistochemical and histopathology examinations were conducted to observe NF-kb expression, osteoblasts and osteoclasts. Results: It was known that in group induced with the combination of Aloe vera and xenograft concelous bovine, the growth of osteoblasts was high, while NF-kb expression and osteoclasts reduced. Conclusion: It can be concluded that the induction of the combination of Aloe vera and XCB into the tooth extraction sockets can reduce NF-kb expression and osteoclast, as a result, alveolar bone resorption risks decrease, and osteoblast increase.Latar belakang: Trauma mekanis akibat pencabutan gigi asli menyebabkan keradangan. Keradangan memicu proliferasi osteoklas sehingga menyebabkan resorpsi tulang alveolararis. Pada pembuatan gigi tiruan, resorpsi tulang alveolar yang terjadi, sangat tidak diinginkan, sebab resorpsi tulang alveolar mengurangi keberhasilan

  7. Changes of NF-KB activity in colon carcinoma cells treated with different crude extracts of abrotani herba

    Institute of Scientific and Technical Information of China (English)

    Feng Pan; Yuying Chen; Li Yang; Zhiheng Bian; Houjie Liang

    2008-01-01

    Objective: To study changes of NF-KB activity in colon carcinoma cell lines treated with different crude extracts of abrotani herba obtained through solvent extraction methods.Methods: Crude extracts of abrotani herba were extracted with ligarine, chloroform, acetoacetate and n-butanol in separating funnel.Exposure concentration of crude extracts were obtained through detecting viability of HT-29 cells by MTT.Then HT-29 cells and Lovo cells were treated with different crude extracts respectively.Changes of NF-KB activity in HT-29 cells and Lovo cells using different crude extracts were observed by EMSA.Results: Successfully extracted different crude extracts of abrotani herba and called them ligarine extract, chloroform extract,acetoacetate extract, n-butanol extract and remaining extract for short.NF-KB activity was significantly inhibited in HT-29 cells treated with chloroform extract, there were no significant differences in other groups compared with the control.The same change of NF-KB activity was observed in Lovo calls using different crude extracts of abrotani herba.Conclusion: NF-KB activity can be inhibited in colon carcinoma HT-29 calls and Lovo cells treated with chloroform extract obtained from abrotani herba through the method of solvent extraction.

  8. Sirt1 overexpression protects murine osteoblasts against TNF-α-induced injury in vitro by suppressing the NF-KB signaling pathway

    Institute of Scientific and Technical Information of China (English)

    Wei HUANG; Wei-lin SHANG; Hua-dong WANG; Wen-wen WU; Shu-xun HOU

    2012-01-01

    Sirtuin 1 (Sirt1) is the class III histone/protein deacetylase that interferes with the NF-KB signaling pathway,thereby has antiinflammatory function.This study was undertaken to investigate whether Sirt1 could protect osteoblasts against TNF-α-induced injury in vitro.Methods:Murine osteoblastic cell line,MC3T3-E1,was used.Overexpress of Sirt1 protein in MC3T3-E1 cells was made by transfection the cells with Sirt1-overexpressing adenovirus.The levels of mRNAs and proteins were determined with qRT-PCR and Western blotting,respectively.The activity of NF-κB was examined using NF-κB luciferase assay.The NO concentration was measured using the Griess method.Results:Treatment of MC3T3-E1 cells with TNF-α (2.5-10 ng/mL) suppressed Sirt1 protein expression in a concentration-dependent manner.TNF-α (5 ng/mL) resulted in an increase in apoptosis and a reduction in ALP activity in the cells.Overexpression of Sirt1in the cells significantly attenuated TNF-α-induced injury through suppressing apoptosis,increasing ALP activity,and increasing the expression of Runx2 and osteocalcin mRNAs.Furthermore,overexpression of Sirt1 in the cells significantly suppressed TNF-α-induced NF-κB activation,followed by reducing the expression of iNOS and NO formation.Sirt1 activator resveratrol (10 μmol/L) mimicked the protection of the ceils by Sirt1 overexpression against TNF-α-induced injury,which was reversed by the Sirt1 inhibitor EX-527 (5μmol/L).Conclusion:Overexpression of Sirt1 protects MC3T3-E1 osteoblasts aganst TNF-α-induced cell injury in vitro,at least in part,via suppressing NF-KB signaling.Sirt1 may be a novel therapeutic target for treating rheumatoid arthritis-related bone loss.

  9. The Activation of RAGE and NF-KB in Nerve Biopsies of Patients with Axonal and Vasculitic Neuropathy.

    Science.gov (United States)

    Bekircan-Kurt, Can Ebru; Tan, Ersin; Erdem Özdamar, Sevim

    2015-09-01

    The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor expressed in tissues and cells, which plays a role in immunity. The activation of RAGE results in the translocation of nuclear factor kappa B (NF-κB) to the nucleus for expression of proinflammatory molecules. The role of the RAGE pathway in the pathogenesis of diabetic complications is well determined. We aimed to investigate the role of the RAGE pathway in axonal and vasculitic neuropathy. We immunoreacted nerve biopsy samples from 17 axonal neuropathy (AN), 11 vasculitic neuropathy (VN) and 12 hereditary neuropathy (as a control group) with liability to pressure palsy (HNPP) patients with antibodies to NF-κB and RAGE. Subsequently, we performed double staining with the antibodies to NF-κB or RAGE and T cells, macrophages and Schwann cells. RAGE and NF-κB immunoreactivities were higher in the perivascular cuff and in endoneurial cells in VN than in AN and HNPP. Although there is no significant difference, nerve biopsies with AN showed higher NFκB and RAGE immunoreactivities than HNPP. The colocalization study showed that most of the NFκB- and RAGE-positive cells were CD8 (+) T cells in VN. In AN, all NFκB- and RAGE-positive cells were macrophages, whereas all NFκB- and RAGE-positive cells were Schwann cells in HNPP. The activation of the RAGE pathway predominant in CD8 (+) T cells underscores its role in VN. In AN patients, the immunoreactivity to NFκB and RAGE in macrophages may support their role in axonal degeneration without inflammatory milieu.

  10. Resveratrol Protects against TNF-α-Induced Injury in Human Umbilical Endothelial Cells through Promoting Sirtuin-1-Induced Repression of NF-KB and p38 MAPK.

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    Wei Pan

    Full Text Available Inflammation and reactive oxygen species (ROS play important roles in the pathogenesis of atherosclerosis. Resveratrol has been shown to possess anti-inflammatory and antioxidative stress activities, but the underlying mechanisms are not fully understood. In the present study, we investigated the molecular basis associated with the protective effects of resveratrol on tumor necrosis factor-alpha (TNF-α-induced injury in human umbilical endothelial cells (HUVECs using a variety of approaches including a cell viability assay, reverse transcription and quantitative polymerase chain reaction, western blot, and immunofluorescence staining. We showed that TNF-α induced CD40 expression and ROS production in cultured HUVECs, which were attenuated by resveratrol treatment. Also, resveratrol increased the expression of sirtuin 1 (SIRT1; and repression of SIRT1 by small-interfering RNA (siRNA and the SIRT1 inhibitor Ex527 reduced the inhibitory effects of resveratrol on CD40 expression and ROS generation. In addition, resveratrol downregulated the levels of p65 and phospho-p38 MAPK, but this inhibitory effect was attenuated by the suppression of SIRT1 activity. Moreover, the p38 MAPK inhibitor SD203580 and the nuclear factor (NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC achieved similar repressive effects as resveratrol on TNF-α-induced ROS generation and CD40 expression. Thus, our study provides a mechanistic link between resveratrol and the activation of SIRT1, the latter of which is involved in resveratrol-mediated repression of the p38 MAPK/NF-κB pathway and ROS production in TNF-α-treated HUVECs.

  11. D-TRP(8-γMSH Prevents the Effects of Endotoxin in Rat Skeletal Muscle Cells through TNFα/NF-KB Signalling Pathway.

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    Ana Belén Gómez-SanMiguel

    Full Text Available Sepsis induces anorexia and muscle wasting secondary to an increase in muscle proteolysis. Melanocyte stimulating hormones (MSH is a family of peptides that have potent anti-inflammatory effects. Melanocortin receptor-3 (MC3-R has been reported as the predominant anti-inflammatory receptor for melanocortins. The aim of this work was to analyse whether activation of MC3-R, by administration of its agonist D-Trp(8-γMSH, is able to modify the response of skeletal muscle to inflammation induced by lipopolysaccharide endotoxin (LPS or TNFα. Adult male rats were injected with 250 μg/kg LPS and/or 500 μg/kg D-Trp(8-γMSH 17:00 h and at 8:00 h the following day, and euthanized 4 hours afterwards. D-Trp(8-γMSH decreased LPS-induced anorexia and prevented the stimulatory effect of LPS on hypothalamic IL-1β, COX-2 and CRH as well as on serum ACTH and corticosterone. Serum IGF-I and its expression in liver and gastrocnemius were decreased in rats injected with LPS, but not in those that also received D-Trp(8-γMSH. However, D-Trp(8-γMSH was unable to modify the effect of LPS on IGFBP-3. In the gastrocnemius D-Trp(8-γMSH blocked LPS-induced decrease in pAkt, pmTOR, MHC I and MCH II, as well as the increase in pNF-κB(p65, FoxO1, FoxO3, LC3b, Bnip-3, Gabarap1, atrogin-1, MuRF1 and in LC3a/b lipidation. In L6 myotube cultures, D-Trp(8-γMSH was able to prevent TNFα-induced increase of NF-κB(p65 phosphorylation and decrease of Akt phosphorylation as well as of IGF-I and MHC I expression. These data suggest that MC3-R activation prevents the effect of endotoxin on skeletal wasting by modifying inflammation, corticosterone and IGF-I responses and also by directly acting on muscle cells through the TNFα/NF-κB(p65 pathway.

  12. Evidence of correlation between TGFBR2 gene expression mediated by NF-kB signaling pathways and Kawasaki disease in children.

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    Gao, Qinling; Yuan, Shuhua; Yuan, Dawei

    2017-09-15

    We explored the correlation between the TGFBR2 gene that is mediated by NF-kb signaling pathways and the pathogenesis of Kawasaki disease in children. In this study, 43 children with Kawasaki disease from April 2014 to January 2016 at our hospital were selected as the observation group, and 42 healthy children were selected as the control group. The mRNA expression levels of NF-kb gene and TGFBR2 gene in different groups were detected using fluorescence quantitative PCR. The protein expression levels of the NF-kb and TGFBR2 were detected using enzyme-linked immunosorbent assay (ELISA) in different groups. The expression levels of NF-kb and TGFBR2 in the observation group and the control group were detected using immunohistochemistry. Compared to the control group, the mRNA expression levels of NF-kb and TGFBR2 were 12.3 times and 27.5 times as high as those in the control group respectively and there were significant differences between the two groups (pKawasaki disease were significantly higher than those in healthy subjects (pKawasaki disease than that in healthy children (4.5%); there was significant difference between the two groups (pKawasaki disease in children through NF-kB signaling pathways.

  13. Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats

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    Chen-Hwan Cherng

    2014-08-01

    Conclusion: The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats.

  14. Pioglitazone ameliorates nonalcoholic steatohepatitis by down-regulating hepatic nuclear factor-kappa B and cyclooxygenases-2 expression in rats

    Institute of Scientific and Technical Information of China (English)

    ZHAO Jia-sheng; ZHU Feng-shang; LIU Su; YANG Chang-qing; CHEN Xi-mei

    2012-01-01

    Background Pioglitazone is effective in nonalcoholic steatohepatitis (NASH),but the mechanisms of action are not completely understood.This study was designed to investigate the effects of pioglitazone on hepatic nuclear factor-kappa B (NF-κB) and cyclooxygenases-2 (COX-2) expression in NASH rats.Methods Thirty Sprague-Dawley male rats were randomly assigned to a control group (n=10),NASH group (n=10),and pioglitazone treatment group (n=10).Liver tissues were processed for histology by hematoxylin & eosin and Masson stained.Serum alanine aminotransferase (ALT),cholesterol,triglyceride,fasting blood glucose (FBG),fasting insulin (FINS) levels and biochemical parameters of antioxidant enzyme activities,tumor necrosis factor alpha (TNF-α),prostaglandin E2 (PGE2) levels in serum and liver were measured.The mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARy),NF-κB and COX-2 were determined by real-time polymerase chain reaction,Westem blotting and immunohistochemistry.One-way analysis of variance (ANOVA) and Wilcoxon's signed-rank test was used for the statistical analysis.Results There were severe steatosis,moderate inflammatory cellular infiltration and fibrosis in NASH rats.After pioglitazone treatment,steatosis,inflammation and fibrosis were significantly improved compared with the NASH group(X2=20.40,P <0.001; )X2=20.17,P <0.001; X2=13.98,P=0.002).Serum ALT,cholesterol,triglyceride,FBG,FINS levelswere significantly elevated in the NASH group (P <0.05).In the NASH group,total anti-oxidation competence (T-AOC),superoxide dismutase (SOD),catalase (CAT),glutathione peroxidase (GSH-PX) and malondialdehyde (MDA) levels inserum and liver were conspicuous disordered than those parameters in the control group.Meanwhile,TNF-α and PGE2levels in serum and liver were significantly increased compared with the control group.Immunohistochemistry showedNF-KB and COX-2 expression in liver was significantly elevated.However,PPARy level

  15. Genipin inhibits mitochondrial uncoupling protein 2 expression and ameliorates podocyte injury in diabetic mice.

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    Wenjing Qiu

    Full Text Available Diabetic nephropathy (DN is one of the most common causes of end stage renal disease (ESRD in China, which requires renal replacement therapy. Recent investigations have suggested an essential role of podocyte injury in the initial stage of DN. This study investigated the potential therapeutic role of genipin, an active extract from a traditional Chinese medicine, on progression of DN in diabetic mice induced by intraperitoneally injection of streptozocin (STZ. In diabetic mice, orally administration of genipin postponed the progression of DN, as demonstrated by ameliorating body weight loss and urine albumin leakage, attenuating glomerular basement membrane thickness, restoring the podocyte expression of podocin and WT1 in diabetic mice. The protective role of genipin on DN is probably through suppressing the up-regulation of mitochondrial uncoupling protein 2 (UCP2 in diabetic kidneys. Meanwhile, through inhibiting the up-regulation of UCP2, genipin restores podocin and WT1 expression in cultured podocytes and attenuates glucose-induced albumin leakage through podocytes monolayer. Therefore, these results revealed that genipin inhibited UCP2 expression and ameliorated podocyte injury in DN mice.

  16. Lithium ameliorates lipopolysaccharide-induced neurotoxicity in the cortex and hippocampus of the adult rat brain.

    Science.gov (United States)

    Khan, Muhammad Sohail; Ali, Tahir; Abid, Muhammad Noman; Jo, Myeung Hoon; Khan, Amjad; Kim, Min Woo; Yoon, Gwang Ho; Cheon, Eun Woo; Rehman, Shafiq Ur; Kim, Myeong Ok

    2017-09-01

    Lithium an effective mood stabilizer, primary used in the treatment of bipolar disorders, has been reported as a protective agent in various neurological disorders. In this study, we examined the neuroprotective role of lithium chloride (LiCl) against lipopolysaccharide (LPS) in the cortex and hippocampus of the adult rat brain. We determined that LiCl -attenuated LPS-induced activated toll-like receptor 4 (TLR4) signalling and significantly reduced the nuclear factor-kB (NF-KB) translation factor and various other inflammatory mediators such as interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α). We also analyzed that LiCl significantly abrogated activated gliosis via attenuation of specific markers for activated microglia, ionized calcium-binding adaptor molecule (Iba-1) and astrocytes, glial fibrillary acidic protein (GFAP) in both the cortex and hippocampus of the adult rat brain. Furthermore, we also observed that LiCl treatment significantly ameliorated the increase expression level of apoptotic neurodegeneration protein markers Bax/Bcl2, activated caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1) in the cortex and hippocampus regions of the LPS-treated adult rat brain. In addition, the morphological results of the fluoro-jade B (FJB) and Nissl staining showed that LiCl attenuated the neuronal degeneration in the cortex and hippocampus regions of the LPS-treated adult rat brain. Taken together, our Western blot and morphological results indicated that LiCl significantly prevents the LPS-induced neurotoxicity via attenuation of neuroinflammation and apoptotic neurodegeneration in the cortex and hippocampus of the adult rat brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. THE EFFECTS OF NF-KB ON ICAM-1 PROTEIN EXPRESSIONS OF RAT DURA MATER WITH MIGRAINE%NF-κB上调偏头痛大鼠脑膜ICAM-1蛋白表达

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    何秋; 王怀良; 章新华; 陈磊

    2007-01-01

    目的:探讨核转录因子-κB(nuclear factor-kappa B,NF-κB)在偏头痛脑膜炎症反应中的作用及细胞间黏附分子-1(intercellular adhesion molecules-1,ICAM-1)表达的调控机制.方法采用静脉注射(iv)硝酸甘油(glyceryl trinitrate,GTN)法建立大鼠偏头痛模型,分为对照组、模型组、溶剂对照组、吡咯烷二硫氨基甲酸(pyrrolidine dithiocarbamate,PDTC)组.各组分别包括0.9%生理盐水或GTN iv后1.5,4h两个实验小组.应用Western印迹法分别观察PDTC对GTN iv后1.5h大鼠脑膜NF-κB蛋白表达水平与GTN iv后4h ICAM-1蛋白表达水平的影响.结果:PDTC 50,100,200 mg.kg-1各剂量组GTN iv后1.5h大鼠脑膜NF-κB蛋白表达量较模型组分别降低30%(P<0.05)、52%(P<0.01)和65%(P<0.01),呈剂量依赖性;PDTC 50,100,200 mg.kg-1各剂量组GTN iv后4h大鼠脑膜ICAM-1蛋白表达量较模型组分别降低36%(P<0.05)、71%(P<0.01)和51%(P<0.01),无剂量依赖关系.结论:NF-κB参与偏头痛时脑膜ICAM-1的蛋白合成调控,在偏头痛的脑膜炎症机制中起着重要作用.

  18. Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice.

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    Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar

    2012-09-01

    Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioural and neurochemical abnormalities similar to schizophrenia. In this study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg.d, through drinking water) for 30 d significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioural studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signalling plays an important role in GAD67 regulation by cysteamine.

  19. A study of the association between type A behavior pattern and activity of catecholamine/NF-KB/pro-inflammatory cytokines in young persons%青年人群A型行为与儿茶酚胺/核因子κB/促炎因子通路的关系

    Institute of Scientific and Technical Information of China (English)

    宁淑娥; 曲鹏; 魏刚; 宗大飞; 张兴; 隋政; 郑美丽

    2011-01-01

    目的 探讨青年A型行为与儿茶酚胺/核因子kB(NF-icB)/促炎因子通路的关系,为阐明A型行为与心血管疾病关系提供依据.方法 以明尼苏达多相人格调查表2(MMPI-2)A型行为量表评分将900名大一新生(男476人;女424人)分为A型(≥11分,159人)、中间型(6~10分,539人),B型(<5分,202人)3组;采用酶联免疫吸附法检测血清肾上腺素、去甲肾上腺素、白细胞介素(IL)6,IL-18水平.随机在A型,B型、中间型行为者中各抽取8例(男女各4例),抽取各例外周血20 mL,分成5组,分别在5组中加人多巴酚丁胺.,20,30,40和50 umol/L孵育18h后测定各组血清中IL-6和IL-18浓度,然后提取单核细胞用免疫组化法测定NF-KB蛋白表达变化.结果 血清儿茶酚胺浓度与A型行为人格特征呈正相关((r=0.375^0.662,P<0.01);A型组血清肾上腺素、去甲肾上腺(素高于中间型组和B型组;A型行为人格特征与血清IL-6和IL-18浓度呈正相关(r=0.294~0.778,P<0.05或P<0.01).多巴酚丁胺呈剂量依赖性诱导人单核细胞NF-KB/促炎因子通路激活,以40 umol/L多巴酚丁胺为最适宜剂量;40 umol/L多巴酚丁胺诱导激动后,A和B型行为者的单核细胞NF-kB p65及血清IL-6和IL-18均明显上调(P<0.01或P<0.05);A型行为者的单核细胞NF-tcB p65及血清IL-6和IL-18均高于B型行为(P<0.01).结论 A型行为者非应激与应激时借助血清中较高浓度的儿茶酚胺诱导NF-kB/促炎因子通路持续处于激活状态,这可能是青年A型行为者的一个病理生理学特征.%Objective Nuclear factor-KB (NF-kB) and pro-inflammatory cytokines play an important role in initiation and progression of atherosclerosis and coronary disease, type A behavior pattern (TABP) is lifestyle risk factor.The aim of the study was to investigate the association between TABP and activity of/NF-kB/pro-inflammatory cytokines signaling in young persons, and to explore the possible role of catecholamine in inducing activation

  20. Flavonoids Isolated from Flowers of Lonicera japonica Thunb. Inhibit Inflammatory Responses in BV2 Microglial Cells by Suppressing TNF-α and IL-β Through PI3K/Akt/NF-kb Signaling Pathways.

    Science.gov (United States)

    Han, Min Ho; Lee, Won Sup; Nagappan, Arulkumar; Hong, Su Hyun; Jung, Ji Hyun; Park, Cheol; Kim, Hye Jung; Kim, Gi-Young; Kim, GonSup; Jung, Jin-Myung; Ryu, Chung Ho; Shin, Sung Chul; Hong, Soon Chan; Choi, Yung Hyun

    2016-11-01

    Decoctions of the dried flowers of Lonicera japonica Thunb. (Indongcho) have been utilized in folk remedies against various inflammatory diseases, and it is reported neuroprotective effects. The cytokines release from microglia is closely linked to various chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. It is still unknown whether the neuroprotective effects are associated with the antiinflammatory effects. Here, we determined whether polyphenols extracted from lyophilized Lonicera japonica Thunb. (PELJ) would inhibit inflammatory cytokines and mediators. We stimulated microglia with lipopolysaccharide (LPS) to produce inflammatory cytokines, and then assessed the effects of PELJ on these cytokines. PELJ significantly inhibited LPS-induced interleukin-1β and tumor necrosis factor-α expressions and LPS-induced nitric oxide (NO) and prostaglandin E2 expressions by down-regulating inducible enzyme NO synthase and cyclooxygenase-2 at the protein and mRNA levels. All the suppression of these mediators did not cause any significant cytotoxicity. PELJ also inhibited the nuclear translocation of nuclear factor-kappa B and phosphorylated Akt. These findings suggest that PELJ may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases by inhibiting pro-inflammatory cytokines through inhibiting phosphoinositol 3-kinase /Akt/nuclear factor-kappa B signaling pathway. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. FACTOR NUCLEAR κB (NF-κB: SIGNALOSOMA Y SU IMPORTANCIA EN ENFERMEDADES INFLAMATORIAS Y CÁNCER Nuclear factor kB (NF-KB: signalosoma and its importance in cancer and inflammatories diseases

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    Nancy P Echeverri R

    2008-06-01

    bound to inhibitor proteins (IkB. IkB are phosphorilated by different kinases who are part of signalosome as IéB kinases (IKKα, IKKP and NF-κB essential modulator or NEMO, the mitogenic activated protein kinase (MAPK or p38 and NF-éB inducer kinase (NIK. These kinases are activated by different cytokines and ultraviolet light, IkB phosphorilated induce their ubiquitination and proteosome degradation subsequently NF-κB reléase and nucleus translocation. Nowadays, the NF-κB activation by oxidative stress, genotoxic stress and DNA damage pathways. In contrast with the classical pathway, in this pathway there are a SUMOilation and nuclear translocation of NEMO. In nucleus NEMO interact with ataxia telangiectasia muted which is activated by chromatin changes and DNA damage. The complex ATM/NEMO is later translocated to cytoplasm where IKKß is phosphorilated by ATM bringing to ubiquitination and thus NF-κB releasing which is translocated to nucleus. NF-κB induces survival rising antioxidants enzymes as superoxide dismutase, catalase and glutathione. These enzymes act in the control of oxidative species levels in the cell. NF-κB over expression is related with inflammation and cancer. Nowadays, is development a pharmacological search which can act inhibiting NF-κB signalosome molecules, not only to inflammatory disease whereas to radiotherapy and chemotherapy cancer resistance.

  2. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice.

    Science.gov (United States)

    Kanouchi, Hiroaki; Kakimoto, Toshiaki; Nakano, Hideya; Suzuki, Masahiro; Nakai, Yuji; Shiozaki, Kazuhiro; Akikoka, Kohei; Otomaru, Konosuke; Nagano, Masanobu; Matsumoto, Mitsuharu

    2016-01-01

    Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons.

  3. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice

    Science.gov (United States)

    Kanouchi, Hiroaki; Kakimoto, Toshiaki; Nakano, Hideya; Suzuki, Masahiro; Nakai, Yuji; Shiozaki, Kazuhiro; Akikoka, Kohei; Otomaru, Konosuke; Nagano, Masanobu; Matsumoto, Mitsuharu

    2016-01-01

    Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons. PMID:26943920

  4. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice.

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    Hiroaki Kanouchi

    Full Text Available Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w concentrated Kurozu or 0.5% (w/w Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons.

  5. Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

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    Yong-lin Zhao

    2016-01-01

    Full Text Available Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser 404 (p-tau (S 404 , and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S 404 levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.

  6. Puerarin ameliorates experimental alcoholic liver injury by inhibition of endotoxin gut leakage, Kupffer cell activation, and endotoxin receptors expression.

    Science.gov (United States)

    Peng, Jing-Hua; Cui, Tuan; Huang, Fu; Chen, Liang; Zhao, Yu; Xu, Lin; Xu, Li-Li; Feng, Qin; Hu, Yi-Yang

    2013-03-01

    Puerarin, an isoflavone component extracted from Kudzu (Pueraria lobata), has been demonstrated to alleviate alcohol-related disorders. Our study examined whether puerarin ameliorates chronic alcoholic liver injury through inhibition of endotoxin gut leakage, the subsequent Kupffer cell activation, and endotoxin receptors expression. Rats were provided with the Liber-DeCarli liquid diet for 8 weeks. Puerarin (90 mg/kg or 180 mg/kg daily) was orally administered from the beginning of the third week until the end of the experiment. Chronic alcohol intake caused increased serum alanine aminotransferase, aspartate aminotransferase, hepatic gamma-glutamyl transpeptidase, and triglyceride levels as well as fatty liver and neutrophil infiltration in hepatic lobules as determined by biochemical and histologic assays. A significant increase of liver tumor necrosis factor α was detected by enzyme-linked immunosorbent assay. These pathologic effects correlated with increased endotoxin level in portal vein and upregulated protein expression of hepatic CD68, lipopolysaccharide-binding protein, CD14, Toll-like receptor 2, and Toll-like receptor 4. Meanwhile, the intestinal microvilli were observed to be sparse, shortened, and irregularity in distribution under the transmission electron microscope in conjunction with the downregulated intestinal zonula occludens-1 protein expression. These hepatic pathologic changes were significantly inhibited in puerarin-treated animals as were the endotoxin levels and hepatic CD68 and endotoxin receptors. Moreover, the pathologic changes in intestinal microvillus and the decreased intestinal zonula occludens-1 were also ameliorated with puerarin treatment. These results thus demonstrate that puerarin inhibition of endotoxin gut leakage, Kupffer cell activation, and endotoxin receptors expression is involved in the alleviation of chronic alcoholic liver injury in rats.

  7. Coffee and caffeine ameliorate hyperglycemia, fatty liver, and inflammatory adipocytokine expression in spontaneously diabetic KK-Ay mice.

    Science.gov (United States)

    Yamauchi, Rie; Kobayashi, Misato; Matsuda, Yuji; Ojika, Makoto; Shigeoka, Shigeru; Yamamoto, Yuko; Tou, Yoshie; Inoue, Takashi; Katagiri, Takao; Murai, Atsushi; Horio, Fumihiko

    2010-05-12

    Epidemiological surveys have demonstrated that habitual coffee consumption reduces the risk of type 2 diabetes. The aim of this work was to study the antidiabetic effect of coffee and caffeine in spontaneously diabetic KK-A(y) mice. KK-A(y) mice were given regular drinking water (controls) or 2-fold diluted coffee for 5 weeks. Coffee ingestion ameliorated the development of hyperglycemia and improved insulin sensitivity. White adipose tissue mRNA levels of inflammatory cytokines (MCP-1, IL-6, and TNFalpha), adipose tissue MCP-1 concentration, and serum IL-6 concentration in the coffee group were lower than the control group. Moreover, coffee ingestion improved the fatty liver. Caffeine ingestion as drinking water also caused an amelioration of hyperglycemia and an improvement of fatty liver. These results suggest that coffee exerts a suppressive effect on hyperglycemia by improving insulin sensitivity, partly due to reducing inflammatory cytokine expression and improving fatty liver. Moreover, caffeine may be one of the effective antidiabetic compounds in coffee.

  8. Garlic Supplementation Ameliorates UV-Induced Photoaging in Hairless Mice by Regulating Antioxidative Activity and MMPs Expression.

    Science.gov (United States)

    Kim, Hye Kyung

    2016-01-08

    UV exposure is associated with oxidative stress and is the primary factor in skin photoaging. UV-induced reactive oxygen species (ROS) cause the up-regulation of metalloproteinase (MMPs) and the degradation of dermal collagen and elastic fibers. Garlic and its components have been reported to exert antioxidative effects. The present study investigated the protective effect of garlic on UV-induced photoaging and MMPs regulation in hairless mice. Garlic was supplemented in the diet, and Skh-1 hairless mice were exposed to UV irradiation five days/week for eight weeks. Mice were divided into four groups; Non-UV, UV-irradiated control, UV+1% garlic powder diet group, and UV+2% garlic powder diet group. Chronic UV irradiation induced rough wrinkling of the skin with hyperkeratosis, and administration of garlic diminished the coarse wrinkle formation. UV-induced dorsal skin and epidermal thickness were also ameliorated by garlic supplementation. ROS generation, skin and serum malondialdehyde levels were significantly increased by UV exposure and were ameliorated by garlic administration although the effects were not dose-dependent. Antioxidant enzymes such as superoxide dismutase and catalase activities in skin tissues were markedly reduced by UV irradiation and garlic treatment increased these enzyme activities. UV-induced MMP-1 and MMP-2 protein levels were suppressed by garlic administration. Furthermore, garlic supplementation prevented the UV-induced increase of MMP-1 mRNA expression and the UV-induced decrease of procollagen mRNA expression. These results suggest that garlic may be effective for preventing skin photoaging accelerated by UV irradiation through the antioxidative system and MMP regulation.

  9. Garlic Supplementation Ameliorates UV-Induced Photoaging in Hairless Mice by Regulating Antioxidative Activity and MMPs Expression

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    Hye Kyung Kim

    2016-01-01

    Full Text Available UV exposure is associated with oxidative stress and is the primary factor in skin photoaging. UV-induced reactive oxygen species (ROS cause the up-regulation of metalloproteinase (MMPs and the degradation of dermal collagen and elastic fibers. Garlic and its components have been reported to exert antioxidative effects. The present study investigated the protective effect of garlic on UV-induced photoaging and MMPs regulation in hairless mice. Garlic was supplemented in the diet, and Skh-1 hairless mice were exposed to UV irradiation five days/week for eight weeks. Mice were divided into four groups; Non-UV, UV-irradiated control, UV+1% garlic powder diet group, and UV+2% garlic powder diet group. Chronic UV irradiation induced rough wrinkling of the skin with hyperkeratosis, and administration of garlic diminished the coarse wrinkle formation. UV-induced dorsal skin and epidermal thickness were also ameliorated by garlic supplementation. ROS generation, skin and serum malondialdehyde levels were significantly increased by UV exposure and were ameliorated by garlic administration although the effects were not dose-dependent. Antioxidant enzymes such as superoxide dismutase and catalase activities in skin tissues were markedly reduced by UV irradiation and garlic treatment increased these enzyme activities. UV-induced MMP-1 and MMP-2 protein levels were suppressed by garlic administration. Furthermore, garlic supplementation prevented the UV-induced increase of MMP-1 mRNA expression and the UV-induced decrease of procollagen mRNA expression. These results suggest that garlic may be effective for preventing skin photoaging accelerated by UV irradiation through the antioxidative system and MMP regulation.

  10. 芝麻素对代谢综合症大鼠心肌NT、NF-κB和MMP-9蛋白表达的影响%Sesamin represses protein expression of nitrotyrosine, NF-κB and matrix metalloproteinase-9 in myocardium of metabolic syndrome rats

    Institute of Scientific and Technical Information of China (English)

    孔祥; 杨解人; 张明义; 吴向起

    2011-01-01

    目的 探讨芝麻素改善代谢综合症(metabolic syndrome,MS)大鼠心肌重构的作用机制.方法 采用两肾一夹术伴高脂高糖饮食制备MS大鼠模型,灌服不同剂量芝麻素(120、60、30 mg·kg-1·d-1)8周后处死动物,称全心湿重和左心室湿重,测血清总抗氧化能力(total antioxidant capability,T-AOC),Western blot检测心肌硝基酪氨酸(nitrotyrosine,NT)、核因子-κB(NF-κB)和基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)蛋白表达,HE和Masson染色观察心肌病理变化并测定胶原容积分数.结果 与模型组相比,60、120 mg·kg-1芝麻素组全心湿重降低,T-AOC升高,心肌NT、NF-κB和MMP-9蛋白表达降低.120 mg·kg-1芝麻素组左心室湿重和胶原容积分数降低,心肌病理损伤明显改善.结论 芝麻素具有改善MS大鼠心肌重构的作用,其机制除抗氧化应激外,还与下调NF-κB和MMP-9蛋白表达有关.%Aim To investigate the possible in vivo protective effects of sesamin on myocardial remodeling in metabolic syndrome ( MS ) rats.Methods MS rat model was induced by operation of two-kidneys with one-clip and fed with a high-fat, high-sucrose diet.sesamin ( 120, 60 and 30 mg ·kg -1· d-1 ) was orally administered in MS rats.Eight weeks later.rats were sacrificed, heart wet weight ( HWW ) and left ventricle wet weight ( LVWW ) were recorded , total-antioxidative activity ( T-AOC ) in serum was measured, and protein expression of nitrotyrosine ( NT ), NF-KB and matrix metalloproteinase-9 ( MMP-9 ) in myocardium was detected by Western blot.In addition, pathological changes in myocardium were observed with HE and Masson staining and collagen volume fraction ( CVF ) was measured.Results Compared with MS rats, treatment with 120 and 0 mg·kg-1 sesamin decreased HWW.enhanced T-AOC, and reduced NT, NF-KB and MMP9 protein expression.Treatment with 120 mg· kg-1 sesamin decreased LVWW and CVF.and obviously ameliorated myocardial pathologic lesions

  11. 7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

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    Yang Tan

    2016-11-01

    Full Text Available 7,8-Dihydroxyflavone (7,8-DHF, a tyrosine kinase B (TrkB agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. 5-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5mg/kg or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterwards, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP as well as AEP-derived truncated tauN368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt/glycogen synthase kinase-3β (GSK-3β pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope. These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tauN368.

  12. The restrained expression of NF-kB in renal tissue ameliorates folic acid induced acute kidney injury in mice.

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    Dev Kumar

    Full Text Available The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB represent family of structurally-related eukaryotic transcription factors which regulate diverse array of cellular processes including immunological responses, inflammation, apoptosis, growth & development. Increased expression of NF-kB has often been seen in many diverse diseases, suggesting the importance of genomic deregulation to disease pathophysiology. In the present study we focused on acute kidney injury (AKI, which remains one of the major risk factor showing a high rate of mortality and morbidity. The pathology associated with it, however, remains incompletely known though inflammation has been reported to be one of the major risk factor in the disease pathophysiology. The role of NF-kB thus seemed pertinent. In the present study we show that high dose of folic acid (FA induced acute kidney injury (AKI characterized by elevation in levels of blood urea nitrogen & serum creatinine together with extensive tubular necrosis, loss of brush border and marked reduction in mitochondria. One of the salient observations of this study was a coupled increase in the expression of renal, relA, NF-kB2, and p53 genes and proteins during folic acid induced AKI (FA AKI. Treatment of mice with NF-kB inhibitor, pyrrolidine dithio-carbamate ammonium (PDTC lowered the expression of these transcription factors and ameliorated the aberrant renal function by decreasing serum creatinine levels. In conclusion, our results suggested that NF-kB plays a pivotal role in maintaining renal function that also involved regulating p53 levels during FA AKI.

  13. Nanoparticle-Mediated Expression of a Wnt Pathway Inhibitor Ameliorates Ocular Neovascularization

    Science.gov (United States)

    Wang, Zhongxiao; Cheng, Rui; Lee, Kyungwon; Puneet, Tyagi; Ding, Lexi; Kompella, Uday B.; Chen, Jing; Xu, Xun; Ma, Jian-xing

    2015-01-01

    Objective The deficiency of very low-density lipoprotein receptor (VLDLR) resulted in Wnt signaling activation and neovascularization (NV) in the retina. The present study sought to determine if the VLDLR extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues. Approach and Results A plasmid expressing the soluble VLN was encapsulated with poly (lactide-co-glycolide acid) (PLGA) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain (LN-NP) were used as negative control. MTT, modified Boyden chamber and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell (EC) proliferation, migration and tube formation. Vldlr−/− mice, oxygen-induced retinopathy (OIR) and alkali burn-induced corneal NV models were used to evaluate the effect of VLN-NP on ocular NV. Wnt reporter mice (BAT-gal), Western blotting and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced EC proliferation, migration and tube formation. Intravitreal injection of VLN-NP inhibited abnormal NV in Vldlr−/−, OIR and alkali burn-induced corneal NV models, compared with LN-NP. VLN-NP significantly inhibited the phosphorylation of LRP6, the accumulation of β-catenin and the expression of VEGF in vivo and in vitro. Conclusions Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has anti-angiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathologic ocular angiogenesis and potentially other vascular diseases impacted by Wnt signaling. PMID:25657312

  14. Physical activity ameliorates cartilage degeneration in a rat model of aging: a study on lubricin expression.

    Science.gov (United States)

    Musumeci, G; Castrogiovanni, P; Trovato, F M; Imbesi, R; Giunta, S; Szychlinska, M A; Loreto, C; Castorina, S; Mobasheri, A

    2015-04-01

    Osteoarthritis (OA) is a common musculoskeletal disorder characterized by slow progression and joint tissue degeneration. Aging is one of the most prominent risk factors for the development and progression of OA. OA is not, however, an inevitable consequence of aging and age-related changes in the joint can be distinguished from those that are the result of joint injury or inflammatory disease. The question that remains is whether OA can be prevented by undertaking regular physical activity. Would moderate physical activity in the elderly cartilage (and lubricin expression) comparable to a sedentary healthy adult? In this study we used physical exercise in healthy young, adult, and aged rats to evaluate the expression of lubricin as a novel biomarker of chondrocyte senescence. Immunohistochemistry and western blotting were used to evaluate the expression of lubricin in articular cartilage, while enzyme-linked immunosorbent assay was used to quantify lubricin in synovial fluid. Morphological evaluation was done by histology to monitor possible tissue alterations. Our data suggest that moderate physical activity and normal mechanical joint loading in elderly rats improve tribology and lubricative properties of articular cartilage, promoting lubricin synthesis and its elevation in synovial fluid, thus preventing cartilage degradation compared with unexercised adult rats.

  15. Decreased stathmin expression ameliorates neuromuscular defects but fails to prolong survival in a mouse model of spinal muscular atrophy.

    Science.gov (United States)

    Wen, Hsin-Lan; Ting, Chen-Hung; Liu, Huei-Chun; Li, Hung; Lin-Chao, Sue

    2013-04-01

    Spinal muscular atrophy (SMA), a genetic neurodegenerative disorder, is caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene that result in SMN deficiency. SMN deficiency impairs microtubule networks in Smn-deficient cells and in SMA-like motor neuron cultures. Microtubule defects can be restored by knockdown of the stathmin gene (Stmn), which is upregulated in SMA. However, whether in vivo reduction of stathmin levels could improve the pathology of SMA has not been investigated. Here we generated SMA-like mice in a Stmn knockout (KO) background through a series of genetic crosses. Analyses of motor performance and histology showed that heterozygous StmnKO (Stmn(+/-)) but not homozygous StmnKO (Stmn(-/-)) ameliorates some SMA defects, with increased microtubule densities in sciatic axons, improved motor performance, enhanced NMJ maturation, and mitigated neuroinflammation. However, Stmn deletion does not prolong the lifespan of SMA-like mice, suggesting that stathmin dysregulation and microtubule disruption are not a cause but rather a consequence of SMA pathology. This work demonstrates that limiting the amount of stathmin in SMA-like mice is effective in reducing their neuromuscular defects, whereas induced aberrant expression of stathmin in SMA-like animals is detrimental.

  16. Trichoderma inoculation ameliorates arsenic induced phytotoxic changes in gene expression and stem anatomy of chickpea (Cicer arietinum).

    Science.gov (United States)

    Tripathi, Pratibha; Singh, Poonam C; Mishra, Aradhana; Chaudhry, Vasvi; Mishra, Sandhya; Tripathi, Rudra D; Nautiyal, Chandra S

    2013-03-01

    Arsenic, a carcinogenic metalloid severely affects plant growth in contaminated areas. Present study shows role of Trichoderma reesei NBRI 0716 (NBRI 0716) in ameliorating arsenic (As) stress on chickpea under greenhouse conditions. Arsenic stress adversely affected seed germination (25%), chlorophyll content (44%) and almost eliminated nodule formation that were significantly restored on NBRI 0716 inoculation. It also restored stem anomalies like reduced trichome turgidity and density, deformation in collenchymatous and sclerenchymatous cells induced by As stress. Semi-quantitative RT-PCR of stress responsive genes showed differential expression of genes involved in synthesis of cell wall degrading enzymes, dormancy termination and abiotic stress. Upregulation of drought responsive genes (DRE, EREBP, T6PS, MIPS, and PGIP), enhanced proline content and shrunken cortex cells in the presence of As suggests that it creates water deficiency in plants and these responses were modulated by NBRI 0716 which provides a protective role. NBRI0716 mediated production of As reductase enzyme in chickpea and thus contributed in As metabolism. The study suggests a multifarious role of NBRI0716 in mediating stress tolerance in chickpea towards As. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Deletion of IL-18 Expression Ameliorates Spontaneous Kidney Failure in MRLlpr Mice.

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    Bastian Schirmer

    Full Text Available The role of IL-18 in the pathogenesis of systemic lupus erythematosus is still not definitively solved. In this study, we generated MRLlpr mice, which develop a disease resembling systemic lupus erythematosus, genetically devoid of IL-18 expression. These mice in comparison to IL-18-competent MRLlpr mice show reduced signs of renal pathogenesis, while other parameters such as mean survival time, lymphadenopathy, constitutive interferon-γ production, and frequency of CD3+B220+ abnormal T cells were without differences. We conclude that in the systemic lupus erythematosus syndrom IL-18 is involved specifically in the renal pathogenesis.

  18. Derepressing muscleblind expression by miRNA sponges ameliorates myotonic dystrophy-like phenotypes in Drosophila

    Science.gov (United States)

    Cerro-Herreros, Estefania; Fernandez-Costa, Juan M.; Sabater-Arcis, María; Llamusi, Beatriz; Artero, Ruben

    2016-01-01

    Myotonic Dystrophy type 1 (DM1) originates from alleles of the DMPK gene with hundreds of extra CTG repeats in the 3′ untranslated region (3′ UTR). CUG repeat RNAs accumulate in foci that sequester Muscleblind-like (MBNL) proteins away from their functional target transcripts. Endogenous upregulation of MBNL proteins is, thus, a potential therapeutic approach to DM1. Here we identify two miRNAs, dme-miR-277 and dme-miR-304, that differentially regulate muscleblind RNA isoforms in miRNA sensor constructs. We also show that their sequestration by sponge constructs derepresses endogenous muscleblind not only in a wild type background but also in a DM1 Drosophila model expressing non-coding CUG trinucleotide repeats throughout the musculature. Enhanced muscleblind expression resulted in significant rescue of pathological phenotypes, including reversal of several mis-splicing events and reduced muscle atrophy in DM1 adult flies. Rescued flies had improved muscle function in climbing and flight assays, and had longer lifespan compared to disease controls. These studies provide proof of concept for a similar potentially therapeutic approach to DM1 in humans. PMID:27805016

  19. Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.

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    Soo Jin Yang

    Full Text Available BACKGROUND: Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ on hepatic steatosis. METHODS: To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg⁻¹·day⁻¹ by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes. RESULTS: RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α and Forkhead box O1 (Foxo1 in rat livers. AMP-activated protein kinase (AMPK phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035, suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects. CONCLUSION: Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.

  20. Polydatin impairs mitochondria fitness and ameliorates podocyte injury by suppressing Drp1 expression.

    Science.gov (United States)

    Ni, Zheng; Tao, Liang; Xiaohui, Xu; Zelin, Zhao; Jiangang, Liu; Zhao, Song; Weikang, Huo; Hongchao, Xu; Qiujing, Wang; Xin, Li

    2017-10-01

    Polydatin (PD), a resveratrol glycoside, has been shown to protect renal function in diabetic nephropathy (DN), but the underlying molecular mechanism remains unclear. This study demonstrates that PD stabilize the mitochondrial morphology and attenuate mitochondrial malfunction in both KKAy mice and in hyperglycemia (HG)-induced MPC5 cells. We use Western blot analysis to demonstrate that PD reversed podocyte apoptosis induced by HG via suppressing dynamin-related protein 1 (Drp1). This effect may depend on the ability of PD to inhibit the generation of cellular reactive oxygen species (ROS). In conclusion, we demonstrate that PD may be therapeutically useful in DN, and that, podocyte apoptosis induced by HG can be reversed by PD through suppressing Drp1 expression. © 2017 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.

  1. Electroacupuncture ameliorates learning and memory in rats with cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting p-CREB expression in the hippocampus.

    Science.gov (United States)

    Lin, Ruhui; Lin, Yukun; Tao, Jing; Chen, Bin; Yu, Kunqiang; Chen, Jixiang; Li, Xiaojie; Chen, Li-Dian

    2015-11-01

    The present study aimed to investigate the mechanisms by which electroacupuncture (EA) ameliorates learning and memory in rats with cerebral ischemic‑reperfusion (I/R) injury. Focal cerebral ischemia was induced in adult male Sprague‑Dawley (SD) rats by transient middle cerebral artery occlusion (MCAO). Following MCAO surgery, the rats received EA at the Shenting (DU24) and Baihui (DU20) acupoints. The results of the present study demonstrated that treatment with EA significantly ameliorated neurological deficits and reduced cerebral infarct volume (Plearning and memory ability of the rats, and markedly activated the cyclic adenosine monophosphate (cAMP) response element‑binding protein (CREB) signaling pathway, resulting in the inhibition of cerebral cell apoptosis in the ischemic penumbra. Furthermore, EA increased the activity of superoxide dismutase and glutathione peroxidase, the protein expression levels of phosphorylated‑CREB and B‑cell lymphoma 2 (Bcl‑2), and the mRNA expression levels of Bcl‑2. Conversely, EA decreased the levels of malondialdehyde and inhibited the expression levels of Bcl2‑associated X protein. The results of the present study suggest that treatment with EA may result in the amelioration of learning and memory ability in rats with cerebral I/R injury.

  2. Telmisartan ameliorates adipoR1 and adipoR2 expression via PPAR-γ activation in the coronary artery and VSMCs.

    Science.gov (United States)

    Shen, Xuhua; Li, Hongwei; Li, Weiping; Wu, Xing; Sun, Zhijun; Ding, Xiaosong

    2017-08-21

    The effects of telmisartan on insulin-resistant properties and expression of adiponectin receptors (AdipoRs) were investigated. A diabetic rat model was established using a high-fat diet and streptozotocin (25mg/kg) and primary rat coronary vascular smooth muscle cells (VSMCs) were used to elucidate the underlying mechanisms. The diabetic rats were insulin-resistant and exhibited weight gain, elevated blood pressures, and increased plasma triglyceride levels. These manifestations were ameliorated by elmisartan treatment. Four-week telmisartan therapy increased plasma adiponectin and decreased TNF-α expression in the coronary artery. Moreover, telmisartan significantly decreased AdipoR1 and AdipoR2 expression. Using high glucose-treated rat coronary VSMCs, telmisartan and PPAR-γ agonist GW1929 prominently stimulated PPAR-γ and decreased TNF-α expression. Interestingly, telmisartan or GW1929 also prevented hyperglycemia-induced downregulation of AdipoR1 and AdipoR2 expression. Additionally, GW9662 (PPAR-γ antagonist) significantly decreased the effects of telmisartan on AdipoR1 and AdipoR2 expression. These results demonstrated that telmisartan effectively ameliorated coronary insulin resistance and inflammation in diabetic rats and upregulated AdipoR1/R2 expression via activation of PPAR-γ in the coronary artery and VSMCs. Copyright © 2017. Published by Elsevier Masson SAS.

  3. Amelioration of cholesterol induced atherosclerosis by normalizing gene expression, cholesterol profile and antioxidant enzymes by Vigna unguiculata.

    Science.gov (United States)

    Janeesh, P A; Abraham, Annie

    2013-06-01

    Cardiovascular diseases, especially atherosclerosis, have found to be the dreadful diseases worldwide and therapeutic interventions using plant sources have wide therapeutic value. Vigna unguiculata (VU) leaves have been used as food and therapeutics. Hence, our study was designed to evaluate the hypolipidemic as well as anti-atherogenic potential of VU leaves in normalizing atherogenic gene expression, cholesterol profile, generation of reactive oxygen species (ROS) and antioxidant enzyme system on cholesterol fed rabbit model. For the study New Zealand white rabbits were randomly divided into four groups of six animals each and experimental period was three months; group -i - ND [normal diet (40 g feed)], group-ii- ND (normal diet) +EAVU [ethyl acetate fraction of Vigna unguiculata (150 mg/kg body weight)], group -iii- ND [normal diet ]+ CFD [cholesterol fed diet (cholesterol 1 % of 40 g feed and cholic acid 0.5 % of 40 g feed)] and group-iv - ND [normal diet] +CFD [cholesterol fed diet ]+EAVU [ethyl acetate fraction of Vigna unguiculata (150 mg/kg body weight)]. Atherosclerosis was induced by feeding the rabbit with cholesterol (1 % of 40 g feed) and cholic acid (0.5 % of 40 g feed). Supplementation of EAVU normalized cholesterol profile, generation of reactive oxygen species (ROS), lipid peroxidation products like thiobarbituric acid reactive substance (TBARS), antioxidant system and important genes of cardiovascular diseases like interleukin-10 (IL 10), paraoxanase-1 (PON I), interleukin-6 (IL 6), and cyclooxygenase-2 (Cox 2) to near normal level as compared with normal diet. The result obtained showed the antioxidant as well as anti-atherogenic potential of Vigna unguiculata leaves in ameliorating cholesterol induced atherosclerosis, and thus it is good task to include VU leaves in daily diet for the prevention of cardiovascular diseases especially atherosclerosis.

  4. Dexamethasone Ameliorates H2S-Induced Acute Lung Injury by Alleviating Matrix Metalloproteinase-2 and -9 Expression

    Science.gov (United States)

    Su, Chenglei; Chen, Junjie; Zhu, Baoli; Zhang, Hengdong; Xiao, Hang; Zhang, Jinsong

    2014-01-01

    Acute lung injury (ALI) is one of the fatal outcomes after exposure to high levels of hydrogen sulfide (H2S), and the matrix metalloproteinases (MMPs) especially MMP-2 and MMP-9 are believed to be involved in the development of ALI by degrading the extracellular matrix (ECM) of blood-air barrier. However, the roles of MMP-2 and MMP-9 in H2S-induced ALI and the mechanisms of dexamethasone (DXM) in treating ALI in clinical practice are still largely unknown. The present work was aimed to investigate the roles of MMP-2 and MMP-9 in H2S-induced ALI and the protective effects of DXM. In our study, SD rats were exposed to H2S to establish the ALI model and in parallel, A549 cells were incubated with NaHS (a H2S donor) to establish cell model. The lung HE staining, immunohistochemisty, electron microscope assay and wet/dry ratio were used to identify the ALI induced by H2S, then the MMP-2 and MMP-9 expression in both rats and A549 cells were detected. Our results revealed that MMP-2 and MMP-9 were obviously increased in both mRNA and protein level after H2S exposure, and they could be inhibited by MMP inhibitor doxycycline (DOX) in rat model. Moreover, DXM significantly ameliorated the symptoms of H2S-induced ALI including alveolar edema, infiltration of inflammatory cells and the protein leakage in BAFL via up-regulating glucocorticoid receptor(GR) to mediate the suppression of MMP-2 and MMP-9. Furthermore, the protective effects of DXM in vivo and vitro study could be partially blocked by co-treated with GR antagonist mifepristone (MIF). Our results, taken together, demonstrated that MMP-2 and MMP-9 were involved in the development of H2S-induced ALI and DXM exerted protective effects by alleviating the expression of MMP-2 and MMP-9. Therefore, MMP-2 and MMP-9 might represent novel pharmacological targets for the treatment of H2S and other hazard gases induced ALI. PMID:24722316

  5. Expression of nuclear factor-KB in hepatocellular carcinoma and its relation with .the X protein of hepatitis B virus

    Institute of Scientific and Technical Information of China (English)

    Shuang Ping Guo; Wen Liang Wang; Yu Qiang Zhai; Yi Ling Zhao

    2001-01-01

    AIM In this study we investigated therelationship of the X protein of HBV and nuclearfactor-KB (NF-κB) and the expression of NF-KB inhuman hepatocellular carcinoma tissues.METHODS Immunohistochemistry SP methodwas used to detect the expression of NF-κB and the X protein of HBV in human hepatocellularcarcinoma tissues of 52 cases. Gene transfectionmediated by lipofectamine was used to transfectthe eukaryotic expression vector pCDNA3. 1-HBXof HBV x gene into human hepatocellularcarcinoma cell line HCC-9204 and NF-κB wasdetected.RESULTS NF-κB was widely expressed inhuman hepatocellular carcinoma tissues in atotal of 52 cases and its expression was relatedto the X protein of HBV. NF-KB was localizedboth in the cytoplasm and . The nuclei ofhepatocellular carcinoma cells in 11 cases whichwere positive for the X protein of HBV while in 41cases negative for the X protein of HBV, NF-Kbwas only localized in the cytoplasm ofhepatocellular carcinoma cells but translocatedto the nuclei of hepatocellular carcinoma cellsafter the eukaryotic expression vectorpCDNA3.1-HBX was transfected into HCC-9204cells.CONCLUSION This study strongly suggeststhat the nuclear factor NF-KB is widely expressedin hepatocellular carcinoma tissues in differentstyles according to the expression of the Xprotein of HBV. NF-κB is abnormally activated inhepatocellular carcinoma, which is probablyrelated to the X protein of HBV. The X protein ofHBV can activate NF-κB to translocate into nucleiof hepatocellular carcinoma cells.

  6. A Ca(2+) chelator ameliorates chromium (VI)-induced hepatocyte L-02 injury via down-regulation of voltage-Dependent anion channel 1 (VDAC1) expression.

    Science.gov (United States)

    Yi, Xing; Xiao, Fang; Zhong, Xiali; Duan, Yujie; Liu, Kaihua; Zhong, Caigao

    2017-01-01

    Hexavalent chromium could result in cell malfunctions. Intracellular Ca(2+) ([Ca(2+)]i) content and VDAC1 expression are both important features related to cell survial. This study aimed to explore the mechanism of cell injury induced by Cr(VI) and tentatively offer clues to repairing this cell damage using [Ca(2+)]i and VDAC1. L-02 hepatocytes were treated with Cr(VI)/BAPTA, and the levels of [Ca(2+)]i and cell injury associated with Cr(VI) were determined in addition to the effect of BAPTA. The expression of VDAC1 in Cr(VI)-induced cells was evaluated. The results showed a dose-dependent elevation of the level of VDAC1 and the mRNA level of the VDAC1 biogenesis-related gene Sam50. BAPTA could ameliorate less severe damage induced by 4μM Cr(VI) via reducing VDAC1 and Sam50. Additionally, cell injury caused by less than 4μM Cr(VI) could be ameliorated by VDAC1 knockdown. Taken together, the findings of this study suggest that inhibition of intracellular Ca(2±) overload could protect cells from damage and that VDAC1 plays a considerable role in Cr(VI)-induced liver injury.

  7. A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression.

    Science.gov (United States)

    Chen, Diyu; Zuo, Yangjin; Zhang, Xinhua; Ye, Yuhua; Bao, Xiuqin; Huang, Haiyan; Tepakhan, Wanicha; Wang, Lijuan; Ju, Junyi; Chen, Guangfu; Zheng, Mincui; Liu, Dun; Huang, Shuodan; Zong, Lu; Li, Changgang; Chen, Yajun; Zheng, Chenguang; Shi, Lihong; Zhao, Quan; Wu, Qiang; Fucharoen, Supan; Zhao, Cunyou; Xu, Xiangmin

    2017-07-06

    A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for β-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of β-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from β-thalassemia persons. The present study demonstrates that this common rSNP in the proximal (A)γ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of β-hemoglobinopathy. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

    Energy Technology Data Exchange (ETDEWEB)

    Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang [Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016 China (China); Chonan, Ritsu [Koei Kogyo Co., Ltd., Tokyo, 101-0063 Japan (Japan); Yamahara, Johji [Pharmafood Institute, Kyoto, 602-8136 Japan (Japan); Wang, Jianwei, E-mail: wangjianwei1968@gmail.com [Department of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016 China (China); Li, Yuhao, E-mail: yuhao@sitcm.edu.au [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000 Australia (Australia)

    2014-10-15

    Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

  9. Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomyelitis and ameliorates the clinical symptoms of disease.

    Science.gov (United States)

    Jafarzadeh, A; Mohammadi-Kordkhayli, M; Ahangar-Parvin, R; Azizi, V; Khoramdel-Azad, H; Shamsizadeh, A; Ayoobi, A; Nemati, M; Hassan, Z M; Moazeni, S M; Khaksari, M

    2014-11-15

    The immunomodulatory effects of the IL-27 and IL-33 and the anti-inflammatory effects of ginger have been reported in some studies. The aim was to evaluate the effects of the ginger extract on the expression of IL-27 and IL-33 in a model of experimental autoimmune encephalomyelitis (EAE). In PBS-treated EAE mice the expression of IL-27 P28 was significantly lower whereas the expression of IL-33 was significantly higher than unimmunized control mice. In 200 and 300 mg/kg ginger-treated EAE groups the expression of IL-27 P28 and IL-27 EBI3 was significantly higher whereas the expression of IL-33 was significantly lower than PBS-treated EAE mice. The EAE clinical symptoms and the pathological scores were significantly lower in ginger-treated EAE groups. These results showed that the ginger extract modulates the expression of the IL-27 and IL-33 in the spinal cord of EAE mice and ameliorates the clinical symptoms of disease.

  10. Oral Administration of Apple Procyanidins Ameliorates Insulin Resistance via Suppression of Pro-Inflammatory Cytokine Expression in Liver of Diabetic ob/ob Mice.

    Science.gov (United States)

    Ogura, Kasane; Ogura, Masahito; Shoji, Toshihiko; Sato, Yuichi; Tahara, Yumiko; Yamano, Gen; Sato, Hiroki; Sugizaki, Kazu; Fujita, Naotaka; Tatsuoka, Hisato; Usui, Ryota; Mukai, Eri; Fujimoto, Shimpei; Inagaki, Nobuya; Nagashima, Kazuaki

    2016-11-23

    Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic β-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.

  11. Aerobic exercise ameliorates learning and memory deficits of aging rats induced by D-galactose via promoting SYP and BNDF expression in hippocampus

    Directory of Open Access Journals (Sweden)

    Fu Yan

    2017-01-01

    Full Text Available The aim of this study was to explore the effects of aerobic exercise on learning and memory of aging brain and the underlying potential mechanism. We adopted the method of intraperitoneal administration for 6 weeks to induce aging rat model and gave rats swimming exercise intervention in the process of aging modeling. Then the Morris Water Maze test, immunofluorescence, western blotting and real time PCR technology were adopted to estimate rats’ learning and memory abilities and the expression levels of BDNF and SYP in hippocampus respectively. Compared with the aging model rats induced by D-gal administration, the rats subjected to swimming exercise in the process of aging modeling showed not only faster acquisition and better retention of the maze but also higher expression levels of BDNF and SYP in hippocampus. These findings provide evidence that aerobic exercise could ameliorate learning and memory deficits of aging rats induced by D-gal, which is related to aerobic exercise’ promoting hippocampal BNDF and SYP expression.

  12. Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy.

    Directory of Open Access Journals (Sweden)

    Martha Trindade Manchini

    Full Text Available Low-level laser therapy (LLLT has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI. However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS and Kallikrein-Kinin System (KKS vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO generation.

  13. Ginsenoside Rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice

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    Xizhong Yu

    2015-07-01

    Conclusion: G-Rb1 may improve insulin sensitivity in obese and diabetic db/db mice by reducing hepatic fat accumulation and suppressing adipocyte lipolysis; these effects may be mediated via the upregulation of perilipin expression in adipocytes.

  14. Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

    Science.gov (United States)

    Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

    2016-01-01

    Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH.

  15. Umbelliferone and daphnetin ameliorate carbon tetrachloride-induced hepatotoxicity in rats via nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1 expression.

    Science.gov (United States)

    Mohamed, Mohamed R; Emam, Manal A; Hassan, Nahla S; Mogadem, Abeer I

    2014-09-01

    Among various phytochemicals, coumarins comprise a very large class of plant phenolic compounds that have good nutritive value, in addition to their antioxidant effects. The purpose of the present study was to investigate the protective effects of two coumarin derivatives, umbelliferone and daphnetin, against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats and elucidate the underlying mechanism. Treatment of rats with either umbelliferone or daphnetin significantly improved the CCl4-induced biochemical alterations. In addition, both compounds alleviated the induced-lipid peroxidation and boosted the antioxidant defense system. Moreover, the investigated compounds attenuated CCl4-induced histopathological alterations of the liver. Finally, umbelliferone and daphnetin induced the nuclear translocation of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), thereby inducing the expression and activity of the cytoprotective heme oxygenase-1 (HO-1). These results suggest that umbelliferone and daphnetin ameliorate oxidative stress-related hepatotoxicity via their ability to augment cellular antioxidant defenses by activating Nrf2-mediated HO-1 expression.

  16. Mizoribine ameliorates renal injury and hypertension along with the attenuation of renal caspase-1 expression in aldosterone-salt-treated rats.

    Directory of Open Access Journals (Sweden)

    Toshiki Doi

    Full Text Available Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n = 7 per group: (1 vehicle infusion group, (2 aldosterone infusion group, or (3 aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and α epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.

  17. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus.

    Science.gov (United States)

    Hwang, Lakkyong; Choi, In-Young; Kim, Sung-Eun; Ko, Il-Gyu; Shin, Mal-Soon; Kim, Chang-Ju; Kim, Sang-Hoon; Jin, Jun-Jang; Chung, Jun-Young; Yi, Jae-Woo

    2013-05-01

    Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with a high mortality rate. Dexmedetomidine is an agonist for α2‑adrenoreceptors with sedative, anxiolytic, analgesic and anesthetic effects. In the present study, we investigated the effects of dexmedetomidine on short‑term and spatial learning memory, as well as its effects on apoptosis following the induction of ICH in rats. A rat model of IHC was created by an injection of collagenase into the hippocampus using a stereotaxic instrument. Dexmedetomidine was administered intraperitoneally daily for 14 consecutive days, commencing 1 day after the induction of ICH. The step‑down avoidance test for short‑term memory and the radial 8‑arm maze test for spatial learning memory were conducted. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end-labeling (TUNEL) assay, immunohistochemistry for caspase‑3, and western blot analysis for Bcl‑2, Bax, Bid and caspase-3 expression were performed for the detection of apoptosis in the hippocampus. Western blot analysis for the brain‑derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was also performed for the detection of cell survival in the hippocampus. The induction of ICH deteriorated short‑term and spatial learning memory, increased apoptosis and suppressed BDNF and TrkB expression in the hippocampus. Treatment with dexmedetomidine ameliorated the ICH‑induced impairment of short‑term and spatial learning memory by suppressing apoptosis and enhancing BDNF and TrkB expression. In the normal rats, dexmedetomidine exerted no significant effects on memory function and apoptosis. The present results suggest the possibility that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in stroke patients.

  18. Lettuce glycoside B ameliorates cerebral ischemia reperfusion injury by increasing nerve growth factor and neurotrophin-3 expression of cerebral cortex in rats

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    Heqin Zhan

    2014-01-01

    Full Text Available Aims: The aim of the study was to investigate the effects of LGB on cerebral ischemia-reperfusion (I/R injury in rats and the mechanisms of action of LGB. Materials and Methods: The study involved extracting LGB from P. laciniata, exploring affects of LGB on brain ischemia and action mechanism at the molecular level. The cerebral ischemia reperfusion injury of middle cerebral artery occlusion was established. We measured brain histopathology and brain infarct rate to evaluate the effects of LGB on brain ischemia injury. The expressions of nerve growth factor (NGF and neurotrophin-3 (NT-3 were also measured to investigate the mechanisms of action by the real-time polymerase chain reaction and immunohistochemistry. Statistical analysis: All results were mentioned as mean ± standard deviation. One-way analysis of variance was used to determine statistically significant differences among the groups. Values of P < 0.05 were considered to be statistically significant. Results: Intraperitoneal injection of LGB at the dose of 12, 24, and 48 mg/kg after brain ischemia injury remarkably ameliorated the morphology of neurons and brain infarct rate (P < 0.05 , P < 0.01. LGB significantly increased NGF and NT-3 mRNA (messenger RNA and both protein expression in cerebral cortex at the 24 and 72 h after drug administration (P < 0.05, P < 0.01. Conclusions: LGB has a neuroprotective effect in cerebral I/R injury and this effect might be attributed to its upregulation of NGF and NT-3 expression ability in the brain cortex during the latter phase of brain ischemia.

  19. Freshwater Clam Extract Ameliorates Triglyceride and Cholesterol Metabolism through the Expression of Genes Involved in Hepatic Lipogenesis and Cholesterol Degradation in Rats

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    Thomas Laurent

    2013-01-01

    Full Text Available The freshwater clam (Corbicula spp. is a popular edible bivalve and has been used as a folk remedy for liver disease in Asia. As a Chinese traditional medicine, it is said that freshwater clam ameliorates alcoholic intoxication and cholestasis. In this study, to estimate the practical benefit of freshwater clam extract (FCE, we compared the effects of FCE and soy protein isolate (SPI on triglyceride and cholesterol metabolism in rats. FCE and SPI lowered serum cholesterol, and FCE tended to reduce serum triglycerides. FCE enhanced fecal sterol excretion and hepatic mRNA levels of CYP7A1 and ABCG5 more substantially than SPI; however, both diets reduced hepatic cholesterol. Both of the diets similarly suppressed liver lipids improved Δ9-desaturated fatty acid profile, and FCE was associated with a reduction in FAS and SCD1 mRNA levels. Hepatic transcriptome analysis revealed that inhibition of lipogenesis-related gene expression may contribute to downregulation of hepatic triglycerides by FCE. FCE would have better potential benefits for preventing metabolic disorders, through greater improvement of metabolism of triglycerides and cholesterol, likely through a mechanism similar to SPI.

  20. Harpagoside ameliorates the amyloid-β-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3K pathways.

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    Li, J; Ding, X; Zhang, R; Jiang, W; Sun, X; Xia, Z; Wang, X; Wu, E; Zhang, Y; Hu, Y

    2015-09-10

    So far, no effective disease-modifying therapies for Alzheimer's disease (AD) aiming at protecting or reversing neurodegeneration of the disease have been established yet. The present work aims to elucidate the effect of Harpagoside (abbreviated HAR), an iridoid glycosides purified from the Chinese medicinal herb Scrophularia ningpoensis, on neurodegeneration induced by β-amyloid peptide (Aβ) and the underlying molecular mechanism. Here we show that HAR exerts neuroprotective effects against Aβ neurotoxicity. Rats injected aggregated Aβ₁₋₄₀ into the bilateral hippocampus displayed impaired spatial learning and memory ability in a Y-maze test and novel object recognition test, while HAR treatment ameliorated Aβ₁₋₄₀-induced behavioral deficits. Moreover, administration of HAR increased the expression levels of brain-derived neurotrophic factor (BDNF) and activated the extracellular-regulated protein kinase (ERK) and the phosphatidylinositol 3-kinase (PI3-kinase) pathways both in the cerebral cortex and hippocampus of the Aβ₁₋₄₀-insulted rat model. Furthermore, in cultured primary cortical neurons, Aβ₁₋₄₂ induced significant decrease of choline acetyltransferase (ChAT)-positive neuron number and neurite outgrowth length, both of which were dose dependently increased by HAR. In addition, HAR pretreatment also significantly attenuated the decrease of cell viability in Aβ₁₋₄₂-injured primary cortical neurons. Finally, when K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody were added to the culture medium 2 h prior to HAR addition, the protective effect of HAR on Aβ₁₋₄₂-induced neurodegeneration in the primary cortical neuron was almost inhibited. Taken together, HAR exerting neuroprotection effect and ameliorating learning and memory deficit appears to be associated, at least in part, with up-regulation of BDNF content as well as activating its downstream signaling pathways, e.g., MAPK

  1. H2S improves renal fibrosis in STZ-induced diabetic rats by ameliorating TGF-β1 expression.

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    Li, Yan; Li, Lin; Zeng, Ou; Liu, Jun Mao; Yang, Jun

    2017-11-01

    Nephropathy develops in many patients with type 1 diabetes mellitus (T1DM). However, the specific mechanisms and therapies remain unclear. For this purpose we investigated the effects of hydrogen sulfide (H2S) on renal fibrosis in streptozotocin (STZ) induced diabetic rats and its underlying mechanisms. Experimental rats were randomly divided into four groups: Control group (normal rats), DM group (diabetes rats), DM + NaHS group [diabetes rats treated with sodium hydrosulfide (NaHS)], and NaHS group (normal rats treated with NaHS). The diabetic models were established by intraperitoneal injection of STZ. The NaHS-treated rats were injected with NaHS as an exogenous donor of H2S. At the same time, control group and DM group were administrated with equal doses of normal saline (NS). After eight weeks, the rats' urine samples were collected to measure the renal hydroxyproline content by basic hydrolysis method with a hydroxyproline detection kit. Collagen I and III content was detected by immunohistochemical method, and the pathology morphology of kidney was analyzed by Masson staining. Protein expressions of transforming growth factor beta 1 (TGF-β1), ERK1/2, TIMP1, TIMP2, MMP-2, MMP-7, MMP-8, MMP-11, and MMP-14 were assessed by western blotting. The results showed that significant fibrosis occurred in the kidney of diabetes rats. NaHS treatment downregulated TGF-β1, ERK1/2, TIMP1, TIMP2, MMP-2, MMP-7, MMP-8, MMP-11, and MMP-14 expressions in the kidney of these diabetes rats (p<.01). This result suggests that NaHS treatment could attenuate renal fibrosis by TGF-β1 signaling, and its mechanisms may be correlated with ERK1/2 expression and modulation of MMPs/TIMPs expression. Therefore, H2S may provide a promising option for defensing against diabetic renal fibrosis through TGF-β1 signaling, equilibrating the balance between profibrotic and antifibrotic mediators.

  2. Restoring GM1 ganglioside expression ameliorates axonal outgrowth inhibition and cognitive impairments induced by blast traumatic brain injury

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    Rubovitch, Vardit; Zilberstein, Yael; Chapman, Joab; Schreiber, Shaul; Pick, Chaim G.

    2017-01-01

    Blast induced traumatic brain injury (B-TBI) may cause various degrees of cognitive and behavioral disturbances but the exact brain pathophysiology involved is poorly understood. It was previously suggested that ganglioside alteration on the axon surface as well as axonal regenerating inhibitors (ARIs) such as myelin associated glycoprotein (MAG) were involved in axonal outgrowth inhibition (AOI), leading to brain damage. GM1 ganglioside content in the brain was significantly reduced while GD1 ganglioside was not affected. The axonal regeneration was also reduced as seen by the phosphorylated NF-H expression. Moreover, B-TBI induced a significant elevation in MAG expression in the brains of the injured mice. The blast injured mice exhibited a significant decline in spatial memory as seen by the Y-maze test. In addition, the injured mice showed pronounced damage to the visual memory (as evaluated by the Novel object recognition test). A single low dose of GM1 (2 mg/kg; IP), shortly after the injury, prevented both the cognitive and the cellular changes in the brains of the injured mice. These results enlighten part of the complicated mechanism that underlies the damage induced by B-TBI and may also suggest a potential new treatment strategy for brain injuries. PMID:28112258

  3. Smad3 Deficiency Ameliorates Hepatic Fibrogenesis through the Expression of Senescence Marker Protein-30, an Antioxidant-Related Protein

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    Da-Hee Jeong

    2013-12-01

    Full Text Available Smad3 is a key mediator of the transforming growth factor (TGF-β1 signaling pathway that plays central role in inflammation and fibrosis. In present study, we evaluated the effect of Smad3 deficiency in Smad3−/− mice with carbon tetrachloride (CCl4-induced liver fibrosis. The animals were received CCl4 or olive oil three times a week for 4 weeks. Histopathological analyses were performed to evaluate the fibrosis development in the mice. Alteration of protein expression controlled by Smad3 was examined using a proteomic analysis. CCl4-induced liver fibrosis was rarely detected in Smad3−/− mice compared to Smad3+/+. Proteomic analysis revealed that proteins related to antioxidant activities such as senescence marker protein-30 (SMP30, selenium-binding proteins (SP56 and glutathione S-transferases (GSTs were up-regulated in Smad3−/− mice. Western blot analysis confirmed that SMP30 protein expression was increased in Smad3−/− mice. And SMP30 levels were decreased in CCl4-treated Smad3+/+ and Smad3−/− mice. These results indicate that Smad3 deficiency influences the proteins level related to antioxidant activities during early liver fibrosis. Thus, we suggest that Smad3 deteriorate hepatic injury by inhibitor of antioxidant proteins as well as mediator of TGF-β1 signaling.

  4. Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver.

    Science.gov (United States)

    Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang; Chonan, Ritsu; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

    2014-10-15

    Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation.

  5. Effects of acute prenatal exposure to ethanol on microRNA expression are ameliorated by social enrichment

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    Cherry eIgnacio

    2014-09-01

    Full Text Available Fetal alcohol spectrum disorders (FASDs are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of Social Enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or Social Enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by Social Enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, Glutamate and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for Social Enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression.

  6. Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression.

    Science.gov (United States)

    Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason; Sheibani, Nader; Kent, K Craig; Liu, Bo

    2016-01-01

    Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB-mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms.

  7. Production of VEGF induced by GMCSF via ERK-NF-KB singling 'pathway in human fibroblasts during wound healing%创伤后单核巨噬细胞集落刺激因子调控新生血管化的分子机制

    Institute of Scientific and Technical Information of China (English)

    李晓光; 姚敏; 方勇; 俞为荣; 徐鹏; 王莹; 顾钏; 王毅

    2011-01-01

    fibroblasts were pre-treated with ERK specific inhibitor PD98059 and further treated with GMCSF, then the fibroblasts and the supernatant were collected for detection of protein level of VEGF by means of Western blot. ERK signal pathway was inhibited to detect the activation of NF-κB by means of immunofluorescence staining. Furthermore, the nuclear and cytoplasmic extraction kit was used to separate the cytoplasm and nucleus and Western blot employed for observation of the NF-κB activation. Results The mRNA level and protein level of VEGF were increased significantly with treatment with higher concentration of GMCSF in a dose-dependent manner. VEGF mRNA level was increased two hours after administration with GMCSF and reached peak at 4-6 hours. GMCSF could remarkably activate the ERK phosphorylation. Compared with GMCSF, the ERK specific inhibitor PD98059inhibited significantly the effect of GMCSF in inducing VEGF expression (P < 0.05). Western blot and immunofluorescence staining analyses showed that the activation of NF-ΚB was inhibited with reduced production of VEGF after GMCSF treatment.Conclusion GMCSF up-regulates production of VEGF through activating NF-κB via ERK signal pathway in the human fibroblasts.

  8. Viral vector vaccines expressing nucleoprotein and phosphoprotein genes of avian bornaviruses ameliorate homologous challenge infections in cockatiels and common canaries.

    Science.gov (United States)

    Olbert, Marita; Römer-Oberdörfer, Angela; Herden, Christiane; Malberg, Sara; Runge, Solveig; Staeheli, Peter; Rubbenstroth, Dennis

    2016-11-10

    Avian bornaviruses are causative agents of proventricular dilatation disease (PDD), an often fatal disease of parrots and related species (order Psittaciformes) which is widely distributed in captive psittacine populations and may affect endangered species. Here, we established a vaccination strategy employing two different well described viral vectors, namely recombinant Newcastle disease virus (NDV) and modified vaccinia virus Ankara (MVA) that were engineered to express the phosphoprotein and nucleoprotein genes of two avian bornaviruses, parrot bornavirus 4 (PaBV-4) and canary bornavirus 2 (CnBV-2). When combined in a heterologous prime/boost vaccination regime, NDV and MVA vaccine viruses established self-limiting infections and induced a bornavirus-specific humoral immune response in cockatiels (Nymphicus hollandicus) and common canaries (Serinus canaria forma domestica). After challenge infection with a homologous bornavirus, shedding of bornavirus RNA and viral loads in tissue samples were significantly reduced in immunized birds, indicating that vaccination markedly delayed the course of infection. However, cockatiels still developed signs of PDD if the vaccine failed to prevent viral persistence. Our work demonstrates that avian bornavirus infections can be repressed by vaccine-induced immunity. It represents a first crucial step towards a protective vaccination strategy to combat PDD in psittacine birds.

  9. A role for NF-KB-dependent gene transactivation in sunburn

    NARCIS (Netherlands)

    Abeyama, K.; Eng, W.; Jester, J.V.; Vink, A.A.; Edelbaum, D.; Cockerell, C.J.; Bergstresser, P.R.; Takashima, A.

    2000-01-01

    Exposure of skin to ultraviolet (UV) radiation is known to induce NF-κB activation, but the functional role for this pathway in UV-induced cutaneous inflammation remains uncertain. In this study, we examined whether experimentally induced sunburn reactions in mice could be prevented by blocking UV-i

  10. Baclofen ameliorates spatial working memory impairments induced by chronic cerebral hypoperfusion via up-regulation of HCN2 expression in the PFC in rats.

    Science.gov (United States)

    Luo, Pan; Chen, Cheng; Lu, Yun; Fu, TianLi; Lu, Qing; Xu, Xulin; Li, Changjun; He, Zhi; Guo, Lianjun

    2016-07-15

    Chronic cerebral hypoperfusion (CCH) causes memory deficits and increases the risk of vascular dementia (VD) through several biologically plausible pathways. However, whether CCH causes prefrontal cortex (PFC)-dependent spatial working memory impairments and Baclofen, a GABAB receptor agonist, could ameliorate the impairments is still not clear especially the mechanisms underlying the process. In this study, rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) to induce CCH. Two weeks later, rats were treated with 25mg/kg Baclofen (intraperitioneal injection, i.p.) for 3 weeks. Spatial working memory was evaluated in a Morris water maze using a modified delayed matching-to-place (DMP) procedure. Western blotting and immunohistochemistry were used to quantify the protein levels and protein localization. Our results showed that 2VO caused striking spatial working memory impairments, accompanied with a decreased HCN2 expression in PFC, but the protein levels of protein gene product 9.5 (PGP9.5, a neuron specific protein), glial fibrillary acidic protein (GFAP), synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), parvalbumin (PV) and HCN1 were not distinguishably changed as compared with sham-operated rats. Baclofen treatment significantly improved the spatial working memory impairments caused by 2VO, accompanied with a reversion of 2VO-induced down-regulation of HCN2. Furthermore, there was a co-localization of HCN2 subunits and parvalbumin-positive neurons in PFC. Therefore, HCN2 may target inhibitory interneurons that is implicated in working memory processes, which may be a possible mechanism of the up-regulation of HCN2 by Baclofen treatment that reliefs spatial working memory deficits in rats with CCH.

  11. 4-Hydroxyisoleucine ameliorates an insulin resistant-like state in 3T3-L1 adipocytes by regulating TACE/TIMP3 expression

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    Gao F

    2015-10-01

    Full Text Available Feng Gao,1 Wen Du,1,4 Mohammad Ishraq Zafar,1 Raja Adeel Shafqat,2 Liumeng Jian,1 Qin Cai,1 Furong Lu3 1Department of Endocrinology, Union Hospital, 2Department of Medicine, Tongji Hospital, 3Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 4Chengdu First People’s Hospital, Sichuan, People’s Republic of China Background: Obesity-associated insulin resistance (IR is highly correlated with soluble tumor necrosis factor-α (sTNF-α, which is released from transmembranous TNF-α by TNF-α converting enzyme (TACE. In vivo, TACE activity is suppressed by tissue inhibitor of metalloproteinase 3 (TIMP3. Agents that can interact with TACE/TIMP3 to improve obesity-related IR would be highly valuable. In the current study, we assessed whether (2S,3R,4S-4-hydroxyisoleucine (4-HIL could modulate TACE/TIMP3 and ameliorate an obesity-induced IR-like state in 3T3-L1 adipocytes. Materials and methods: 3T3-L1 adipocytes were incubated in the presence of 25 mM glucose and 0.6 nM insulin to induce an IR-like state, and were then treated with different concentrations of 4-HIL or 10 µM pioglitazone (positive control. The glucose uptake rate was determined using the 2-deoxy-[3H]-d-glucose method, and the levels of sTNF-α in the cell supernatant were determined using ELISA. The protein expression of TACE, TIMP3, and insulin signaling-related molecules was measured using western blotting. Results: Exposure to high glucose and insulin for 18 hours increased the levels of sTNF-α in the cell supernatant. The phosphorylation of insulin receptor substrate-1 (IRS-1 Ser307 and Akt Ser473 was increased, whereas the protein expression of IRS-1, Akt, and glucose transporter-4 was decreased. The insulin-induced glucose uptake was reduced by 67% in 3T3-L1 adipocytes, which indicated the presence of an IR-like state. The above indexes, which demonstrated the

  12. Osthole ameliorates acute myocardial infarction in rats by decreasing the expression of inflammatory-related cytokines, diminishing MMP-2 expression and activating p-ERK.

    Science.gov (United States)

    Duan, Juan; Yang, Yu; Liu, Hong; Dou, Peng-Cheng; Tan, Sheng-Yu

    2016-01-01

    Osthole, the active constituent of Cnidium monnieri extracts, has been shown to have a diverse range of pharmacological properties. In the present study, we aimed to evaluate the cardioprotective effects of osthole in a rat model of acute myocardial infarction (AMI). The rats with AMI were treated with 1, 3 and 10 mg/kg of osthole or the vehicle for 4 weeks. The infarct size of the rats with AMI was measured, and casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) activities in the rats with AMI were analyzed using commercially available kits. The nuclear factor-κB (NF-κB), tumor necrosis factor‑α (TNF-α), interleukin (IL)-1β and IL-6 levels in whole blood from rats with AMI were also detected using commercially available kits. The levels of Toll-like receptors 2/4 (TLR2/4) and nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) were also detected by RT-qPCR. Moreover, the protein expression levels of endothelial nitric oxide synthase (eNOS) and mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, cyclooxygenase-2 (COX-2), as well as matrix metalloproteinase-2 (MMP-2) were all assayed by western blot analysis. Our results revealed that osthole markedly reduced the infarct size, and the levels of CK, CK-MB, LDH and cTnT in the rats with AMI, and that these cardioprotective effects may be associated with the inhibition of inflammatory reactions, the reduction in MMP-2 activity and the activation of MAPK cascades.

  13. Original Article. Toxic effect of sodium fluoride on hydroxyproline level and expression of collagen-1 gene in rat bone and its amelioration by Tamrindus indica L. fruit pulp extract

    Directory of Open Access Journals (Sweden)

    Gupta Amit Raj

    2016-03-01

    Full Text Available Excessive fluoride intoxication plays an important role in the development of dental, skeletal and non-skeletal fluorosis. The aim of this study was to ascertain the toxic effect of excessive fluoride ingestion on the level of hydroxyproline and expression of type 1 collagen gene in rat bone and its amelioration by supplementation with Tamarindus indica fruit pulp extract. Forty albino rats were randomly assigned to four groups. The first group served as control and received only tap water. The second group received sodium fluoride (200 ppm through drinking water. The third group received T. indica fruit pulp extract (200 mg/kg body weight alone and the fourth group received the T. indica fruit pulp extract (200 mg/kg body weight along with fluorinated drinking water (200 ppm daily by gavage for a period of 90 days. The level of hydroxyproline and expression of type 1 collagen gene using quantitative real time PCR in the tibia bone decreased significantly with continuous exposure to sodium fluoride. Co-administration of T. indica fruit pulp extract during exposure to fluoride through drinking water restored the level of calcium, phosphorus and alkaline phosphatase in serum and the concentration of hydroxyproline in urine. It increased the level of hydroxyproline and expression of type 1 collagen gene in the tibia as compared to untreated fluoride-exposed rats. It is concluded that T. indica fruit pulp extract has an ameliorative potential to protect the bone from fluoride induced collagen damage.

  14. Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Guang-Jin Yuan; Xiao-Rong Zhou; Zuo-Jiong Gong; Pin Zhang; Xiao-Mei Sun; Shi-Hua Zheng

    2006-01-01

    AIM: To study the expression and activity of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in rats with ethanol-induced liver injury and their relation with liver damage, activation of nuclear factor-KB (NF-кB) and tumor necrosis factor-α (TNF-α)expression in the liver.METHODS: Female Sprague-Dawley rats were given fish oil (0.5 mL) along with ethanol or isocaloric dextrose daily via gastrogavage for 4 or 6 wk. Liver injury was assessed using serum alanine aminotransferase (ALT)activity and pathological analysis. Liver malondialdehyde (MDA), nitric oxide contents, iNOS and eNOS activity were determined. NF-KB p65, iNOS, eNOS and TNF-αprotein or mRNA expression in the liver were detected by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR).RESULTS: Chronic ethanol gavage for 4 wk caused steatosis, inflammation and necrosis in the liver, and elevated serum ALT activity. Prolonged ethanol administration (6 wk) enhanced the liver damage. These responses were accompanied with increased lipid peroxidation, NO contents, iNOS activity and reduced eNOS activity. NF-кB p65, iNOS and TNF-α protein or mRNA expression were markedly induced after chronic ethanol gavage, whereas eNOS mRNA expression remained unchanged. The enhanced iNOS activity and expression were positively correlated with the liver damage, especially the necro-inflammation, activation of NF-кB, and TNF-α mRNA expression.CONCLUSION: iNOS expression and activity are induced in the liver after chronic ethanol exposure in rats, which are correlated with the liver damage, especially the necro-inflammation, activation of NF-KB and TNF-αexpression. eNOS activity is reduced, but its mRNA expression is not affected.

  15. Resolvin-D1 inhibits interleukin-8 and hydrogen peroxide production induced by cigarette smoke extract in 16HBE cells via attenuating NF-κB activation

    Institute of Scientific and Technical Information of China (English)

    Dong Jiajia; Zhang Mingke; Liao Zenglin; Wu Wei; Wang Tao; Chen Lei; Yang Ting

    2014-01-01

    Background Cigarette smoke induced airway inflammation plays a role in pathogenesis of airway inflammation.Resolvin-D1 derived from omega-3 polyunsaturated fatty acids is an endogenous anti-inflammatory and proresolving lipid mediator.Resolvin-D1 ameliorated inflammatory responses in lung injury,asthma,peritonitis and atherosclerosis.We investigated whether resolvin-D1 suppressed the productions of chemokines and oxidative stress induced by cigarette smoke extract (CSE) in vitro and its possible mechanism.Methods We examined the proinfiammatory chemokine interleukin-8 and hydrogen peroxide (H2O2)productions induced by CSE in 16 human bronchial epithelial (16HBE)cells after resolvin-D1 treatment and their mechanisms.16HBE cells were treated with resolvin-D1 at up to 10 nmol/L,for 30 minutes before CSE up to 16% (v/v) exposure.Release of interlukin-8 proteins was assessed by enzyme linked immunosort assay (ELISA) and its mRNA level by RT-PCR.We evaluated extracellular H2O2 expression in the supematant.Phosphorylation of NF-KB/p65 and degradation of Ⅰ-KB in 16HBE cells were determined by Westem blotting analysis and NF-KB DNA binding activity by electrophoretic mobility shift assay (EMSA).Results 16HBE cells treated with 8% CSE showed significantly higher interlukin-8 production.Resolvin-D1 pretreatment inhibited CSE induced intedukin-8 production (mRNA and protein) in a dose and time dependent manner.Extracellular H2O2 level decreased after resolvin-D1 treatment.Resolvin-D1 attenuated CSE triggered Ⅰ-KB degradation and NF-KB/p65 activation dose dependently and inhibited NF-KB DNA binding activity.Conclusion Resolvin-D1 inhibits CSE induced interlukin-8 and H2O2 production in 16HBE cells by modulating NF-KB activation and has therapeutic potential for pulmonary inflammation.

  16. Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression.

    Science.gov (United States)

    Le Tulzo, Y; Shenkar, R; Kaneko, D; Moine, P; Fantuzzi, G; Dinarello, C A; Abraham, E

    1997-04-01

    The expression of proinflammatory and immunoregulatory cytokines rapidly increases in the lungs after hemorrhage, and such alterations contribute to the frequent development of acute inflammatory lung injury in this setting. Blood loss also produces elevations in catecholamine concentrations in the pulmonary and systemic circulation. In the present experiments, we used alpha- and beta-adrenergic receptor blockade to examine in vivo interactions between hemorrhage-induced adrenergic stimulation and pulmonary cytokine expression. Treatment of mice with the alpha-adrenergic receptor antagonist phentolamine prevented not only the elevation in mRNA levels of IL-1beta, TNF-alpha, and TGF-beta1, the increase in IL-1beta protein, but also the activation of nuclear factor (NF)-KB and cyclic AMP response element binding protein, which occurred in lung cells of untreated animals during the first hour after hemorrhage. In contrast, treatment before hemorrhage with the beta-adrenergic receptor antagonist propranolol was associated with increases in mRNA levels for IL-1beta, TNF-alpha, and TGF-beta1, which were greater than those present in untreated hemorrhaged mice, and did not prevent hemorrhage-associated increases in lung IL-1beta protein. Treatment with propranolol prevented hemorrhage-induced phosphorylation of cyclic AMP response element binding protein, but increased hemorrhage-associated activation of NF-KB. These results demonstrate that hemorrhage initially increases pulmonary cytokine expression through alpha- but not beta-adrenergic stimulation, and suggest that such alpha-adrenergic-mediated effects occur through activation of the transcriptional regulatory factor NF-kappaB.

  17. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

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    Sárvári, Anitta K., E-mail: anittasarvari@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); Veréb, Zoltán, E-mail: jzvereb@gmail.com [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); Uray, Iván P., E-mail: ipuray@mdanderson.org [Clinical Cancer Prevention Department, The University of Texas, MD Anderson Cancer Center, Houston, TX (United States); Fésüs, László, E-mail: fesus@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); MTA DE Apoptosis, Genomics and Stem Cell Research Group of the Hungarian Academy of Sciences (Hungary); Balajthy, Zoltán, E-mail: balajthy@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary)

    2014-08-08

    Highlights: • Antipsychotics modulate the expression of adipogenic genes in human adipocytes. • Secretion of proinflammatory cytokine IL8 and MCP-1 is induced by antipsychotics. • Adipocyte-dependent inflammatory abnormality could develop during chronic treatment. • Infiltrated macrophages would further enhance proinflammatory cytokine production. - Abstract: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin

  18. Resveratrol ameliorates renal damage, increases expression of heme oxygenase-1, and has anti-complement, anti-oxidative, and anti-apoptotic effects in a murine model of membranous nephropathy.

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    Chia-Chao Wu

    Full Text Available Idiopathic membranous nephropathy (MN is an autoimmune-mediated glomerulonephritis and a common cause of nephrotic syndrome in adults. There are limited available treatments for MN. We assessed the efficacy of resveratrol (RSV therapy for treatment of MN in a murine model of this disease.Murine MN was experimentally induced by daily subcutaneous administration of cationic bovine serum albumin, with phosphate-buffered saline used in control mice. MN mice were untreated or given RSV. Disease severity and pathogenesis was assessed by determination of metabolic and histopathology profiles, lymphocyte subsets, immunoglobulin production, oxidative stress, apoptosis, and production of heme oxygenase-1 (HO1.MN mice given RSV had significantly reduced proteinuria and a marked amelioration of glomerular lesions. RSV also significantly attenuated immunofluorescent staining of C3, although there were no changes of serum immunoglobulin levels or immunocomplex deposition in the kidneys. RSV treatment of MN mice also reduced the production of reactive oxygen species (ROS, reduced cell apoptosis, and upregulated heme oxygenase 1 (HO1. Inhibition of HO1 with tin protoporphyrin IX partially reversed the renoprotective effects of RSV. The HO1 induced by RSV maybe via Nrf2 signaling.Our results show that RSV increased the expression of HO1 and ameliorated the effects of membranous nephropathy in a mouse model due to its anti-complement, anti-oxidative, and anti-apoptotic effects. RSV appears to have potential as a treatment for MN.

  19. Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.

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    Haiyan Zhang

    Full Text Available Nordihydroguaiaretic acid (NDGA, the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS, lowering blood glucose, free fatty acids (FFA and triglyceride (TG levels in several models of dyslipidemia, as well as improving body weight (obesity, insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD fed rat model of hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36, and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors. Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt, AMPK activity (P-AMPK, MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1. These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.

  20. Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.

    Science.gov (United States)

    Zhang, Haiyan; Li, Yihang; Hu, Jie; Shen, Wen-Jun; Singh, Madhurima; Hou, Xiaoming; Bittner, Alex; Bittner, Stefanie; Cortez, Yuan; Tabassum, Juveria; Kraemer, Fredric B; Azhar, Salman

    2015-01-01

    Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.

  1. Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo

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    Littman Dan R

    2009-01-01

    Full Text Available Abstract Background Cells derived from native rodents have limits at distinct steps of HIV replication. Rat primary CD4 T-cells, but not macrophages, display a profound transcriptional deficit that is ameliorated by transient trans-complementation with the human Tat-interacting protein Cyclin T1 (hCycT1. Results Here, we generated transgenic rats that selectively express hCycT1 in CD4 T-cells and macrophages. hCycT1 expression in rat T-cells boosted early HIV gene expression to levels approaching those in infected primary human T-cells. hCycT1 expression was necessary, but not sufficient, to enhance HIV transcription in T-cells from individual transgenic animals, indicating that endogenous cellular factors are critical co-regulators of HIV gene expression in rats. T-cells from hCD4/hCCR5/hCycT1-transgenic rats did not support productive infection of prototypic wild-type R5 HIV-1 strains ex vivo, suggesting one or more significant limitation in the late phase of the replication cycle in this primary rodent cell type. Remarkably, we identify a replication-competent HIV-1 GFP reporter strain (R7/3 YU-2 Env that displays characteristics of a spreading, primarily cell-to-cell-mediated infection in primary T-cells from hCD4/hCCR5-transgenic rats. Moreover, the replication of this recombinant HIV-1 strain was significantly enhanced by hCycT1 transgenesis. The viral determinants of this so far unique replicative ability are currently unknown. Conclusion Thus, hCycT1 expression is beneficial to de novo HIV infection in a transgenic rat model, but additional genetic manipulations of the host or virus are required to achieve full permissivity.

  2. Glycyrrhizin Ameliorates Imiquimod-Induced Psoriasis-like Skin Lesions in BALB/c Mice and Inhibits TNF-a-Induced ICAM-1 Expression via NF-κB/MAPK in HaCaT Cells

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    Hui Xiong

    2015-02-01

    Full Text Available Background/Aim: Glycyrrhizin (GL is an important derivative of certain herbal medicines used in Asian countries. Currently, GL is used to treat hepatitis and allergic disease worldwide because of its anti-viral and anti-allergy effects. In addition to these prominent functions, GL likely regulates cellular functions such as tumor cell growth and cellular immunity. However, how GL affects the keratinocyte inflammation response remains poorly understood. The current paper investigates the effect of GL on psoriasis and explores the mechanisms involved. Methods: We used an in vitro cell model of tumor necrosis factor (TNF-a-induced keratinocyte inflammation and the topical application of imiquimod (IMQ using an animal model (mouse skin of IMQ-induced psoriasis-like inflammation (IPI to investigate the effect of GL on skin inflammation. Cell viability was analyzed using the Cell Counting Kit-8 (CCK8. Carboxyfluorescein succinimidyl ester (CFSE labeling was used to trace monocyte adherence to keratinocytes. A Western blot analysis was used to detect the expression of intercellular adhesion molecule 1 (ICAM-1 and the activation of the nuclear factor (NF-κB/mitogen-activated protein kinase (MAPK signaling pathway. A modified version of the Psoriasis Area Severity Index (PASI was used to monitor disease severity. Hematoxylin and eosin (H&E staining was used to observe pathological changes. An immunohistochemistry (IHC analysis was used to detect ICAM-1 expression in mouse skin. Results: GL treatment significantly reduced the levels of ICAM-1 in TNF-a-stimulated HaCaT cells, inhibited subsequent monocyte adhesion to keratinocytes, and suppressed the nuclear translation and phosphorylation of p65 following the degradation of inhibitor κB (IκB. GL treatment blocked the phosphorylation of extracellular signal-regulated kinase (ERK/p38 MAPK. GL effectively delayed the onset of IPI in mice and ameliorated ongoing IPI, thereby reducing ICAM-1 expression in

  3. Activation of aryl hydrocarbon receptor (AhR leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis.

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    Narendra P Singh

    Full Text Available BACKGROUND: Aryl hydrocarbon receptor (AhR, a transcription factor of the bHLH/PAS family, is well characterized to regulate the biochemical and toxic effects of environmental chemicals. More recently, AhR activation has been shown to regulate the differentiation of Foxp3(+ Tregs as well as Th17 cells. However, the precise mechanisms are unclear. In the current study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a potent AhR ligand, on epigenetic regulation leading to altered Treg/Th17 differentiation, and consequent suppression of colitis. METHODOLOGY/PRINCIPAL FINDINGS: Dextran sodium sulphate (DSS administration induced acute colitis in C57BL/6 mice, as shown by significant weight loss, shortening of colon, mucosal ulceration, and increased presence of CXCR3(+ T cells as well as inflammatory cytokines. Interestingly, a single dose of TCDD (25 µg/kg body weight was able to attenuate all of the clinical and inflammatory markers of colitis. Analysis of T cells in the lamina propria (LP and mesenteric lymph nodes (MLN, during colitis, revealed decreased presence of Tregs and increased induction of Th17 cells, which was reversed following TCDD treatment. Activation of T cells from AhR(+/+ but not AhR (-/- mice, in the presence of TCDD, promoted increased differentiation of Tregs while inhibiting Th17 cells. Analysis of MLN or LP cells during colitis revealed increased methylation of CpG islands of Foxp3 and demethylation of IL-17 promoters, which was reversed following TCDD treatment. CONCLUSIONS/SIGNIFICANCE: These studies demonstrate for the first time that AhR activation promotes epigenetic regulation thereby influencing reciprocal differentiation of Tregs and Th17 cells, and amelioration of inflammation.

  4. Serum Amyloid P Component Ameliorates Neurological Damage Caused by Expressing a Lysozyme Variant in the Central Nervous System of Drosophila melanogaster.

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    Linda Helmfors

    Full Text Available Lysozyme amyloidosis is a hereditary disease in which mutations in the gene coding for lysozyme leads to misfolding and consequently accumulation of amyloid material. To improve understanding of the processes involved we expressed human wild type (WT lysozyme and the disease-associated variant F57I in the central nervous system (CNS of a Drosophila melanogaster model of lysozyme amyloidosis, with and without co-expression of serum amyloid p component (SAP. SAP is known to be a universal constituent of amyloid deposits and to associate with lysozyme fibrils. There are clear indications that SAP may play an important role in lysozyme amyloidosis, which requires further elucidation. We found that flies expressing the amyloidogenic variant F57I in the CNS have a shorter lifespan than flies expressing WT lysozyme. We also identified apoptotic cells in the brains of F57I flies demonstrating that the flies' neurological functions are impaired when F57I is expressed in the nerve cells. However, co-expression of SAP in the CNS prevented cell death and restored the F57I flies' lifespan. Thus, SAP has the apparent ability to protect nerve cells from damage caused by F57I. Furthermore, it was found that co-expression of SAP prevented accumulation of insoluble forms of lysozyme in both WT- and F57I-expressing flies. Our findings suggest that the F57I mutation affects the aggregation process of lysozyme resulting in the formation of cytotoxic species and that SAP is able to prevent cell death in the F57I flies by preventing accumulation of toxic F57I structures.

  5. Lactobacillus sakei OK67 ameliorates high-fat diet-induced blood glucose intolerance and obesity in mice by inhibiting gut microbiota lipopolysaccharide production and inducing colon tight junction protein expression.

    Science.gov (United States)

    Lim, Su-Min; Jeong, Jin-Ju; Woo, Kyung Hee; Han, Myung Joo; Kim, Dong-Hyun

    2016-04-01

    A high-fat diet (HFD) induces obesity and the associated increases in blood glucose and inflammation through changes in gut microbiota, endotoxemia, and increased gut permeability. To counteract this, researchers have suggested that the use of probiotics that suppress production of proinflammatory lipopolysaccharide (LPS). Here, we tested whether Lactobacillus sakei OK67, which inhibits gut microbiota LPS production selected from among the lactic acid bacteria isolated from kimchi, exerted antihypoglycemic or anti-inflammatory effects in HFD-fed mice. Mice were randomly divided into 2 groups and fed an HFD or a low-fat diet for 4 weeks. These groups were further subdivided; 1 subgroup was treated with L sakei OK67 and fed the experimental diet for 4.5 weeks, whereas the other subgroup was fed the experimental diet alone. L sakei OK67 treatment lowered HFD-elevated LPS levels in blood and colonic fluid and significantly decreased HFD-elevated fasting blood glucose levels and the area under the curve in an oral glucose tolerance test. L sakei OK67 treatment inhibited HFD-induced body and epididymal fat weight gains, suppressed HFD-induced tumor necrosis factor-α and interleukin-1β expression and nuclear factor-κB activation in the colon, and significantly increased HFD-suppressed interleukin-10 and tight junction protein expression in the colon. Oral administration of L sakei OK67 significantly downregulated HFD-induced expression of peroxisome proliferator-activated receptor γ, fatty acid synthase, and tumor necrosis factor-α in adipose tissue. In addition, L sakei OK67 treatment strongly inhibited nuclear factor-κB activation in LPS-stimulated peritoneal macrophages. We report that L sakei OK67 ameliorates HFD-induced hyperglycemia and obesity by reducing inflammation and increasing the expression of colon tight junction proteins in mice.

  6. Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling.

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    Shasha Yang

    Full Text Available Growth factor receptor-bound protein 10 (Grb10 is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R. The IGF1-1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up-regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication.

  7. Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling

    Science.gov (United States)

    Yang, Shasha; Deng, Huacong; Zhang, Qunzhou; Xie, Jing; Zeng, Hui; Jin, Xiaolong; Ling, Zixi; Shan, Qiaoyun; Liu, Momo; Ma, Yuefei; Tang, Juan; Wei, Qianping

    2016-01-01

    Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R). The IGF1-1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up-regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication. PMID:26986757

  8. Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling.

    Science.gov (United States)

    Yang, Shasha; Deng, Huacong; Zhang, Qunzhou; Xie, Jing; Zeng, Hui; Jin, Xiaolong; Ling, Zixi; Shan, Qiaoyun; Liu, Momo; Ma, Yuefei; Tang, Juan; Wei, Qianping

    2016-01-01

    Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R). The IGF1-1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up-regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication.

  9. Lycopene Ameliorates Transplant Arteriosclerosis in Vascular Allograft Transplantation by Regulating the NO/cGMP Pathways and Rho-Associated Kinases Expression.

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    He, Yunqiang; Xia, Peng; Jin, Hao; Zhang, Yan; Chen, Bicheng; Xu, Ziqiang

    2016-01-01

    Objective. Transplant arteriosclerosis is considered one of the major factors affecting the survival time of grafts after organ transplantation. In this study, we proposed a hypothesis of whether lycopene can protect grafted vessels through regulating key proteins expression involved in arteriosclerosis. Methods. Allogeneic aortic transplantation was performed using Brow-Norway rats as donors and Lewis rats as recipients. After transplantation, the recipients were divided into two groups: the allograft group and the lycopene group. Negative control rats (isograft group) were also established. Histopathological staining was performed to observe the pathological changes, and the expression levels of Ki-67, caspase-3, Rho-associated kinases, intercellular adhesion molecules (ICAM-1), and eNOS were assessed. Western blotting analysis and real-time PCR were also performed for quantitative analysis. Results. The histopathological staining showed that vascular stenosis and intimal thickening were not evident after lycopene treatment. The Ki-67, ROCK1, ROCK2, and ICAM-1 expression levels were significantly decreased. However, eNOS expression in grafted arteries and plasma cGMP concentration were increased after lycopene treatment. Conclusions. Lycopene could alleviate vascular arteriosclerosis in allograft transplantation via downregulating Rho-associated kinases and regulating key factor expression through the NO/cGMP pathways, which may provide a potentially effective method for transplant arteriosclerosis in clinical organ transplantation.

  10. Lycopene Ameliorates Transplant Arteriosclerosis in Vascular Allograft Transplantation by Regulating the NO/cGMP Pathways and Rho-Associated Kinases Expression

    Science.gov (United States)

    Xia, Peng; Jin, Hao; Zhang, Yan

    2016-01-01

    Objective. Transplant arteriosclerosis is considered one of the major factors affecting the survival time of grafts after organ transplantation. In this study, we proposed a hypothesis of whether lycopene can protect grafted vessels through regulating key proteins expression involved in arteriosclerosis. Methods. Allogeneic aortic transplantation was performed using Brow-Norway rats as donors and Lewis rats as recipients. After transplantation, the recipients were divided into two groups: the allograft group and the lycopene group. Negative control rats (isograft group) were also established. Histopathological staining was performed to observe the pathological changes, and the expression levels of Ki-67, caspase-3, Rho-associated kinases, intercellular adhesion molecules (ICAM-1), and eNOS were assessed. Western blotting analysis and real-time PCR were also performed for quantitative analysis. Results. The histopathological staining showed that vascular stenosis and intimal thickening were not evident after lycopene treatment. The Ki-67, ROCK1, ROCK2, and ICAM-1 expression levels were significantly decreased. However, eNOS expression in grafted arteries and plasma cGMP concentration were increased after lycopene treatment. Conclusions. Lycopene could alleviate vascular arteriosclerosis in allograft transplantation via downregulating Rho-associated kinases and regulating key factor expression through the NO/cGMP pathways, which may provide a potentially effective method for transplant arteriosclerosis in clinical organ transplantation. PMID:28050227

  11. Lycopene Ameliorates Transplant Arteriosclerosis in Vascular Allograft Transplantation by Regulating the NO/cGMP Pathways and Rho-Associated Kinases Expression

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    Yunqiang He

    2016-01-01

    Full Text Available Objective. Transplant arteriosclerosis is considered one of the major factors affecting the survival time of grafts after organ transplantation. In this study, we proposed a hypothesis of whether lycopene can protect grafted vessels through regulating key proteins expression involved in arteriosclerosis. Methods. Allogeneic aortic transplantation was performed using Brow-Norway rats as donors and Lewis rats as recipients. After transplantation, the recipients were divided into two groups: the allograft group and the lycopene group. Negative control rats (isograft group were also established. Histopathological staining was performed to observe the pathological changes, and the expression levels of Ki-67, caspase-3, Rho-associated kinases, intercellular adhesion molecules (ICAM-1, and eNOS were assessed. Western blotting analysis and real-time PCR were also performed for quantitative analysis. Results. The histopathological staining showed that vascular stenosis and intimal thickening were not evident after lycopene treatment. The Ki-67, ROCK1, ROCK2, and ICAM-1 expression levels were significantly decreased. However, eNOS expression in grafted arteries and plasma cGMP concentration were increased after lycopene treatment. Conclusions. Lycopene could alleviate vascular arteriosclerosis in allograft transplantation via downregulating Rho-associated kinases and regulating key factor expression through the NO/cGMP pathways, which may provide a potentially effective method for transplant arteriosclerosis in clinical organ transplantation.

  12. Artesunate ameliorates severe acute pancreatitis (SAP) in rats by inhibiting expression of pro-inflammatory cytokines and Toll-like receptor 4.

    Science.gov (United States)

    Cen, Yanyan; Liu, Chao; Li, Xiaoli; Yan, Zifei; Kuang, Mei; Su, Yujie; Pan, Xichun; Qin, Rongxin; Liu, Xin; Zheng, Jiang; Zhou, Hong

    2016-09-01

    Severe acute pancreatitis (SAP) is a severe clinical condition with significant morbidity and mortality. Multiple organs dysfunction (MOD) is the leading cause of SAP-related death. The over-release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α is the underlying mechanism of MOD; however, there is no effective agent against the inflammation. Herein, artesunate (AS) was found to increase the survival of SAP rats significantly when injected with 3.5% sodium taurocholate into the biliopancreatic duct in a retrograde direction, improving their pancreatic pathology and decreasing serum amylase and pancreatic lipase activities along with substantially reduced pancreatic IL-1β and IL-6 release. In vitro, AS-pretreatment strongly inhibited IL-1β and IL-6 release and their mRNA expressions in the pancreatic acinar cells treated with lipopolysaccharide (LPS) but exerted little effect on TNF-α release. Additionally, AS reduced the mRNA expressions of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) p65 as well as their protein expressions in the pancreatic acinar cells. In conclusion, our results demonstrated that AS could significantly protect SAP rats, and this protection was related to the reduction of digestive enzyme activities and pro-inflammatory cytokine expressions via inhibition of TLR4/NF-κB signaling pathway. Therefore, AS may be considered as a potential therapeutic agent against SAP.

  13. PPARα、PPARγ在左卡尼汀改善结肠癌小鼠恶病质中的作用%L-carnitine Ameliorates Colonic Cancer Cachexia in Mice by Regulating the Expressions of PPARα and PPARγ

    Institute of Scientific and Technical Information of China (English)

    张祎; 易苏红; 蒋芳; 仇月华; 陈汉章; 刘苏; 朱樑

    2013-01-01

    Background: The role of L-carnitine ( LC ) in ameliorating cachexia has been focused on increasingly in recent years. Aims: To investigate the role of PPARα, PPARγ in ameliorating colonic cancer cachexia by LC in mice. Methods: Colonic cancer cachexia model was established in mice. Mice were randomly divided into tumor bearing group treated with LC ( LC group ), tumor bearing group treated with LC palmitoyl-transferase ( CPT ) inhibitor ( ILC group ), tumor bearing group treated with normal saline ( NST group ), and non-tumor bearing mice were served as normal controls ( NTB group ). On the 19th day, all the mice were sacrificed. Body weight, tumor-free body weight, food consumption were measured. Serum levels of albumin, glucose, cholesterol were determined by automatic biochemistry analyzer. ELISA assay was used to detect serum levels of TNF-α and IL-6. mRNA and protein expressions of PPARa, PPARγ in liver tissue were determined by real time quantitive PCR and Western blotting, respectively. Results: Compared with NST group and ILC group, body weight, tumor-free body weight, food consumption, serum levels of albumin and glucose in LC group were significantly increased ( P < 0. 05 ), serum levels of cholesterol, TNF-α, IL-6 were significantly decreased ( P < 0. 05 ), mRNA and protein expressions of PPARa, PPAR-γ were significantly increased ( P < 0. 05 ). Conclusions: PPARa, PPARγ may be involved in the formation of colonic cancer cachexia in mice. The ameliorating of cancer cachexia by LC may be related to the regulating of PPARa-, PPARγ-related signaling pathway of hepatic lipid metabolism.%背景:左卡尼汀(LC)改善恶病质的作用已日渐受到关注.目的:探讨PPARα、PPARγ在LC改善结肠癌小鼠恶病质中的作用.方法:建立结肠癌小鼠恶病质模型,并分为LC组、左卡尼汀棕榈酸酰基转移酶(CPT)抑制剂(ILC)组、阴性对照组(NST),另设立正常对照组(NTB).实验第19 d处死所有小鼠.测定小鼠体质

  14. Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key β-cell factors under diabetic conditions

    Energy Technology Data Exchange (ETDEWEB)

    Shimo, Naoki [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Matsuoka, Taka-aki, E-mail: matsuoka@endmet.med.osaka-u.ac.jp [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Miyatsuka, Takeshi [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunky-ku, Tokyo, 113-8421 (Japan); Takebe, Satomi; Tochino, Yoshihiro; Takahara, Mitsuyoshi [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Kaneto, Hideaki [Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama, 701-0192 (Japan); Shimomura, Iichiro [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan)

    2015-11-27

    Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic β-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key β-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice. Moreover, compared to the pretreatment levels, Mafa and insulin 1 expression increased in empagliflozin-treated mice, and Slc2a2 increased in combination-treated mice. In addition, empagliflozin treatment enhanced β-cell proliferation assessed by Ki-67 immunostaining. Our date clearly demonstrated that the one-week selective alleviation of glucotoxicity led to the better expression levels of the key β-cell factors critical for β-cell function over pretreatment levels, and that the alleviation of lipotoxicity along with glucotoxicity augmented the favorable effects under diabetic conditions. - Highlights: • One-week selective reduction of gluco- and lipo-toxicity in db/db mice was performed. • Selective glucotoxicity reduction increases key pancreatic β-cell factors expression. • Selective glucotoxicity reduction improves β-cell factors over pretreatment levels. • Selective glucotoxicity reduction turns β-cell mass toward increase. • Lipotoxicity reduction has additive effects on glucotoxicity reduction.

  15. Sesamin ameliorates arterial dysfunction in spontaneously hypertensive rats via downregulation of NADPH oxidase subunits and upregulation of eNOS expression

    Institute of Scientific and Technical Information of China (English)

    Jun-xiu ZHANG; Jie-ren YANG; Guo-xiang CHEN; Li-juan TANG; Wen-xing LI; Hui YANG; Xiang KONG

    2013-01-01

    Aim:Sesamin is one of the major lignans in sesame seeds with antihyperlipidemic,antioxidative and antihypertensive activities.The aim of this study was to examine the effects of sesamin on arterial function in spontaneously hypertensive rats (SHRs).Methods:SHRs were orally administered sesamin (40,80 and 160 mg·kg-1·d-1) for 16 weeks.After the rats were killed,thoracic aortas were dissected out.The vasorelaxation responses of aortic rings to ACh and nitroprusside were measured.The expression of eNOS and NADPH oxidase subunits p4Tphox and p22phox in aortas were detected using Western blotting and immunohistochemistry.Aortic nitrotyrosine was measured with ELISA.The total antioxidant capacity (T-AOC) and MDA levels in aortas were also determined.Results:The aortic rings of SHRs showed significantly smaller ACh-induced and nitroprusside-induced relaxation than those of control rats.Treatment of SHRs with sesamin increased both the endothelium-dependent and endothelium-independent relaxation of aortic rings in a dose-dependent manner.In aortas of SHRs,the level of T-AOC and the expression of nitrotyrosine,p22phox and p47phox proteins were markedly increased,while the level of MDA and the expression of eNOS protein were significantly decreased.Treatment of SHRs with sesamin dose-dependently reversed these biochemical and molecular abnormalities in aortas.Conclusion:Long-term treatment with sesamin improves arterial function in SHR through the upregulation of eNOS expression and downregulation of p22phox and p47phox expression.

  16. Maternal high-fat diet-induced programing of gut taste receptor and inflammatory gene expression in rat offspring is ameliorated by CLA supplementation.

    Science.gov (United States)

    Reynolds, Clare M; Segovia, Stephanie A; Zhang, Xiaoyuan D; Gray, Clint; Vickers, Mark H

    2015-10-01

    Consumption of a high-fat (HF) diet during pregnancy and lactation influences later life predisposition to obesity and cardiometabolic disease in offspring. The mechanisms underlying this phenomenon remain poorly defined, but one potential target that has received scant attention and is likely pivotal to disease progression is that of the gut. The present study examined the effects of maternal supplementation with the anti-inflammatory lipid, conjugated linoleic acid (CLA), on offspring metabolic profile and gut expression of taste receptors and inflammatory markers. We speculate that preventing high-fat diet-induced metainflammation improved maternal metabolic parameters conferring beneficial effects on adult offspring. Sprague Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA) throughout gestation and lactation. Plasma/tissues were taken at day 24 and RT-PCR was carried out on gut sections. Offspring from HF mothers were significantly heavier at weaning with impaired insulin sensitivity compared to controls. This was associated with increased plasma IL-1β and TNFα concentrations. Gut Tas1R1, IL-1β, TNFα, and NLRP3 expression was increased and Tas1R3 expression was decreased in male offspring from HF mothers and was normalized by maternal CLA supplementation. Tas1R1 expression was increased while PYY and IL-10 decreased in female offspring of HF mothers. These results suggest that maternal consumption of a HF diet during critical developmental windows influences offspring predisposition to obesity and metabolic dysregulation. This may be associated with dysregulation of taste receptor, incretin, and inflammatory gene expression in the gut.

  17. Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer’s Disease Mouse Model

    Science.gov (United States)

    Wang, Erming; Zhu, Haihao; Wang, Xiaofan; Gower, Adam C.; Wallack, Max; Blusztajn, Jan Krzysztof; Kowall, Neil; Qiu, Wei Qiao

    2017-01-01

    Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer’s disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD. PMID:27911303

  18. Ameliorating effect of vitamin C and selenium against nicotine induced oxidative stress and changes of p53 expression in pregnant albino rats

    Directory of Open Access Journals (Sweden)

    Khadiga A. Hassan

    2016-12-01

    Full Text Available Objective: This study was aimed to evaluate the effects of daily intake of vitamin C or selenium against deleterious effects of nicotine toxicity on pregnant albino rats. Materials and methods: Forty albino pregnant rats were equally distributed into four groups. Group A was considered as control. Group B was administered with nicotine dosed at 1 mg/kg body weight (bwt daily for 7 weeks (wks from 1st day of gestation until the postnatal 4 wks. Group C was treated with nicotine and vitamin C dosed at 1 mg/kg bwt orally for 7 wks, group D was treated with nicotine and sodium selenite dosed at 1 ug/100 g bwt concurrently for 7 wks. The levels of catalase (CAT, superoxide dismutase (SOD, protein carbonyl (PC and thiobarbituric acid reactive substances (TBARS, were estimated in homogenates of the lung, kidney and liver. Histopathological studies using hematoxylin and eosin as well as immunohistochemical studies using p53 antibody were also done. Results: Nicotine significantly elevated the levels of TBARS and PC as compared to control rats. Groups C and D showed decrease in these levels significantly. CAT and SOD activities of group B were decreased significantly. Significant elevation of CAT and SOD activities was detected in both groups C and D. Vitamin C elevated the antioxidant enzymes activities to normal levels, however selenium administration improved these levels but still lower than those of group A. Expression of p53 was decreased in group B as compared to group A. Vitamin C completely reversed the expression of p53 as group A. However, group D did not showed any significant changes in expressions as compared to group B. Conclusion: It is concluded that vitamin C intake was useful than selenium in prevention against nicotine-induced oxidative stress including p53 expression in the lung, kidney and liver of pregnant rats. [J Adv Vet Anim Res 2016; 3(4.000: 321-331

  19. Eupafolin ameliorates COX-2 expression and PGE2 production in particulate pollutants-exposed human keratinocytes through ROS/MAPKs pathways.

    Science.gov (United States)

    Lee, Chiang-Wen; Lin, Zih-Chan; Hsu, Lee-Fen; Fang, Jia-You; Chiang, Yao-Chang; Tsai, Ming-Horng; Lee, Ming-Hsueh; Li, Shu-Yu; Hu, Stephen Chu-Sung; Lee, I-Ta; Yen, Feng-Lin

    2016-08-02

    Eupafolin is a major bioactive compound derived from the methanolic extract of the medicinal herb Phyla nodiflora, which has been used in traditional Chinese medicine to treat various inflammatory diseases. Recently, particulate air pollutants have been shown to induce inflammation of the skin. In this study, we seek to determine whether eupafolin can inhibit the production of inflammatory mediators in a human skin keratinocyte cell line exposed to particulate air pollutants (particulate matter, PM), and determine the molecular mechanisms involved. Human keratinocyte HaCaT cells were treated with PM in the presence or absence of eupafolin. Cyclooxygenase-2 (COX-2) protein and gene expression levels were determined by Western blotting, RT-PCR and luciferase activity assay. Prostaglandin E2 (PGE2) production was evaluated by the enzyme immunoassay method. Generation of intracellular reactive oxygen species (ROS) was measured by the dichlorofluorescin (DCFH) oxidation assay, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was determined by a chemiluminescence assay. For in vivo studies, COX-2 expression in the skin of BALB/c nude mice was analyzed by immunohistochemistry. Eupafolin inhibited PM-induced COX-2 protein and gene expression and PGE2 production in HaCaT cells. In addition, eupafolin suppressed PM-induced intracellular ROS generation, NADPH oxidase activity, MAPK (ERK, JNK and p38) activation and NK-κB activation. In vivo studies showed that topical treatment with eupafolin inhibited COX-2 expression in the epidermal keratinocytes of PM-treated mice. Eupafolin exerts anti-inflammatory and antioxidant effects on skin keratinocytes exposed to particulate air pollutants, and may have potential use in the treatment or prevention of air pollutant-induced inflammatory skin diseases in the future. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Amelioration of cancer stem cells in macrophage colony stimulating factor-expressing U87MG-human glioblastoma upon 5-fluorouracil therapy.

    Directory of Open Access Journals (Sweden)

    S Chockalingam

    Full Text Available Macrophage colony stimulating factor (MCSF regulates growth, proliferation and differentiation of haematopoietic cell lineages. Many cancers are known to secrete high level of MCSF, which recruit macrophages into the tumour micro-environment, supporting tumour growth. Herein, we report the cloning of MCSF and subsequent generation of U87MG expressing MCSF stable cell line (U87-MCSF. Cytotoxicity of anti-cancer drug 5-fluorouracil (5-FU was evaluated on both U87MG and U87-MCSF cells. Interestingly, the proliferation of U87-MCSF cells was less (p<0.001 than that of U87MG cells alone, after treatment with 5-FU. Significant decrease in expression levels of cyclin E and A2 quantified by real time PCR analysis corroborated the reduced proliferation of 5-FU treated U87-MCSF cells. However, JC-1 staining did not reveal any apoptosis upon 5-FU treatment. Notch-1 upregulation induced a possible epithelial-mesenchymal transition in U87-MCSF cells, which accounted for an increase in the proportion of CD24(high/CD44(less cancer stem cells in U87-MCSF cells after 5-FU treatment. The elevated resistance of U87-MCSF cells towards 5-FU was due to the increase in the expressions (10.2 and 6 fold of ABCB1 and mdm2, respectively. Furthermore, increase in expressions of ABCG1, mdm2 and CD24 was also observed in U87MG cells after prolonged incubation with 5-FU. Our studies provided mechanistic insights into drug resistance of U87MG cells and also described the pivotal role played by MCSF in augmenting the resistance of U87MG cells to 5-FU.

  1. Bofutsushosan ameliorates obesity in mice through modulating PGC-la expression in brown adipose tissues and inhibiting inflammation in white adipose tissues

    Institute of Scientific and Technical Information of China (English)

    CHEN Ying-Ying; YAN Yan; ZHAO Zheng; SHI Mei-Jing; ZHANG Yu-Bin

    2016-01-01

    The inducible co-activator PGC-1a plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT).Meanwhile,chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity.Bofutsushosan (BF),a traditional Chinese medicine composed of 17 crude drugs,has been widely used to treat obesity in China,Japan,and other Asia countries.However,the mechanism underlying anti-obesity remains to be elucidated.In the present study,we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05),including blood glucose (Glu),total cholesterol (TC),triglyceride (TG),low density lipoprotein (LDL-C) and insulin.Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT.Moreover,BF also reduced the expression of inflammatory cytokines in WAT,such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.

  2. Endocrine expression of the active form of TGF-beta1 in the TGF-beta1 null mice fails to ameliorate lethal phenotype.

    Science.gov (United States)

    Longenecker, Glenn; Thyagarajan, Tamizchelvi; Nagineni, Chandrasekharam N; Flanders, Kathleen C; Factor, Valentina; Miller, Georgina; Ward, Jerrold M; Nalca, Aysegul; Rangnekar, Vivek M; Thorgeirsson, Snorri; Kulkarni, Ashok B

    2002-04-01

    TGF-beta1 null mice die by 3 to 4 weeks of age due to a severe autoimmune-mediated multifocal inflammation resulting in multi-organ failure. To assess the therapeutic potential of circulating levels of active TGF-beta1, we generated mice with endocrine expression of active TGF-beta1 on a TGF-beta1 null background (TGF-beta1 (-/-/TG)) by crossing TGF-beta1(+/-) mice with transgenic mice (TG) that express recombinant TGF-beta1 specifically in the liver and secrete it in the blood. The TGF-beta1 (-/-/TG) mice exhibit a survival profile similar to the TGF-beta1 (-/-) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-beta1 levels in the TGF-beta1 (-/-/TG) mice were restored to near normal levels with expression in all the tissues, notably in the kidney and spleen. Histopathology showed reduced inflammation in the target tissues, especially in the heart. Interestingly, unlike TGF-beta1 (-/-) mice, the TGF-beta1 (-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-beta1 (-/-/TG) animal model indicates the potential role of circulating active-TGF-beta1 in reducing inflammation, but its failure to rescue lethality in TGF-beta1 null mice indicates a critical autocrine role of TGF-beta1.

  3. Chromium-histidinate ameliorates productivity in heat-stressed Japanese quails through reducing oxidative stress and inhibiting heat-shock protein expression.

    Science.gov (United States)

    Akdemir, F; Sahin, N; Orhan, C; Tuzcu, M; Sahin, K; Hayirli, A

    2015-04-01

    An experiment was conducted to evaluate the effects of a histidine complex of chromium (chromium histidinate, CrHis) on egg production, lipid peroxidation and the expression of hepatic nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and heat-shock proteins (HSPs) in Japanese quails (Coturnix coturnix japonica) exposed to heat stress (HS). A total of 180 5-week-old female quails were reared either at 22°C for 24 h/d (thermoneutral, TN) or 34°C for 8 h/d (heat stress, HS) for 12 weeks. Birds in both environments were randomly given one of three diets: basal diet and basal diet supplemented with 400 or 800 µg of elemental Cr as CrHis per kg of diet. Blood, egg yolk and liver samples collected at the end of the trial were analysed to determine concentrations of cholesterol and malondialdehyde (MDA) and expressions of transcription and heat-shock proteins. Exposure to HS caused reductions in feed intake (-8.1%) and egg production (-15.8%), elevations in serum (14.8%) and egg-yolk (29.0%) cholesterol concentrations, decreases in serum (113%) and egg-yolk (73.0%) MDA concentrations and increases in the expressions of hepatic NF-κB (52.3%) and HSPs (averaging 53.6%). The effects of increasing supplemental CrHis on the response variables were more notable in the HS environment than in the TN environment. There were considerable improvements in feed intake and egg production, decreases in serum and egg-yolk cholesterol concentrations and suppressions in the expressions of hepatic nuclear protein and HSPs in response to increasing supplemental CrHis concentration in the diet of quails reared under the HS environment. In conclusion, supplemental CrHis improves productivity through alleviating oxidative stress and modulating the expressions of hepatic NF-κB and HSPs in heat-stressed quails.

  4. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP.

    Directory of Open Access Journals (Sweden)

    Eleonora Distrutti

    Full Text Available The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP, is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.

  5. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP.

    Science.gov (United States)

    Distrutti, Eleonora; O'Reilly, Julie-Ann; McDonald, Claire; Cipriani, Sabrina; Renga, Barbara; Lynch, Marina A; Fiorucci, Stefano

    2014-01-01

    The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.

  6. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway.

    Science.gov (United States)

    Jo, Hee Kyung; Kim, Go Woon; Jeong, Kyung Ju; Kim, Do Yeon; Chung, Sung Hyun

    2014-01-01

    Beneficial effect of eugenol on fatty liver was examined in hepatocytes and liver tissue of high fat diet (HFD)-fed C57BL/6J mice. To induce a fatty liver, palmitic acid or isolated hepatocytes from HFD-fed Sprague-Dawley (SD) rats were used in vitro studies, and C57BL/6J mice were fed HFD for 10 weeks. Lipid contents were markedly decreased when hepatocytes were treated with eugenol for up to 24 h. Gene expressions of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes were suppressed but those of lipolysis-related proteins were increased. As a regulatory kinase for lipogenic transcriptional factors, the AMP-activated protein kinase (AMPK) signaling pathway was examined. Protein expressions of phosphorylated Ca(2+)-calmodulin dependent protein kinase kinase (CAMKK), AMPK and acetyl-CoA carboxylase (ACC) were significantly increased and those of phosphorylated mammalian target of rapamycin (mTOR) and p70S6K were suppressed when the hepatocytes were treated with eugenol at up to 100 µM. These effects were all reversed in the presence of specific inhibitors of CAMKK, AMPK or mTOR. In vivo studies, hepatic triglyceride (TG) levels and steatosis score were decreased by 45% and 72%, respectively, in eugenol-treated mice. Gene expressions of fibrosis marker protein such as α-smooth muscle actin (α-SMA), collagen type I (Col-I) and plasminogen activator inhibitor-1 (PAI-1) were also significantly reduced by 36%, 63% and 40% in eugenol-treated mice. In summary, eugenol may represent a potential intervention in populations at high risk for fatty liver.

  7. Dietary resveratrol increases the expression of hepatic 7α-hydroxylase and ameliorates hypercholesterolemia in high-fat fed C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Chen Qiong

    2012-05-01

    Full Text Available Abstract Background Resveratrol (RSV, a naturally occurring polyphenolic stilbenoid, is known to possess potent anti-atherogenic properties; however, the effect of RSV on hypercholesterolemia is not fully understood. We hypothesized that RSV decreases blood cholesterol levels through the activation of cholesterol 7α-hydroxylase (CYP7A1-mediated bile acid synthetic pathway pathways in vitro and in vivo. Methods In this study, we evaluated body weight, serum lipid concentrations, hepatic lipid content and the size of the bile acid pool in high-fat diet (HFD-fed C57BL/6 J mice that were treated with RSV. In addition, we characterized the underlying mechanism of the effects of RSV in HepG2 hepatocytes by Western blot analysis. Results RSV (200 mg/kg per day reduced body weight and liver weight gains, improved serum lipid parameters, reduced hepatic cholesterol accumulation and increased the bile acid pool size in mice fed an HFD for 8 wks. RSV significantly increased liver expression of CYP7A1 mRNA and protein and CYP7A1 enzyme activity. Furthermore, RSV treatment upregulated CYP7A1 expression and induced liver X receptor alpha (LXRα activation in a time- and dose-dependent manner in HepG2 cells. In addition, the specific liver X receptor alpha (LXRα inhibitor geranylgeranyl pyrophosphate (GGPP inhibited the RSV-induced expression of CYP7A1 in HepG2 hepatocytes. Conclusion The beneficial effects of RSV on HFD-induced hypercholesterolemia are mediated through LXRα signaling pathways, suggesting a potential target for the prevention of dyslipidemia.

  8. Regulation Of Nf=kb And Mnsod In Low Dose Radiation Induced Adaptive Protection Of Mouse And Human Skin Cells

    Energy Technology Data Exchange (ETDEWEB)

    Jian Li

    2012-11-07

    A sampling of publications resulting from this grant is provided. One is on the subject of NF-κB-Mediated HER2 Overexpression in Radiation-Adaptive Resistance. Another is on NF-κB-mediated adaptive resistance to ionizing radiation.

  9. NF-KB downregulation may be involved the depression of tumor cell proliferation mediated by human mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    Ling QIAO; Tie-jun ZHAO; Feng-ze WANG; Chang-liang SHAN; Li-hong YE; Xiao-dong ZHANG

    2008-01-01

    Aim:It has been reported that stem cells are able to home to tumorigenesis and inhibit the proliferation of tumor cells.The purpose of our study was to demon-strate the molecular mechanism of the inhibitory proliferation of hepatoma cells and breast cancer cells mediated by human mesenchymal stem cells (hMSCs).Methods:The proliferation of H7402 human hepatoma cells and MCF-7 human breast cancer cells was measured by the 5-bromodeoxyuridine (BrdU) incorpora-tion assay and flow cytometry assay after the treatment with conditioned media from hMSCs culture,such as Z3 cells or BMMS-03 cells.The role of NF-kB or the phosphorylation of inhibitor kBoα (p-IkBα) in the depression of hepatoma or breast cancer cells treated with conditioned media from Z3 cells or BMMS-03 cells was examined by reporter gene assay,quantitative real-time PCR,and Western blot analysis,respectively.Results:The proliferation of H7402 cells and MCF-7 cells was decreased significantly by the BrdU incorporation assay and flow cytometry assay after treatment.The transcriptional activity and mRNA level of NF-kB were downregulated in the treated cells by reporter gene assay and quantitative real-time PCR in a dose-dependent manner.At the protein level,NF-kB and p-IkBα decreased in the treated cells by Western blot analysis.Conclusion:Conditioned media from hMSCs are able to inhibit the proliferation of tumor cells.NF-kB downregulation is one of reasons for the depression of tumor cell proliferation mediated by hMSCs.

  10. DESREGULACION DE LA ACTIVIDAD DEL FACTOR DE TRANSCRIPCION NF-KB MEDIADA POR CALCIO EN CELULAS MUSCULARES DISTROFICAS MDX

    OpenAIRE

    ALTAMIRANO FULLA, FRANCISCO JAVIER; ALTAMIRANO FULLA; FRANCISCO JAVIER

    2012-01-01

    La Distrofia Muscular de Duchenne (DMD) es una enfermedad genética recesiva,ligada al cromosoma X, que afecta a 1 de cada 3500 hombres nacidos. La causa de esta enfermedad es la mutación del gen de la distrofina en humanos y en ratones mdx (modelo animal de DMD). La DMD es una enfermedad progresiva que se caracteriza por daños en la membrana de las fibras musculares, infiltración de células inmunes en el músculo,inflamación crónica, daño de sarcómeros, muerte celular y degeneración severa del...

  11. Somatic Mutations in the Notch, NF-KB, PIK3CA, and Hedgehog Pathways in Human Breast Cancers

    OpenAIRE

    Jiao, Xiang; Wood, Laura; Lindman, Monica; Jones, Sian,; Buckhaults, Phillip; Polyak, Kornelia; Sukumar, Saraswati; Carter, Hannah; Kim, Dewey; Karchin, Rachel; Sjöblom, Tobias

    2012-01-01

    Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings st...

  12. Acute exercise reduces insulin resistance-induced TRB3 expression and amelioration of the hepatic production of glucose in the liver of diabetic mice.

    Science.gov (United States)

    Lima, Athos F; Ropelle, Eduardo R; Pauli, José R; Cintra, Dennys E; Frederico, Marisa J S; Pinho, Ricardo A; Velloso, Lício A; De Souza, Cláudio T

    2009-10-01

    TRB3 (a mammalian homolog of Drosophila) is emerging as an important player in the regulation of insulin signaling. TRB3 can directly bind to Ser/Thr protein kinase Akt, the major downstream kinase of insulin signaling. Conversely, physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity; however, the molecular mechanisms by which exercise improves glucose homeostasis, particularly in the hepatic tissue, are only partially known. Here, we demonstrate that acute exercise reduces fasting glucose in two models diabetic mice. Western blot analysis showed that 8 h after a swimming protocol, TRB3 expression was reduced in the hepatic tissue from diet-induced obesity (Swiss) and leptin-deficient (ob/ob) mice, when compared with respective control groups at rest. In parallel, there was an increase in insulin responsiveness in the canonical insulin-signaling pathway in hepatic tissue from DIO and ob/ob mice after exercise. In addition, the PEPCK expression was reduced in the liver after the exercise protocol, suggesting that acute exercise diminished hepatic glucose production through insulin-signaling restoration. Thus, these results provide new insights into the mechanism by which physical activity improves glucose homeostasis in type 2 diabetes.

  13. 3,5,4′-tri-O-acetylresveratrol Ameliorates Seawater Exposure-Induced Lung Injury by Upregulating Connexin 43 Expression in Lung

    Directory of Open Access Journals (Sweden)

    Lijie Ma

    2013-01-01

    Full Text Available The aim of the present study was to examine the effects of 3,5,4′-tri-O-acetylresveratrol on connexin 43 (Cx43 in acute lung injury (ALI in rats induced by tracheal instillation of artificial seawater. Different doses (50, 150, and 450 mg/kg of 3,5,4′-tri-O-acetylresveratrol were administered orally for 7 days before modeling. Four hours after seawater inhalation, histological changes, contents of TNF-α, IL-1β and IL-10, and the expression of Cx43 in lungs were detected. Besides, the gap junction communication in A549 cells and human umbilical vein endothelial cells (HUVECs challenged by seawater was also evaluated. Histological changes, increased contents of inflammatory factors, upregulation in gene level, and deregulation in protein level of Cx43 in lungs stimulated by seawater were observed. On the other hand, pretreatment with 3,5,4′-tri-O-acetylresveratrol significantly inhibited infiltration of inflammation, development of pulmonary edema, and contents of inflammatory mediators in lungs. Above all, 3,5,4′-tri-O-acetylresveratrol upregulated the expression of Cx43 in both gene and protein levels, and its intermediate metabolite, resveratrol, also enhanced the gap junction communication in the two cell lines. The results of the present study suggested that administration of 3,5,4′-tri-O-acetylresveratrol may be beneficial for treatment of inflammatorycellsin lung.

  14. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice.

    Science.gov (United States)

    Yin, Xinru; Gong, Xia; Jiang, Rong; Kuang, Ge; Wang, Bin; Zhang, Li; Xu, Ge; Wan, Jingyuan

    2014-11-01

    Emodin has been reported to possess anti-inflammatory and anti-oxidant activities. The aim of this study was to explore the effect and mechanism of emodin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in D-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with emodin inhibited the elevation of plasma aminotransferases, alleviated the hepatic histopathological abnormalities and improved the survival rate of LPS/D-GalN-primed mice. Moreover, emodin markedly attenuated the increased serum and hepatic tumor necrosis factor-α (TNF-α) production, and activated hepatic p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signal pathways in LPS/D-GalN-challenged mice. Furthermore, using an in vitro experiment, we found that emodin dose-dependently suppressed TNF-α production, dampened AP-1 and NF-κB activation, and blocked toll-like receptor (TLR) 4/myeloid differentiation factor (MD) 2 complex expression in LPS-elicited RAW264.7 mouse macrophage cells. Taken together, these data suggested that emodin could effectively prevent LPS-induced FHF, which might be mediated by inhibition of TNF-α production, deactivation of MAPKs and NF-κB, and blockade of TLR4/MD2 complex expression.

  15. Moringa oleifera leaf extract ameliorates alloxan-induced diabetes in rats by regeneration of β cells and reduction of pyruvate carboxylase expression.

    Science.gov (United States)

    Abd El Latif, Amira; El Bialy, Badr El Said; Mahboub, Hamada Dahi; Abd Eldaim, Mabrouk Attia

    2014-10-01

    Moringa oleifera Lam. contains many active ingredients with nutritional and medicinal values. It is commonly used in folk medicine as an antidiabetic agent. The present study was designed to investigate how an aqueous extract from the leaves of M. oleifera reveals hypoglycemia in diabetic rats. M. oleifera leaf extract counteracted the alloxan-induced diabetic effects in rats as it normalized the elevated serum levels of glucose, triglycerides, cholesterol, and malondialdehyde, and normalized mRNA expression of the gluconeogenic enzyme pyruvate carboxylase in hepatic tissues. It also increased live body weight gain and normalized the reduced mRNA expression of fatty acid synthase in the liver of diabetic rats. Moreover, it restored the normal histological structure of the liver and pancreas damaged by alloxan in diabetic rats. This study revealed that the aqueous extract of M. oleifera leaves possesses potent hypoglycemic effects through the normalization of elevated hepatic pyruvate carboxylase enzyme and regeneration of damaged hepatocytes and pancreatic β cells via its antioxidant properties.

  16. Oral collagen-derived dipeptides, prolyl-hydroxyproline and hydroxyprolyl-glycine, ameliorate skin barrier dysfunction and alter gene expression profiles in the skin.

    Science.gov (United States)

    Shimizu, Jun; Asami, Naoto; Kataoka, Aya; Sugihara, Fumihito; Inoue, Naoki; Kimira, Yoshifumi; Wada, Masahiro; Mano, Hiroshi

    2015-01-09

    Oral supplementation with collagen hydrolysate (CH) has been shown to improve the condition of the skin in humans and experimental animals. Several hydroxyproline-containing oligo-peptides were previously detected in human peripheral blood after the ingestion of CH, and the two dipeptides, prolyl-hydroxyproline (PO) and hydroxyprolyl-glycine (OG), have been proposed to have beneficial effects on human health. When HR-1 hairless mice were fed a HR-AD diet, which lacked magnesium and zinc, transepidermal water loss (TEWL) increased and water content of stratum corneum decreased. In the present study, we investigated the effects of dietary PO and OG on skin barrier dysfunction in HR-1 hairless mice. Mice were fed a HR-AD diet with or without PO (0.15%) and OG (0.15%) for 35 consecutive days. The administration of PO and OG significantly decreased TEWL, and significantly increased water content of stratum corneum. A DNA microarray analysis of the dorsal skin revealed differences in gene expression between the group administered PO and OG and the control group. We also identified muscle-related Gene Ontology as a result of analyzing the up-regulated genes. These results suggested that the administration of PO and OG improved skin barrier dysfunction and altered muscle-related gene expression.

  17. Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues.

    Science.gov (United States)

    Chen, Ying-Ying; Yan, Yan; Zhao, Zheng; Shi, Mei-Jing; Zhang, Yu-Bin

    2016-06-01

    The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.

  18. Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats.

    Science.gov (United States)

    Montez, Priscilla; Vázquez-Medina, José Pablo; Rodríguez, Rubén; Thorwald, Max A; Viscarra, José A; Lam, Lisa; Peti-Peterdi, Janos; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M

    2012-12-01

    Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg·d × 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water × 6 wk), and 5) OLETF + ARB + HG (ARB/HG × 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50-120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity.

  19. Abrogation of cisplatin-induced nephrotoxicity in mice by alpha lipoic acid through ameliorating oxidative stress and enhancing gene expression of antioxidant enzymes.

    Science.gov (United States)

    El-Beshbishy, Hesham A; Bahashwan, Saleh A; Aly, Hamdy A A; Fakher, Hesham A

    2011-10-01

    Cisplatin is chemotherapeutic drug used in treatment of malignancies. However, its clinical utility is limited by nephrotoxicity. The purpose of present study is to investigate biochemical and molecular effects of alpha lipoic acid (ALA) to protect against cisplatin-induced nephrotoxicity in mice. Cisplatin (12 mg/kg/day) was administered i.p. for 4 days. Group of mice were given ALA (20 mg/kg/day) for 18 days. Another set were administered ALA for 4 days before and 14 days after cisplatin intoxication. The results obtained revealed that kidney/body weight ratio of cisplatin-treated mice was increased by +40%. ALA intake declined the ratio by -19%. Serum creatinine and urea levels were increased in cisplatin-treated mice by +375% and +69%, respectively. These changes were moved to normalcy upon ALA intake. Cisplatin treatment elevated malondialdehyde (MDA) by 27 fold and declined reduced glutathione (GSH) by -49%. Cisplatin decreased catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes by -47%, -49% and -59%, respectively. ALA decreased the MDA by -286% and increased the GSH, catalase, SOD and GPx levels by +60%, +81%, +90% and +38%, respectively. ALA increased mRNA expression of catalase, CuZn SOD and GPx genes near to normalcy compared to cisplatin-treated mice. Cisplatin-treated mice increased caspase-3-activity by +223%, nitric oxide (NO) by +74% and inducible nitric oxide synthase (iNOS) by 10 fold. ALA intake declined these changes by -43%, -45% and -73%, respectively. ALA may play renoprotective role on cisplatin-induced nephrotoxicity through antioxidant and antiapoptotic mechanisms combined with initiation of mRNA expression of antioxidant genes.

  20. Curcumin nanoparticles ameliorate ICAM-1 expression in TNF-α-treated lung epithelial cells through p47 (phox and MAPKs/AP-1 pathways.

    Directory of Open Access Journals (Sweden)

    Feng-Lin Yen

    Full Text Available Upregulation of intercellular adhesion molecule-1 (ICAM-1 involves adhesions between both circulating and resident leukocytes and the human lung epithelial cells during lung inflammatory reactions. We have previously demonstrated that curcumin-loaded polyvinylpyrrolidone nanoparticles (CURN improve the anti-inflammatory and anti-oxidative properties of curcumin in hepatocytes. In this study, we focused on the effects of CURN on the expression of ICAM-1 in TNF-α-treated lung epithelial cells and compared these to the effects of curcumin water preparation (CURH. TNF-αinduced ICAM-1 expression, ROS production, and cell-cell adhesion were significantly attenuated by the pretreatment with antioxidants (DPI, APO, or NAC and CURN, but not by CURH, as revealed by western blot analysis, RT-PCR, promoter assay, and ROS detection and adhesion assay. In addition, treatment of TNF-α-treated cells with CURN and antioxidants also resulted in an inhibition of activation of p47 (phox and phosphorylation of MAPKs, as compared to that using CURH. Our findings also suggest that phosphorylation of MAPKs may eventually lead to the activation of transcription factors. We also observed that the effects of TNF-α treatment for 30 min, which includes a significant increase in the binding activity of AP-1 and phosphorylation of c-jun and c-fos genes, were reduced by CURN treatment. In vivo studies have revealed that CURN improved the anti-inflammation activities of CURH in the lung epithelial cells of TNF-α-treated mice. Our results indicate that curcumin-loaded polyvinylpyrrolidone nanoparticles may potentially serve as an anti-inflammatory drug for the treatment of respiratory diseases.

  1. Dexamethasone ameliorates H2S-induced acute lung injury by increasing claudin-5 expression via the PI3K pathway.

    Science.gov (United States)

    Geng, P; Ma, T; Xing, J; Jiang, L; Sun, H; Zhu, B; Zhang, H; Xiao, H; Wang, J; Zhang, J

    2017-01-01

    Acute lung injury (ALI) is a major outcome of exposure to high levels of hydrogen sulfide (H2S). Dexamethasone (DXM) has been used to treat ALI. However, the mechanisms involved in H2S-induced ALI and the protective mechanisms of DXM in treating ALI are still nebulous. To explore the mechanisms involved, we evaluated the role of claudin-5 in the protective effect of DXM against H2S-induced ALI. Sprague-Dawley rats were exposed to H2S to establish the ALI model. In parallel with the animal model, a cell model was also established by incubating human umbilical vein endothelial cells (HUVECs) with NaHS. Lung hematoxylin-eosin staining, electron microscope assay, and wet/dry ratio were used to identify whether the ALI was successfully induced by H2S, and changes in claudin-5 expression were detected in both rats and HUVECs. Our results revealed that claudin-5 was markedly decreased after H2S exposure and that DXM significantly attenuated the H2S-induced downregulation of claudin-5 in both rats and HUVECs. In the animal experiment, p-Akt and p-FoxO1 presented a similar tendency as claudin-5, but their levels decreased 6 h prior to the levels of claudin-5. In a further investigation, the DXM-induced protective effect on ALI and rescue effect on downregulation of claudin-5 were both blocked by LY294002. The current study demonstrated that claudin-5 was involved in the development of H2S-induced ALI and that DXM exerted protective effects through increasing claudin-5 expression by activating the phosphatidylinositol 3-kinase pathway. Therefore, claudin-5 might represent a novel pharmacological target for treating ALI induced by H2S and other hazardous gases.

  2. Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

    Directory of Open Access Journals (Sweden)

    José Sereno

    2014-01-01

    Full Text Available Protocols of conversion from cyclosporin A (CsA to sirolimus (SRL have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n=6 were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks. Classical and emergent serum, urinary, and kidney tissue (gene and protein expression markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κβ, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions, while NGAL (serum versus urine seems to be a feasible biomarker of CsA replacement to SRL.

  3. Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

    Science.gov (United States)

    Sereno, José; Nunes, Sara; Rodrigues-Santos, Paulo; Rocha-Pereira, Petronila; Fernandes, João; Teixeira, Frederico; Reis, Flávio

    2014-01-01

    Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κ β, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL. PMID:24971338

  4. β-防御素-2、IFN-γ和NF-κB p65在寻常型银屑病皮损中表达的研究%Study on the Expression of β-defensin-2, Interferon-gamma and Nuclear- factor-κB p65 in the Lesions of Psoriasis Vulgaris

    Institute of Scientific and Technical Information of China (English)

    曹彦明; 甄莉

    2011-01-01

    Objective To investigate the expressions of β - defensin -2 ( HBD -2) , interferon - gamma ( IFN - γ) . and nuclear - factor - KB p65 ( NF - KBp65) in the epidemis of psoriasis vulgaris and study their correlation with disease severity in psoriatic patients. Methods Forty - five samples of lesional psoriatic skin. forty - five samples of nonlesional psoriatic skin and fifteen samples of normal skin were analyzed by Elivision immunohistochemical technique for the expressions of HBD - 2 , IFN - γ and NF - KB p65. Correlation analysis was performed among the expressions of the three factors as well as between the expressions and disease severity.Results Compared with those of normal epidermis and nonlesional psoriatic epidermis.HBD - 2. IFN - γ and NF - KB p65 were more highly expressed in lesional epidermis from patients with psoriasis ( all P < 0. 05 ) . In nonlesional psoriatic epidermis, HBD - 2 , IFN - γ expression was also upregulated compared with that of normal epidermis( P < 0. 05 ) . The expressions of HBD - 2 , IFN - γ and NF - KBp65 in lesional epidermis positively correlated individually with the psoriasis area and severity index ( PASI) scores in patients( all P < 0. 05 ) .Positive correlation was also found between the expressions of any two factors( HBD - 2,IFN - γ or NF - KB p65 ) in lesional epidermis ( all P < 0. 05) . Conclusion The upregulation of HBD - 2 ,IFN - γ and NF - KB p65 expressions in psoriatic lesions mav be involved in the pathogenesis of psoriasis.%目的 研究β-防御素-2 (HBD-2)、IFN-γ、NF-κB p65在寻常型银屑病患者皮损中的表达及其与银屑病严重程度的关系.方法 采用SP免疫组化法检测45例银屑病患者皮损组织、45例银屑病患者非皮损组织及15例正常皮肤组织石蜡标本中HBD-2、IFN-γ、NF-κB p65的表达,对其在皮损中的表达进行相关性分析,并将结果与PASI评分进行相关性分析.结果 与正常人皮肤组织和银屑病患者非皮

  5. Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging.

    Science.gov (United States)

    Ismail, Basma; deKemp, Rob A; Croteau, Etienne; Hadizad, Tayebeh; Burns, Kevin D; Beanlands, Rob S; DaSilva, Jean N

    2017-01-01

    ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8-10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18-20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

  6. Quercetin ameliorates chronic unpredicted stress-mediated memory dysfunction in male Swiss albino mice by attenuating insulin resistance and elevating hippocampal GLUT4 levels independent of insulin receptor expression.

    Science.gov (United States)

    Mehta, Vineet; Parashar, Arun; Sharma, Arun; Singh, Tiratha Raj; Udayabanu, Malairaman

    2017-03-01

    Chronic stress is associated with impaired neuronal functioning, altered insulin signaling, and behavioral dysfunction. Quercetin has shown neuroprotective and antidiabetic effects, besides modulating cognition and insulin signaling. Therefore, in the present study, we explored whether or not quercetin ameliorates stress-mediated cognitive dysfunction and explored the underlying mechanism. Swiss albino male mice were subjected to an array of unpredicted stressors for 21days, during which 30mg/kg quercetin treatment was given orally. The effect of chronic unpredicted stress (CUS) and quercetin treatment on cognition were evaluated using novel object recognition (NOR) and Morris water maze (MWM) tests. Hippocampal neuronal integrity was observed by histopathological examination. Blood glucose, serum corticosterone, and insulin levels were measured by commercial kits and insulin resistance was evaluated in terms of HOMA-IR index. Hippocampal insulin signaling was determined by immunofluorescence staining. CUS induced significant cognitive dysfunction (NOR and MWM) and severely damaged hippocampal neurons, especially in the CA3 region. Quercetin treatment alleviated memory dysfunction and rescued neurons from CUS-mediated damage. Fasting blood glucose, serum corticosterone, and serum insulin were significantly elevated in stressed animals, besides, having significantly higher HOMA-IR index, suggesting the development of insulin resistance. Quercetin treatment alleviated insulin resistance and attenuated altered biochemical parameters. CUS markedly down-regulated insulin signaling in CA3 region and quercetin treatment improved neuronal GLUT4 expression, which seemed to be independent of insulin and insulin receptor levels. These results suggest that intact insulin functioning in the hippocampus is essential for cognitive functions and quercetin improves CUS-mediated cognitive dysfunction by modulating hippocampal insulin signaling. Copyright © 2016 Elsevier Inc. All

  7. Cacao polyphenols ameliorate autoimmune myocarditis in mice.

    Science.gov (United States)

    Zempo, Hirofumi; Suzuki, Jun-ichi; Watanabe, Ryo; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Komuro, Issei; Isobe, Mitsuaki

    2016-04-01

    Myocarditis is a clinically severe disease; however, no effective treatment has been established. The aim of this study was to determine whether cacao bean (Theobroma cacao) polyphenols ameliorate autoimmune myocarditis. We used an experimental autoimmune myocarditis (EAM) model in Balb/c mice. Mice with induced EAM were treated with a cacao polyphenol extract (CPE, n=12) or vehicle (n=12). On day 21, hearts were harvested and analyzed. Elevated heart weight to body weight and fibrotic area ratios as well as high cardiac cell infiltration were observed in the vehicle-treated EAM mice. However, these increases were significantly suppressed in the CPE-treated mice. Reverse transcriptase-PCR revealed that mRNA expressions of interleukin (Il)-1β, Il-6, E-selectin, vascular cell adhesion molecule-1 and collagen type 1 were lower in the CPE group compared with the vehicle group. The mRNA expressions of nicotinamide adenine dinucleotide phosphate-oxidase (Nox)2 and Nox4 were increased in the vehicle-treated EAM hearts, although CPE treatment did not significantly suppress the transcription levels. However, compared with vehicle treatment of EAM hearts, CPE treatment significantly suppressed hydrogen peroxide concentrations. Cardiac myeloperoxidase activity, the intensity of dihydroethidium staining and the phosphorylation of nuclear factor-κB p65 were also lower in the CPE group compared with the vehicle group. Our data suggest that CPE ameliorates EAM in mice. CPE is a promising dietary supplement to suppress cardiovascular inflammation and oxidative stress.

  8. PHLPP phosphatase:a key mediator integrating multiple signaling pathways

    Institute of Scientific and Technical Information of China (English)

    Hui ZHONG

    2010-01-01

    @@ Cellular responses to bacterial or viral infections and to stress require rapid and accurate transmission of signals from cell-surface receptors to the nucleus (Karin and Hunter, 1995).These signaling pathways, relying on extensive protein phosphorylation events, lead to the activation of specific transcription factors that induce the expression of appropriate target genes.Among the activated transcription factors, nuclear factor KB (NF-KB)is essential for inflammation, immunity, cell proliferation and apoptosis.NF-KB requires a signaling pathway for activation.Such NF-KB-activating pathways can be triggered by a variety of extracellular stimuli, which lead to the phosphorylation and subsequent proteasomemediated degradation of inhibitory molecules, the inhibitor of NF-KB (hcB) proteins (Karin and Ben-Neriah, 2000).Activated NF-KB migrates into the nucleus to regulate the expression of multiple target genes.

  9. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression.

    Directory of Open Access Journals (Sweden)

    Byungwoo Ryu

    specific genes identified within each class of transcripts are novel. In addition, the transcription factor NF-KB was specifically identified as being a potential "master regulator" of melanoma invasion since NF-KB binding sites were identified as consistent consensus sequences within promoters of progression-associated genes. CONCLUSIONS/SIGNIFICANCE: We conclude that tumor cell lines are a valuable resource for the early identification of gene signatures associated with malignant progression in tumors with significant heterogeneity like melanoma. We further conclude that the development of novel data reduction algorithms for analysis of microarray studies is critical to allow for optimized mining of important, clinically-relevant datasets. It is expected that subsequent validation studies in primary human tissues using such an approach will lead to more rapid translation of such studies to the identification of novel tumor biomarkers and therapeutic targets.

  10. Anti-inflammatory action of type I interferons deduced from mice expressing interferon beta.

    Science.gov (United States)

    Boscá, L; Bodelón, O G; Hortelano, S; Casellas, A; Bosch, F

    2000-05-01

    Type I interferons (IFN) are widely used for the therapeutic treatment of viral infections, tumor growth and various chronic diseases such as multiple sclerosis. Antagonism between type I IFNs and IFN-gamma has been described in cells of the immune system, in particular in the activation of macrophages. To study the systemic effects of type I IFNs we used transgenic mice carrying a human IFN-beta (hIFN-beta) gene under the control of the rat insulin I promoter. These animals expressed high levels of hIFN-beta in beta-pancreatic cells, and the ability of the macrophages to respond to pro-inflammatory stimuli was analyzed. Transgenic mice exhibited an increased extravasation of cells to the peritoneal cavity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-gamma. Analysis of the mechanisms leading to this attenuated inflammatory response showed a decrease in the serum levels of TNF-alpha and an inhibition of the activation of the transcription factor NF-KB in various tissues. These results indicate that systemic administration of IFN-beta might influence the response to pro-inflammatory stimuli, in particular through the antagonism of IFN-gamma signaling.

  11. Pregnancy amelioration of arthritis in SKG mice corresponds with alterations in serum amyloid A3 levels.

    Science.gov (United States)

    Shaw, Laura A; Stefanski, Adrianne L; Peterson, Lisa K; Rumer, Kristen K; Vondracek, Andrea; Phang, Tzu L; Sakaguchi, Shimon; Winn, Virginia D; Dragone, Leonard L

    2012-06-30

    OBJECTIVES: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission. METHODS: Cohorts of zymosan-treated pregnant SKG mice and controls were monitored for arthritis progression. Microarray analysis evaluated alterations in gene expression in maternal PBMCs at embryonic day 14.5 (E14.5) between arthritic and pregnancy-remitted mice. A selected target, serum amyloid A3 (SAA3), was further investigated using quantitative reverse transcriptase PCR (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Pregnancy resulted in complete or partial remission in the majority of the zymosan-treated SKG mice. Twenty-seven transcripts were differentially expressed in the PBMCs between arthritic and pregnancy-remitted mice. Expression and plasma SAA3 levels decreased with pregnancy-induced arthritis amelioration and plasma SAA3 levels correlated with arthritis severity. CONCLUSIONS: These results establish the SKG mouse as a model system to study pregnancy-induced amelioration of arthritis. These studies also establish SAA3 as a biomarker of arthritis amelioration in SKG mice. This model can be used to elucidate the molecular and cellular mechanisms underlying the impact of pregnancy on the maternal immune system that results in arthritis amelioration.

  12. HSP70和NF-κB在大鼠肾缺血再灌注损伤中的表达及洛伐他汀的干预研究%Intervention of Lovastatin in the expression of HSP70 and NF-κB after renal ischemia-reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    李鹏; 郝雷; 高进; 傅亮

    2013-01-01

    目的 探讨洛伐他汀(Lovastatin,Lov)对大鼠肾缺血再灌注损伤(RIRI)热休克蛋白70 (HSP70)和核因子-κB (NF-κB)表达的影响.方法 90只Wistar大鼠随机分为3组:假手术(Sham)组、缺血再灌注模型(IR)组、洛伐他汀(Lov)组.IR组和Lov组大鼠采用夹闭肾动脉60 min后再灌注的方法制备RIRI模型,Lov组于动脉夹闭前给予洛伐他汀2mg/(kg·d)灌胃,各组大鼠在再灌注4、12、24 h时分别处死10只取标本.测定各组大鼠的血肌酐(Scr)、尿素氮(BUN)水平,免疫组化法检测肾组织HSP70和NF-κB表达,镜下观察肾组织形态学改变.结果 与Sham组大鼠相比,IR组大鼠在再灌注4、12、24 h时点的Scr和BUN含量均显著升高;肾组织HSP70和NF-κB表达均明显增强,差异均有统计学意义(P均<0.05).与IR组相比,Lov组大鼠在各时点的Scr和BUN含量均显著降低(P均<0.01);HSP70表达均升高(P均<0.05);NF-κB表达减少,再灌注4、12 h时,两者差异有统计学意义(P<0.05);镜下病理改变减轻.结论 Lov可通过增加肾脏HSP70、下调NF-κB达而抑制炎症反应过程,减轻肾脏损害,对大鼠RIRI起到一定的保护作用.%Objective To investigate the possible effects of Lovastatin on the expression of HSP70 and NF-KB in rats after renal ischemia-reperfusion injury (RIRI). Methods Ninety Wistar rats were randomly divided into 3 groups, sham-operated group, IR group and Lov group. The model of RIRI in IR and Lov groups was established by the clamping of the kidney artery for 60 minutes. Lovastatin was given 2mg/(kg·d) by oral gavage to the rats in the Lov group before clamping of the kidney artery. Ten rats in each group were executed at 4, 12, and 24 hours after reperfusion. The concentrations of serum creatinine (Cr) and urea nitrogen (BUN) were detected, and the expression of HSP70 and NF-KB in renal tissues was detected by immunohistochemistry. The pathologic changes of renal tissues were observed by microscope

  13. Roscovitine ameliorates endotoxin-induced uveitis through neutrophil apoptosis.

    Science.gov (United States)

    Jiang, Zhao-Xin; Qiu, Suo; Lou, Bing-Sheng; Yang, Yao; Wang, Wen-Cong; Lin, Xiao-Feng

    2016-08-01

    Neutrophils have been recognized as critical response cells during the pathogenesis of endotoxin‑induced uveitis (EIU). Apoptosis of neutrophils induced by roscovitine has previously been demonstrated to ameliorate inflammation in several in vivo models. The present study aimed to assess whether roscovitine ameliorates EIU. EIU was induced in female C57BL/6 mice by a single intravitreal injection of lipopolysaccharide (LPS; 250 ng). The mice were divided into three groups as follows: LPS alone, LPS plus vehicle, LPS plus roscovitine (50 mg/kg). The mice were euthanized 12, 24, 48 and 72 h after LPS‑induced uveitis. Accumulation of inflammatory cells in the vitreous body was confirmed by immunohistochemistry, and quantified following hematoxylin and eosin staining. Terminal deoxynucleotidyl transferase dUTP nick‑end labeling was performed to detect of apoptotic cells. The mRNA levels of inflammatory cytokines were analyzed by reverse transcription‑quantitative polymerase chain reaction and the changes in protein levels were analyzed by western blotting. Inflammatory cells accumulated in the vitreous near the optic nerve head and the quantity peaked at 24 h after LPS injection. Immunohistochemistry revealed that the majority of the inflammatory cells were neutrophils. The number of infiltrating cells was similar in the LPS and LPS plus vehicle groups, while there were significantly less in the roscovitine group at 24 h. Apoptosis of neutrophils was observed between 12 and 48 h after roscovitine injection, while no apoptosis was observed in the other groups. The mRNA expression levels of GMCSF, CINC‑1 and ICAM‑1 peaked at 12 h after LPS injection, and decreased to normal levels at 72 h. This trend in mRNA expression was similar in the LPS and LPS plus vehicle groups; however, the expression levels decreased more quickly in the roscovitine group at 24 and 48 h. Following roscovitine administration, upregulated cleaved caspase 3 expression levels

  14. Black ginseng extract ameliorates hypercholesterolemia in rats

    Directory of Open Access Journals (Sweden)

    Evelyn Saba

    2016-04-01

    Conclusion: Administration of BG extracts to Sprague Dawley rats fed with high-cholesterol diet ameliorated hypercholesterolemia, which was mediated via modulation of cholesterol-metabolizing marker genes. This data throw a light on BG's cardioprotective effects.

  15. Dietary amelioration of Helicobacter infection.

    Science.gov (United States)

    Fahey, Jed W; Stephenson, Katherine K; Wallace, Alison J

    2015-06-01

    We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability, and cultural acceptability. This review, therefore, highlights specific foods, food components, and food products, grouped as follows: bee products (eg, honey and propolis); probiotics; dairy products; vegetables; fruits; oils; essential oils; and herbs, spices, and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and preclinical evidence must now be followed up with rationally designed, unambiguous human trials. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Dietary Amelioration of Helicobacter Infection

    Science.gov (United States)

    Fahey, Jed W.; Stephenson, Katherine K.; Wallace, Alison J.

    2015-01-01

    We review herein the basis for using dietary components to treat and/or prevent Helicobacter pylori infection, with emphasis on: (a) work reported in the last decade, (b) dietary components for which there is mechanism-based plausibility, and (c) components for which clinical results on H. pylori amelioration are available. There is evidence that a diet-based treatment may reduce the levels and/or the virulence of H. pylori colonization without completely eradicating the organism in treated individuals. This concept was endorsed a decade ago by the participants in a small international consensus conference held in Honolulu, Hawaii, USA, and interest in such a diet-based approach has increased dramatically since then. This approach is attractive in terms of cost, treatment, tolerability and cultural acceptability. This review therefore highlights specific foods, food components, and food products, grouped as follows: bee products (e.g. honey and propolis), probiotics, dairy products, vegetables, fruits, oils, essential oils, and herbs, spices and other plants. A discussion of the small number of clinical studies that are available is supplemented by supportive in vitro and animal studies. This very large body of in vitro and pre-clinical evidence must now be followed up with rationally designed, unambiguous human trials. PMID:25799054

  17. Fucoidan Extracts Ameliorate Acute Colitis.

    Science.gov (United States)

    Lean, Qi Ying; Eri, Rajaraman D; Fitton, J Helen; Patel, Rahul P; Gueven, Nuri

    2015-01-01

    Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent

  18. Effects on 5-ASA on the Expressions of TL1A and Nuclear Factor-Kappa B in TNBS-Induced Rat Colitis%5-氨基水杨酸对TNBS结肠炎大鼠中TL1A、NF-KB表达的影响

    Institute of Scientific and Technical Information of China (English)

    董渊; 朱瑞平; 夏冰

    2011-01-01

    目的:通过检测三硝基环磺酸(TNBS)诱导的结肠炎大鼠结肠组织中TL1A、NF-kB的表达及5-氨基水杨酸(5-ASA)干预后的表达,探讨它们和克罗恩病(CD)之间的关系及5-ASA干预后的影响.方法:选用雌性健康Wistar大鼠30只,均分为A、B、C组.A为正常对照组,B、C两组大鼠采用TNBS/乙醇灌肠制作大鼠结肠炎模型.造模后,B组每天给予0.9%氯化钠溶液1 ml灌肠;C组每天给予5-ASA l ml灌肠(100 mg/kg).于造模后第7天处死所有大鼠,按疾病活动指数(DAI)的评分标准进行大体损伤评分,HE染色进行组织损伤评分.同时取结肠病变部位组织,生化法检测MPO活性,应用荧光定量PCR检测TL1A、NF-kB的表达的变化.结果:与A组比较,B组和C组的DAI评分、大体损伤形态和组织学损伤评分及MPO活性均升高(P<0.05),但B组高于C组(P<0.05).与A组相比,B、C组的TL1A、NF-kB水平升高(P<0.05),分别为0.09±0.51比0.91±0.17和0.35±0.05、0.11±0.06比0.82±0.17和0.33±0.14,且B组高于C组.结论:在TNBS诱导的大鼠炎性肠病模型中TL1A、NF-kB的表达增高,5-ASA对肠道炎症的治疗作用可能是通过抑制TL1A、NF-kB实现的.%Objective: To investigate the relationship among TL1A, NFkB, and colitis, and the therapeutic effects of 5-aminosalicylic acid (5-ASA) on colitis by investigating the expression of TL1A and NF-Kb in TNBS-induced rat colitis. Methods: Thirty female Wistar rats were randomly divided into three groups with 10 rats in each. Group A was served as normal control. The rats in group B and C were infused with TNBS/alcohol per rectum. After the induction of colitis, the rats in group C were treated daily with 1 ml of 5-ASA (100 mg/kg) per rectum, and those in group B were treated daily with 1 ml normal saline. All the animals were sacrificed at day 7 after induction of colitis. The macroscopic changes of the colon were evaluated according to disease activity index (DAI) scoring and histological

  19. Ubiquitous Over-Expression of Chromatin Remodeling Factor SRG3 Ameliorates the T Cell-Mediated Exacerbation of EAE by Modulating the Phenotypes of both Dendritic Cells and Macrophages.

    Science.gov (United States)

    Lee, Sung Won; Park, Hyun Jung; Jeon, Sung Ho; Lee, Changjin; Seong, Rho Hyun; Park, Se-Ho; Hong, Seokmann

    2015-01-01

    Although SWI3-related gene (SRG3), a chromatin remodeling factor, is critical for various biological processes including early embryogenesis and thymocyte development, it is unclear whether SRG3 is involved in the differentiation of CD4+ T cells, the key mediator of adaptive immune responses. Because it is known that experimental autoimmune encephalomyelitis (EAE) development is determined by the activation of CD4+ T helper cells, here, we investigated the role of SRG3 in EAE development using SRG3 transgenic mouse models exhibiting two distinct SRG3 expression patterns: SRG3 expression driven by either the CD2 or β-actin promoter. We found that the outcome of EAE development was completely different depending on the expression pattern of SRG3. The specific over-expression of SRG3 using the CD2 promoter facilitated EAE via the induction of Th1 and Th17 cells, whereas the ubiquitous over-expression of SRG3 using the β-actin promoter inhibited EAE by promoting Th2 differentiation and suppressing Th1 and Th17 differentiation. In addition, the ubiquitous over-expression of SRG3 polarized CD4+ T cell differentiation towards the Th2 phenotype by converting dendritic cells (DCs) or macrophages to Th2 types. SRG3 over-expression not only reduced pro-inflammatory cytokine production by DCs but also shifted macrophages from the inducible nitric oxide synthase (iNOS)-expressing M1 phenotype to the arginase-1-expressing M2 phenotype during EAE. In addition, Th2 differentiation in β-actin-SRG3 Tg mice during EAE was associated with an increase in the basophil and mast cell populations and in IL4 production. Furthermore, the increased frequency of Treg cells in the spinal cord of β-actin-SRG3 Tg mice might induce the suppression of and accelerate the recovery from EAE symptoms. Taken together, our results provide the first evidence supporting the development of a new therapeutic strategy for EAE involving the modulation of SRG3 expression to induce M2 and Th2 polarization

  20. Constitutive Activation of NF-KB in Prostate Carcinoma Cells Through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (IKKi)

    Science.gov (United States)

    2005-08-01

    IKKi immunoprecipitation to ensure the stability of IKKi–protein complexes. Currently, we are analyzing IKKi- interacting proteins by western...blotting. In FY03 we plan to continue analysis of the IKKi- interacting proteins using 2-D gel electrophoresis following Mass-Spectroscopy analysis of

  1. Participación del factor transcripcional NF-KB en la endocitosis de staphylococcus aureus en células de epitelio marino bovino estimuladas por prolactina

    OpenAIRE

    Lara Zárate, Leticia

    2011-01-01

    La mastitis bovina es considerada una de las enfermedades de mayor relevancia en la ganadería lechera a nivel mundial. Esta patología se caracteriza por una respuesta inflamatoria de la glándula mamaria de origen multifactorial, ocasionada principalmente por infecciones bacterianas.

  2. Constitutive Activation of NF-Kb in Prostate Carcinoma Cells through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (Ikki)

    Science.gov (United States)

    2007-08-01

    Targeting the transcription factor NF-kB and up-stream kinases for intervention of prostate and skin cancer . Ludwig Institute for Cancer Research...1998;12:941–53. 19. Lu S, Tsai SY, Tsai MJ. Regulation of androgen-dependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4 , and CKI...recognized association of prostate inflammation and prostate cancer that offers one of the greatest opportunities for preventing malignant conversion

  3. Increased expression of TLR-2, COX-2, and SOD-2 genes in the peripheral blood leukocytes of opisthorchiasis patients induced by Opisthorchis viverrini antigen.

    Science.gov (United States)

    Yongvanit, Puangrat; Thanan, Raynoo; Pinlaor, Somchai; Sithithaworn, Paiboon; Loilome, Watcharin; Namwat, Nisana; Techasen, Anchalee; Dechakhamphu, Somkid

    2012-05-01

    Re-infection with liver fluke, Opisthorchis viverrini, increases proinflammatory molecules involved in inflammation-mediated disease and carcinogenesis in an animal model. To clarify whether these genes respond to parasite antigen in peripheral blood leukocytes (PBL) of opisthorchiasis patients, we examined the transcriptional level of oxidant-generating (toll-like receptor 2 (TLR-2), nuclear factor-kappa B (NF-KB), and cyclooxygenase 2 (COX-2)), anti-oxidant-generating (manganese superoxide dismutase 2 (SOD-2) and catalase (CAT)), proinflammatory cytokine (interleukin (IL)-1β), and anti-inflammatory cytokine (IL-10), in PBL exposed to parasite antigen in O. viverrini-infected patients compared with healthy individuals in an in vitro experiment. After O. viverrini antigen-treated PBL, quantitative RT-PCR analysis revealed that increased expression of cytokines and oxidant-generating genes in PBL was similar between O. viverrini-infected and healthy groups. Interestingly, compared with healthy subjects, increase of TLR-2, COX-2, and SOD-2 and decreased CAT mRNA expression levels were observed in O. viverrini-infected group. The results indicate that O. viverrini antigen induces upregulation of TLR-2, COX-2, and SOD-2 and downregulation of CAT genes in opisthorchiasis patients, suggesting that imbalance of oxidant/anti-oxidant transcripts during re-infection may be involved in the inflammatory-driven carcinogenesis. These molecules may be used as the chemopreventive target for intervention of opisthorchiasis patients in an endemic area.

  4. Effects of erythropoietin on the expression of nuclear factor-κB in rats with cerebral ischemia-reperfusion injury%促红细胞生成素对脑缺血再灌注大鼠脑内NF-κB表达的影响研究

    Institute of Scientific and Technical Information of China (English)

    牟华

    2012-01-01

    Objective lo observe the effect of erythropoietin on the expression of nuclear tactor-κB m bram of rat during ischemia-reperfusion injury. Methods 45 rats were randomly divided into sham operation group, model group and therapeutic group. Model mice of middle cerebral artery occlusion with ischemia-reperfusion injury was established. The score of the deficient neural function and the behavior were observed at 4 h,24 h and 72 h hour after ischemia-reperfusion; the volume of cerebral infraction was compared; the expression of NF-ΚB and neurona poptosis in brain tissue were detectived by Immunohistoehemistry and TUNEL. Results The volumes of cerebral infarcts, expression of NF-KB and The proportion of apoptosis in therapeutic groups were lower than that in model group; the neural function grades and the behavior grades therapeutic group were lower than that in model group in 12 h and 24 h. Conclusion EPO might protect neurons by markedly reduce the expression of NF-KB of the rats with ischemia-reperfusion.%目的 研究促红细胞生成素(EPO)对大鼠缺血再灌注后核因子-κB(NF-κB)表达的影响.方法 将45只SD大鼠随机分为假手术组、脑缺血再灌注模型组(模型组)以及EPO治疗组(治疗组).构建SD大鼠大脑中动脉闭塞脑缺血/再灌注模型,观测缺血再灌注后4、12、24 h的神经功能缺损评分;比较脑梗死体积,免疫组织化学检测NF-κB蛋白的表达,TUNEL法检测神经元凋亡率.结果 与模型组比较,治疗组12、24 h的神经功能缺损评分降低;脑梗死体积显著减小;脑内NF-κB蛋白的表达与神经元凋亡率明显降低.结论 EPO可通过降低NF-κB蛋白表达对大鼠脑缺血再灌注损伤起保护作用.

  5. Linoleic and alpha linolenic acids ameliorate streptozotocin-induced diabetes in mice.

    Science.gov (United States)

    Canetti, Lea; Werner, Haim; Leikin-Frenkel, Alicia

    2014-02-01

    Streptozotocin (STZ)-induced diabetes in mice progresses with decreased desaturase activities and alterations in the metabolism of essential fatty acids (EFA). Based on our previous studies with soybean oil that ameliorated the STZ damage in mice, we tested here the accountability of its main EFA components, i.e. linoleic acid (LA) and alpha linolenic acid (ALA), in the prevention of pancreas damage and Δ6 desaturase decrease. Seven days after injection with STZ and EFA gavage, ICR mice were sacrificed. Plasma glucose and insulin levels, pancreas histology and liver fatty acid desaturases were analysed. EFA reduced pancreas damage, insulin and glucose plasma levels and restored Δ6 desaturase activity and mRNA expression levels. By reducing pancreas damage, EFA ameliorated insulin levels, Δ6 desaturase and fatty acid metabolism. LA further enhanced Fads2 promoter activity. EFA ameliorate STZ induced diabetes in mice.

  6. Apigenin accelerates lipopolysaccharide induced apoptosis in mesenchymal stem cells through suppressing vitamin D receptor expression

    Institute of Scientific and Technical Information of China (English)

    ZHANG Huan-tian; ZHA Zhen-gang; CAOJia-hui; LIANG Zu-jian; WU Hao; HE Ming-tao; ZANG Xiao; YAO Ping; ZHANG Jia-qing

    2011-01-01

    Background Transplantation of mensenchymal stem cells (MSCs) has been proposed as a promising way for tissue engineering.However,the application of MSCs for transplantation will undergo apoptosis due to the extremely harsh microenvironment such as excessive inflammation.Apigenin (API) has been reported to protect cells against inflammatory damage and cell death by exhibiting anti-inflammatory and anti-oxidative capacity.Here we investigated the modulatory effects of API in lipopolysaccharide (LPS)-mediated inflammation and apoptosis of MSCs,and further defined the underlying mechanism.Methods Effects of different concentrations of API (0,5,10,20,40 and 80 μmol/L) for 24 hours,and LPS (0,0.5 and 5.0 μg/ml) for 6 hours and 24 hours on MSCs viability were assayed by MTT.Based on this,MSCs were pretreated with different concentrations of API (0-40 μmol/L) at the indicated times (6,12 and 24 hours) followed by exposure to 5 μg/ml LPS for 24 hours.MTT,phase-contrast microscopy,annexinV/propidium iodide (PI) double stain flow cytometry (FCM) and Hoechst staining were applied to explore the effects of API on MSCs induced by 5 μg/ml LPS for 24 hours.In addition,reverse-transcription polymerase chain reaction (RT-PCR) was applied to detect the mRNA expression of pro-inflammatory factors including cyclooxygenase-2 (COX-2),inducible nitric oxide synthase (iNOS),nuclear factor-kappa B (NF-KB),pro-apoptotic gene caspase-3,Bad,and anti-apoptotic gene Bcl-2.Moreover,AutoDock software was used to imitate the docking score of API and vitamin D receptor (VDR).In parallel,Western blotting and RT-PCR were used to investigate protein and mRNA expression of VDR.Results MSCs stimulated with LPS 5 μg/ml for 24 hours was used as a model of apoptosis induced by over inflammatory stimulus.API (0-40 μmol/L) had non-toxic effect on MSCs; however,it could decrease mRNA expression of COX-2,iNOS and NF-KB at different time points in MSCs induced by LPS,except for API at the concentration of

  7. ANTIOXIDANTS AMELIORATION OF ARSENICAL-INDUCED EFFECTS IN VIVO

    Science.gov (United States)

    Antioxidant amelioration of arsenical-induced effects in vivo. ES Hunter and EH Rogers. Reproductive Toxicology Division, NHEERL, US EPA, RTP, NC. Antioxidants have been reported to ameliorate the effects of many developmental toxicants. We tested the hypothesis that oxi...

  8. Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms.

    Science.gov (United States)

    Nyström, Alexander; Thriene, Kerstin; Mittapalli, Venugopal; Kern, Johannes S; Kiritsi, Dimitra; Dengjel, Jörn; Bruckner-Tuderman, Leena

    2015-07-20

    Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)-a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms.

  9. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

    Science.gov (United States)

    Giridharan, Vijayasree V; Thandavarayan, Rajarajan A; Arumugam, Somasundaram; Mizuno, Makoto; Nawa, Hiroyuki; Suzuki, Kenji; Ko, Kam M; Krishnamurthy, Prasanna; Watanabe, Kenichi; Konishi, Tetsuya

    2015-01-01

    Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

  10. Schisandrin B Ameliorates ICV-Infused Amyloid β Induced Oxidative Stress and Neuronal Dysfunction through Inhibiting RAGE/NF-κB/MAPK and Up-Regulating HSP/Beclin Expression.

    Directory of Open Access Journals (Sweden)

    Vijayasree V Giridharan

    Full Text Available Amyloid β (Aβ-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD. Our previous studies have demonstrated that schisandrin B (Sch B, an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1-40-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β, IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE, nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology.

  11. GL-V9, a new synthetic flavonoid derivative, ameliorates DSS-induced colitis against oxidative stress by up-regulating Trx-1 expression via activation of AMPK/FOXO3a pathway.

    Science.gov (United States)

    Zhao, Yue; Sun, Yang; Ding, Youxiang; Wang, Xiaoping; Zhou, Yuxin; Li, Wenjun; Huang, Shaoliang; Li, Zhiyu; Kong, Lingyi; Guo, Qinglong; Lu, Na

    2015-09-22

    GL-V9, a new synthesized flavonoid derivative, has been reported to possess anti-cancer properties in our previous studies. Uncontrolled overproduction of reactive oxygen species (ROS) has been implicated in oxidative damage of inflammatory bowel disease (IBD). In this study, we aimed to investigate the protective effect of GL-V9 against dextran sulfate sodium (DSS)-induced colitis. GL-V9 attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. GL-V9 also inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. Moreover, GL-V9 inhibited ROS and malondialdehyde (MDA) generation, but enhanced superoxide dismutase (SOD), glutathione (GSH) and total antioxidant capacity. GL-V9 reduced pro-inflammatory cytokines production in serum and colon as well. Mechanically, GL-V9 could increase Trx-1 via activation of AMPK/FOXO3a to suppress DSS-induced colonic oxidative stress. Furthermore, GL-V9 decreased pro-inflammatory cytokines and ROS production and increased the antioxidant defenses in the mouse macrophage cells RAW264.7 by promoting Trx-1 expression. In conclusion, our study demonstrated that GL-V9 attenuated DSS-induced colitis against oxidative stress by up-regulating Trx-1 via activation of AMPK/FOXO3a pathway, suggesting that GL-V9 might be a potential effective drug for colitis.

  12. Granulocyte and monocyte adsorptive apheresis ameliorates sepsis in rats.

    Science.gov (United States)

    Ma, Shuai; Xu, Qingqing; Deng, Bo; Zheng, Yin; Tian, Hongyan; Wang, Li; Ding, Feng

    2017-12-01

    Overwhelming activation of granulocytes and monocytes is central to inflammatory responses during sepsis. Granulocyte and monocyte adsorptive apheresis (GMA) is an extracorporeal leukocyte apheresis device filled with cellulose acetate beads and selectively adsorbs granulocytes and monocytes from the peripheral blood. In this study, septic rats received the GMA treatment for 2 h at 18 h after cecal ligation and puncture. GMA selectively adsorbed activated neutrophils and monocytes from the peripheral blood, reduced serum inflammatory cytokine expression, and seemed to improve organ injuries and animal survival. GMA potentially reduced lung injury by alleviating the infiltration of inflammatory cells and the secretion of cytokines. This study showed that selective granulocyte and monocyte adsorption with cellulose acetate beads might ameliorate cecal ligation and puncture (CLP)-induced sepsis and improve survival and organ function.

  13. Calcium ameliorates diarrhea in immune compromised children

    OpenAIRE

    Cheng, Sam X.; Bai, Harrison X.; Gonzalez-Peralta, Regino; Mistry, Pramod K.; Gorelick, Fred S.

    2013-01-01

    Treatment of infectious diarrheas remains a challenge, particularly in immunocompromised patients in whom infections usually persist and resultant diarrhea is often severe and protracted. Children with infectious diarrhea who become dehydrated are normally treated with oral or intravenous rehydration therapy. Although rehydration therapy can replace the loss of fluid, it does not ameliorate diarrhea. Thus, over the past decades, there has been continuous effort to search for ways to safely st...

  14. Expression

    Directory of Open Access Journals (Sweden)

    Wang-Xia Wang

    2014-02-01

    Full Text Available The miR-15/107 family comprises a group of 10 paralogous microRNAs (miRNAs, sharing a 5′ AGCAGC sequence. These miRNAs have overlapping targets. In order to characterize the expression of miR-15/107 family miRNAs, we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members, and other selected miRNAs, in 11 human tissues obtained at autopsy including the cerebral cortex, frontal cortex, primary visual cortex, thalamus, heart, lung, liver, kidney, spleen, stomach and skeletal muscle. miR-103, miR-195 and miR-497 were expressed at similar levels across various tissues, whereas miR-107 is enriched in brain samples. We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations (enriched for cortical neurons, astrocytes and microglia, respectively. In primary cultures of rat brain cells, several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system (CNS. In addition to mature miRNAs, we also examined the expression of precursors (pri-miRNAs. Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors. In summary, we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.

  15. Hypomethylating agent 5-aza-2'-deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models.

    Science.gov (United States)

    Mangano, Katia; Fagone, Paolo; Bendtzen, Klaus; Meroni, Pier Luigi; Quattrocchi, Cinzia; Mammana, Santa; Di Rosa, Michelino; Malaguarnera, Lucia; Coco, Marinella; Magro, Gaetano; Di Marco, Roberto; Nicoletti, Ferdinando

    2014-12-01

    Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2'-deoxycytidine (DAC) in two murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease was associated with a reduction in the number of spinal cord infiltrating lymphocytes and amelioration of the histopathological signs associated with EAE. In addition, increased transcript levels of anti-inflammatory cytokines and decreased mRNA expression of pro-inflammatory mediators were also observed. Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3.

  16. Toll-like receptor 4/nuclear factor-kappa B signaling detected in brain after early subarachnoid hemorrhage

    Institute of Scientific and Technical Information of China (English)

    MA Chun-xiao; YIN Wei-ning; CAI Bo-wen; WU Jian; WANG Jun-yi; HE Min; SUN Hong; DING Jun-li; YOU Chao

    2009-01-01

    Background Inflammation and immunity play a vital role in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor-kappa B (NF-KB) regulates many genes essential for inflammation and immunity and is activated by toll-like receptor (TLR). This study aimed to detect the expression of the toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-KB) signaling in the rat brain after early SAH. Methods The rats were decapitated and their brains were removed at 0, 2, 4, 6, 12, 24 and 48 hours after a single injection of blood into the prechiasmatic cistern, mRNA expression of TLR4 was measured by Taqman real-time RT-PCR, and protein expression by immunohistochemistry and Western blotting. NF-KB activity and concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-lbeta (IL-β) and intedeukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).Results TaqMan real-time RT-PCR and Western blotting identified a biphasic change in TLR4 expression in both mRNA and protein: an initial peak (2-6 hours) and a sustained elevation (12-48 hours). Immunohistochemical staining showed the inducible expression of TLR4-1ike immunoreactions predominantly in glial cells and vascular endothelium. A similar biphasic change in the activation of NF-KB subunit p65 as well as the production of NF-KB-regulated proinflammatory cytokines (TNF-α, IL-1β and IL-6) were detected by ELISA. Conclusions These data suggest that experimental SAH induces significant up-regulation of TLR4 expression and the NF-KB signaling in early brain injury. Activation of the TLR4/NF-KB signaling may regulate the inflammatory responses after SAH.

  17. Acetylcholinesterase inhibition ameliorates deficits in motivational drive

    Directory of Open Access Journals (Sweden)

    Martinowich Keri

    2012-03-01

    Full Text Available Abstract Background Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. Methods We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. Results CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Conclusions Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive.

  18. Yangjing Capsule Ameliorates Spermatogenesis in Male Mice Exposed to Cyclophosphamide

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    Hongle Zhao

    2015-01-01

    Full Text Available Yangjing capsule (YC, a traditional Chinese compound herbal preparation, has been proven as an effective drug to improve spermatogenesis in clinical practice. However, its pharmacological mechanisms were not fully clarified. This study was designed to investigate the protective effects of YC on spermatogenesis in the mouse model of spermatogenesis dysfunction induced by cyclophosphamide (CP. The administration of YC significantly increased the epididymal index, sperm count, and sperm motility of model mice. Histopathological changes demonstrated that CP caused obvious structural damage to testis, which were reversed by the administration of YC. Results from TUNEL assay showed that treatment with YC dramatically decreased the apoptosis of spermatogenic cell induced by CP. Moreover, YC treatment could inhibit the mRNA and protein expression of Bax to Bcl-2 and also raised expression of AR at both mRNA and protein levels. These data suggest that YC might ameliorate spermatogenesis in male mice exposed to CP through inhibiting the apoptosis of spermatogenic cell and enhancing the actions of testosterone in spermatogenesis.

  19. Probiotic BIFICO cocktail ameliorates Helicobacter pylori induced gastritis.

    Science.gov (United States)

    Yu, Hong-Jing; Liu, Wei; Chang, Zhen; Shen, Hui; He, Li-Juan; Wang, Sha-Sha; Liu, Lu; Jiang, Yuan-Ying; Xu, Guo-Tong; An, Mao-Mao; Zhang, Jun-Dong

    2015-06-07

    To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection. Colonization of BIFICO strains in the mouse stomach was determined by counting colony-forming units per gram of stomach tissue. After treatment with or without BIFICO, inflammation and H. pylori colonization in the mouse stomach were analyzed by hematoxylin and eosin and Giemsa staining, respectively. Cytokine levels were determined by enzyme-linked immunosorbent assay and Milliplex. The activation of nuclear factor (NF)-κB and MAPK signaling in human gastric epithelial cells was evaluated by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was used to quantify TLR2, TLR4 and MyD88 mRNA expression in the mouse stomach. We demonstrated that BIFICO, which contains a mixture of Enterococcus faecalis, Bifidobacterium longum and Lactobacillus acidophilus, was tolerant to the mouse stomach environment and was able to survive both the 8-h and 3-d courses of administration. Although BIFICO treatment had no effect on the colonization of H. pylori in the mouse stomach, it ameliorated H. pylori-induced gastritis by significantly inhibiting the expression of cytokines and chemokines such as TNF-α, IL-1β, IL-10, IL-6, G-CSF and MIP-2 (P gastritis by inhibiting the inflammatory response in gastric epithelial cells.

  20. Emodin ameliorates lipopolysaccharides-induced corneal inflammation in rats

    Institute of Scientific and Technical Information of China (English)

    Guo-Ling; Chen; Jing-Jing; Zhang; Xin; Kao; Lu-Wan; Wei; Zhi-Yu; Liu

    2015-01-01

    · AIM: To investigate the effect of emodin on pseudomonas aeruginosa lipopolysaccharides(LPS)-induced corneal inflammation in rats.· METHODS: Corneal infection was induced by pseudomonas aeruginosa LPS in Wistar rats. The inflammation induced by LPS were examined by slit lamp microscope and cytological checkup of aqueous humor.Corneal tissue structure was observed by hematoxylin and eosin(HE) staining. The activation of nuclear factor kappa B(NF-κB) was determined by Western blot.Messenger ribonucleic acid(m RNA) of tumor necrosis factor-α(TNF-α) and intercellular adhesion molecule-1(ICAM-1) in LPS-challenged rat corneas were measured with reverse transcription-polymerase chain reaction(RT-PCR).· RESULTS: Typical manifestations of acute corneal inflammation were observed in LPS-induce rat model,and the corneal inflammatory response and structure were improved in rats pretreated with emodin. Treatment with emodin could improve corneal structure, reduce corneal injure by reducing corneal inflammatory response. Emodin could inhibit the decreasing lever of inhibitor of kappa B alpha(IкBα) express, and the m RNA expression of TNF-α and ICAM-1 in corneal tissues was also inhibited by emodin. The differences were statistically significant between groups treated with emodin and those without treatment(P <0.01).·CONCLUSION: Emodin could ameliorate LPS-induced corneal inflammation, which might via inhibiting the activation of NF-κB.

  1. Heregulin ameliorates the dystrophic phenotype in mdx mice.

    Science.gov (United States)

    Krag, Thomas O B; Bogdanovich, Sasha; Jensen, Claus J; Fischer, M Dominik; Hansen-Schwartz, Jacob; Javazon, Elisabeth H; Flake, Alan W; Edvinsson, Lars; Khurana, Tejvir S

    2004-09-21

    Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin. Utrophin's ability to compensate for dystrophin during development and when transgenically overexpressed has provided an important impetus for identifying activators of utrophin expression. The utrophin promoter A is transcriptionally regulated in part by heregulin-mediated, extracellular signal-related kinase-dependent activation of the GABP(alpha/beta) transcription factor complex. Therefore, this pathway offers a potential mechanism to modulate utrophin expression in muscle. We tested the ability of heregulin to improve the dystrophic phenotype in the mdx mouse model of DMD. Intraperitoneal injections of a small peptide encoding the epidermal growth factor-like region of heregulin ectodomain for 3 months in vivo resulted in up-regulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction mediated damage, and a reduction of muscle pathology. The amelioration of dystrophic phenotype by heregulin-mediated utrophin up-regulation offers a pharmacological therapeutic modality and obviates many of the toxicity and delivery issues associated with viral vector-based gene therapy for DMD.

  2. Chitosan oilgosaccharides suppress LPS-induced IL-8expression in human umbilical vein endothelial cells through blockade of p38 and Akt protein kinases

    Institute of Scientific and Technical Information of China (English)

    Hong-tao LIU; Pei HUANG; Pan MA; Qi-shun LIU; Chao YU; Yu-guang DUL

    2011-01-01

    Aim:To investigate whether and how COS inhibited IL-8 production in LPS-induced human urnbilical vein endothelial cells(HUVECs).Methods:RT-PCR,enzyme-linked immunosorbent assays(ELISA)and Western blotting were used to study IL-8 expression and related signaling pathway.Wound healing migration assays and monocytic cell adhesion analysis were used to explore the chemotactic andadhesive aCtivities of HUVEcs.Results:COS 50-200 μg/mL exerted a significant inhibitory effect on LPS 100 μg/mL-induced IL-8 expression in HUVECs at both the transcriptional and translational levels.In addition, COS 50-200 μg/mL inhibited LPS-induced HUVEC migration and U937 monocyte adhesion to HUVECs in a concentration-dependent manner.Signal transduction studies suggest that COS blocked LPS-induced activation of nuclear factor-KB(NF-KB)and activator protein-1(AP-1)as well as phosphorylation of p38 mitogen-activated protein kinase (MAPK)and phosphokinase Akt.Further,the over-expression of LPS-induced IL-8 mRNA in HUVEcs was suppressed by a p38 MAPK inhibitor(SB203580.25 pmol/L)or a phosphatidylinositol 3-kinase(P13K)inhibitor(LY294002.50 μmol/L).Conclusion:COS inhibited LPS-induced IL-8 expression in HUVECs through the blockade of the p38 MAPK and P13K/Akt signaling pathways.

  3. Cardiotrophin-1 induces intercellular adhesion molecule-1 expression by nuclear factor κB activation in human umbilical vein endothelial cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background In addition to elevated concentrations of cytokines, patients with congestive heart failure (CHF) show endothelial dysfunction and increased plasma concentrations of adhesion molecules like intercellular adhesion molecule-1 (ICAM-1). Furthermore, the concentration of cardiotrophin-1 (CT-1) - a cytokine of the interleukin-6 superfamily - is increased in CHF. We tested the hypothesis whether CT-1 is able to induce ICAM-1 in human umbilical vein endothelial cells (HUVEC). Furthermore we examined the signalling mechanisms of CT-1 mediated ICAM-1 expression. Methods Confluent layers of HUVEC were incubated with increasing concentrations of CT-1 (5 to 100 ng/ml) for different periods. ICAM-1 mRNA was determined by real-time polymerase chain reaction (PCR) and ICAM-1 surface expression by fluorescence-activated cell sorter (FACS) analysis and soluble ICAM-1 (slCAM-1) in the culture supematant by enzyme linked immunosorbent assay (ELISA). To clarify the signalling pathway of CT-1 induced ICAM-1 expression we used various inhibitors of possible signal transducing molecules, electromobility shift assay (EMSA) and Western blot analysis. Results CT-1 induced ICAM-1 mRNA (1.8i-0.8 fold increase compared to unstimulated cells after 6 hours) and protein (1.4~-0.2 fold increase compared to unstimulated cells after 48 hours) in HUVEC in a time- and concentration-dependent manner. EMSA experiments show that CT-1 causes nuclear factor (NF) KB activation. Because parthenolide could inhibit CT-1 induced ICAM-1 expression NFKB activation is required in this pathway. CT-1 did not activate extraceUular signal regulated kinases (ERK), c-Jun N-terminal kinase (JNK) and p38. Conclusion CT-1 is able to induce ICAM-1 in endothelial cells by NFKB activation. These results may explain in part elevated ICAM-1 concentrations in patients with CHF and endothelial dysfunction.

  4. Use of Coffee Pulp and Minerals for Natural Soil Ameliorant

    Directory of Open Access Journals (Sweden)

    Pujiyanto Pujiyanto

    2007-05-01

    Full Text Available In coffee plantation, solid waste of coffee pulp is usually collected as heap nearby processing facilities for several months prior being used as compost. The practice is leading to the formation of odor and liquid which contaminate the environment. Experiments to evaluate the effect of natural soil ameliorant derived from coffee pulp and minerals were conducted at The Indonesian Coffee and Cocoa Research Institute in Jember, East Java. The experiments were intended to optimize the use of coffee pulp to support farming sustainability and minimize negative impacts of solid waste disposal originated from coffee cherry processing. Prior to applications, coffee pulp was hulled to organic paste. The paste was then mixed with 10% minerals (b/b. Composition of the minerals was 50% zeolite and 50% rock phosphate powder. The ameliorant was characterized for their physical and chemical properties. Agronomic tests were conducted on coffee and cocoa seedling. The experiments were arranged according to Randomized Completely Design with 2 factors, consisted of natural ameliorant and inorganic fertilizer respectively. Natural ameliorant derived from coffee pulp was applied at 6 levels: 0, 30, 60, 90, 120 and 150 g dry ameliorant/seedling of 3 kg soil, equivalent to 0, 1, 2, 3, 4 and 5% (b/b of ameliorant respectively. Inorganic fertilizer was applied at 2 levels: 0 and 2 g fertilizer/application of N-P-K compound fertilizer of 15-15-15 respectively. The inorganic fertilizer was applied 4 times during nursery of coffee and cocoa. The result of the experiment indicated that coffee pulp may be used as natural soil ameliorant. Composition of ameliorant of 90% coffee pulp and 10% of minerals has good physical and chemical characteristics for soil amelioration. The composition has high water holding capacity; cations exchange capacity, organic carbon and phosphorus contents which are favorable to increase soil capacity to support plant growth. Application of

  5. Ameliorated GA approach for base station planning

    Science.gov (United States)

    Wang, Andong; Sun, Hongyue; Wu, Xiaomin

    2011-10-01

    In this paper, we aim at locating base station (BS) rationally to satisfy the most customs by using the least BSs. An ameliorated GA is proposed to search for the optimum solution. In the algorithm, we mesh the area to be planned according to least overlap length derived from coverage radius, bring into isometric grid encoding method to represent BS distribution as well as its number and develop select, crossover and mutation operators to serve our unique necessity. We also construct our comprehensive object function after synthesizing coverage ratio, overlap ratio, population and geographical conditions. Finally, after importing an electronic map of the area to be planned, a recommended strategy draft would be exported correspondingly. We eventually import HongKong, China to simulate and yield a satisfactory solution.

  6. 芪苈强心胶囊通过抑制血管紧张素Ⅱ改善压力超负荷致小鼠心肌肥厚%Qiliqiangxin Capsules Ameliorate Pressure Overload-Induced Cardiac Hypertrophy in Mice Via Reducing the Expression of Angiotensin Ⅱ

    Institute of Scientific and Technical Information of China (English)

    叶勇; 邹云增; 李磊; 蒋国良; 吴剑; 周宁; 马宏; 关爱丽; 龚惠; 葛均波

    2011-01-01

    gastric tube. Echocardiography and hemodyriBmic measurement were performed a! 2 weeks after TAC. And cardiac histology and hypcrtrophic gene expression was annlyred. Ang II levels in serum and myocardium were measured by ELISA. The expression of AT, receptor ami phosphorylaiion of ERK were delected by western bio! Method. Results TAC for 2 week induced apparently cardiac hypertrophy marked by distinguished elevated aorta blood pressure)ABP) and left ventricle end-systolic pressurc(LVI£SP). Qiliqiangxin Capsules had ?> significant effect on them both in WT and flJ(I-I- mice. In WT miee. Qiliqiangxin Capsules greatly suppressed the increase of Angll level in scrum and myocardium, and it also abolished Ihe uprcgulalion of hypertropluc gcnc.AT, recerXor and p-ERK expression. Besides.it signilicanlly suprcssed cardiac hypcrtroplw characierizod by enhanwd left ventricular anlcnor wall M end-iiiastohU LVAWd). Left ventricular posterior wall al cnttdiastolic(l-VPWd). Aots-sectional area(CSA)and fibrotf area in WT micclPO-O?). \\\\\\ATCf mieeiiowever.with the absence of Angd.Tlie two TAC group mice showed no striking diflrence in LVAWd. LVPWd .CSA. Fibrolic area and hypertrophic geneATI recepUir ,p-ERK expression!F=O,05). Conclusions Qiliqiongnin Capsule* ameliorate pressure overload-inducwl cardiac hypertrophy ihrough the inhibiting ihe socreuon of Ang II .which in turn, attenuated the expression of AT I receptor. It could nol directly af-fisn the expression nf ATI nxeploi tndueed by meehanical strciL-h such as pressure overload.

  7. GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.

    Science.gov (United States)

    Nagahara, Yuki; Shimazawa, Masamitsu; Ohuchi, Kazuki; Ito, Junko; Takahashi, Hitoshi; Tsuruma, Kazuhiro; Kakita, Akiyoshi; Hara, Hideaki

    2017-08-01

    Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Sex differences regarding the amelioration of wrinkles due to skin dryness by the administration of tranexamic acid.

    Science.gov (United States)

    Hiramoto, Keiichi; Sugiyama, Daijiro; Iizuka, Yasutaka; Yamaguchi, Tomohiko

    2016-10-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) exerts an amelioration effect on wrinkle formation due to skin dryness. We examined the sex differences in this effect. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to male and female Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In the treated female mice, the amelioration effect on the wrinkle score, deterioration of transepidermal water loss (TEWL), capacitance, and decrease in the expression of collagen type I was stronger than in the male treated mice. Furthermore, the level of β-endorphin in the plasma and the expression of β-endorphin, μ-opioid receptor, and macrophages in the dorsal skin increased after the administration of tranexamic acid, and this increase was higher in female mice than in males. In addition, the macrophage production was increased by the administration of tranexamic acid in the ovary but did not change after administration in the testes. A histological examination revealed that these macrophages produce the β-endorphin, clarifying the source of the elevated levels. The amelioration effect in the female treated mice was decreased by the administration of clophosome (a macrophage inhibitor) to a degree that did not markedly differ from the effect observed in the male treated mice. These results suggest that the amelioration effect on wrinkles is stronger in female NOA mice than in males and that β-endorphin produced by macrophages plays an important role in this sex difference.

  9. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Lee, Sik [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of)

    2014-08-08

    deficiency of SIRT2 ameliorates iNOS, NO expression and reactive oxygen species production with suppressing LPS-induced activation of NFκB in macrophages.

  10. Bushen Yisui Capsule ameliorates axonal injury in experimental autoimmune encephalomyelitis

    Institute of Scientific and Technical Information of China (English)

    Ling Fang; Lei Wang; Qi Zheng; Tao Yang; Hui Zhao; Qiuxia Zhang; Kangning Li; Li Zhou; Haiyang Gong; Yongping Fan

    2013-01-01

    A preliminary clinical study by our group demonstrated Bushen Yisui Capsule (formerly cal ed Er-huang Formula) in combination with conventional therapy is an effective prescription for the treat-ment of multiple sclerosis. However, its effect on axonal injury during early multiple sclerosis re-mains unclear. In this study, a MOG 35-55-immunized C57BL/6 mouse model of experimental au-toimmune encephalomyelitis was intragastrical y administered Bushen Yisui Capsule. The results showed that Bushen Yisui Capsule effectively improved clinical symptoms and neurological function of experimental autoimmune encephalomyelitis. In addition, amyloid precursor protein expression was down-regulated and microtubule-associated protein 2 was up-regulated. Experimental findings indicate that the disease-preventive mechanism of Bushen Yisui Capsule in experimental autoim-mune encephalomyelitis was mediated by amelioration of axonal damage and promotion of rege-neration. But the effects of the high-dose Bushen Yisui Capsule group was not better than that of the medium-dose and low-dose Bushen Yisui Capsule group in preventing neurological dysfunction.

  11. Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice.

    Science.gov (United States)

    Lee, Hyun Gyu; Cho, Nam-Chul; Jeong, Ae Jin; Li, Yu-Chen; Rhie, Sung-Ja; Choi, Jung Sook; Lee, Kwang-Ho; Kim, Youngsoo; Kim, Yong-Nyun; Kim, Myoung-Hwan; Pae, Ae Nim; Ye, Sang-Kyu; Kim, Byung-Hak

    2016-01-01

    T-cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathologic immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite that multiple pharmacologic properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T-cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited TCR-mediated Akt and NF-κB signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as 2,4,6-trinitrochlorobenzene-induced contact and atopic dermatitis and IL-23-induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and overall immune responses.

  12. The amelioration effect of tranexamic acid in wrinkles induced by skin dryness.

    Science.gov (United States)

    Hiramoto, Keiichi; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2016-05-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medical amino acid widely used as an anti-inflammatory and a whitening agent. This study examined the effect of tranexamic acid administration in wrinkle formation following skin dryness. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In these NOA mice, deterioration of transepidermal water loss (TEWL), generation of wrinkles, decrease of collagen type I, and increases in mast cell proliferation and tryptase and matrix metalloproteinase (MMP-1) release were observed. However, these symptoms were improved by tranexamic acid treatment. Moreover, the increase in the β-endorphin level in the blood and the expression of μ-opioid receptor on the surface of fibroblasts increased by tranexamic acid treatment. In addition, when the fibroblasts induced by tranexamic acid treatment were removed, the amelioration effect by tranexamic acid treatment was halved. On the other hand, tranexamic acid treated NOA mice and mast cell removal in tranexamic acid treated NOA mice did not result in changes in the wrinkle amelioration effect. Additionally, the amelioration effect of mast cell deficient NOA mice was half that of tranexamic acid treated NOA mice. These results indicate that tranexamic acid decreased the proliferation of mast cells and increases the proliferation of fibroblasts, subsequently improving wrinkles caused by skin dryness.

  13. Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?

    Science.gov (United States)

    Crow, Andrew R; Song, Seng; Suppa, Sara J; Ma, Shuhua; Reilly, Michael P; Andre, Pierrette; McKenzie, Steven E; Lazarus, Alan H

    2011-01-20

    To explore the potential for monoclonal antibodies as a treatment for immune thrombocytopenia (ITP) and to further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP and found 4 antibodies that could successfully ameliorate ITP; 2 of these antibodies function at a full 3-log fold lower dosage compared with IVIg. Further characterization of the 2 most successful antibodies (5035-41.1D and KM114) demonstrated that, similar to IVIg: (1) the presence of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function, (2) complement-deficient mice responded to anti-CD44 treatment, and (3) human transgenic FcγRIIA-expressing mice also responded to the CD44 therapeutic modality. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and that they could potentially provide a very-low-dose recombinant therapy for the amelioration of human ITP.

  14. A mucoactive drug carbocisteine ameliorates steroid resistance in rat COPD model.

    Science.gov (United States)

    Song, Yun; Yu, Ping; Lu, Juan-Juan; Lu, Hao-Zhong; Zhu, Liang; Yu, Zhi-Hua; Chen, Hong-Zhuan; Cui, Yong-Yao

    2016-08-01

    Steroid insensitivity has been commonly found in chronic obstructive pulmonary disease (COPD) patients, which is mediated by the reduction of histone deacetylase (HDAC) 2. Here we aimed to establish a steroid resistant model on experimental COPD rats and evaluate the effect of carbocisteine (S-CMC), a mucoactive drug. Exposure to cigarette smoke (CS) caused marked pathological features of COPD which are insensitive to DEX associated with the down-regulation of HDAC2 expression/activity. The DEX insensitivity observed in COPD featured rats was improved by S-CMC in the aspects of inhibiting chronic lung inflammation (total and differential inflammatory cell counts, inflammatory cytokines release and inflammatory cells infiltration); ameliorating airway remodeling (thickness of airway epithelium and smooth muscle, airway fibrosis, and the level of α-SMA and TGF-β1); improving emphysema (emphysema index D2, level of MMP-9 in BALF and the expression of alpha-1 antitrypsin) and preventing impairments of lung function (PEF, IP and IP-slope). Simultaneously, down-regulation of HDAC2 expression/activity was ameliorated by S-CMC treatment. These results indicate that the rat COPD model with steroid resistance was established by active smoking in a short time frame and demonstrate that the failure of steroid therapy can be restored by S-CMC accompanied by increasing HDAC2 expression/activity, providing additional evidence that S-CMC might be used for GC resistance in COPD.

  15. Enhancing Mitofusin/Marf ameliorates neuromuscular dysfunction in Drosophila models of TDP-43 proteinopathies.

    Science.gov (United States)

    Khalil, Bilal; Cabirol-Pol, Marie-Jeanne; Miguel, Laetitia; Whitworth, Alexander J; Lecourtois, Magalie; Liévens, Jean-Charles

    2017-06-01

    Transactive response DNA-binding protein 43 kDa (TDP-43) is considered a major pathological protein in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The precise mechanisms by which TDP-43 dysregulation leads to toxicity in neurons are not fully understood. Using TDP-43-expressing Drosophila, we examined whether mitochondrial dysfunction is a central determinant in TDP-43 pathogenesis. Expression of human wild-type TDP-43 in Drosophila neurons results in abnormally small mitochondria. The mitochondrial fragmentation is correlated with a specific decrease in the mRNA and protein levels of the Drosophila profusion gene mitofusin/marf. Importantly, overexpression of Marf ameliorates defects in spontaneous walking activity and startle-induced climbing response of TDP-43-expressing flies. Partial inactivation of the mitochondrial profission factor, dynamin-related protein 1, also mitigates TDP-43-induced locomotor deficits. Expression of TDP-43 impairs neuromuscular junction transmission upon repetitive stimulation of the giant fiber circuit that controls flight muscles, which is also ameliorated by Marf overexpression. We show here for the first time that enhancing the profusion gene mitofusin/marf is beneficial in an in vivo model of TDP-43 proteinopathies, serving as a potential therapeutic target. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice.

    Science.gov (United States)

    Diaz-Castroverde, Sabela; Gómez-Hernández, Almudena; Fernández, Silvia; García-Gómez, Gema; Di Scala, Marianna; González-Aseguinolaza, Gloria; Fernández-Millán, Elisa; González-Rodríguez, Águeda; García-Bravo, María; Chambon, Pierre; Álvarez, Carmen; Perdomo, Liliana; Beneit, Nuria; Escribano, Oscar; Benito, Manuel

    2016-11-01

    Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte--specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus.

  17. Amelioration of cisplatin-induced nephrotoxicity by statins

    Directory of Open Access Journals (Sweden)

    Rajesh A Maheshwari

    2013-01-01

    Conclusions: This finding suggests that simvastatin and rosuvastatin may have a protective effect against cisplatin-induced kidney damage via amelioration of lipid peroxidation as well as due to improvement of renal function, and lipid-lowering effects.

  18. Effect of Qingre Huoxue Tiaoqi Recipe on Expression of Toll-like Receptor 4 and Nuclear Factor Kappa B and Bacterial Translocation in Neonatal Rat Model of Necrotizing Enterocolitis%清热活血调气方对坏死性小肠结肠炎模型新生大鼠Toll样受体4、核因子-κB表达及细菌易位的影响

    Institute of Scientific and Technical Information of China (English)

    陈晓晴; 许华; 罗文; 王晓芹

    2012-01-01

    [目的]探讨清热活血调气方对坏死性小肠结肠炎(NEC)模型新生大鼠回肠组织Toll样受体4(TLR4) mRNA、核因子-κB (NF-κB) mRNA表达及细菌易位的影响.[方法]选用3日龄SD新生大鼠随机分为3组:正常对照组、NEC模型组及治疗组.采用鼠代乳品人工喂养及缺氧冷刺激的方法,复制新生大鼠NEC模型.治疗组采用鼠乳代用品+清热活血调气方(15 g·kg-1·次-1,3次/d)人工喂养,同时予以缺氧冷刺激;正常对照组鼠乳喂养,不进行任何干预.第4天心脏穿刺采血后处死大鼠取近回盲部末端回肠2 cm,采用实时荧光定量PCR法检测回肠组织TLR4 mRNA、NF-κB mRNA 表达水平及血标本中细菌16S rRNA进而得出细菌易位发生率.[结果]与模型组比较,治疗组TLR4 mRNA、NF-κB mRNA 表达水平显著下降(P<0.01),细菌易位发生率显著降低(P<0.05).[结论]清热活血调气方可下调NEC模型新生大鼠回肠组织TLR4 mRNA、NF-κB mRNA表达,减少细菌易位的发生.%Objective To observe the effect of Qingre Huoxue Tiaoqi Recipe (QHTR) on mRNA expression of Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-KB) and on bacterial translocation in neonatal ramodel of necrotizing enterocolitis (NEC). Methods Three-day-old neonatal SD rats were randomly divided into three groups; normal control group, NEC model group and treatment group. NEC rat model was established by feeding with rat-milk substitutes, and by exposing to 100% nitrogen gas for 90s and cold stress (4℃ ) for 10 min, twice per day for 3 days. The rats in the treatment group received QHTR ( 15 g o kg-1 each time, 3 times per day) mixed into the milk substitutes, and were simultaneously given hypoxia and cold stress. Rats in the normal control group were raised by their mothers and had no any intervention. After blood sampling via cardiac puncture, the rats were executed and 2-cm terminal ileum segment proximal to the ileocecal valve were obtained from the

  19. PEG minocycline-liposomes ameliorate CNS autoimmune disease.

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    Wei Hu

    Full Text Available BACKGROUND: Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS. Minocycline, a potent inhibitor of matrix metalloproteinase (MMP-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG minocycline liposomes are effective in treating EAE. FINDINGS: Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs, we determined that PEG minocycline-liposome preparations stabilized with CaCl(2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number. CONCLUSIONS: Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

  20. Matrine ameliorates spontaneously developed colitis in interleukin-10-deficient mice.

    Science.gov (United States)

    Wu, Cong; Xu, Zheng; Gai, Renhua; Huang, Kehe

    2016-07-01

    Interleukin-10 (IL-10)-deficient mice spontaneously develop T cell-mediated colitis. Previous reports have shown that Matrine may reduce the symptoms of acute colitis induced by trinitrobenzene sulfonic acid (TNBS). However, whether Matrine impacts chronic colitis remains unknown. In this study, we investigated whether Matrine could limit the symptoms of spontaneously developed colitis and its potential molecular mechanisms. IL-10 deficient mice were given Matrine or a PBS control by oral gavage daily for 4weeks and were euthanized at week 2 or week 4. We measured body weight, colon length and weight, and histological scores. We also evaluated the spontaneous secretion of IL-12/23p40, IFN-γ and IL-17 in colon explant cultures as well as IFN-γ and IL-17 secretion in unseparated mesenteric lymph node (MLN) cells, and assessed IFN-γ, IL-17, IL-1β and IL-6 mRNA expression in colon tissue. In addition, we analyzed the proportions of CD4-positive and CD8-positive cells in unseparated MLN cells. Our results show that Matrine-treated mice exhibited better body weight recovery than controls and that histological scores and spontaneously secreted IL-12/23p40, IFN-γ and IL-17 in colon tissue were significantly decreased in treated mice compared with controls. The proportion of CD4-positive cells of MLNs in treated mice was significantly smaller than that in controls at week 4. Both cytokine production and mRNA expression of IFN-γ and IL-17 were significantly reduced in treated mice compared with controls. Taken together, our results indicate that Matrine may ameliorate spontaneously developed chronic colitis and could be considered as a therapeutic alternative for chronic colitis.

  1. Resveratrol Pretreatment Ameliorates TNBS Colitis in Rats.

    Science.gov (United States)

    Yildiz, Gulserap; Yildiz, Yuksel; Ulutas, Pinar A; Yaylali, Asl; Ural, Muruvvet

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease in humans constituting a major health concern today whose prevalence has been increasing over the world. Production of reactive oxygen species (ROS) and disturbed capacity of antioxidant defense in IBD subjects have been reported. Antioxidants may play a significant role in IBD treatment. This study aimed at evaluating ameliorative effects of intraperitoneal resveratrol pretreatment on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Thirty five Wistar-Albino female rats were divided equally into five groups. Inflammation was induced by the intrarectal administration of TNBS under anesthesia. Intraperitoneal administration of resveratrol (RSV) at a concentration of 10mg/kg/day for 5 days before the induction of colitis significantly reduced microscopy score and malondialdehyde (MDA) levels and increased glutathione peroxidase (GSH Px) activity compared to TNBS and vehicle groups. Also an insignificant increase in catalase (CAT) activity was observed in the RSV treated group compared to TNBS and vehicle groups. In this paper, the most recent patent on the identification and treatment of IBD was indicated. In conclusion, antioxidant RSV proved to have a beneficial effect on TNBS colitis in rats. In light of these advantageous results, the RSV can be considered as adjuvant agent in IBD treatments.

  2. Rutin ameliorates obesity through brown fat activation.

    Science.gov (United States)

    Yuan, Xiaoxue; Wei, Gang; You, Yilin; Huang, Yuanyuan; Lee, Hyuek Jong; Dong, Meng; Lin, Jun; Hu, Tao; Zhang, Hanlin; Zhang, Chuanhai; Zhou, Huiqiao; Ye, Rongcai; Qi, Xiaolong; Zhai, Baiqiang; Huang, Weidong; Liu, Shunai; Xie, Wen; Liu, Qingsong; Liu, Xiaomeng; Cui, Chengbi; Li, Donghao; Zhan, Jicheng; Cheng, Jun; Yuan, Zengqiang; Jin, Wanzhu

    2017-01-01

    Increasing energy expenditure through activation of brown adipose tissue (BAT) is a critical approach to treating obesity and diabetes. In this study, rutin, a natural compound extracted from mulberry and a drug used as a capillary stabilizer clinically for many years without any side effects, regulated whole-body energy metabolism by enhancing BAT activity. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both genetically obese (Db/Db) and diet-induced obesity (DIO) mice. Rutin also induced brown-like adipocyte (beige) formation in subcutaneous adipose tissue in both obesity mouse models. Mechanistically, we found that rutin directly bound to and stabilized SIRT1, leading to hypoacetylation of peroxisome proliferator-activated receptor γ coactivator-1α protein, which stimulated Tfam transactivation and eventually augmented the number of mitochondria and UCP1 activity in BAT. These findings reveal that rutin is a novel small molecule that activates BAT and may provide a novel therapeutic approach to the treatment of metabolic disorders.-Yuan, X., Wei, G., You, Y., Huang, Y., Lee, H. J., Dong, M., Lin, J., Hu, T., Zhang, H., Zhang, C., Zhou, H., Ye, R., Qi, X., Zhai, B., Huang, W., Liu, S., Xie, W., Liu, Q., Liu, X., Cui, C., Li, D., Zhan, J., Cheng, J., Yuan, Z., Jin, W. Rutin ameliorates obesity through brown fat activation. © FASEB.

  3. Amelioration of safety management in infrastructure projects

    Directory of Open Access Journals (Sweden)

    Mr. Gopinath S.Mohite

    2014-11-01

    Full Text Available Accidents are a major public health concern, resulting in an estimated 1.2 million deaths and 50 million injuries worldwide each year specifically, the relationships between drivers' characteristics and road accidents are not fully understood. Many factors are involved in the accident occurrence at construction site. Some important elements that create a significant portion of accidents include: safety management error, poor training programs, human element, act of god, outdated procedure and no clear monitoring policy. Although some of these items are inevitable, but the occurrence of the largest part can be prevented. Therefore, for ameliorating the safety in a project each of these items should be analyzed and a practical approach introduced. In general, near miss, incident and accident are three dependent levels that mainly lead to injury. Risk and hazard are allocated in first level which means near miss, therefore, no on-time identification of hazard and risk causes to create incident and preventing accident in incident stage is unavoidable.

  4. Wnt7a treatment ameliorates muscular dystrophy.

    Science.gov (United States)

    von Maltzahn, Julia; Renaud, Jean-Marc; Parise, Gianni; Rudnicki, Michael A

    2012-12-11

    Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.

  5. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    Energy Technology Data Exchange (ETDEWEB)

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Pillai, Ayyappan Harikrishna [Division of Animal Biochemistry, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Harikumar, Sankaran Kutty; Mishra, Santosh Kumar [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Sarkar, Souvendra Nath, E-mail: snsarkar1911@rediffmail.com [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India)

    2014-11-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

  6. Regulation on the expression of Clara cell secretory protein in the lungs of the rats with acute lung injury by growth hormone

    Institute of Scientific and Technical Information of China (English)

    MIN Jia; LUO Fo-quan; ZHAO Wei-lu

    2012-01-01

    Background Clara cell secretory protein (CC16) is an important lung derived protective factor and may play an important role on the pathogenesis of acute lung injury (ALl) induced by endotoxemia.Growth hormone (GH) is an important anabolism hormone secreted by GH cells of the hypophysis.Pravious research showed that GH would significantly exacerbate ALl induced by endotoxemia,but the mechanism is not very clear yet.Whether the effects are related to CC16 or not is undetermined.Methods One hundred and twelve male Sprague-Dawley rats were randomly divided into an ALl group and a GH group.The rats in the two groups were subdivided into seven subgroups,according to injection with lipopolysaccharides (LPS) or not,then according to different intervals of time after LPS injection; 0 hour (pre-injection of LPS,acted as control group),0.5 hour,1 hour,2 hours,4 hours,6 hours and 24 hours for subgroups.Pulmonary alveolar septa area density (PASAD) and ploymorphonuclear cells (PMN) in the lungs were analyzed morphometrically.The levels of tumor necrosis factor (TNF) and interleukin 6 (1L-6) were determined by radioimmunoassay.To analyze the expression and activation of nuclear factor kappa B (NF-kB),the numbers of NF-kB positive cells in lungs were counted after immunofluorescence staining.and the levels of NF-KB inhibitory protein-α (1KB-α) in lung homogenates of rats were detected by Western blotting.The expression levels of CC16 mRNA in lungs of the rats with ALl were determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).The levels of CC16 protein in lung homogenates were detected by Western blotting.Results Half an hour after LPS injury both the PASAD and PMN numbers in lungs of the rats with ALl began to increase significantly and peaked at 6-hour post-injury.They then began to recover and reached normal levels at 24-hour post-injury.Both the PASAD and PMN numbers in the GH group increased more significantly than those in the ALl group

  7. Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Naoya Matsunaga

    2016-11-01

    Full Text Available Chronic kidney disease (CKD is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2 ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif ligand 2 (Ccl2 was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK, did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.

  8. Salvianolic acid A as a multifunctional agent ameliorates doxorubicin-induced nephropathy in rats.

    Science.gov (United States)

    Fan, Hua-Ying; Yang, Ming-Yan; Qi, Dong; Zhang, Zuo-Kai; Zhu, Lin; Shang-Guan, Xiu-Xin; Liu, Ke; Xu, Hui; Che, Xin

    2015-07-21

    Nephrotic syndrome (NS) is still a therapeutic challenge. To date there is no ideal treatment. Evidence suggest that multidrug therapy has more effect than monotherapy in amelioration of renal injury. Salvianolic acid A (SAA) is the major active component of Salviae Miltiorrhizae Bunge. Previous studies have demonstrated that SAA is a multi-target agent and has various pharmacological activities. The pleiotropic properties of SAA predict its potential in the treatment of NS. The study investigated the effect of SAA on doxorubicin-induced nephropathy. The kidney function related-biochemical changes, hemorheological parameters and oxidative stress status were determined, and histological examination using light and transmission electron microcopies and western blot analysis were also performed. Results revealed that treatment with SAA alleviated histological damages, relieved proteinuria, hypoalbuminemia and hyperlipidemia, reduced oxidative stress, as well as improving hemorheology. Furthermore, SAA restored podocin expression, down-regulated the expression of NF-κB p65 and p-IκBα while up-regulating IκBα protein expression. Overall, as a multifunctional agent, SAA has a favorable renoprotection in doxorubicin-induced nephropathy. The anti-inflammation, antioxidant, amelioration of podocyte injury, improvement of hemorheology and hypolipidemic properties may constituent an important part of its therapeutic effects. All these indicate that SAA is likely to be a promising agent for NS.

  9. Honey Supplementation in Spontaneously Hypertensive Rats Elicits Antihypertensive Effect via Amelioration of Renal Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Omotayo O. Erejuwa

    2012-01-01

    Full Text Available Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP in spontaneously hypertensive rats (SHR. It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2 and glutathione S-transferase (GST were significantly downregulated while total antioxidant status (TAS and activities of GST and catalase (CAT were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.

  10. Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients.

    Science.gov (United States)

    Shucheng, Gu; Chunkang, Chang; Youshan, Zhao; Juan, Guo; Chengming, Fei; Xi, Zhang; Chao, Xiao; Xiao, Li

    2015-04-01

    In order to research how does hypomethylating agents ameliorate iron metabolism in myelodysplastic syndrome (MDS), we performed methylation-specific, polymerase chain reaction (MSP), bisulfate genomic sequencing polymerase chain reaction (BSP), quantitative real-time PCR and western blot of hemojuvelin (HJV) and ELISA assay for hepcidin before and after demethylating therapy (decitabine) to determine whether the change of HJV methylation status would have an influence on hepcidin expression. Eleven of 22 MDS patients achieved CR or PR according to IWG criteria (50%). HJV mRNA was induced in decitabine responders (p = .006 comparing pre/post decitabine treatment) but not in non-responders (p = .121). Similarly, hepcidin serum expression increased from 320.77 ± 34.8 μg/L to 366.77 ± 21.90 μg/L (p = .012) in responders but did not significantly change in non-responders (p = .058), while no difference of adjusted serum ferritin (ASF) was found. In conclusion, hypermethylation of HJV promoter region could silence the gene expression and demethylating therapy might ameliorate iron-overload through HJV demethylation.

  11. Bone marrow mesenchymal stem cells ameliorate inflammatory factor-induced dysfunction of INS-1 cells on chip.

    Science.gov (United States)

    Sun, Yu; Yao, Zhina; Lin, Peng; Hou, Xinguo; Chen, Li

    2014-05-01

    Using a microfluidic chip, we have investigated whether bone marrow mesenchymal stem cells (BM-MSCs) could ameliorate IL-1β/IFN-γ-induced dysfunction of INS-1 cells. BM-MSCs were obtained from diabetes mellitus patients and their cell surface antigen expression profiles were analyzed by flow cytometric. INS-1 cells were cocultured with BM-MSCs on a microfluidic chip with persistent perfusion of medium containing 1 ng/mL IL-1β and 2.5 U/mL IFN-γ for 72 h. BM-MSCs could partially rescue INS-1 cells from cytokine-induced dysfunction and ameliorate the expression of insulin and PDX-1 gene in INS-1 cells. Thus BM-MSCs can be viewed as a promising stem cell source to depress inflammatory factor-induced dysfunction of pancreatic β cells in diabetic patients.

  12. Pomegranate: a fruit that ameliorates metabolic syndrome.

    Science.gov (United States)

    Medjakovic, Svjetlana; Jungbauer, Alois

    2013-01-01

    Pomegranate is an ancient fruit that is still part of the diet in the Mediterranean area, the Middle East, and India. Health-promoting effects have long been attributed to this fruit. Modern research corroborates the use of pomegranate as a folk remedy for diabetes and metabolic syndrome, and is responsible for a new evaluation of nutritional and pharmaceutical aspects of pomegranate in the general public. In the last decade, industry and agricultural production have been adapted to meet higher market demands for pomegranate. In vivo and in vitro studies have demonstrated that pomegranate exerts hypoglycaemic effects, including increased insulin sensitivity, inhibition of α-glucosidase, and impact on glucose transporter type 4 function, but is also responsible for a reduction of total cholesterol, and the improvement of blood lipid profiles, as well as anti-inflammatory effects through the modulation of peroxisome proliferator-activated receptor pathways. These effects may also explain how pomegranate-derived compounds function in the amelioration of adverse health effects caused by metabolic syndrome. Pomegranate contains polyphenols such as ellagitannins and anthocyanins, as well as phenolic acids, fatty acids and a variety of volatile compounds. Ellagitannins are some of the most prevalent compounds present in pomegranate, and may be responsible for certain benevolent characteristics associated with pomegranate. A brief overview of rising health problems due to obesity will be provided, followed by characterisation of the biological activity, bioavailability, and safety of pomegranate and pomegranate-derived compounds. Although the fruit is consumed in many countries, epidemiological and clinical studies are unavailable. Additional research is necessary to corroborate the promise of current in vivo and in vitro findings.

  13. Low concentrations of human neutrophil peptide ameliorate experimental murine colitis.

    Science.gov (United States)

    Maeda, Takuro; Sakiyama, Toshio; Kanmura, Shuji; Hashimoto, Shinichi; Ibusuki, Kazunari; Tanoue, Shiroh; Komaki, Yuga; Arima, Shiho; Nasu, Yuichiro; Sasaki, Fumisato; Taguchi, Hiroki; Numata, Masatsugu; Uto, Hirofumi; Tsubouchi, Hirohito; Ido, Akio

    2016-12-01

    Human neutrophil peptides (HNPs) not only have antimicrobial properties, but also exert multiple immunomodulatory effects depending on the concentration used. We have previously demonstrated that the intraperitoneal administration of high-dose HNP-1 (100 µg/day) aggravates murine dextran sulfate sodium (DSS)-induced colitis, suggesting a potential pro-inflammatory role for HNPs at high concentrations. However, the role of low physiological concentrations of HNPs in the intestinal tract remains largely unknown. The aim of this study was to examine the effects of low concentrations of HNPs on intestinal inflammation. We first examined the effects of the mild transgenic overexpression of HNP-1 in DSS-induced colitis. HNP-1 transgenic mice have plasma HNP-1 levels similar to the physiological concentrations in human plasma. Compared to wild-type mice treated with DSS, HNP-1 transgenic mice treated with DSS had significantly lower clinical and histological scores, and lower colonic mRNA levels of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. We then injected low-dose HNP-1 (5 µg/day) or phosphate-buffered saline (PBS) intraperitoneally into C57BL/6N and BALB/c mice administered DSS. The HNP-1-treated mice exhibited significantly milder colitis with reduced expression levels of pro-inflammatory cytokines compared with the PBS-treated mice. Finally, we examined the in vitro effects of HNP-1 on the expression of cytokines associated with macrophage activation. Low physiological concentrations of HNP-1 did not significantly affect the expression levels of IL-1β, TNF-α, IL-6 or IL-10 in colonic lamina propria mononuclear cells activated with heat-killed Escherichia coli, suggesting that the anti-inflammatory effects of HNP-1 on murine colitis may not be exerted by direct action on intestinal macrophages. Collectively, our data demonstrated a biphasic dose-dependent effect of HNP-1 on DSS-induced colitis: an

  14. C-PEPTIDE AMELIORATES KIDNEY INJURY FOLLOWING HEMORRHAGIC SHOCK

    Science.gov (United States)

    Chima, Ranjit S; Maltese, Giuseppe; LaMontagne, Timberly; Piraino, Giovanna; Denenberg, Alvin; O’Connor, Michael; Zingarelli, Basilia

    2013-01-01

    Reperfusion injury following hemorrhagic shock is accompanied by the development of a systemic inflammatory state that may lead to organ failure. C-peptide has been shown to exert anti-inflammatory effects in sepsis and myocardial ischemia-reperfusion injury, and to ameliorate renal dysfunction in diabetic animals. Hence, we investigated the effect of C-peptide on kidney injury following hemorrhagic shock. We hypothesized that C-peptide would exert reno-protective effects by blunting inflammation. Hemorrhagic shock was induced in male rats (3–4 months old) by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3h at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, one group of animals received C-peptide (280 nmol/kg intravenously) while another group received vehicle. Hemorrhagic shock resulted in significant rise in plasma levels of creatinine and elevated kidney neutrophil infiltration as evaluated by myeloperoxidase (MPO) activity in vehicle-treated rats in comparison with sham rats, thus suggesting kidney injury. Treatment with C-peptide significantly attenuated the rise in creatinine and kidney MPO activity when compared to vehicle group. At a molecular level these effects of C-peptide were associated with reduced expression of the c-Fos subunit and reduced activation of the pro-inflammatory kinases, extracellular signal-regulated kinase (ERK 1/2) and c-Jun N-terminal kinase (JNK) and subsequently, reduced DNA binding of activator protein-1 (AP-1) in the kidney. Thus, our data suggest that C-peptide may exert reno-protective effects following hemorrhagic shock by modulating AP-1 signaling. PMID:21263384

  15. Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

    Science.gov (United States)

    Atawia, Reem T; Esmat, Ahmed; Elsherbiny, Doaa A; El-Demerdash, Ebtehal

    2017-02-01

    This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg(-1) , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg(-1) , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg(-1) ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg(-1) ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg(-1) ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg(-1) didn't show significant efficacy above 3 mg kg(-1) which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

  16. Zinc Deficiency in Humans and its Amelioration

    Directory of Open Access Journals (Sweden)

    Yashbir Singh Shivay

    2015-01-01

    Full Text Available Zinc (Zn deficiency in humans has recently received considerable attention. Global mortality in children under 5 years of age in 2004 due to Zn deficiency was estimated at 4,53,207 as against 6,66,771 for vitamin A deficiency; 20,854 for iron deficiency and 3,619 for iodine deficiency. In humans 2800-3000 proteins contain Zn prosthetic group and Zn is an integral component of zinc finger prints that regulate DNA transcription. Zinc is a Type-2 nutrient, which means that its concentration in blood does not decrease in proportion of the Zn deficiency. Adverse effects of Zn deficiency vary with age: low weight gain, diarrhoea, aneroxia and neurobehavioral disturbances are observed in infants, while skin changes and dwarfism are frequent in toddlers and adolescents. Common manifestations of Zn deficiency among elderly include hypogeusia, chronic non-healing ulcers and recurrent infections.Ameliorative measures of Zn deficiency in humans can be classified in two groups, namely, nutraceutical and biofortification of food grains. Nutraceutical interventions include pharmaceutical supplements, dietary supplements and dietary diversification, while biofortification of food grains can be achieved by genetic modification (GM of crops or by agronomic techniques that include soil or/and foliar fertilization of crops.The major disadvantage of nutraceutical approaches is that the major beneficiaries are urban people and the poor rural masses that need adequate Zn nutrition most are left out. Genetic biofortification of food grains requires large amounts of funds and a fairly long-period of time. Further, a large number of countries have not yet accepted genetically modified (GM foods. On the other hand agronomic biofortification of food grains yields immediate effects and rural and urban people are equally benefitted. Our studies have shown that Zn concentration in cereals (rice, wheat etc and pulses can be considerably increased by soil or/and foliar

  17. LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice.

    Science.gov (United States)

    Sun, Jun-Jun; Ren, Qing-Guo; Xu, Lin; Zhang, Zhi-Jun

    2015-09-18

    More than 50% of multiple sclerosis patients develop cognitive impairment. However, the underlying mechanisms are still unclear, and there is no effective treatment. LINGO-1 (LRR and Ig domain containing NOGO receptor interacting protein 1) has been identified as an inhibitor of oligodendrocyte differentiation and myelination. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, we assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our results suggest that demyelination in the PHC and fimbria-fornix might contribute to cognitive deficits and the LINGO-1 antibody could ameliorate these deficits by promoting myelin growth in the PHC. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients.

  18. Amelioration of the cytotoxic effects of chemotherapeutic agents by grape seed proanthocyanidin extract.

    Science.gov (United States)

    Joshi, S S; Kuszynski, C A; Benner, E J; Bagchi, M; Bagchi, D

    1999-01-01

    Anticancer chemotherapeutic agents are effective in inhibiting growth of cancer cells in vitro and in vivo, however, toxicity to normal cells is a major problem. In this study, we assessed the effect of a novel IH636 grape seed proanthocyanidin extract (GSPE) to ameliorate chemotherapy-induced toxic effects in cultured Chang epithelial cells, established from nonmalignant human tissue. These cells were treated in vitro with idarubicin (Ida) (30 nM) or 4-hydroxyperoxycyclophosphamide (4HC) (1 microg/ml) with or without GSPE (25 microg/ml). The cells were grown in vitro and the growth rate of the cells was determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; thiazolyl blue] assay. Our results showed that GSPE decreased the growth inhibitory and cytotoxic effects of Ida as well as 4HC on Chang epithelial cells in vitro. Because these chemotherapeutic agents are known to induce apoptosis in the target cells, we analyzed the Chang epithelial cells for apoptotic cell population by flow cytometry. There was a significant decrease in the number of cells undergoing apoptosis following treatment with GSPE. We also found increased expression of the anti-apoptotic protein Bcl-2 in GSPE-treated cells using western blot techniques. Thus, these results indicate that GSPE can be a potential candidate to ameliorate the toxic effects associated with chemotherapeutic agents and one of the mechanisms of action of GSPE includes upregulation of Bcl-2 expression.

  19. Sesamin Ameliorates High-Fat Diet–Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress

    Science.gov (United States)

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-01-01

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia. PMID:27171111

  20. Sesamin Ameliorates High-Fat Diet-Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress.

    Science.gov (United States)

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-05-09

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia.

  1. Sesamin Ameliorates High-Fat Diet–Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Ruijuan Zhang

    2016-05-01

    Full Text Available The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day. Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV and α-smooth muscle actin (α-SMA were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia.

  2. Intermedin ameliorates IgA nephropathy by inhibition of oxidative stress and inflammation.

    Science.gov (United States)

    Wang, Yanhong; Tian, Jihua; Guo, Haixiu; Mi, Yang; Zhang, Ruijing; Li, Rongshan

    2016-05-01

    IgA nephropathy (IgAN) is the most frequent form of glomerulonephritis worldwide. The role of oxidative stress and inflammation in the pathogenesis of IgAN has been reported. Intermedin (IMD) is a newly discovered peptide that is closely related to adrenomedullin. We have recently reported that IMD can significantly reduce renal ischemia/reperfusion injury by diminishing oxidative stress and suppressing inflammation. The present study was designed to explore whether IMD ameliorates IgAN via oxidative stress- and inflammation-dependent mechanisms. Our results showed that IMD administration resulted in the prevention of albuminuria and ameliorated renal pathomorphological changes. These findings were associated with (1) decreased renal TGF-β1 and collagen IV expression, (2) an increased SOD level and reduced MDA level, (3) the inhibition of the renal activation of NF-κB p65 and (4) the downregulation of the expression of inflammatory factors (TNF-α, MCP-1 and MMP-9) in the kidney. These results indicate that IMD in the kidney protects against IgAN by reducing oxidative stress and suppressing inflammation.

  3. Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function.

    Science.gov (United States)

    Xu, Bin; Li, Yan-Li; Xu, Ming; Yu, Chang-Chun; Lian, Meng-Qiao; Tang, Ze-Yao; Li, Chuan-Xun; Lin, Yuan

    2017-03-06

    Geniposide is an iridoid glycosides purified from the fruit of Gardenia jasminoides Ellis, which is known to have antiinflammatory, anti-oxidative and anti-tumor activities. The present study aimed to investigate the effects of geniposide on experimental rat colitis and to reveal the related mechanisms. Experimental rat colitis was induced by rectal administration of a TNBS solution. The rats were treated with geniposide (25, 50 mg·kg(-1)·d(-1), ig) or with sulfasalazine (SASP, 100 mg·kg(-1)·d(-1), ig) as positive control for 14 consecutive days. A Caco-2 cell monolayer exposed to lipopolysaccharides (LPS) was used as an epithelial barrier dysfunction model. Transepithelial electrical resistance (TER) was measured to evaluate intestinal barrier function. In rats with TNBS-induced colitis, administration of geniposide or SASP significantly increased the TNBS-decreased body weight and ameliorated TNBS-induced experimental colitis and related symptoms. Geniposide or SASP suppressed inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and neutrophil infiltration (myeloperoxidase activity) in the colon. In Caco-2 cells, geniposide (25-100 μmol/L) ameliorated LPS-induced endothelial barrier dysfunction via dose-dependently increasing transepithelial electrical resistance (TER). The results from both in vivo and in vitro studies revealed that geniposide down-regulated NF-κB, COX-2, iNOS and MLCK protein expression, up-regulated the expression of tight junction proteins (occludin and ZO-1), and facilitated AMPK phosphorylation. Both AMPK siRNA transfection and AMPK overexpression abrogated the geniposide-reduced MLCK protein expression, suggesting that geniposide ameliorated barrier dysfunction via AMPK-mediated inhibition of the MLCK pathway. In conclusion, geniposide ameliorated TNBS-induced experimental rat colitis by both reducing inflammation and modulating the disrupted epithelial barrier function via activating the AMPK signaling pathway..

  4. Amelioration of painful crises in sickle cell disease by venesections.

    Science.gov (United States)

    Rombos, Yannis; Tzanetea, Revekka; Kalotychou, Vassiliki; Konstantopoulos, Kostas; Simitzis, Spyros; Tassiopoulos, Thomas; Aessopos, Athanasios; Fessas, Phaedon

    2002-01-01

    Sickle cell disease patients who acquire iron deficiency may experience a degree of amelioration from painful crises in terms of frequency, severity, and duration. This observation prompted us to identify the potential utility of iron load reduction in the management of this disease. Thirteen sickle cell patients not ameliorated by conventional treatment entered a weekly venesection protocol. Hematological values and painful crises of all degrees of severity were recorded and compared to those of the last 12 months before venesection for each case separately ("historical controls"). A decrease was noted in the frequency and intensity of several types of painful crises. Reduction of iron load by venesection seems to be a simple, safe, side-effect-free, and efficient way of preventing and ameliorating to a large extent painful crises in sickle cell disease. The biological effects of venesection on other parameters of sickle cell disease remain to be determined.

  5. Effects of hyperbaric oxygen therapy in enhancing expressions of e-NOS, TNF-α and VEGF in wound healing

    Science.gov (United States)

    Susilo, Imam; Devi, Anita; Purwandhono, Azham; Hadi Warsito, Sunaryo

    2017-05-01

    Wound healing is a physiological process that occurs progressively through overlapping phases. Tissue oxygenation is an important part of the complex regulation for wound healing. Hyperbaric Oxygen (HBO) therapy is a method of increasing oxygen delivery to tissues. The therapy improves tissue oxygenation and stimulates the formation of H2O2 as a secondary messenger for Tumour Necrosis Factor alpha (TNF α), e-NOS, VEGF and Nuclear Factor Kappa Beta phosphorylation (NF-Kb) which play an important role in the rapid transcription of a wide variety of genes in response to extracellular stimuli. This study aims to determine the effects of Hyperbaric Oxygen therapy in enhancing the expressions of e-NOS, TNF-α, VEGF and wound healing. This study is an animal study with a ‘randomized control group of pre-test and post test design’ on 28 Wistar rats. Randomly, the rats were divided into 4 groups with 7 rats in each group. The HBO treatment group 1 received 5 sessions of HBO 2.4 ATA in 3 × 30 minutes; the HBO treatment group 2 received 10 sessions of HBO 2.4 ATA in 3 × 30 minutes; and each of the control groups were without HBO. Each of the 28 male rats were given a full thickness excisional wound of 1 × 1cm. Examinations of e-NOS, TNF-α, VEGF expressions and wound healing were performed on day-0 (pre-HBO) and day-5 HBO or on day-0 (pre-HBO) and day-10 HBO. The resultsshowthat the Hyperbaric Oxygen therapy can improve e-NOS (p=0.02), TNF-α (p= 0.02), VEGF expression (p=0.02) and wound healing (p=0.002) significantly in the provision of HBO 2.4 ATA for 3 × 30 minutes in 5 sessions over 5 consecutive days. While the 10 sessions of HBO 2.4 ATA for 3 × 30 minutes over 10 consecutive days only increase e-NOS (p=0.02), TNF-α (p=0.04), VEGF expression significantly (p=0.03) but do not improve wound healing significantly (p=0.3) compared with no HBO. The study concludes that HBO can improve the expressions of e-NOS, TNF-α, VEGF and wound healing in the provision of HBO

  6. Polymerase I pathway inhibitor ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Achiron, Anat; Mashiach, Roi; Zilkha-Falb, Rina; Meijler, Michael M; Gurevich, Michael

    2013-10-15

    Applying high throughput gene expression microarrays we identified that the suppression of polymerase 1 (POL1) pathway is associated with benign course of multiple sclerosis (MS). This finding supports the rationale for direct targeting of the POL1 transcription machinery as an innovative strategy to suppress MS. To evaluate the effects of a specific polymerase I inhibitor (POL1-I) on experimental autoimmune encephalomyelitis (EAE), we immunized female C57BL/6J mice (8 weeks) with MOG35-55/CFA. A new POL1-I was administered at a daily dose of 12.5mg/kg body weight by oral gavage either from the day of immunization until disease onset (EAE score 1.0, immunization model), at disease onset (EAE score=1.0) for the following 14 days (treatment model), or by alternate daily dose of 25.0mg/kg body weight, by oral gavage from the day of immunization for the following 25 days (combined model). POL1-I remarkably suppressed EAE in the immunization model; while in the Vehicle group the onset of EAE occurred on day 10.0±0.4 with maximal clinical score of 3.2±0.2, in the POL1-I treated mice onset was significantly delayed and occurred on day 16.9±1.1 (p=0.001), and maximal disease score 2.0±0.1 was reduced (p=0.004). In the treatment model POL1-I treatment significantly reduced disease activity; maximal score was 2.0±0.5 while in the Vehicle group it reached a mean maximal score of 3.9±0.1, (p=0.0008). In the combined model, POL1-I treatment completely inhibited disease activity. The effect of POL1-I treatment was modulated through decreased expression of POL1 pathway key-related genes LRPPRC, pre-RNA, POLR1D and RRN3 together with activation of P53 dependent apoptosis of CD4+ splenocytes. Our findings demonstrate that POL1 pathway inhibition delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs.

  7. Keratinocyte growth factor gene therapy ameliorates ulcerative colitis in rats

    Institute of Scientific and Technical Information of China (English)

    Chun-Jie Liu; Ji-De Jin; Tong-De Lv; Zu-Ze Wu; Xiao-Qin Ha

    2011-01-01

    AIM: To investigate the effect of keratinocyte growth factor (KGF) gene therapy in acetic acid-induced ulcerative colitis in rat model. METHODS: The colitis of Sprague-Dawley rats was induced by intrarectal infusion of 1 mL 5% (v/v) acetic acid. Twenty-four hours after exposed to acetic acid, rats were divided into three experimental groups: control group, attenuated Salmonella typhimurium Ty21a strain (SP) group and SP strain carrying human KGF gene (SPK) group, and they were separately administered orally with 10% NaHCO3, SP or SPK. Animals were sacrificed and colonic tissues were harvested respectively on day 3, 5, 7 and 10 after administration. Weights of rats, colonic weight/ length ratio and stool score were evaluated. Histological changes of colonic tissues were examined by hematoxylin and eosin (HE) staining method. The expression of KGF, KGF receptor (KGFR) and TNF-α were measured either by enzyme-linked immunosorbent assay or Western blotting. Immunohistochemistry was used to detect the cellular localization of KGFR and Ki67. In addition, superoxide dismutase (SOD) activity and malondialdehyde (MDA) contents in the homogenate were measured. RESULTS: Body weight and colonic weight/length ratio were declined in SPK group compared with SP and control groups (body weight: 272.78 ± 17.92 g vs 243.72 ± 14.02 g and 240.68 ± 12.63 g, P < 0.01; colonic weight/length ratio: 115.76 ± 7.47 vs 150.32 ± 5.99 and 153.67 ± 5.50 mg/cm, P < 0.01). Moreover, pathological changes of damaged colon were improved in SPK group as well. After administration of SPK strain, KGF expression increased markedly from the 3rd d, and remained at a high level till the 10th d. Furthermore, KGFR expression and Ki67 expression elevated, whereas TNF-α expression was inhibited in SPK group. In the group administered with SPK, SOD activity increased significantly (d 5: 26.18 ± 5.84 vs 18.12 ± 3.30 and 18.79 ± 4.74 U/mg, P < 0.01; d 7: 35.48 ± 3.35 vs 22.57 ± 3.44 and 21.69 ± 3.94 U

  8. AGEs对兔软骨细胞TNF-α和MMP-13表达的影响及其机制研究%The effects of advanced glycation end products on expression of tumor necrosis factor-αand matrix metalloproteinase-13 in rabbit chondrocytes and its mechanism

    Institute of Scientific and Technical Information of China (English)

    陈铖; 马翅; 张莹; 肖钧; 蔡巍; 谭海涛

    2013-01-01

    目的:探讨晚期糖基化终末产物(AGEs)对兔软骨细胞肿瘤坏死因子-α(TNF-α)和基质金属蛋白酶-13(MMP-13)的影响及可能机制。方法:不同浓度的AGEs与兔软骨细胞共孵育48h后采用RT-PCR方法检测TNF-α和MMP-13的mRNA表达量,试剂盒方法检测过氧化氢酶(CAT)、超氧化物歧化酶(SOD)活性及丙二醛(MDA)水平,荧光探针法检测细胞内活性氧(ROS)水平。AGEs与兔软骨细胞共孵育的同时,分别加入AGEs受体的抗体(Anti-RAGE)及核因子-κB(NF-κB)的特异性阻断剂PDTC处理,同法检测TNF-α和MMP-13的mRNA表达量。结果:与AGEs共孵育48h后兔软骨细胞TNF-α及MMP-13表达明显增多,CAT、SOD活性降低,MDA、ROS含量增多,均呈浓度依赖性;分别加入Anti-RAGE 及PDTC 处理后软骨细胞TNF-α及MMP-13表达明显低于AGEs单独处理组(P0.05)。结论:AGEs能诱导软骨细胞TNF-α和MMP-13表达增多,其机制与激活RAGE,诱导ROS生成增多,激活NF-κB信号通路有关。%Objective To detect the effects of advanced glycation end products (AGEs) on expression of tu-mor necrosis factor-α(TNF-α) and matrix metalloproteinase-13(MMP-13) in rabbit chondrocytes and its mecha-nism. Methods The chondrocytes were incubated with different concentrations of AGEs for 48h, the expression of TNF-αand MMP-13 mRNA were detected by reverse transcription polymerase chain reaction(RT-PCR),the lev-el of catalase (CAT), Malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were detected by kits, and the level of ROS is measured by the method of Fluorescent probe. The effect of anti-RAGE(Receptor for AGEs) and PDTC(the inhibitor of NF-KB) on the expression of TNF-αand MMP-13 induced by AGEs were also measured by RT-PCR. Results After chondrocytes were incubated with AGEs, dose-dependly increased the ex-pression of TNF-αand MMP-13 (P0.05). Conclusion AGEs can induce the TNF-αand MMP-13 expression. It's mechanism may

  9. Phytoestrogen calycosin-7-O-β-D-glucopyranoside ameliorates advanced glycation end products-induced HUVEC damage.

    Science.gov (United States)

    Xu, Youhua; Feng, Liang; Wang, Shanshan; Zhu, Quan; Lin, Jing; Lou, Chihan; Xiang, Ping; He, Bao; Zheng, Zhaoguang; Tang, Dan; Zuo, Guoying

    2011-10-01

    Vasculopathy including endothelial cell (EC) apoptosis and inflammation contributes to the high incidence of stroke and myocardial infarction in diabetic patients. The aim of the present study was to investigate the effect of calycosin-7-O-β-D-glucopyranoside (CG), a phytoestrogen, on advanced glycation end products (AGEs)-induced HUVEC damage. We observed that CG can significantly ameliorate AGEs-induced HUVEC oxidative stress and apoptosis. The ratio of SOD/MDA was significantly increased to the normal level by CG pretreatment. CG preincubation dramatically increased anti-apoptotic Bcl-2 while decreased pro-apoptotic Bax and Bad expressions as detected by immunocytochemistry. Moreover, CG ameliorated macrophage migration and adhesion to HUVEC; the monocyte chemotactic protein-1 and interleukin-6 levels in the culture supernatant were dramatically reduced by CG as determined by ELISA; the expressions of inflammatory proteins including ICAM-1, TGF-β1, and RAGE in both protein and mRNA levels were significantly reduced to the normal level by CG pretreatment as determined by immunocytochemistry and real-time RT-PCR. The intracellular investigation suggests that CG can reverse AGEs-activated ERK1/2 and NF-κB phosphorylation, in which estrogen receptors were involved in. Our results strongly indicate that CG can modulate EC dysfunction by ameliorating AGEs-induced cell apoptosis and inflammation.

  10. EGCG ameliorates diet-induced metabolic syndrome associating with the circadian clock.

    Science.gov (United States)

    Mi, Yashi; Qi, Guoyuan; Fan, Rong; Ji, Xiaohua; Liu, Zhigang; Liu, Xuebo

    2017-06-01

    In response to the daily light-dark (LD) cycle, organisms on Earth have evolved with the approximately 24-h endogenous oscillations to coordinate behavioral and physiological processes, including feeding, sleep, and metabolism homeostasis. Circadian desynchrony triggered by an energy-dense diet rich in fats and fructose is intimately connected with a series of metabolic disorders. Previous studies revealed that (-)-Epigallocatechin-3-gallate (EGCG) could mitigate metabolic misalignment; however, only a few reports have focused on its potential effect on directly manipulating circadian rhythms to ameliorate metabolic syndrome. Our goal was to investigate the regulating effect of EGCG treatment on metabolic misalignment triggered by a high-fat and high-fructose diet (HFFD) associating with the circadian clock. Our results indicated that HFFD treatment partially exhibited poor circadian oscillations of the core clock gene and the clock-controlled gene in the liver and fat relative to the control group. EGCG administration may ameliorate the diet-dependent decline in circadian function by controlling the Sirt1-PGC1αloop, implying the existence of an EGCG-entrainable oscillator. Subsequently, reducing fatty acid synthesis and elevating β-oxidation in the liver coupled with the increasing brown adipose tissue (BAT) energy expenditure observed in the EGCG group of mice prevented the adipocyte hypertrophy and fat accumulations common to BAT and white adipose tissue (WAT) derived from the HFFD mice. This study is the first to provide compelling evidences that EGCG may ameliorate diet-induced metabolic misalignment by regulating the rhythmic expression of the circadian clock genes in the liver and fat. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. CD44 antibodies and immune thrombocytopenia in the amelioration of murine inflammatory arthritis.

    Directory of Open Access Journals (Sweden)

    Patrick J Mott

    Full Text Available Antibodies to CD44 have been used to successfully ameliorate murine models of autoimmune disease. The most often studied disease model has been murine inflammatory arthritis, where a clear mechanism for the efficacy of CD44 antibodies has not been established. We have recently shown in a murine passive-model of the autoimmune disease immune thrombocytopenia (ITP that some CD44 antibodies themselves can induce thrombocytopenia in mice, and the CD44 antibody causing the most severe thrombocytopenia (IM7, also is known to be highly effective in ameliorating murine models of arthritis. Recent work in the K/BxN serum-induced model of arthritis demonstrated that antibody-induced thrombocytopenia reduced arthritis, causing us to question whether CD44 antibodies might primarily ameliorate arthritis through their thrombocytopenic effect. We evaluated IM7, IRAWB14.4, 5035-41.1D, KM201, KM114, and KM81, and found that while all could induce thrombocytopenia, the degree of protection against serum-induced arthritis was not closely related to the length or severity of the thrombocytopenia. CD44 antibody treatment was also able to reverse established inflammation, while thrombocytopenia induced by an anti-platelet antibody targeting the GPIIbIIIa platelet antigen, could not mediate this effect. While CD44 antibody-induced thrombocytopenia may contribute to some of its therapeutic effect against the initiation of arthritis, for established disease there are likely other mechanisms contributing to its efficacy. Humans are not known to express CD44 on platelets, and are therefore unlikely to develop thrombocytopenia after CD44 antibody treatment. An understanding of the relationship between arthritis, thrombocytopenia, and CD44 antibody treatment remains critical for continued development of CD44 antibody therapeutics.

  12. miR-200b precursor can ameliorate renal tubulointerstitial fibrosis.

    Directory of Open Access Journals (Sweden)

    Shigeyoshi Oba

    Full Text Available Members of the miR-200 family of micro RNAs (miRNAs have been shown to inhibit epithelial-mesenchymal transition (EMT. EMT of tubular epithelial cells is the mechanism by which renal fibroblasts are generated. Here we show that miR-200 family members inhibit transforming growth factor-beta (TGF-beta-induced EMT of tubular cells. Unilateral ureter obstruction (UUO is a common model of EMT of tubular cells and subsequent tubulointerstitial fibrosis. In order to examine the role of miR-200 family members in tubulointerstitial fibrosis, their expression was investigated in the kidneys of UUO mice. The expression of miR-200 family miRNAs was increased in a time-dependent manner, with induction of miR-200b most pronounced. To clarify the effect of miR-200b on tubulointerstitial fibrosis, we injected miR-200b precursor intravenously. A single injection of 0.5 nM miR-200b precursor was sufficient to inhibit the increase of collagen types I, III and fibronectin in obstructed kidneys, and amelioration of fibrosis was confirmed by observation of the kidneys with Azan staining. miR-200 family members have been previously shown to inhibit EMT by reducing the expression of ZEB-1 and ZEB-2 which are known repressors of E-cadherin. We demonstrated that expression of ZEB-1 and ZEB-2 was increased after ureter obstruction and that administration of the miR-200b precursor reversed this effect. In summary, these results indicate that miR-200 family is up-regulated after ureter obstruction, miR-200b being strongly induced, and that miR-200b ameliorates tubulointerstitial fibrosis in obstructed kidneys. We suggest that members of the miR-200 family, and miR-200b specifically, might constitute novel therapeutic targets in kidney disease.

  13. Antibiotics can ameliorate circulatory complications of liver cirrhosis

    DEFF Research Database (Denmark)

    Madsen, Bjørn Stæhr; Schaffalitzky de Muckadell, Ove B

    2011-01-01

    . This review focuses on how broad spectrum antibiotics can ameliorate the haemodynamic consequences of bacterial translocation. It is possible that the use of broad spectrum antibiotics in the future may be used to prevent other complications of liver cirrhosis than spontaneous bacterial peritonitis...

  14. Dose-Dependent Amelioration of Gentamicin-Induced ...

    African Journals Online (AJOL)

    Dose-Dependent Amelioration of Gentamicin-Induced Nephrotoxicity in Adult Swiss Albino ... Purpose: To evaluate the effect of vitamin B-complex on the nephrotoxicity of ... increase in serum urea and creatine while 3ml/kg of the same drug ...

  15. Designing urban parks that ameliorate the effects of climate change

    NARCIS (Netherlands)

    Brown, R.D.; Vanos, J.; Kenny, N.; Lenzholzer, S.

    2015-01-01

    Many inhabitants of cities throughout the world suffer from health problems and discomfort that are caused by overheating of urban areas, and there is compelling evidence that these problems will be exacerbated by global climate change. Most cities are not designed to ameliorate these effects althou

  16. Social buffering ameliorates conditioned fear responses in female rats.

    Science.gov (United States)

    Ishii, Akiko; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

    2016-05-01

    The stress experienced by an animal is ameliorated when the animal is exposed to distressing stimuli along with a conspecific animal(s). This is known as social buffering. Previously, we found that the presence of an unfamiliar male rat induced social buffering and ameliorated conditioned fear responses of a male rat subjected to an auditory conditioned stimulus (CS). However, because our knowledge of social buffering is highly biased towards findings in male subjects, analyses using female subjects are crucial for comprehensively understanding the social buffering phenomenon. In the present studies, we assessed social buffering of conditioned fear responses in female rats. We found that the estrus cycle did not affect the intensity of the rats' fear responses to the CS or their degree of vigilance due to the presence of a conspecific animal. Based on these findings, we then assessed whether social buffering ameliorated conditioned fear responses in female rats without taking into account their estrus cycles. When fear conditioned female rats were exposed to the CS without the presence of a conspecific, they exhibited behavioral responses, including freezing, and elevated corticosterone levels. By contrast, the presence of an unfamiliar female rat suppressed these responses. Based on these findings, we conclude that social buffering can ameliorate conditioned fear responses in female rats.

  17. Glycine preconditioning to ameliorate pulmonary ischemia reperfusion injury in rats

    NARCIS (Netherlands)

    Sommer, Sebastian-Patrick; Sommer, Stefanie; Sinha, Bhanu; Leyh, Rainer G.

    2012-01-01

    This study examines the impact of glycine (Gly) preconditioning on ischemia reperfusion (IR)-induced pulmonary mitochondrial injury to research the previously, in pig lungs, demonstrated Gly-dependent amelioration of pulmonary IR injury. IR injury was induced in rat lungs by 30 min pulmonary hilum c

  18. Designing urban parks that ameliorate the effects of climate change

    NARCIS (Netherlands)

    Brown, R.D.; Vanos, J.; Kenny, N.; Lenzholzer, S.

    2015-01-01

    Many inhabitants of cities throughout the world suffer from health problems and discomfort that are caused by overheating of urban areas, and there is compelling evidence that these problems will be exacerbated by global climate change. Most cities are not designed to ameliorate these effects

  19. Dietary abscisic acid ameliorates influenza-virus-associated disease and pulmonary immunopathology through a PPARγ-dependent mechanism.

    Science.gov (United States)

    Hontecillas, Raquel; Roberts, Paul C; Carbo, Adria; Vives, Cristina; Horne, William T; Genis, Sandra; Velayudhan, Binu; Bassaganya-Riera, Josep

    2013-06-01

    The anti-inflammatory phytohormone abscisic acid (ABA) modulates immune and inflammatory responses in mouse models of colitis and obesity. ABA has been identified as a ligand of lanthionine synthetase C-like 2, a novel therapeutic target upstream of the peroxisome proliferator-activated receptor γ (PPARγ) pathway. The goal of this study was to investigate the immune modulatory mechanisms underlying the anti-inflammatory efficacy of ABA against influenza-associated pulmonary inflammation. Wild-type (WT) and conditional knockout mice with defective PPARγ expression in lung epithelial and hematopoietic cells (cKO) treated orally with or without ABA (100 mg/kg diet) were challenged with influenza A/Udorn (H3N2) to assess ABA's impact in disease, lung lesions and gene expression. Dietary ABA ameliorated disease activity and lung inflammatory pathology, accelerated recovery and increased survival in WT mice. ABA suppressed leukocyte infiltration and monocyte chemotactic protein 1 mRNA expression in WT mice through PPARγ since this effect was abrogated in cKO mice. ABA ameliorated disease when administered therapeutically on the same day of the infection to WT but not mice lacking PPARγ in myeloid cells. We also show that ABA's greater impact is between days 7 and 10 postchallenge when it regulates the expression of genes involved in resolution, like 5-lipoxygenase and other members of the 5-lipoxygenase pathway. Furthermore, ABA significantly increased the expression of the immunoregulatory cytokine interleukin-10 in WT mice. Our results show that ABA, given preventively or therapeutically, ameliorates influenza-virus-induced pathology by activating PPARγ in pulmonary immune cells, suppressing initial proinflammatory responses and promoting resolution.

  20. Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

    Science.gov (United States)

    Carneiro, Priscila J.; Clevelario, Amanda L.; Padilha, Gisele A.; Silva, Johnatas D.; Kitoko, Jamil Z.; Olsen, Priscilla C.; Capelozzi, Vera L.; Rocco, Patricia R. M.; Cruz, Fernanda F.

    2017-01-01

    Silicosis is an occupational lung disease for which no effective therapy exists. We hypothesized that bosutinib, a tyrosine kinase inhibitor, might ameliorate inflammatory responses, attenuate pulmonary fibrosis, and thus improve lung function in experimental silicosis. For this purpose, we investigated the potential efficacy of bosutinib in the treatment of experimental silicosis induced in C57BL/6 mice by intratracheal administration of silica particles. After 15 days, once disease was established, animals were randomly assigned to receive DMSO or bosutinib (1 mg/kg/dose in 0.1 mL 1% DMSO) by oral gavage, twice daily for 14 days. On day 30, lung mechanics and morphometry, total and differential cell count in alveolar septa and granuloma, levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, transforming growth factor (TGF)-β, and vascular endothelial growth factor in lung homogenate, M1 and M2 macrophages, total leukocytes, and T cells in BALF, lymph nodes, and thymus, and collagen fiber content in alveolar septa and granuloma were analyzed. In a separate in vitro experiment, RAW264.7 macrophages were exposed to silica particles in the presence or absence of bosutinib. After 24 h, gene expressions of arginase-1, IL-10, IL-12, inducible nitric oxide synthase (iNOS), metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, and caspase-3 were evaluated. In vivo, in silicotic animals, bosutinib, compared to DMSO, decreased: (1) fraction area of collapsed alveoli, (2) size and number of granulomas, and mononuclear cell granuloma infiltration; (3) IL-1β, TNF-α, IFN-γ, and TGF-β levels in lung homogenates, (4) collagen fiber content in lung parenchyma, and (5) viscoelastic pressure and static lung elastance. Bosutinib also reduced M1 cell counts while increasing M2 macrophage population in both lung parenchyma and granulomas. Total leukocyte, regulatory T, CD4+, and CD8+ cell counts in the lung-draining lymph

  1. Peripheral oxytocin treatment ameliorates obesity by reducing food intake and visceral fat mass.

    Science.gov (United States)

    Maejima, Yuko; Iwasaki, Yusaku; Yamahara, Yui; Kodaira, Misato; Sedbazar, Udval; Yada, Toshihiko

    2011-12-01

    Recent studies suggest that oxytocin (Oxt) is implicated in energy metabolism. We aimed to explore acute and sub-chronic effects of peripheral Oxt treatment via different routes on food intake and energy balance. Intraperitoneal (ip) injection of Oxt concentration-dependently decreased food intake in mice. Ip Oxt injection induced c-Fos expression in the hypothalamus and brain stem including arcuate nucleus (ARC), paraventricular nucleus (PVN) and nucleus tractus solitarius (NTS). Subcutaneous (sc) injection of Oxt suppressed food intake in normal and high fat diet-induced obese (DIO) mice. Daily sc injection of Oxt for 17 days in DIO mice reduced food intake for 6 days and body weight for the entire treatment period and additional 9 days after terminating Oxt. Oxt infusion by sc implanted osmotic minipumps for 13 days in DIO mice reduced food intake, body weight, and visceral fat mass and adipocyte size. Oxt infusion also decreased respiratory quotient specifically in light phase, ameliorated fatty liver and glucose intolerance, without affecting normal blood pressure in DIO mice. These results demonstrate that peripheral Oxt treatment reduces food intake and visceral fat mass, and ameliorates obesity, fatty liver and glucose intolerance. Peripheral Oxt treatment provides a new therapeutic avenue for treating obesity and hyperphagia.

  2. Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment.

    Science.gov (United States)

    Hota, Sunil Kumar; Barhwal, Kalpana; Baitharu, Iswar; Prasad, Dipti; Singh, Shashi Bala; Ilavazhagan, Govindasamy

    2009-04-01

    Hypobaric hypoxia induced memory impairment has been attributed to several factors including increased oxidative stress, depleted mitochondrial bioenergetics, altered neurotransmission and apoptosis. This multifactorial response of the brain to hypobaric hypoxia limits the use of therapeutic agents that target individual pathways for ameliorating hypobaric hypoxia induced memory impairment. The present study aimed at exploring the therapeutic potential of a bacoside rich leaf extract of Bacopa monniera in improving the memory functions in hypobaric conditions. The learning ability was evaluated in male Sprague Dawley rats along with memory retrieval following exposure to hypobaric conditions simulating an altitude of 25,000 ft for different durations. The effect of bacoside administration on apoptosis, cytochrome c oxidase activity, ATP levels, and oxidative stress markers and on plasma corticosterone levels was investigated. Expression of NR1 subunit of N-methyl-d-aspartate receptors, neuronal cell adhesion molecules and was also studied along with CREB phosphorylation to elucidate the molecular mechanisms of bacoside action. Bacoside administration was seen to enhance learning ability in rats along with augmentation in memory retrieval and prevention of dendritic atrophy following hypoxic exposure. In addition, it decreased oxidative stress, plasma corticosterone levels and neuronal degeneration. Bacoside administration also increased cytochrome c oxidase activity along with a concomitant increase in ATP levels. Hence, administration of bacosides could be a useful therapeutic strategy in ameliorating hypobaric hypoxia induced cognitive dysfunctions and other related neurological disorders.

  3. Rikkunshito Ameliorates Cancer Cachexia Partly through Elevation of Glucarate in Plasma

    Directory of Open Access Journals (Sweden)

    Katsuya Ohbuchi

    2015-01-01

    Full Text Available Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient’s morbidity and mortality. We previously showed that rikkunshito (RKT, a Japanese traditional herbal medicine (Kampo, ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma.

  4. Ameliorative Effect of Ginsenoside Rg1 on Lipopolysaccharide-Induced Cognitive Impairment: Role of Cholinergic System.

    Science.gov (United States)

    Jin, Yang; Peng, Jian; Wang, Xiaona; Zhang, Dong; Wang, Tianyin

    2017-01-11

    Bacterial endotoxin lipopolysaccharide (LPS) can induce systemic inflammation, and therefore disrupt learning and memory processes. Ginsenoside Rg1, a major bioactive component of ginseng, is shown to greatly improve cognitive function. The present study was designed to further investigate whether administration of ginsenoside Rg1 can ameliorate LPS-induced cognitive impairment in the Y-maze and Morris water maze (MWM) task, and to explore the underlying mechanisms. Results showed that exposure to LPS (500 μg/kg) significantly impaired working and spatial memory and that repeated treatment with ginsenoside Rg1 (200 mg/kg/day, for 30 days) could effectively alleviate the LPS-induced cognitive decline as indicated by increased working and spatial memory in the Y-maze and MWM tests. Furthermore, ginsenoside Rg1 treatment prevented LPS-induced decrease of acetylcholine (ACh) levels and increase of acetylcholinesterase (AChE) activity. Ginsenoside Rg1 treatment also reverted the decrease of alpha7 nicotinic acetylcholine receptor (α7 nAChR) protein expression in the prefrontal cortex (PFC) and hippocampus of LPS-treated rats. These findings suggest that ginsenoside Rg1 has protective effect against LPS-induced cognitive deficit and that prevention of LPS-induced changes in cholinergic system is crucial to this ameliorating effect.

  5. Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

    Directory of Open Access Journals (Sweden)

    Lei Liu

    2015-07-01

    Full Text Available Background/Aims: Intracellular calcium concentration ([Ca2+]i homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ- AMP-activated protein kinase (AMPK-mammalian target of rapamycin (mTOR pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.

  6. Calhex₂₃₁ Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro.

    Science.gov (United States)

    Liu, Lei; Wang, Chao; Sun, Dianjun; Jiang, Shuangquan; Li, Hong; Zhang, Weihua; Zhao, Yajun; Xi, Yuhui; Shi, Sa; Lu, Fanghao; Tian, Ye; Xu, Changqing; Wang, Lina

    2015-01-01

    Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson’s trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)– AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy. © 2015 S. Karger AG, Basel.

  7. Bioinformatics analysis of coding regions of NF-KB1 gene among species%不同物种NF-κB1基因编码区生物信息分析

    Institute of Scientific and Technical Information of China (English)

    张军杰; 李祥龙; 周荣艳; 李兰会; 任玉红; 赵驻军

    2012-01-01

    为了解不同物种NF-κB1基因编码区(CDS)的遗传变异,本试验使用生物信息学的方法比较分析了小家鼠、褐家鼠、人、黑猩猩、狨、毛猩猩、猕猴、家马、大熊猫、野猪、家短尾负鼠、牛、狼、非洲象和白颊长臂猿NF-κB1基因编码区的遗传多样性,并对该基因的氨基酸序列、跨膜结构域、导肽、信号肽和结构域进行了预测和分析,对有关NF-κB1基因功能的一些研究热点进行了回顾。结果表明:在15个物种36条基因序列中共检测到968个多态位点,生成24种单倍型,NF-κB1基因序列编码区在物种间存在丰富的遗传多样性;理论等电点均低于5.5,NF-κB1编码的蛋白呈酸性,N端无信号肽、导肽,无跨膜结构域,肽链表现为亲水性;这些蛋白均含有1个Rel同源域,6~7个Ankyrin重复,在结构上保守。%In order to study the genetic variation of the NF-kB 1 gene CDS in different species, the genetic diversity of the CDS of NF-xB 1 gene sequences from Mus musculus, Rattus norvegicus, Homo sapiens, Pan troglodytes, Calithrix jacchus,Pongo abelii, Macaca mulatta, Equus caballus, Ailuropoda melanoleuca, Sus scrofa, Monodelphis domestica, Bos Taurus,Canis lupus,Loxodonta Africana and Nomascus leucogenys was analyzed using the method of bioinfor- matics. The characteristics of composition of nucleic acid sequences and amino acid sequences,leader peptides, signal peptide,trans-membrane to pological structure and structure domain was also analyzed, and some of the loci of intense investigation on the function of NF-kB1 were reviewed. The results showed that a total of 968 polymorphic sites were detected from 36 sequences of 15 species,from which 24 hapolotypes were sorted. The genetic diversity of the NF-kB1 gene CDS was rich among species. The NF-xB 1 was a non trans-membrane protein without leader pep- tides and signal peptide in N-terminal,and the polypeptide chain presented hydrophilic. These proteins contain a Rel homology domain and 6-7 Ankyrin repeat,conservative in structure.

  8. A PPARδ-selective antagonist ameliorates IMQ-induced psoriasis-like inflammation in mice.

    Science.gov (United States)

    Wang, Xuguo; Hao, Yangyang; Wang, Xiaohuan; Wang, Lumei; Chen, Yongchun; Sun, Jun; Hu, Jinhong

    2016-11-01

    PPARδ is highly expressed in skin, especially keratinocytes, and its expression is increased in psoriatic lesions. However, the potential role of PPARδ in the pathogenesis of psoriasis remains undefined. Mice treated with Imiquimod (IMQ) to induce psoriasis can be used to evaluate the pathogenesis of psoriasis, and this model has become one of the most important in vivo research tools for research on the disease. In the current study, we showed that PPARδ was highly expressed in the skin of IMQ-induced psoriasis mice. To further understand the impact of PPARδ in psoriasis, we used these mice in a series of experiments to evaluate the pathogenesis of psoriasis. We found that PPARδ was highly expressed in both psoriatic lesions and normal skin in IMQ-induced psoriasis mice. Furthermore, the expression of PPARδ-relevant lipases was also significantly increased. The PPARδ-selective antagonist GSK3787 ameliorated the observed inflammation in the skin of the experimental mice. Based on these results, PPARδ may be a potential target for the effective treatment of psoriasis. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Melatonin ameliorates metabolic risk factors, modulates apoptotic proteins, and protects the rat heart against diabetes-induced apoptosis.

    Science.gov (United States)

    Amin, Ali H; El-Missiry, Mohamed A; Othman, Azza I

    2015-01-15

    The present study investigated the ability of melatonin in reducing metabolic risk factors and cardiac apoptosis induced by diabetes. Streptozotocin (60 mg/kg, i.p.) was injected into male rats, and after diabetic induction melatonin (10mg/kg i.g.) was administered orally for 21 days. Diabetic hearts showed increased number of apoptotic cells with downregulation of Bcl-2 and activation of p53 and CD95 as well as the caspases 9, 8 and 3. In addition, there was a significant decrease in insulin level, hyperglycemia, elevated HOMA-IR, glycosylated hemoglobin (HbA1c), total lipids, triglycerides, total cholesterol, low and very low-density lipoprotein and decreased high-density lipoprotein. These changes were coupled with a significant increase in the activities of creatin kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in the serum of the diabetic rats indicating myocardium injury. Oral administration of melatonin for 3 weeks after diabetes induction ameliorated the levels of hyperglycemia, insulin, HbA1c, lipids profile and HOMA-IR. The oral melatonin treatment of diabetic rats significantly decreased the number of apoptotic cells in the heart compared to diabetic rats. It enhanced Bcl-2 expression and blocked the activation of CD95 as well as caspases 9, 8 and 3. These changes were accompanied with significant improvement of CK-MB and LDH in the serum indicating the ameliorative effect of melatonin on myocardium injury. Melatonin effectively ameliorated diabetic myocardium injury, apoptosis, reduced the metabolic risk factors and modulated important steps in both extrinsic and intrinsic pathways of apoptosis. Thus, melatonin may be a promising pharmacological agent for ameliorating potential cardiomyopathy associated with diabetes.

  10. Application of actinomycetes to soil to ameliorate water repellency.

    Science.gov (United States)

    McKenna, F; El-Tarabily, K A; Petrie, S; Chen, C; Dell, B

    2002-01-01

    The aim of this study was to develop a novel isolation technique using a mixture of Bacillus and Streptomyces phages to selectively isolate wax-utilizing non-streptomycete actinomycetes effective in ameliorating water repellency in a problem soil. Phages added to a soil suspension reduced the dominance of Bacillus and Streptomyces isolates and significantly increased the number of non-streptomycete actinomycetes on isolation plates. Promising isolates, grown on a medium containing beeswax as sole carbon source, were selected for application to water repellent soil. Their addition significantly reduced water repellency. Phage application significantly increased the isolation of non-streptomycete actinomycetes. Wax-utilizing isolates were found to significantly reduce water repellency in a problem soil. The phage technique can be used for the routine isolation of non-streptomycete actinomycetes. Beeswax medium can be used to selectively isolate wax-utilizing micro-organisms with the potential to ameliorate water repellency in soil.

  11. Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions.

    Directory of Open Access Journals (Sweden)

    Satoshi Nishiwaki

    Full Text Available Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP, a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

  12. Hypomethylating agent 5-aza-2'-deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models

    DEFF Research Database (Denmark)

    Mangano, Katia; Fagone, Paolo; Bendtzen, Klaus

    2014-01-01

    Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2'-deoxycytidine (DAC) in two...... murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease....... Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3....

  13. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells

    Science.gov (United States)

    Jiang, Hong; Zhang, Yuanyuan; Tian, Kewei; Wang, Beibei; Han, Shu

    2017-01-01

    Placental derived mesenchymal stem cells (PMSCs) have been suggested as a possible source of cells to treat multiple sclerosis (MS) due to their immunomodulatory functions, lack of ethical concerns, and potential to differentiate into neurons and oligodendrocytes. To investigate whether PMSCs share similar characteristics with embryonic mesenchymal stem cells (EMSCs), and if transplanted PMSCs have the ability to integrate and replace degenerated neural cells, we transplanted rat PMSCs and EMSCs into the central nervous system (CNS) of Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our findings demonstrated that transplanted PMSCs, similar to EMSCs, were effective in decreasing infiltrating inflammatory cells, preserving axons, and ameliorating demyelination, thereby improving the neurological functions of animals. Moreover, both PMSCs and EMSCs had the ability to migrate into inflamed tissues and express neural–glial lineage markers. These findings suggest that PMSCs may replace EMSCs as a source of cells in MS stem cell therapy. PMID:28186117

  14. Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity.

    Science.gov (United States)

    Askenasy, Nadir

    2013-08-01

    Regulatory T cells (Treg) are pivotal suppressor elements in immune homeostasis with potential therapeutic applications in inflammatory and autoimmune disorders. Using Treg as vehicles for targeted immunomodulation, a short-lived Fas-ligand (FasL) chimeric protein (killer Treg) was found efficient in preventing the progression of autoimmune insulitis in NOD mice, and amelioration of chronic colitis and graft versus host disease. The main mechanisms of disease suppression by killer Treg are: a) in the acute phase induction of apoptosis in effector cells at the site of inflammation decreases the pathogenic burden, and b) persistent increase in FoxP3⁺ Treg with variable CD25 co-expression induced by FasL sustains disease suppression over extended periods of time. Reduced sensitivity of Treg to receptor-mediated apoptosis under inflammatory conditions makes them optimal vehicles for targeted immunotherapy using apoptotic agents.

  15. Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis

    Directory of Open Access Journals (Sweden)

    Bo Young Nam

    2017-06-01

    Full Text Available Peritoneal fibrosis is a major complication in peritoneal dialysis (PD patients, which leads to dialysis discontinuation. Periostin, increased by transforming growth factor β1 (TGF-β1 stimulation, induces the expression of extracellular matrix (ECM genes. Aberrant periostin expression has been demonstrated to be associated with PD-related peritoneal fibrosis. Therefore, the effect of periostin inhibition by an aptamer-based inhibitor on peritoneal fibrosis was evaluated. In vitro, TGF-β1 treatment upregulated periostin, fibronectin, α-smooth muscle actin (α-SMA, and Snail expression and reduced E-cadherin expression in human peritoneal mesothelial cells (HPMCs. Periostin small interfering RNA (siRNA treatment ameliorated the TGF-β1-induced periostin, fibronectin, α-SMA, and Snail expression and restored E-cadherin expression in HPMCs. Similarly, the periostin-binding DNA aptamer (PA also attenuated fibronectin, α-SMA, and Snail upregulation and E-cadherin downregulation in TGF-β1-stimulated HPMCs. In mice treated with PD solution for 4 weeks, the expression of periostin, fibronectin, α-SMA, and Snail was significantly increased in the peritoneum, whereas E-cadherin expression was significantly decreased. The thickness of the submesothelial layer and the intensity of Masson’s trichrome staining in the PD group were significantly increased compared to the untreated group. These changes were significantly abrogated by the intraperitoneal administration of PA. These findings suggest that PA can be a potential therapeutic strategy for peritoneal fibrosis in PD patients.

  16. Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Tingting; Zhao, Ling; Liu, Mengyu; Xie, Fei; Ma, Xuemei, E-mail: xmma@bjut.edu.cn; Zhao, Pengxiang; Liu, Yunqi; Li, Jiala; Wang, Minglian; Yang, Zhaona; Zhang, Yutong

    2014-10-01

    Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75 mg/kg body weight (1/20 LD{sub 50}) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity. - Highlights: • Hydrogen molecules protect rats from CPF-induced damage of hippocampal neurons. • The increased GFAP expression induced by CPF can also be ameliorated by hydrogen. • Hydrogen molecules attenuated the increase in CPF-induced oxidative stress. • Hydrogen molecules attenuated AChE inhibition in vivo

  17. Resveratrol ameliorates hypoxia/ischemia-induced brain injury in the neonatal rat via the miR-96/Bax axis.

    Science.gov (United States)

    Bian, Hongen; Shan, Haijun; Chen, Tuanying

    2017-07-18

    This study was aimed to investigate the mechanism of resveratrol on amelioration of hypoxia/ischemia (H/I)-induced brain injury. The RT-PCR and western blot were used to detect the mRNA and protein expressions, respectively. The PC12 cell induced by OGD/R was as in vitro H/I brain injury model. The luciferase reporter assay was used to prove the relationship between Bax and miR-96, and the cell apoptosis was detected by MTT assay. The loss of MBP+ area in neonatal rats analyzed by immunohistochemistry was to evaluate the extent of brain injury. The miR-96 expression was decreased in the hippocampus and cerebral cortex of neonatal rats with H/I brain injury and the oxygenglucose deprivation/re-oxygenation (OGD/R)-induced PC12 cell, while Bax expression was opposite. And then the H/I rats and OGD/R-induced PC12 cell were treated with resveratrol (RSV); the results showed that the RSV could reverse the miR-96 and Bax expressions. Next, the luciferase reporter assay proved that Bax was a target of miR-96. We used the miR-96 inhibitor to suppress miR-96 expression in OGD/R-induced PC12 cell, and found that RSV regulated Bax expression and prevented OGD/R-induced PC12 cell apoptosis via miR-96. In addition, the immunohistochemistry was used to analyze the loss of MBP+ area in neonatal rats, and the result showed that the RSV significantly reduced the brain damage, increased miR-96 expression, and decreased Bax expression, while inhibition of miR-96 aggravated the brain damage and reversed the effect of RSV. Resveratrol ameliorates hypoxia/ischemia-induced brain injury in neonatal rat via the miR-96/ Bax axis.

  18. Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection.

    Directory of Open Access Journals (Sweden)

    Marie Samanovic

    2009-01-01

    Full Text Available Innate immunity is the first line of defense against invading microorganisms. Trypanosome Lytic Factor (TLF is a minor sub-fraction of human high-density lipoprotein that provides innate immunity by completely protecting humans from infection by most species of African trypanosomes, which belong to the Kinetoplastida order. Herein, we demonstrate the broader protective effects of human TLF, which inhibits intracellular infection by Leishmania, a kinetoplastid that replicates in phagolysosomes of macrophages. We show that TLF accumulates within the parasitophorous vacuole of macrophages in vitro and reduces the number of Leishmania metacyclic promastigotes, but not amastigotes. We do not detect any activation of the macrophages by TLF in the presence or absence of Leishmania, and therefore propose that TLF directly damages the parasite in the acidic parasitophorous vacuole. To investigate the physiological relevance of this observation, we have reconstituted lytic activity in vivo by generating mice that express the two main protein components of TLFs: human apolipoprotein L-I and haptoglobin-related protein. Both proteins are expressed in mice at levels equivalent to those found in humans and circulate within high-density lipoproteins. We find that TLF mice can ameliorate an infection with Leishmania by significantly reducing the pathogen burden. In contrast, TLF mice were not protected against infection by the kinetoplastid Trypanosoma cruzi, which infects many cell types and transiently passes through a phagolysosome. We conclude that TLF not only determines species specificity for African trypanosomes, but can also ameliorate an infection with Leishmania, while having no effect on T. cruzi. We propose that TLFs are a component of the innate immune system that can limit infections by their ability to selectively damage pathogens in phagolysosomes within the reticuloendothelial system.

  19. Ghrelin ameliorates the human alveolar epithelial A549 cell apoptosis induced by lipopolysaccharide

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chunrong; Zheng, Haichong; He, Wanmei; Lu, Guifang; Li, Xia [Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080 (China); Deng, Yubin, E-mail: dengyub@mail.sysu.edu.cn [Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080 (China); Zeng, Mian, E-mail: zengmian2004@163.com [Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080 (China)

    2016-05-20

    Ghrelin is a gastric acyl-peptide that plays an inhibitory role in cell apoptosis. Herein we investigate the protective effects of ghrelin in LPS-induced apoptosis of human alveolar epithelial A549 cells, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of A549 cells significantly in concentration- and time-dependent manners embodied in increased Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Simultaneously, LPS remarkably decreased the expression of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinas (ERK) in A549 cells. However, ghrelin'pretreatment ameliorated LPS-caused alterations in the ratio of Bax/Bcl-2 and cleaved caspase-3 expression, whereas activated the PI3K/Akt and ERK signaling. These results demonstrate that ghrelin lightens LPS-induced apoptosis of human alveolar epithelial cells partly through activating the PI3K/Akt and ERK pathway and thereby might benefit alleviating septic ALI. -- Graphical abstract: Ghrelin ameliorates the human alveolar epithelial A549 cells apoptosis induced by lipopolysaccharide partly through activating the PI3K/Akt and ERK pathway. Display Omitted -- Highlights: •It has been observed that LPS insult significantly increased apoptosis in A549 cells. •Both Akt and ERK signaling are critical adapter molecules to mediate the ghrelin-mediated proliferative effect. •Ghrelin may have a therapeutic effect in the prevention of LPS-induced apoptosis.

  20. Biochar from commercially cultivated seaweed for soil amelioration

    Science.gov (United States)

    Roberts, David A.; Paul, Nicholas A.; Dworjanyn, Symon A.; Bird, Michael I.; de Nys, Rocky

    2015-01-01

    Seaweed cultivation is a high growth industry that is primarily targeted at human food and hydrocolloid markets. However, seaweed biomass also offers a feedstock for the production of nutrient-rich biochar for soil amelioration. We provide the first data of biochar yield and characteristics from intensively cultivated seaweeds (Saccharina, Undaria and Sargassum – brown seaweeds, and Gracilaria, Kappaphycus and Eucheuma – red seaweeds). While there is some variability in biochar properties as a function of the origin of seaweed, there are several defining and consistent characteristics of seaweed biochar, in particular a relatively low C content and surface area but high yield, essential trace elements (N, P and K) and exchangeable cations (particularly K). The pH of seaweed biochar ranges from neutral (7) to alkaline (11), allowing for broad-spectrum applications in diverse soil types. We find that seaweed biochar is a unique material for soil amelioration that is consistently different to biochar derived from ligno-cellulosic feedstock. Blending of seaweed and ligno-cellulosic biochar could provide a soil ameliorant that combines a high fixed C content with a mineral-rich substrate to enhance crop productivity. PMID:25856799

  1. Arsenic toxicity in mice and its possible amelioration

    Institute of Scientific and Technical Information of China (English)

    R. J. Verma; Archana Vasu, Abdu; Alim Saiyed

    2004-01-01

    Oral administration of arsenic trioxide(3 and 6 mg/kg body weight/d) for 30 d caused, as compared with vehicle control, dose- dependent significant reductions in body weight, absolute weight, protein, glycogen, as well as, total, dehydro and reduced ascorbic acid contents both in the liver) and kidney of arsenic- treated mice. Succinic dehydrogenase(SDH) and phosphorylase(only in the liver activities were significantly reduced in a dose-dependent manner. Acid phosphatase activity was significantly decreased in the liver of low dose arsenic-treated animals; however, significant rise in its activity was observed in high dose group. As compared with vehicle control, treatment also caused significant dose-dependent reductions in SDH, alkaline phosphatase and acid phosphatase activities in the kidney of mice. Vitamin E cotreatment as well as, 30 d withdrawal of arsenic trioxide treatment with or without vitamin E caused significant amelioration in arsenic-induced toxicity in mice. Administration of vitamin E during withdrawal of treatment also caused significant amelioration as compared from only withdrawal of the treatment. It is concluded that vitamin E ameliorates arsenic-induced toxicities in the liver and kidney of mice.

  2. Sesamin ameliorates doxorubicin-induced cardiotoxicity: involvement of Sirt1 and Mn-SOD pathway.

    Science.gov (United States)

    Su, Suwen; Li, Qian; Liu, Yi; Xiong, Chen; Li, Junxia; Zhang, Rong; Niu, Yujie; Zhao, Lijuan; Wang, Yongli; Guo, Huicai

    2014-01-13

    Oxidative stress caused by doxorubicin (DOX) is believed to be a major underlying molecular mechanism of DOX-induced cardiotoxicity. Sesamin (Ses), an active component extracted from sesame seeds, exhibits antioxidative and anti-inflammatory effects. In the present study, possible protective mechanisms of Ses on DOX-induced cardiotoxicity were investigated in rats and cultured H9C2 cells. We demonstrated that Ses exhibits a significant protective effect on cardiac tissue in animal and cell models of DOX-induced cardiac injury. Moreover, Ses can ameliorate DOX-induced oxidative stress and mitochondrial damage. Further studies suggested that Ses is able to up-regulate the protein expression of Mn-SOD in normal rats and to restore the decreased expression of Mn-SOD in DOX-induced cardiac injury rats. Exposure to Ses or DOX alone slightly increased the protein expression of Sirt1; however, a more remarkable increase in Sirt1 protein level was detected in the Ses+DOX group. Treatment with a pan-sirtuin inhibitor (nicotinamide) or a Sirt1-specific inhibitor (EX-527) partially antagonised the effect of Ses on DOX-induced mitochondrial damage and completely abolished the effect of Ses on Mn-SOD expression. These findings indicate that the protective mechanisms of Ses on DOX-induced cardiotoxicity are involved in the alleviation of oxidative stress injury and Mn-SOD dysfunction, partially via the activation of Sirt1.

  3. Neural correlates underlying naloxone-induced amelioration of sexual behavior deterioration due to an alarm pheromone

    Directory of Open Access Journals (Sweden)

    Tatsuya eKobayashi

    2015-02-01

    Full Text Available Sexual behavior is suppressed by various types of stressors. We previously demonstrated that an alarm pheromone released by stressed male Wistar rats is a stressor to other rats, increases the number of mounts needed for ejaculation, and decreases the hit rate (described as the number of intromissions/sum of the mounts and intromissions. This deterioration in sexual behavior was ameliorated by pretreatment with the opioid receptor antagonist naloxone. However, the neural mechanism underlying this remains to be elucidated. Here, we examined Fos expression in 31 brain regions of pheromone-exposed rats and naloxone-pretreated pheromone-exposed rats 60 min after 10 intromissions. As previously reported, the alarm pheromone increased the number of mounts and decreased the hit rate. In addition, Fos expression was increases in the anterior medial division, anterior lateral division and posterior division of the bed nucleus of the stria terminalis, parvocellular part of the paraventricular nucleus of the hypothalamus, arcuate nucleus, dorsolateral and ventrolateral periaqueductal gray, and nucleus paragigantocellularis. Fos expression decreased in the magnocellular part of the paraventricular nucleus of the hypothalamus. Pretreatment with naloxone blocked the pheromone-induced changes in Fos expression in the magnocellular part of the paraventricular nucleus of the hypothalamus, ventrolateral periaqueductal gray, and nucleus paragigantocellularis. Based on these results, we hypothesize that the alarm pheromone deteriorated sexual behavior by activating the ventrolateral periaqueductal gray-nucleus paragigantocellularis cluster and suppressing the magnocellular part of the paraventricular nucleus of the hypothalamus via the opioidergic pathway.

  4. Tetrandrine Ameliorates Cirrhosis and Portal Hypertension by Inhibiting Nitric Oxide in Cirrhotic Rats

    Institute of Scientific and Technical Information of China (English)

    王海; 陈孝平

    2004-01-01

    To examine the role and effect of nitric oxide synthase type Ⅱ (NOSⅡ) in cirrhotic rats,expression of NOSⅡ mRNA was detected by real time RT-PCR. The enzymatic activity of nitric oxide synthase and the circulating levels of NO, systemic and portal hemodynamics and quantification of cirrhosis were measured. Chinese traditional medicine was used to treat cirrhotic rats and the effect of NO was evaluated. Double-blind method was used in experiment. Our results showed the concentration of NO and the enzymatic activity of NOS increased markedly at all stages of cirrhosis and iNOSmRNA was strongly expressed. Meanwhile, the portal-venous-pressure (PVP) and portal-venous-flow (PVF) were significantly increased. NO, NOS and iNOSmRNA were positively correlated to the degree of hepatic fibrosis. Tetrandrine significantly inhibited NO production and the expression of iNOSmRNA. Our results suggested that increased hepatic expression of NOS Ⅱ is one of the important factors causing cirrhosis and portal hypertension. Tetrandrine can significantly ameliorate cirrhosis and portal hypertension.

  5. BAFF receptor mAb treatment ameliorates development and progression of atherosclerosis in hyperlipidemic ApoE(-/- mice.

    Directory of Open Access Journals (Sweden)

    Tin Kyaw

    Full Text Available AIMS: Option to attenuate atherosclerosis by depleting B2 cells is currently limited to anti-CD20 antibodies which deplete all B-cell subtypes. In the present study we evaluated the capacity of a monoclonal antibody to B cell activating factor-receptor (BAFFR to selectively deplete atherogenic B2 cells to prevent both development and progression of atherosclerosis in the ApoE(-/- mouse. METHODS AND RESULTS: To determine whether the BAFFR antibody prevents atherosclerosis development, we treated ApoE(-/- mice with the antibody while feeding them a high fat diet (HFD for 8 weeks. Mature CD93(- CD19(+ B2 cells were reduced by treatment, spleen B-cell zones disrupted and spleen CD20 mRNA expression decreased while B1a cells and non-B cells were spared. Atherosclerosis was ameliorated in the hyperlipidemic mice and CD19(+ B cells, CD4(+ and CD8(+ T cells were reduced in atherosclerotic lesions. Expressions of proinflammatory cytokines, IL1β, TNFα, and IFNγ in the lesions were also reduced, while MCP1, MIF and VCAM-1 expressions were unaffected. Plasma immunoglobulins were reduced, but MDA-oxLDL specific antibodies were unaffected. To determine whether anti-BAFFR antibody ameliorates progression of atherosclerosis, we first fed ApoE(-/- mice a HFD for 6 weeks, and then instigated anti-BAFFR antibody treatment for a further 6 week-HFD. CD93(- CD19(+ B2 cells were selectively decreased and atherosclerotic lesions were reduced by this treatment. CONCLUSION: Anti-BAFFR monoclonal antibody selectively depletes mature B2 cells while sparing B1a cells, disrupts spleen B-cell zones and ameliorates atherosclerosis development and progression in hyperlipidemic ApoE(-/- mice. Our findings have potential for clinical translation to manage atherosclerosis-based cardiovascular diseases.

  6. The RhoA/ROCK Pathway Ameliorates Adhesion and Inflammatory Infiltration Induced by AGEs in Glomerular Endothelial Cells.

    Science.gov (United States)

    Rao, Jialing; Ye, Zengchun; Tang, Hua; Wang, Cheng; Peng, Hui; Lai, Weiyan; Li, Yin; Huang, Wanbing; Lou, Tanqi

    2017-01-05

    A recent study demonstrated that advanced glycation end products (AGEs) play a role in monocyte infiltration in mesangial areas in diabetic nephropathy. The Ras homolog gene family, member A Rho kinase (RhoA/ROCK) pathway plays a role in regulating cell migration. We hypothesized that the RhoA/ROCK pathway affects adhesion and inflammation in endothelial cells induced by AGEs. Rat glomerular endothelial cells (rGECs) were cultured with AGEs (80 μg/ml) in vitro. The ROCK inhibitor Y27632 (10 nmol/l) and ROCK1-siRNA were used to inhibit ROCK. We investigated levels of the intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein1 (MCP-1) in rGECs. Db/db mice were used as a diabetes model and received Fasudil (10 mg/kg/d, n = 6) via intraperitoneal injection for 12 weeks. We found that AGEs increased the expression of ICAM-1 and MCP-1 in rGECs, and the RhoA/ROCK pathway inhibitor Y27632 depressed the release of adhesion molecules. Moreover, blocking the RhoA/ROCK pathway ameliorated macrophage transfer to the endothelium. Reduced expression of adhesion molecules and amelioration of inflammatory cell infiltration in the glomerulus were observed in db/db mice treated with Fasudil. The RhoA/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in glomerular endothelial cells induced by AGEs.

  7. Ameliorative Effect of Grape Seed Proanthocyanidin Extract on Cadmium-Induced Meiosis Inhibition During Oogenesis in Chicken Embryos.

    Science.gov (United States)

    Hou, Fuyin; Xiao, Min; Li, Jian; Cook, Devin W; Zeng, Weidong; Zhang, Caiqiao; Mi, Yuling

    2016-04-01

    Cadmium (Cd) is an environmental endocrine disruptor that has toxic effects on the female reproductive system. Here the ameliorative effect of grape seed proanthocyanidin extract (GSPE) on Cd-induced meiosis inhibition during oogenesis was explored. As compared with controls, chicken embryos exposed to Cd (3 µg/egg) displayed a changed oocyte morphology, decreased number of meiotic germ cells, and decreased expression of the meiotic marker protein γH2AX. Real time RT-PCR also revealed a significant down-regulation in the mRNA expressions of various meiosis-specific markers (Stra8, Spo11, Scp3, and Dmc1) together with those of Raldh2, a retinoic acid (RA) synthetase, and of the receptors (RARα and RARβ). In addition, exposure to Cd increased the production of H2 O2 and malondialdehyde in the ovaries and caused a corresponding reduction in glutathione and superoxide dismutase. Simultaneous supplementation of GSPE (150 µg/egg) markedly alleviated the aforementioned Cd-induced embryotoxic effects by upregulating meiosis-related proteins and gene expressions and restoring the antioxidative level. Collectively, the findings provided novel insights into the underlying mechanism of Cd-induced meiosis inhibition and indicated that GSPE might potentially ameliorate related reproductive disorders. © 2016 Wiley Periodicals, Inc.

  8. Mesenchymal Stem Cell-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Ameliorate Diabetic Polyneuropathy in Mice

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    Tatsuhito Himeno

    2013-01-01

    Full Text Available Background. Although pathological involvements of diabetic polyneuropathy (DPN have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN. Research Design and Methods. For induction into MSC-like cells, GFP-expressing iPSCs were cultured with retinoic acid, followed by adherent culture for 4 months. The MSC-like cells, characterized with flow cytometry and RT-PCR analyses, were transplanted into muscles of streptozotocin-diabetic mice. Three weeks after the transplantation, neurophysiological functions were evaluated. Results. The MSC-like cells expressed MSC markers and angiogenic/neurotrophic factors. The transplanted cells resided in hindlimb muscles and peripheral nerves, and some transplanted cells expressed S100β in the nerves. Impairments of current perception thresholds, nerve conduction velocities, and plantar skin blood flow in the diabetic mice were ameliorated in limbs with the transplanted cells. The capillary number-to-muscle fiber ratios were increased in transplanted hindlimbs of diabetic mice. Conclusions. These results suggest that MSC-like cell transplantation might have therapeutic effects on DPN through secreting angiogenic/neurotrophic factors and differentiation to Schwann cell-like cells.

  9. Purified Betacyanins from Hylocereus undatus Peel Ameliorate Obesity and Insulin Resistance in High-Fat-Diet-Fed Mice.

    Science.gov (United States)

    Song, Haizhao; Chu, Qiang; Xu, Dongdong; Xu, Yang; Zheng, Xiaodong

    2016-01-13

    Natural bioactive compounds in food have been shown to be beneficial in preventing the development of obesity, diabetes, and other metabolic diseases. Increasing evidence indicates that betacyanins possess free-radical-scavenging and antioxidant activities, suggesting their beneficial effects on metabolic disorders. The main objective of this study was to isolate and identify the betaycanins from Hylocereus undatus (white-fleshed pitaya) peel and evaluate their ability to ameliorate obesity, insulin resistance, and hepatic steatosis in high-fat-diet (HFD)-induced obese mice. The purified pitaya peel betacyanins (PPBNs) were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and the male C57BL/6 mice were fed a low-fat diet, HFD, or HFD supplemented with PPBNs for 14 weeks. Our results showed that the white-fleshed pitaya peel contains 14 kinds of betacyanins and dietary PPBNs reduced HFD-induced body weight gain and ameliorated adipose tissue hypertrophy, hepatosteatosis, glucose intolerance, and insulin resistance. Moreover, the hepatic gene expression analysis indicated that PPBN supplementation increased the expression levels of lipid-metabolism-related genes (AdipoR2, Cpt1a, Cpt1b, Acox1, PPARγ, Insig1, and Insig2) and FGF21-related genes (β-Klotho and FGFR1/2) but decreased the expression level of Fads2, Fas, and FGF21, suggesting that the protective effect of PPBNs might be associated with the induced fatty acid oxidation, decreased fatty acid biosynthesis, and alleviated FGF21 resistance.

  10. Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines

    Directory of Open Access Journals (Sweden)

    Yi Tan

    2015-01-01

    Full Text Available The aim of this study was to determine whether inhibition of resistin by a synthetic antiresistin RNA (oligonucleotide oligo ameliorates metabolic and histological abnormalities in nonalcoholic fatty liver disease (NAFLD induced by high-fat diet (HFD in mice. The antiresistin RNA oligo and a scrambled control oligo (25 mg/kg of body weight were i.p. injected to HFD mice. Serum metabolic parameters and hepatic enzymes were measured after 4-week treatment. The treatment significantly reduced epididymal fat and attenuated the elevated serum resistin, cholesterol, triglycerides, glucose, and insulin with an improved glucose tolerance test. Antiresistin RNA oligo also normalized serum AST and ALT levels with improved pathohistology of NAFLD. Immunoblotting and qRT-PCR revealed that decreased protein and mRNA expression of resistin in fat and liver tissues of the treated mice were associated with reduction of adipose TNF-α and IL-6 expression and secretion into circulation. mRNA and protein expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK and sterol regulatory element-binding protein-1c (SREBP-1c were also significantly decreased in the treated mice. Our results suggest that resistin may exacerbate NAFLD in metabolic syndrome through upregulating inflammatory cytokines and hepatic PEPCK and SREBP-1c. Antiresistin RNA oligo ameliorated metabolic abnormalities and histopathology of NAFLD through attenuating proinflammatory cytokines.

  11. Atorvastatin ameliorates contrast medium-induced renal tubular cell apoptosis in diabetic rats via suppression of Rho-kinase pathway.

    Science.gov (United States)

    Su, Jinzi; Zou, Wenbo; Cai, Wenqin; Chen, Xiuping; Wang, Fangbing; Li, Shuizhu; Ma, Wenwen; Cao, Yangming

    2014-01-15

    Contrast medium-induced acute kidney injury (CI-AKI) remains a leading cause of iatrogenic, drug-induced acute renal failure. This study aimed to investigate the protective effects of atorvastatin against renal tubular cell apoptosis in diabetic rats and the related mechanisms. CI-AKI was induced by intravenous administration of iopromide (12ml/kg) in streptozotocin-induced diabetic rats. Atorvastatin (ATO) was administered intragastrically at the dose of 5, 10 and 30mg/kg/d in different groups, respectively, for 5 days before iopromide injection. Renal function parameters, kidney histology, renal tubular cell apoptosis, the expression of apoptosis regulatory proteins, caspase-3 and Rho-associated protein kinase 1 (ROCK-1), and the phosphorylation of myosin phosphatase target subunit -1 (MYPT-1), were determined. Atorvastatin was shown to notably ameliorate contrast medium induced medullary damage, restore renal function, and suppress renal tubular apoptosis. Meanwhile, atorvastatin up-regulated the expression of Bcl-2, down-regulated the expression of Bax, caspase-3 and ROCK-1, restored the ratio of Bcl-2/Bax, and suppressed the phosphorylation of MYPT-1 in a dose-dependent manner. Thus, atorvastatin pretreatment could dose-dependently ameliorate the development of CI-AKI, which was partly attributed to its suppression of renal tubular cell apoptosis by inhibiting the Rho/ROCK pathway.

  12. Linker molecules between laminins and dystroglycan ameliorate laminin-alpha2-deficient muscular dystrophy at all disease stages.

    Science.gov (United States)

    Meinen, Sarina; Barzaghi, Patrizia; Lin, Shuo; Lochmüller, Hanns; Ruegg, Markus A

    2007-03-26

    Mutations in laminin-alpha2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-alpha2 are dystroglycan and alpha7beta1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to alpha7beta1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302-307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326-332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy.

  13. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders.

    Science.gov (United States)

    Chen, Zhimin; Wang, Guo-Xiao; Ma, Sara L; Jung, Dae Young; Ha, Hyekyung; Altamimi, Tariq; Zhao, Xu-Yun; Guo, Liang; Zhang, Peng; Hu, Chun-Rui; Cheng, Ji-Xin; Lopaschuk, Gary D; Kim, Jason K; Lin, Jiandie D

    2017-08-01

    Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and iii) to explore whether Nrg4 regulates adipose tissue secretome gene expression and adipokine secretion. We examined the correlation of adipose Nrg4 expression with obesity in a cohort of diet-induced obese mice and investigated the upstream signals that regulate Nrg4 expression. We performed metabolic cage and hyperinsulinemic-euglycemic clamp studies in Nrg4 transgenic mice to dissect the metabolic pathways regulated by Nrg4. We investigated how Nrg4 regulates hepatic lipid metabolism in the fasting state and explored the effects of Nrg4 on adipose tissue gene expression, particularly those encoding secreted factors. Adipose Nrg4 expression is inversely correlated with adiposity and regulated by pro-inflammatory and anti-inflammatory signaling. Transgenic expression of Nrg4 increases energy expenditure and augments whole body glucose metabolism. Nrg4 protects mice from diet-induced hepatic steatosis in part through activation of hepatic fatty acid oxidation and ketogenesis. Finally, Nrg4 promotes a healthy adipokine profile during obesity. Nrg4 exerts pleiotropic beneficial effects on energy balance and glucose and lipid metabolism to ameliorate obesity-associated metabolic disorders. Biologic therapeutics based on Nrg4 may improve both type 2

  14. Kinetic mRNA Profiling in a Rat Model of Left-Ventricular Hypertrophy Reveals Early Expression of Chemokines and Their Receptors

    Science.gov (United States)

    Nemska, Simona; Monassier, Laurent; Gassmann, Max; Frossard, Nelly; Tavakoli, Reza

    2016-01-01

    Left-ventricular hypertrophy (LVH), a risk factor for heart failure and death, is characterized by cardiomyocyte hypertrophy, interstitial cell proliferation, and leukocyte infiltration. Chemokines interacting with G protein-coupled chemokine receptors may play a role in LVH development by promoting recruitment of activated leukocytes or modulating left-ventricular remodeling. Using a pressure overload-induced kinetic model of LVH in rats, we examined during 14 days the expression over time of chemokine and chemokine receptor mRNAs in left ventricles from aortic-banded vs sham-operated animals. Two phases were clearly distinguished: an inflammatory phase (D3-D5) with overexpression of inflammatory genes such as il-1ß, tnfa, nlrp3, and the rela subunit of nf-kb, and a hypertrophic phase (D7-D14) where anp overexpression was accompanied by a heart weight/body weight ratio that increased by more than 20% at D14. No cardiac dysfunction was detectable by echocardiography at the latter time point. Of the 36 chemokines and 20 chemokine receptors analyzed by a Taqman Low Density Array panel, we identified at D3 (the early inflammatory phase) overexpression of mRNAs for the monocyte chemotactic proteins CCL2 (12-fold increase), CCL7 (7-fold increase), and CCL12 (3-fold increase), for the macrophage inflammatory proteins CCL3 (4-fold increase), CCL4 (2-fold increase), and CCL9 (2-fold increase), for their receptors CCR2 (4-fold increase), CCR1 (3-fold increase), and CCR5 (3-fold increase), and for CXCL1 (8-fold increase) and CXCL16 (2-fold increase). During the hypertrophic phase mRNA expression of chemokines and receptors returned to the baseline levels observed at D0. Hence, this first exhaustive study of chemokine and chemokine receptor mRNA expression kinetics reports early expression of monocyte/macrophage-related chemokines and their receptors during the development of LVH in rats, followed by regulation of inflammation as LVH progresses. PMID:27525724

  15. Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling

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    Craigon Marie

    2009-08-01

    Full Text Available Abstract Background Interferons (IFNs are potent antiviral cytokines capable of reprogramming the macrophage phenotype through the induction of interferon-stimulated genes (ISGs. Here we have used targeted RNA interference to suppress the expression of a number of key genes associated with IFN signalling in murine macrophages prior to stimulation with interferon-gamma. Genome-wide changes in transcript abundance caused by siRNA activity were measured using exon-level microarrays in the presence or absence of IFNγ. Results Transfection of murine bone-marrow derived macrophages (BMDMs with a non-targeting (control siRNA and 11 sequence-specific siRNAs was performed using a cationic lipid transfection reagent (Lipofectamine2000 prior to stimulation with IFNγ. Total RNA was harvested from cells and gene expression measured on Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. Network-based analysis of these data revealed six siRNAs to cause a marked shift in the macrophage transcriptome in the presence or absence IFNγ. These six siRNAs targeted the Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2 transcripts. The perturbation of the transcriptome by the six siRNAs was highly similar in each case and affected the expression of over 600 downstream transcripts. Regulated transcripts were clustered based on co-expression into five major groups corresponding to transcriptional networks associated with the type I and II IFN response, cell cycle regulation, and NF-KB signalling. In addition we have observed a significant non-specific immune stimulation of cells transfected with siRNA using Lipofectamine2000, suggesting use of this reagent in BMDMs, even at low concentrations, is enough to induce a type I IFN response. Conclusion Our results provide evidence that the type I IFN response in murine BMDMs is dependent on Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2, and that siRNAs targeted to these genes results in perturbation of key transcriptional networks associated

  16. Vitamin D Can Ameliorate Chlorhexidine Gluconate-Induced Peritoneal Fibrosis and Functional Deterioration through the Inhibition of Epithelial-to-Mesenchymal Transition of Mesothelial Cells

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    Yi-Che Lee

    2015-01-01

    Full Text Available Background. Peritoneal dialysis (PD can induce fibrosis and functional alterations in PD patients’ peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT in peritoneal mesothelial cells (MCs. Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. Methods. Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG intraperitoneal injection for 21 days, with and without 1α,25(OH2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-β1 (TGF-β1 in the absence or presence of 1α,25(OH2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. Results. 1α,25(OH2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of α-SMA and downregulation of E-cadherin expression. Meanwhile, 1α,25(OH2D3 also ameliorated TGF-β1-induced decrease in E-cadherin expression, increase in Snai1 and α-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. Conclusion. 1α,25(OH2D3 can ameliorate CG-induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT.

  17. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  18. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model.

    Science.gov (United States)

    Shim, Sehwan; Jang, Hyo-Sun; Myung, Hyun-Wook; Myung, Jae Kyung; Kang, Jin-Kyu; Kim, Min-Jung; Lee, Seung Bum; Jang, Won-Suk; Lee, Sun-Joo; Jin, Young-Woo; Lee, Seung-Sook; Park, Sunhoo

    2017-08-15

    Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Palatable cafeteria diet ameliorates anxiety and depression-like symptoms following an adverse early environment.

    Science.gov (United States)

    Maniam, Jayanthi; Morris, Margaret J

    2010-06-01

    Early trauma contributes to psychosocial disorders later in life. An adverse early environment induced by maternal separation (MS) is known to alter behavioural and stress responses in rats. Palatable food dampens stress responses. We investigated the influence of palatable cafeteria high-fat diet (HFD) on behavioural responses following MS or non-handling (NH), versus 15min brief separation. After littering, Sprague-Dawley rats were exposed to short separation, S15 (15min), prolonged separation, S180 (180min) daily from postnatal days 2 to 14 or were non-handled. Pups were assigned to HFD or chow at weaning. We assessed depression and anxiety-like behaviour with sucrose preference test (SPT) and elevated plus maze (EPM) respectively, and measured hypothalamic CRH and hippocampal glucocorticoid receptor (GR) expression. S180 rats showed increased anxiety-and depression-like behaviours, with increased plasma corticosterone, hypothalamic CRH, and reduced hippocampal GR expression versus S15 rats. Similar effects were observed across gender. These were normalized by provision of HFD, with greater beneficial effects in males. S15 showed no benefit of HFD. NH female rats had less adverse impacts; HFD had beneficial impact on behaviour in NH males. Thus behavioural deficits and gene expression changes induced by early life stress were ameliorated by HFD. These results highlight the important place of palatable food in reducing central stress responses supporting the therapeutic value of 'comfort food'.

  20. Blockade of PLD2 Ameliorates Intestinal Mucosal Inflammation of Inflammatory Bowel Disease

    Science.gov (United States)

    Zhou, Guangxi; Yu, Lin; Yang, Wenjing; Wu, Wei; Fang, Leilei

    2016-01-01

    Background. Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronically remittent and progressive inflammatory disorders. Phospholipase D2 (PLD2) is reported to be involved in the pathogenesis of several inflammatory diseases. However, the exact role of PLD2 in IBD is obscure. Methods. PLD2 expression was determined in peripheral blood cells and inflamed mucosa from patients with IBD by qRT-PCR. Colonic biopsies were also obtained from CD patients before and after infliximab (IFX) treatment to examine PLD2 expression. PLD2 selective inhibitor (CAY10594) was administrated daily by oral gavage in DSS-induced colitis mice. Bone marrow neutrophils from colitis mice were harvested to examine the migration using Transwell plate. Results. PLD2 was found to be significantly increased in peripheral blood cells and inflamed mucosa in patients with active IBD. Treatment with IFX could significantly decrease PLD2 expression in intestinal mucosa in patients with CD. Moreover, blockade of PLD2 with CAY10594 could markedly ameliorate DSS-induced colitis in mice and promote neutrophil migration. Conclusions. PLD2 plays a critical role in the pathogenesis of IBD. Blockade of PLD2 may serve as a new therapeutic approach for treatment of IBD. PMID:27721573

  1. Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats

    Science.gov (United States)

    Baek, Seung-Soo; Kim, Sang-Hoon

    2016-01-01

    Alzheimer disease (AD) is a most common form of dementia and eventually causes impairments of learning ability and memory function. In the present study, we investigated the effects of treadmill exercise on the symptoms of AD focusing on the microglial activation-induced apoptosis. AD was made by bilateral intracerebroventricular injection of streptozotocin. The rats in the exercise groups were made to run on a treadmill once a day for 30 min during 4 weeks. The distance and latency in the Morris water maze task and the latency in the step-down avoidance task were increased in the AD rats, in contrast, treadmill exercise shortened these parameters. The numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive and caspase-3-positive cells in the hippocampal dentate gyrus were decreased in the AD rats, in contrast, treadmill exercise suppressed these numbers. Expressions of glial fibrillary acidic protein (GFAP) and cluster of differentiation molecule 11B (CD11b) in the hippocampal dentate gyrus were increased in the AD rats, in contrast, treadmill exercise suppressed GFAP and CD11b expressions. Bax expression was increased and Bcl-2 expression was decreased in the hippocampus of AD rats, in contrast, treadmill exercise decreased Bax expression and increased Bcl-2 expression. The present results demonstrated that treadmill exercise ameliorated AD-induced impairments of spatial learning ability and short-term memory through suppressing apoptosis. The antiapoptotic effect of treadmill exercise might be ascribed to the inhibitory effect of treadmill exercise on microglial activation. PMID:28119873

  2. Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats.

    Science.gov (United States)

    Baek, Seung-Soo; Kim, Sang-Hoon

    2016-12-01

    Alzheimer disease (AD) is a most common form of dementia and eventually causes impairments of learning ability and memory function. In the present study, we investigated the effects of treadmill exercise on the symptoms of AD focusing on the microglial activation-induced apoptosis. AD was made by bilateral intracerebroventricular injection of streptozotocin. The rats in the exercise groups were made to run on a treadmill once a day for 30 min during 4 weeks. The distance and latency in the Morris water maze task and the latency in the step-down avoidance task were increased in the AD rats, in contrast, treadmill exercise shortened these parameters. The numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive and caspase-3-positive cells in the hippocampal dentate gyrus were decreased in the AD rats, in contrast, treadmill exercise suppressed these numbers. Expressions of glial fibrillary acidic protein (GFAP) and cluster of differentiation molecule 11B (CD11b) in the hippocampal dentate gyrus were increased in the AD rats, in contrast, treadmill exercise suppressed GFAP and CD11b expressions. Bax expression was increased and Bcl-2 expression was decreased in the hippocampus of AD rats, in contrast, treadmill exercise decreased Bax expression and increased Bcl-2 expression. The present results demonstrated that treadmill exercise ameliorated AD-induced impairments of spatial learning ability and short-term memory through suppressing apoptosis. The antiapoptotic effect of treadmill exercise might be ascribed to the inhibitory effect of treadmill exercise on microglial activation.

  3. Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways.

    Science.gov (United States)

    Lian, Jiamei; Huang, Xu-Feng; Pai, Nagesh; Deng, Chao

    2014-10-01

    Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.

  4. Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates contractile dysfunction of pressure-overloaded heart in mice.

    Science.gov (United States)

    Ogata, Tsuyoshi; Ito, Kenta; Shindo, Tomohiko; Hatanaka, Kazuaki; Eguchi, Kumiko; Kurosawa, Ryo; Kagaya, Yuta; Monma, Yuto; Ichijo, Sadamitsu; Taki, Hirofumi; Kanai, Hiroshi; Shimokawa, Hiroaki

    2017-01-01

    Chronic left ventricular (LV) pressure overload causes relative ischemia with resultant LV dysfunction. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS) improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we thus examined whether LIPUS also ameliorates contractile dysfunction in LV pressure-overloaded hearts. Chronic LV pressure overload was induced with transverse aortic constriction (TAC) in mice. LIPUS was applied to the whole heart three times in the first week after TAC and was repeated once a week for 7 weeks thereafter (n = 22). Animals in the control groups received the sham treatment without LIPUS (n = 23). At 8 weeks after TAC, LV fractional shortening was depressed in the TAC-Control group, which was significantly ameliorated in the TAC-LIPUS group (30.4±0.5 vs. 36.2±3.8%, P<0.05). Capillary density was higher and perivascular fibrosis was less in the LV in the TAC-LIPUS group than in the TAC-Control group. Myocardial relative ischemia evaluated with hypoxyprobe was noted in the TAC-Control group, which was significantly attenuated in the TAC-LIPUS group. In the TAC-LIPUS group, as compared with the control group, mRNA expressions of BNP and collagen III were significantly lower (both P<0.05) and protein expressions of VEGF and eNOS were significantly up-regulated associated with Akt activation (all P<0.05). No adverse effect related to the LIPUS therapy was noted. These results indicate that the LIPUS therapy ameliorates contractile dysfunction in chronically pressure-overloaded hearts through enhanced myocardial angiogenesis and attenuated perivascular fibrosis. Thus, the LIPUS therapy may be a promising, non-invasive treatment for cardiac dysfunction due to chronic pressure overload.

  5. Pu-erh Tea Extract Ameliorates Ovariectomy-Induced Osteoporosis in Rats and Suppresses Osteoclastogenesis In Vitro

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    Titi Liu

    2017-05-01

    Full Text Available Background and Objective: Tea drinking is associated with positive effects on bone health and may protect against osteoporosis, especially in elderly women. Pu-erh tea has many beneficial effects on human health; however, whether Pu-erh tea has anti-osteoporotic potential remains unclear. Thus, we investigated the effects of Pu-erh tea extract (PTE on ovariectomy-induced osteoporosis in rats and on osteoclastogenesis in vitro.Methods: Female Wistar rats were divided into six groups: the sham, model, and Xian-Ling-Gu-Bao capsule (XLGB groups, and the low-, medium-, and high-dose PTE groups. Ovariectomized (OVX rats were used as an animal model of osteoporosis. The animals were intragastrically administered distilled water, XLGB, or different concentrations of PTE for 13 weeks. Body weight, blood biochemical indicators, relative organ coefficients, femoral bone mineral density (BMD, bone biomechanical properties, and bone microarchitecture were examined and analyzed. Additionally, the in vitro effects of PTE on osteoclastic activities were investigated using the RAW 264.7 cell line as an osteoclast differentiation model. The effects of PTE on osteoclast differentiation and the expression of osteoclast-specific genes and proteins were determined.Results: PTE reduced OVX-induced body weight gain after 6 weeks of treatment, and the high-dose exerted a significant effect. High-dose PTE significantly ameliorated OVX-induced estradiol (E2 deficiency. PTE treatment maintained calcium and phosphorus homeostasis and improved other blood biochemical parameters to various degrees. In addition, PTE treatment improved organ coefficients of the femur, uterus, and vagina and improved femoral BMD and bone biomechanical properties. PTE treatment strikingly ameliorated bone microarchitecture. Moreover, in the in vitro studies, osteoclast differentiation using the differentiation cell model was significantly inhibited by PTE without cytotoxic effects. Additionally

  6. Resveratrol ameliorates hyperglycemia-induced renal tubular oxidative stress damage via modulating the SIRT1/FOXO3a pathway.

    Science.gov (United States)

    Wang, Xueling; Meng, Linghang; Zhao, Long; Wang, Zengfu; Liu, Haiying; Liu, Gang; Guan, Guangju

    2017-04-01

    Oxidative stress plays an important role in the development and progression of diabetic nephropathy (DN). We aimed to investigate if resveratrol (RSV) could ameliorate hyperglycemia-induced oxidative stress in renal tubules via modulating the SIRT1/FOXO3a pathway. The effects of RSV on diabetes rats were assessed by periodic acid-Schiff, Masson staining, immunohistochemistry, and western blot analyses. Additionally, oxidative indicators (such as catalase, superoxide dismutase, reactive oxygen species, and malondialdehyde), the deacetylase activity of SIRT1 and protein expressions of SIRT1, FOXO3a, and acetylated-FOXO3a were measured. These indicators were similarly evaluated in an in vitro study. Furthermore, the silencing of SIRT1 was used to confirm its role in the resistance to oxidative stress and the relationship between SIRT1 and FOXO3a in vitro. After 16weeks of RSV treatment, the renal function and glomerulosclerosis of rats with DN was dramatically ameliorated. RSV treatment increased SIRT1 deacetylase activity, subsequently decreasing the expression of acetylated-FOXO3a and inhibiting the oxidative stress caused by hyperglycemia both in vivo and in vitro. The silencing of SIRT1 in HK-2 cells aggravated the high glucose-induced oxidative stress and overexpression of acetylated-FOXO3a; RSV treatment failed to protect against these effects. RSV modulates the SIRT1/FOXO3a pathway by increasing SIRT1 deacetylase activity, subsequently ameliorating hyperglycemia-induced renal tubular oxidative stress damage. This mechanism provides the basis for a new approach to developing an effective DN treatment, which is of great clinical significance for reducing the morbidity and mortality associated with DN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP act by a mechanism distinct from that of IVIg.

    Science.gov (United States)

    Song, Seng; Crow, Andrew R; Siragam, Vinayakumar; Freedman, John; Lazarus, Alan H

    2005-02-15

    The mechanism of action of intravenous immunoglobulin (IVIg) and polyclonal anti-D-mediated reversal of immune thrombocytopenia (ITP) is still unclear. However, in a murine model of ITP, the therapeutic effect of IVIg appears to be wholly dependent upon the expression of the inhibitory Fc receptor, Fc gamma RIIB. We previously demonstrated that, similar to anti-D in humans, 2 erythrocyte-reactive monoclonal antibodies (TER119 and M1/69) ameliorated murine ITP and inhibited reticuloendothelial system (RES) function at doses that protected against thrombocytopenia. The current study evaluated the involvement of the inhibitory and activating Fc receptors, Fc gamma RIIB and Fc gamma RIIIA, respectively, in the TER119 and M1/69-mediated inhibition of thrombocytopenia. In contrast to IVIg, in Fc gamma RIIB-deficient mice, both monoclonal antibodies ameliorated ITP and both significantly down-regulated the level of expression of the activating Fc gamma RIIIA in splenic macrophages. These results indicate that anti-erythrocyte antibodies that ameliorate ITP act independently of Fc gamma RIIB expression but are dependent upon the activating Fc gamma RIIIA.

  8. Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion.

    Science.gov (United States)

    Tsubouchi, Hironobu; Yanagi, Shigehisa; Miura, Ayako; Mogami, Sachiko; Yamada, Chihiro; Iizuka, Seiichi; Hattori, Tomohisa; Nakazato, Masamitsu

    2014-10-01

    Cachexia is a frequent complication in patients with respiratory failure, such as lung fibrosis, and it is a determining factor for functional capacity, health status, and mortality. Reductions in body weight and skeletal muscle mass are key features of cachexia that are resistant to current therapies. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment for patients with gastrointestinal symptoms and known to stimulate ghrelin secretion. By using bleomycin (BLM)-induced lung fibrosis mice in this study, we tested our hypothesis that RKT administration could ameliorate pulmonary cachexia. After BLM administration, mice were provided with either RKT or distilled water on a daily basis. Compared with the BLM-injected mice, the RKT-treated mice had smaller reductions of food intake and body weight. Skeletal muscle weights were retained in the RKT-treated mice, in conjunction with reduced expressions of MuRF-1 and atrogin-1 in the lysates of skeletal muscle found in lung fibrosis. Rikkunshito administration restored the plasma concentrations of ghrelin in BLM-injected mice. The anticachectic efficacies of RKT administration in BLM-injected mice were canceled by the concurrent treatment of a ghrelin receptor antagonist. Rikkunshito administration did not decrease the degree of loss of body weight or food intake reduction in either ghrelin-deficient mice or growth hormone secretagogue receptor-deficient mice. Our results indicate that RKT administration exerts protective effects on pulmonary cachexia by ameliorating skeletal muscle wasting and food intake reduction as mediated by the ghrelin system and, thus, highlight RKT as a potential therapeutic agent for the management of lung fibrosis.

  9. Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice

    Science.gov (United States)

    Xu, Guoshun; Wu, Hongying; Zhang, Junling; Li, Deguan; Wang, Yueying; Wang, Yingying; Zhang, Heng; Lu, Lu; Li, Chengcheng; Huang, Song; Xing, Yonghua; Zhou, Daohong; Meng, Aimin

    2016-01-01

    Exposure to ionizing radiation (IR) increases the production of reactive oxygen species (ROS) not only by the radiolysis of water but also through IR-induced perturbation of the cellular metabolism and disturbance of the balance of reduction/oxidation reactions. Our recent studies showed that the increased production of intracellular ROS induced by IR contributes to IR-induced late effects, particularly in the hematopoietic system, because inhibition of ROS production with an antioxidant after IR exposure can mitigate IR-induced long-term bone marrow (BM) injury. Metformin is a widely used drug for the treatment of type 2 diabetes. Metformin also has the ability to regulate cellular metabolism and ROS production by activating AMP-activated protein kinase. Therefore, we examined whether metformin can ameliorate IR-induced long-term BM injury in a total-body irradiation (TBI) mouse model. Our results showed that the administration of metformin significantly attenuated TBI-induced increases in ROS production and DNA damage and upregulation of NADPH oxidase 4 expression in BM hematopoietic stem cells (HSCs). These changes were associated with a significant increase in BM HSC frequency, a considerable improvement in in vitro and in vivo HSC function, and complete inhibition of upregulation of p16Ink4a in HSCs after TBI. These findings demonstrate that metformin can attenuate TBI-induced long-term BM injury at least in part by inhibiting the induction of chronic oxidative stress in HSCs and HSC senescence. Therefore, metformin has the potential to be used as a novel radioprotectant to ameliorate TBI-induced long-term BM injury. PMID:26086617

  10. Reducing Timp3 or Vitronectin Ameliorates Disease Manifestations in CADASIL Mice

    Science.gov (United States)

    Capone, Carmen; Cognat, Emmanuel; Ghezali, Lamia; Baron-Menguy, Céline; Aubin, Déborah; Mesnard, Laurent; Stöhr, Heidi; Domenga-Denier, Valérie; Nelson, Mark T.; Joutel, Anne

    2017-01-01

    Objective CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3ECD) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3ECD-containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes. Methods Timp3 and vitronectin expression were genetically reduced in TgNotch3R169C mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3ECD deposition, were evaluated between 6 and 20 months of age. Results CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3R169C and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3R169C mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3R169C mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3ECD deposition in brain vessels. Interpretation Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3ECD deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions. PMID:26648042

  11. Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats.

    Science.gov (United States)

    Fu, Wan; Xie, Heng; Laudon, Moshe; Zhou, Shouhong; Tian, Shaowen; You, Yong

    2016-06-01

    Previous studies have demonstrated that piromelatine (a melatonin and serotonin 5-HT1A and 5-HT1D agonist) exerts an antidepressant activity in rodent models of acute stress and improves cognitive impairments in a rat model of Alzheimer's disease (AD). However, the role of piromelatine in chronic stress-induced memory dysfunction remains unclear. The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. Rats were exposed randomly to chronic mild stressors for 7 weeks to induce anhedonia (reflected by a significant decrease in sucrose intake), which was used to select rats vulnerable (CMS-anhedonic, CMSA) or resistant (CMS-resistant, CMSR) to stress. Piromelatine (50 mg/kg) was administered daily during the last 2 weeks of CMS. The tail suspension and forced swimming tests were adopted to further characterize vulnerable and resilient rats. The Y-maze and novel object recognition (NOR) tests were used to evaluate memory performance. Brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB), and cytogenesis were measured in the hippocampus. We found that only CMSA rats displayed significant increases in immobility time in the tail suspension and forced swimming tests; memory deficits in the Y-maze and NOR tests; significant decreases in hippocampal BDNF, CREB, and pCREB expression; and cytogenesis. All these anhedonia-associated effects were reversed by piromelatine. Piromelatine ameliorates memory deficits associated with CMS-induced anhedonia in rats and this effect may be mediated by restoring hippocampal BDNF, CREB, and cytogenesis deficits.

  12. A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.

    Directory of Open Access Journals (Sweden)

    Takako Niikura

    Full Text Available Humanin (HN, a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD-related cytotoxicities, including exposure to amyloid beta (Abeta, in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe, tau(P310L, and PS-1(M146V that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

  13. Combination of telmisartan with sildenafil ameliorate progression of diabetic nephropathy in streptozotocin-induced diabetic model.

    Science.gov (United States)

    El-Mahdy, Nageh Ahmed; El-Sayad, Magda El-Sayed; El-Kadem, Aya Hassan

    2016-07-01

    Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the world. Several signaling pathways are involved in the pathogenesis of DN including elevation in level of angiotensin II, formation of advanced glycation end products (AGE), activation of protein kinase c (PKC), and lipid accumulation. These pathways activate one another mutually leading to oxidative stress, increasing expression of transforming growth factor beta-1(TGF-β 1) and release of interleukins and adhesion molecules, so the aim of this study is to interrupt more than pathogenic pathway to ameliorate the progression of DN. In the present study, white male rats (N=48) were divided into six groups (8 rats each), the first two groups served as normal control and a control vehicle group while the remaining four groups were rendered diabetic by a single intraperitoneal injection of Streptozotocin (STZ) and being left for 4 weeks to develop DN. Thereafter, the rats were divided into DN group, DN group receiving Telmisartan or Sildenafil or Telmisartan Sildenafil combination. After the specified treatment period, urine samples were collected (using metabolic cages) to measure proteinuria, animals were then euthanized, blood and tissue samples were collected for measurement of Blood glucose,BUN, S.Cr, LDL, NO, TGF-β1, IL-1β, AGEPs, and SOD. The combination therapy showed significant decrease in BUN, S.Cr,LDL, TGF-β1, IL-1β, Proteinuria and AGEPs and significant increase in SOD and NO. The findings showed that combination therapy was able to ameliorate DN and that the effects were superior to the single drugs alone.

  14. Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model

    Science.gov (United States)

    Jiang, Chun-Bin; Cheng, Mei-Lien; Liu, Chia-Yuan; Chang, Szu-Wen; Chiang Chiau, Jen-Shiu; Lee, Hung-Chang

    2015-01-01

    Background and Aims Intestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model. Methods Seventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orally administrated daily saline, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi). Diarrhea score, pro-inflammatory cytokines serum levels, intestinal villus height and crypt depth and total RNA from tissue were assessed. Samples of blood, liver and spleen tissues were assessed for translocation. Results Marked diarrhea developed in the 5-FU groups but was attenuated after oral Lcr35 and LaBi administrations. Diarrhea scores decreased significantly from 2.64 to 1.45 and 0.80, respectively (Pprobiotics administration. We also found TNF-α, IL-1β and IL-6 mRNA expressions were up-regulated in intestinal mucositis tissues following 5-FU treatment (TNF-α: 4.35 vs. 1.18, IL-1β: 2.29 vs. 1.07, IL-6: 1.49 vs. 1.02) and that probiotics treatment suppressed this up-regulation (Pprobiotics Lcr35 and LaBi can ameliorate chemotherapy-induced intestinal mucositis in a mouse model. This suggests probiotics may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in the future. PMID:26406888

  15. Landscape Planning of Forest Amelioration on Irrigated Soils

    Directory of Open Access Journals (Sweden)

    Ruleva Olga Vasilyevna

    2015-09-01

    Full Text Available The authors study the landscape program which supposes the formation of land use system aimed at connection of protective shelterbelts to geo-morphological watershed elements, relief, unsimilarity of agricultural territories, adapted to the dynamically balanced state of substance and energy within a landscape. Such approach favors the development of agricultural lands estimation system by means of forest amelioration. It happens due to transformation (reorganization of qualitative and quantitative characteristics of energy mass transfer. Consequently, the radiation, heat, soil, hydrophysical and hydrodynamical processes change as well. So, the area adjoining the protective forest belt is the area of determined processes, while further from the forest belt the space is open for changes of all the characteristics. While estimating lands geoecology, the agroforest landscape was considered as a modification of agricultural landscape forming and functioning under the influence of protective shelterbelts. The landscape unsimilarity of the territory should be taken into account during the optimum organization of irrigated farming. It was made by means of desiphering space photos. According to bioclimatical zonal indications, the dry steppe and desert steppe agrolandscape types have been determined. The irrigated soils of the Volgograd region are located mainly in dry steppe agroforest landscapes on dark-chestnut and chestnut soils within natural ameliorative areas of Privolzhskaya and Ergeninskaya Hills and partly in Zavolzhskaya river delta plain; in semi-desert agroforest landscapes on light-chestnut soils within Zavolzhskaya river delta plain and Sarpinskaya lowlands. The favourable hydrogeological ameliorative situation on the territory of southern Privolzhskaya Hill gives the opportunity to revive the irrigation in the Volgograd region and therefore to increase the productivity and sustainability of agricultural production on a higher scientific

  16. A note on inventory model for ameliorating items with time dependent second order demand rate

    Directory of Open Access Journals (Sweden)

    Gobinda Chandra Panda

    2013-03-01

    Full Text Available Background: This paper is concerned with the development of ameliorating inventory models. The ameliorating inventory is the inventory of goods whose utility increases over the time by ameliorating activation. Material and Methods: This study is performed according to two areas: one is an economic order quantity (EOQ model for the items whose utility is ameliorating in accordance with Weibull distribution, and the other is a partial selling quantity (PSQ model developed for selling the surplus inventory accumulated by ameliorating activation with linear demand. The aim of this paper was to develop a mathematical model for inventory type concerned in the paper. Numerical examples were presented show the effect of ameliorating rate on inventory polices.  Results and Conclusions:  The inventory model for items with Weibull ameliorating is developed. For the case of small ameliorating rate (less than linear demand rate, EOQ model is developed, and for the case where ameliorating rate is greater than linear demand rate, PSQ model is developed.  .  

  17. Biochar Ameliorate Drought and Salt Stress in Plants

    DEFF Research Database (Denmark)

    Saleem Akhtar, Saqib

    objectives of the present PhD project were to reveal the mechanisms by which biochar addition mitigates negative effect of drought and salinity stress on plants and to test the efficacy of biochar when applied in combination with already existing drought (like DI and PRD) and salt management (inoculation...... integrated drought (i.e., DI and PRD) and salt (i.e., inoculating plant with PGPB) management approaches. It is concluded that incorporation of biochar could be successfully used to ameliorate drought and salt stress in plants. However, further research is warranted under drought prone and salt affected...

  18. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation.

    Science.gov (United States)

    Jhun, JooYeon; Kwon, Jeong-Eun; Kim, Se-Young; Jeong, Jeong-Hee; Na, Hyun Sik; Kim, Eun-Kyung; Lee, Seung Hoon; Jung, KyungAh; Min, Jun-Ki; Cho, Mi-La

    2017-01-01

    The oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases.

  19. Biochar Ameliorate Drought and Salt Stress in Plants

    DEFF Research Database (Denmark)

    Saleem Akhtar, Saqib

    objectives of the present PhD project were to reveal the mechanisms by which biochar addition mitigates negative effect of drought and salinity stress on plants and to test the efficacy of biochar when applied in combination with already existing drought (like DI and PRD) and salt management (inoculation...... integrated drought (i.e., DI and PRD) and salt (i.e., inoculating plant with PGPB) management approaches. It is concluded that incorporation of biochar could be successfully used to ameliorate drought and salt stress in plants. However, further research is warranted under drought prone and salt affected...

  20. Heregulin ameliorates the dystrophic phenotype in mdx mice

    DEFF Research Database (Denmark)

    Krag, Thomas O B; Bogdanovich, Sasha; Jensen, Claus J

    2004-01-01

    Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin is a chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with dystrophin. Utrophin's ability to compensate for dystrophin during development and when...... ectodomain for 3 months in vivo resulted in up-regulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction mediated damage, and a reduction of muscle pathology. The amelioration of dystrophic phenotype by heregulin-mediated utrophin...

  1. Ameliorative effect of zinc oxide and silver nanoparticles on antioxidant system in the brain of diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Mohamed Afifi; Aaser Mohamed Abdelazim

    2015-01-01

    Objective:To test the ability of both zinc oxide nanoparticles (ZnONPs) and silver nanoparticles (SNPs) to ameliorate the oxidative stress resulted from diabetes in diabetic rats. Methods: Fifty male albino rats were used; ten of them were served as control group and forty, as the experiment group, were injected with streptozotocin at the single intraperitoneal dose of 100 mg/kg. Then, the experiment group was subdivided into, diabetic, diabetic +ZnONPs, diabetic +SNPs and diabetic + insulin groups. The activities and mRNA expression levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase were determined in brain tissues. Malondialdehyde, total antioxidant capacity, zinc and silver concentrations were estimated in the brain tissues of all rats. Results:A significant increase in the activities and mRNA expression levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase was shown. Malondialdehyde levels were significantly decreased while there was a significant increase in the zinc, silver concentrations and total antioxidant capacity in brain ofZnONPs andSNPs treated rats, compared with diabetic or diabetic + insulin group and their control group. Conclusions:ZnONPs andSNPs can be used to ameliorate the oxidative stress in brain resulted from diabetes mellitus.

  2. Ameliorative effect of zinc oxide and silver nanoparticles on antioxidant system in the brain of diabetic rats简

    Institute of Scientific and Technical Information of China (English)

    Mohamed; Afifi; Aaser; Mohamed; Abdelazim

    2015-01-01

    Objective: To test the ability of both zinc oxide nanoparticles(Zn ONPs) and silver nanoparticles(SNPs) to ameliorate the oxidative stress resulted from diabetes in diabetic rats.Methods: Fifty male albino rats were used; ten of them were served as control group and forty, as the experiment group, were injected with streptozotocin at the single intraperitoneal dose of 100 mg/kg. Then, the experiment group was subdivided into, diabetic,diabetic + Zn ONPs, diabetic + SNPs and diabetic + insulin groups. The activities and m RNA expression levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase were determined in brain tissues. Malondialdehyde, total antioxidant capacity, zinc and silver concentrations were estimated in the brain tissues of all rats.Results: A significant increase in the activities and m RNA expression levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase was shown.Malondialdehyde levels were significantly decreased while there was a significant increase in the zinc, silver concentrations and total antioxidant capacity in brain of Zn ONPs and SNPs treated rats, compared with diabetic or diabetic + insulin group and their control group.Conclusions: Zn ONPs and SNPs can be used to ameliorate the oxidative stress in brain resulted from diabetes mellitus.

  3. miR-196a Ameliorates Cytotoxicity and Cellular Phenotype in Transgenic Huntington’s Disease Monkey Neural Cells

    Science.gov (United States)

    Carter, Richard L.; Prucha, Melinda S.; Yang, Jinjing; Parnpai, Rangsun; Chan, Anthony W. S.

    2016-01-01

    Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) tract that leads to motor, cognitive and psychiatric impairment. Currently there is no cure for HD. A transgenic HD nonhuman primate (HD-NHP) model was developed with progressive development of clinical and pathological features similar to human HD, which suggested the potential preclinical application of the HD-NHP model. Elevated expression of miR-196a was observed in both HD-NHP and human HD brains. Cytotoxicity and apoptosis were ameliorated by the overexpression of miR-196a in HD-NHP neural progenitor cells (HD-NPCs) and differentiated neural cells (HD-NCs). The expression of apoptosis related gene was also down regulated. Mitochondrial morphology and activity were improved as indicated by mitotracker staining and the upregulation of CBP and PGC-1α in HD-NPCs overexpressing miR-196a. Here we demonstrated the amelioration of HD cellular phenotypes in HD-NPCs and HD-NCs overexpressing miR-196a. Our results also suggested the regulatory role of miR-196a in HD pathogenesis that may hold the key for understanding molecular regulation in HD and developing novel therapeutics. PMID:27631085

  4. Amelioration of murine passive immune thrombocytopenia by IVIg and a therapeutic monoclonal CD44 antibody does not require the Myd88 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Andrew R Crow

    Full Text Available Immune thrombocytopenia (ITP is an autoimmune bleeding disorder characterized by a low platelet count and the production of anti-platelet antibodies. The majority of ITP patients have antibodies to platelet integrin α(IIbβ₃ (GPIIbIIIa which can direct platelet phagocytosis by macrophages. One effective treatment for patients with ITP is intravenous immunoglobulin (IVIg which rapidly reverses thrombocytopenia. The exact mechanism of IVIg action in human patients is unclear, although in mouse models of passive ITP, IVIg can rapidly increase platelet counts in the absence of adaptive immunity. Another antibody therapeutic that can similarly increase platelet counts independent of adaptive immunity are CD44 antibodies. Toll-like receptors (TLRs are pattern recognition receptors which play a central role in helping direct the innate immune system. Dendritic cells, which are notable for their expression of TLRs, have been directly implicated in IVIg function as an initiator cell, while CD44 can associate with TLR2 and TLR4. We therefore questioned whether IVIg, or the therapeutic CD44 antibody KM114, mediate their ameliorative effects in a manner dependent upon normal TLR function. Here, we demonstrate that the TLR4 agonist LPS does not inhibit IVIg or KM114 amelioration of antibody-induced thrombocytopenia, and that these therapeutics do not ameliorate LPS-induced thrombocytopenia. IVIg was able to significantly ameliorate murine ITP in C3H/HeJ mice which have defective TLR4. All known murine TLRs except TLR3 utilize the Myd88 adapter protein to drive TLR signaling. Employing Myd88 deficient mice, we found that both IVIg and KM114 ameliorate murine ITP in Myd88 deficient mice to the same extent as normal mice. Thus both IVIg and anti-CD44 antibody can mediate their ameliorative effects in murine passive ITP independent of the Myd88 signaling pathway. These data help shed light on the mechanism of action of IVIg and KM114 in the amelioration of

  5. N-acetylcysteine Ameliorates Prostatitis via miR-141 Regulating Keap1/Nrf2 Signaling.

    Science.gov (United States)

    Wang, Liang-Liang; Huang, Yu-Hua; Yan, Chun-Yin; Wei, Xue-Dong; Hou, Jian-Quan; Pu, Jin-Xian; Lv, Jin-Xing

    2016-04-01

    Chronic prostatitis was the most common type of prostatitis and oxidative stress was reported to be highly elevated in prostatitis patients. In this study, we determined the effect of N-acetylcysteine (NAC) on prostatitis and the molecular mechanism involved in it. Male Sprague-Dawley rats were divided into three groups: control group (group A, n = 20), carrageenan-induced chronic nonbacterial prostatitis (CNP) model group (group B, n = 20), and carrageenan-induced CNP model group with NAC injection (group C, n = 20). Eye score, locomotion score, inflammatory cell count, cyclooxygenase 2 (COX2) expression, and Evans blue were compared in these three groups. The expression of miR-141 was determined by quantitative real-time PCR (qRT-PCR). Moreover, protein expressions of Kelch-like ECH-associated protein-1 (Keap1) and nuclear factor erythroid-2 related factor 2 (Nrf2) and its target genes were examined by Western blot. Luciferase reporter assay was performed in RWPE-1 cells transfected miR-141 mimic or inhibitor and the plasmid carrying 3'-UTR of Keap1. The value of eye score, locomotion score, inflammatory cell count, and Evans blue were significantly decreased in group C, as well as the expression of COX2, when comparing to that of group B. These results indicated that NAC relieved the carrageenan-induced CNP. Further, we found that NAC increased the expression of miR-141 and activated the Keap1/Nrf2 signaling. Luciferase reporter assay revealed that miR-141 mimic could suppress the activity of Keap1 and stimulate the downstream target genes of Nrf2. In addition, miR-141 inhibitor could reduce the effect of NAC on prostatitis. NAC ameliorates the carrageenan-induced prostatitis and prostate inflammation pain through miR-141 regulating Keap1/Nrf2 signaling.

  6. Salvianolic Acid B Ameliorates Hyperglycemia and Dyslipidemia in db/db Mice through the AMPK Pathway

    Directory of Open Access Journals (Sweden)

    Ming-Qing Huang

    2016-12-01

    Full Text Available Background/Aims: Salvianolic acid B (Sal B, a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism. Methods: Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg or metformin (positive drug, 300 mg/kg for 6 weeks. Results: Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4 and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα and phosphorylated acetyl CoA carboxylase (p-ACC protein expressions in liver. Conclusion: Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.

  7. Induction of Heat Shock Protein 70 Ameliorates Ultraviolet-Induced Photokeratitis in Mice

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    Yukihiro Horie

    2013-01-01

    Full Text Available Acute ultraviolet (UV B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse and UVB-exposed (400 mJ/cm2, GGA-untreated UVB-exposed (400 mJ/cm2, GGA-treated (500 mg/kg/mouse but not exposed and naive controls. Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL. HSP70, reactive oxygen species (ROS production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and protein kinase B (Akt expression were also evaluated. Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0.01. Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0.01. Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0.05. ROS signal was not affected by GGA. NF-κB activation was reduced but phospho-(Ser/Ther Akt substrate expression was increased in corneas after irradiation when treated with GGA. GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-κB activation and possibly increased Akt phosphorilation.

  8. Protein kinase CK2α catalytic subunit ameliorates diabetic renal inflammatory fibrosis via NF-κB signaling pathway.

    Science.gov (United States)

    Huang, Junying; Chen, Zhiquan; Li, Jie; Chen, Qiuhong; Li, Jingyan; Gong, Wenyan; Huang, Jiani; Liu, Peiqing; Huang, Heqing

    2017-02-23

    Activation of casein kinase 2 (CK2) is closely linked to the body disturbance of carbohydrate metabolism and inflammatory reaction. The renal chronic inflammatory reaction in the setting of diabetes is one of the important hallmarks of diabetic renal fibrosis. However, it remains unknown whether CK2 influences the process of diabetic renal fibrosis. The current study is aimed to investigate if CK2α ameliorates renal inflammatory fibrosis in diabetes via NF-κB pathway. To explore potential regulatory mechanism of CK2α, the expression and activity of CK2α, which were studied by plasmid transfection, selective inhibitor, small-interfering RNA (siRNA) and adenovirus infection in vitro or in vivo, were analyzed by means of western blotting (WB), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The following findings were observed: (1) Expression of CK2α was upregulated in kidneys of db/db and KKAy diabetic mice; (2) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression suppressed high glucose-induced expressions of FN and ICAM-1 in glomerular mesangial cells (GMCs); (3) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression not only restrained IκB degradation, but also suppressed HG-induced nuclear accumulation, transcriptional activity and DNA binding activity of NF-κB in GMCs; (4) Treatment of TBB or CK2α RNAi adenovirus infection ameliorated renal fibrosis in diabetic animals; (5) Treatment of TBB or CK2α RNAi adenovirus infection suppressed IκB degradation and NF-κB nuclear accumulation in glomeruli of diabetic animals. This study indicates the essential role of CK2α in regulating the diabetic renal pathological process of inflammatory fibrosis via NF-κB pathway, and inhibition of CK2α may serve as a promising therapeutic strategy for diabetic nephropathy.

  9. Incremental Beliefs About Ability Ameliorate Self-Doubt Effects

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    Qin Zhao

    2015-12-01

    Full Text Available Past research has typically shown negative effects of self-doubt on performance and psychological well-being. We suggest that these self-doubt effects largely may be due to an underlying assumption that ability is innate and fixed. The present research investigated the main hypothesis that incremental beliefs about ability might ameliorate negative effects of self-doubt. We examined our hypotheses using two lab tasks: verbal reasoning and anagram tasks. Participants’ self-doubt was measured and beliefs about ability were measured after participants read articles advocating either for incremental or entity theories of ability. American College Testing (ACT scores were obtained to index actual ability level. Consistent with our hypothesis, for participants who believed ability was relatively fixed, higher self-doubt was associated with increased negative affect and lower task performance and engagement. In contrast, for participants who believed that ability was malleable, negative self-doubt effects were ameliorated; self-doubt was even associated with better task performance. These effects were further moderated by participants’ academic ability. These findings suggest that mind-sets about ability moderate self-doubt effects. Self-doubt may have negative effects only when it is interpreted as signaling that ability is immutably low.

  10. Phytoceramide Shows Neuroprotection and Ameliorates Scopolamine-Induced Memory Impairment

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    Seikwan Oh

    2011-10-01

    Full Text Available The function and the role phytoceramide (PCER and phytosphingosine (PSO in the central nervous system has not been well studied. This study was aimed at investigating the possible roles of PCER and PSO in glutamate-induced neurotoxicity in cultured neuronal cells and memory function in mice. Phytoceramide showed neuro-protective activity in the glutamate-induced toxicity in cultured cortical neuronal cells. Neither phytosphingosine nor tetraacetylphytosphingosine (TAPS showed neuroproective effects in neuronal cells. PCER (50 mg/kg, p.o. recovered the scopolamine-induced reduction in step-through latency in the passive avoidance test; however, PSO did not modulate memory function on this task. The ameliorating effects of PCER on spatial memory were confirmed by the Morris water maze test. In conclusion, through behavioral and neurochemical experimental results, it was demonstrated that central administration of PCER produces amelioration of memory impairment. These results suggest that PCER plays an important role in neuroprotection and memory enhancement and PCER could be a potential new therapeutic agent for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

  11. Ameliorative Influence of Green Tea Extract on Copper Nanoparticle-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Ibrahim, Marwa A.; Khalaf, A. A.; Galal, Mona K.; Ogaly, Hanan A.; H. M. Hassan, Azza

    2015-09-01

    The potential toxicity of copper nanoparticles (CNPs) to the human health and environment remains a critical issue. In the present study, we investigated the protective influence of an aqueous extract of green tea leaves (GTE) against CNPs-induced (20-30 nm) hepatotoxicity. Four different groups of rats were used: group I was the control, group II received CNPs (40 mg/kg BW), group III received CNPs plus GTE, and group IV received GTE alone. We highlighted the hepatoprotective effect of GTE against CNPs toxicity through monitoring the alteration of liver enzyme activity, antioxidant defense mechanism, histopathological alterations, and DNA damage evaluation. The rats that were given CNPs only had a highly significant elevation in liver enzymes, alteration in oxidant-antioxidant balance, and severe pathological changes. In addition, we detected a significant elevation of DNA fragmentation percentage, marked DNA laddering, and significance over expression of both caspase-3 and Bax proteins. The findings for group III clarify the efficacy of GTE as a hepatoprotectant on CNPs through improving the liver enzyme activity, antioxidant status, as well as suppressing DNA fragmentation and the expression of the caspase-3 and Bax proteins. In conclusion, GTE was proved to be a potential hepatoprotective additive as it significantly ameliorates the hepatotoxicity and apoptosis induced by CNPs.

  12. bFGF Protects Pre-oligodendrocytes from Oxygen/Glucose Deprivation Injury to Ameliorate Demyelination.

    Science.gov (United States)

    Qu, Xuebin; Guo, Rui; Zhang, Zhenzhong; Ma, Li; Wu, Xiuxiang; Luo, Mengjiao; Dong, Fuxing; Yao, Ruiqin

    2015-10-01

    One of the pathological hallmarks of periventricular white matter injury is the vulnerability of pre-oligodendrocytes (preOLs) to hypoxia-ischemia (HI). There is increasing evidence that basic fibroblast growth factor (bFGF) is an important signaling molecule for neurogenesis and neuroprotection in the central nervous system. However, it is unknown whether bFGF protects preOLs from oxygen/glucose deprivation (OGD) damage in vitro and promotes remyelination in HI-induced rats. In this present study, bFGF exerted a protective effect on myelin by increasing the myelin thickness, the number of myelinated axons, and myelin basic protein expression in the HI-induced demyelinated neonatal rat corpus callosum. In vitro, bFGF ameliorated the impaired mitochondria and cell processes induced by OGD to promote the survival of isolated O4-positive preOLs. Additionally, the expression of fibroblast growth factor receptor 3 (FGFR3) was dramatically up-regulated in the preOLs after bFGF administration in vivo and in vitro. Thus, bFGF-stimulated remyelination in HI-induced rats by protecting the preOLs from hypoxic injury, and the mechanism involved may be mediated by FGFR3.

  13. Sesamin Ameliorates Advanced Glycation End Products-Induced Pancreatic β-Cell Dysfunction and Apoptosis.

    Science.gov (United States)

    Kong, Xiang; Wang, Guo-Dong; Ma, Ming-Zhe; Deng, Ru-Yuan; Guo, Li-Qun; Zhang, Jun-Xiu; Yang, Jie-Ren; Su, Qing

    2015-06-09

    Advanced glycation end products (AGEs), the direct modulators of β-cells, have been shown to cause insulin-producing β-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS) production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked β-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg) and orally treated with sesamin (160 mg/kg) for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and β-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 μM) and then exposed to AGEs (200 mg/L) for 24 h. Insulin secretion, β-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced β-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67(phox) and p22(phox), and reduced NADPH oxidase activity. These results suggest that sesamin protects β-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.

  14. Topical application of glycyrrhizin preparation ameliorates experimentally induced colitis in rats

    Institute of Scientific and Technical Information of China (English)

    Tomohiro Kudo; Shinichi Okamura; Yajing Zhang; Takashige Masuo; Masatomo Mori

    2011-01-01

    AIM: To examine the efficacy of glycyrrhizin preparation (GL-p) in the treatment of a rat model of ulcerative colitis (UC). METHODS: Experimental colitis was induced by oral administration of dextran sodium sulfate. Rats with colitis were intrarectally administered GL-p or saline. The extent of colitis was evaluated based on body weight gain,colon wet weight,and macroscopic damage score. The expression levels of pro-inflammatory cytokines and chemokines in the inflamed mucosa were measured by cytokine antibody array analysis. The effect of GL-p on myeloperoxidase (MPO) activity in the inflamed mucosa and purified enzyme was assayed. RESULTS: GL-p treatment significantly ameliorated the extent of colitis compared to sham treatment with saline. Cytokine antibody array analysis showed that GL-p treatment significantly decreased the expression levels of pro-inflammatory cytokines and chemokines,including interleukin (IL)-1β,IL-6,tumor necrosis factor-α,cytokine-induced neutrophil chemoattractant-2,and monocyte chemoattractant protein-1 in the inflamed mucosa. Furthermore,GL-p inhibited the oxidative activity of mucosal and purified MPO. CONCLUSION: GL-p enema has a therapeutic effect on experimental colitis in rats and may be useful in the treatment of UC.

  15. Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice.

    Science.gov (United States)

    Guo, Shuling; Casu, Carla; Gardenghi, Sara; Booten, Sheri; Aghajan, Mariam; Peralta, Raechel; Watt, Andy; Freier, Sue; Monia, Brett P; Rivella, Stefano

    2013-04-01

    β-Thalassemia and HFE-related hemochromatosis are 2 of the most frequently inherited disorders worldwide. Both disorders are characterized by low levels of hepcidin (HAMP), the hormone that regulates iron absorption. As a consequence, patients affected by these disorders exhibit iron overload, which is the main cause of morbidity and mortality. HAMP expression is controlled by activation of the SMAD1,5,8/SMAD4 complex. TMPRSS6 is a serine protease that reduces SMAD activation and blocks HAMP expression. We identified second generation antisense oligonucleotides (ASOs) targeting mouse Tmprss6. ASO treatment in mice affected by hemochromatosis (Hfe(-/-)) significantly decreased serum iron, transferrin saturation and liver iron accumulation. Furthermore, ASO treatment of mice affected by β-thalassemia (HBB(th3/+) mice, referred to hereafter as th3/+ mice) decreased the formation of insoluble membrane-bound globins, ROS, and apoptosis, and improved anemia. These animals also exhibited lower erythropoietin levels, a significant amelioration of ineffective erythropoiesis (IE) and splenomegaly, and an increase in total hemoglobin levels. These data suggest that ASOs targeting Tmprss6 could be beneficial in individuals with hemochromatosis, β-thalassemia, and related disorders.

  16. AMIGO2 modulates T cell functions and its deficiency in mice ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Li, Zhilin; Khan, Mohd Moin; Kuja-Panula, Juha; Wang, Hongyun; Chen, Yu; Guo, Deyin; Chen, Zhi Jane; Lahesmaa, Riitta; Rauvala, Heikki; Tian, Li

    2017-05-01

    The immune function of AMIGO2 is currently unknown. Here, we revealed novel roles of AMIGO2 in modulating T-cell functions and EAE using Amigo2-knockout (AMG2KO) mice. Amigo2 was abundantly expressed by murine T helper (Th) cells. Its deficiency impaired transplanted T-cell infiltration into the secondary lymphoid organs and dampened Th-cell activation, but promoted splenic Th-cell proliferation and abundancy therein. AMG2KO Th cells had respectively elevated T-bet in Th1- and GATA-3 in Th2-lineage during early Th-cell differentiation, accompanied with increased IFN-γ and IL-10 but decreased IL-17A production. AMG2KO mice exhibited ameliorated EAE, dampened spinal T-cell accumulation, decreased serum IL-17A levels and enhanced splenic IL-10 production. Adoptive transfer of encephalitogenic AMG2KO T cells induced milder EAE and dampened spinal Th-cell accumulation and Tnf expression. Mechanistically, Amigo2-overexpression in 293T cells dampened NF-kB transcriptional activity, while Amigo2-deficiency enhanced Akt but suppressed GSK-3β phosphorylation and promoted nuclear translocations of NF-kB and NFAT1 in Th-cells. Collectively, our data demonstrate that AMIGO2 is important in regulating T-cell functions and EAE, and may be harnessed as a potential therapeutic target for multiple sclerosis.

  17. Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection.

    Directory of Open Access Journals (Sweden)

    Kalliopi Pitarokoili

    Full Text Available Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78 of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

  18. Resveratrol Ameliorated Vascular Calcification by Regulating Sirt-1 and Nrf2.

    Science.gov (United States)

    Zhang, P; Li, Y; Du, Y; Li, G; Wang, L; Zhou, F

    2016-12-01

    Pathologic vascular calcification is a significant reason for mortality and morbidity in patients who suffer from end-stage renal disease (ESRD). Resveratrol, a scavenger for many free radicals, is a crucial compound for biomedicine. However, the role and mechanism of resveratrol in vascular calcification is still unknown. In this study, to mimic vascular calcification in ESRD, we used β-glyceophosphate to stimulate the rat vascular smooth muscle cells (RASMCs). We investigate the therapeutic role of resveratrol pretreatment in vascular calcification. In the current in vitro study, we observe the effects of resveratrol on improving intracellular calcium deposition and protecting against mitochondria dysfunction in calcific RASMCs. Resveratrol decreased the mRNA level of fibroblast growth factor-23, then increased the mRNA level of klotho and the nuclear transcription factor NF-E2-related factor 2 (nuclear factor-erythroid 2-related factor 2 [Nrf2]) in RASMCs after calcification. Further, resveratrol activated the expression of sirtuin-1 and Nrf2, and inhibited the expression of osteopontin, runt-related transcription factor 2, and heme oxygenase-1. Our study shows that resveratrol could ameliorate oxidative injury of RASMCs by preventing vascular calcification-induced calcium deposition and mitochondria dysfunction through involving sirtuin-1 and Nrf2. These results might indicate a novel role for resveratrol in resistance to oxidative stress for ESRD patients suffering from vascular calcification.

  19. FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity.

    Science.gov (United States)

    Xiong, Xiao-Qing; Chen, Dan; Sun, Hai-Jian; Ding, Lei; Wang, Jue-Jin; Chen, Qi; Li, Yue-Hua; Zhou, Ye-Bo; Han, Ying; Zhang, Feng; Gao, Xing-Ya; Kang, Yu-Ming; Zhu, Guo-Qing

    2015-09-01

    Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5), and contributes to the beneficial effects of exercise on metabolism. Here we report the therapeutical effects of FNDC5/irisin on metabolic derangements and insulin resistance in obesity, and show the lipolysis effect of irisin and its signal molecular mechanism. In obese mice, lentivirus mediated-FNDC5 overexpression enhanced energy expenditure, lipolysis and insulin sensitivity, and reduced hyperlipidemia, hyperglycemia, hyperinsulinism, blood pressure and norepinephrine levels; it increased hormone-sensitive lipase (HSL) expression and phosphorylation, and reduced perilipin level and adipocyte diameter in adipose tissues. Subcutaneous perfusion of irisin reduced hyperlipidemia and hyperglycemia, and improved insulin resistance. Either FNDC5 overexpression or irisin perfusion only induced a tendency toward a slight decrease in body weight in obese mice. In 3T3-L1 adipocytes, irisin enhanced basal lipolysis rather than isoproterenol-induced lipolysis, which were prevented by inhibition of adenylate cyclase or PKA; irisin increased the HSL and perilipin phosphorylation; it increased PKA activity, and cAMP and HSL mRNA levels, but reduced perilipin expression. These results indicate that FNDC5/irisin ameliorates glucose/lipid metabolic derangements and insulin resistance in obese mice, and enhances lipolysis via cAMP-PKA-HSL/perilipin pathway. FNDC5 or irisin can be taken as an effective therapeutic strategy for metabolic disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Rapamycin ameliorates chitosan nanoparticle-induced developmental defects of preimplantation embryos in mice

    Science.gov (United States)

    Choi, Yun-Jung; Gurunathan, Sangiliyandi; Kim, DaSom; Jang, Hyung Seok; Park, Woo-Jin; Cho, Ssang-Goo; Park, Chankyu; Song, Hyuk; Seo, Han Geuk; Kim, Jin-Hoi

    2016-01-01

    Chitosan nanoparticles (CSNPs) are used as drug or gene delivery vehicles. However, a detailed understanding of the effects of CSNPs on embryonic development remains obscure. Here, we show that CSNPs can be internalized into mouse blastocysts, such as the zona pellucida, the perivitelline space, and the cytoplasm. Consequently, CSNPs-induced endoplasmic reticulum (ER) stress increases both of Bip/Grp78, Chop, Atf4, Perk, and Ire1a mRNAs expression levels, and reactive oxygen species. Moreover, CSNPs show double- and multi-membraned autophagic vesicles, and lead to cell death of blastocoels. Conversely, treatment with rapamycin, which plays an important role as a central regulator of cellular proliferation and stress responses, decreased CSNPs-induced mitochondrial Ca+2 overloading, apoptosis, oxidative stress, ER stress, and autophagy. In vivo studies demonstrated that CSNPs injection has significant toxic effect on primordial and developing follicles. Notably, rapamycin rescued oxidative stress-induced embryonic defects via modulating gene expression of sirtuin and mammalian target of rapamycin. Interestingly, CSNPs treatment alters epigenetic reprogramming in mouse embryos. Overall, these observations suggest that rapamycin treatment could ameliorate CSNPs-induced developmental defects in preimplantation embryos. The data from this study would facilitate to understand the toxicity of these CSNPs, and enable the engineering of safer nanomaterials for therapeutic applications. PMID:27463007

  1. Tempol, a Superoxide Dismutase-Mimetic Drug, Ameliorates Progression of Renal Disease in CKD Mice

    Directory of Open Access Journals (Sweden)

    Wei Ding

    2015-07-01

    Full Text Available Background: Oxidative stress has been implicated in the pathogenesis of chronic kidney disease (CKD and antioxidants may ameliorate disease progression. We investigate the beneficial effect of Tempol, a superoxide dismutase-mimetic drug, on progression of disease in a mouse model of CKD. Methods: CKD was surgically induced in c57BL/6 mice by 5/6 nephrectomy. Mice were randomly divided into 3 groups: sham group, 5/6 nephrectomized group (Nx and Nx+Tempol (2 mmol/l in drinking water. Mice were sacrificed at the end of 12 weeks. Renal function, structure as well as expression of key molecules involved in the pathogenesis of inflammation, fibrosis and progression in mice were measured. Results: Reduced body weight and impaired renal function (elevation on serum creatinine, blood urea nitrogen, urine albumin, segmental sclerosis and tubulointerstitial damage was demonstrated in Nx mice but was significantly improved by Tempol administration. Nx animals exhibited significantly elevated proinflammatory and profibrotic factors, activation of NF-κB, increased expression of NADPH oxidase related subunits (p47phox, p67phox, gp91phox, and elevated activation of TGF-ß/Smad3, EGFR, MAPK signaling pathway. Tempol inhibited NF-κB mediated inflammation, TGF-ß/Smad3-induced renal fibrosis as well as EGFR and MAPK signaling pathway activation. Conclusions: Tempol administration attenuated renal injury in CKD mice through NF-κB, TGF-ß/Smad3, redox-senstive EGFR activation and c-Raf/MEK/ERK pathways.

  2. Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.

    Science.gov (United States)

    Bi, Pengpeng; Shan, Tizhong; Liu, Weiyi; Yue, Feng; Yang, Xin; Liang, Xin-Rong; Wang, Jinghua; Li, Jie; Carlesso, Nadia; Liu, Xiaoqi; Kuang, Shihuan

    2014-08-01

    Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.

  3. Sesamin Ameliorates Advanced Glycation End Products-Induced Pancreatic β-Cell Dysfunction and Apoptosis

    Directory of Open Access Journals (Sweden)

    Xiang Kong

    2015-06-01

    Full Text Available Advanced glycation end products (AGEs, the direct modulators of β-cells, have been shown to cause insulin-producing β-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked β-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg and orally treated with sesamin (160 mg/kg for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and β-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 μM and then exposed to AGEs (200 mg/L for 24 h. Insulin secretion, β-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced β-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67phox and p22phox, and reduced NADPH oxidase activity. These results suggest that sesamin protects β-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.

  4. Treadmill exercise ameliorates motor disturbance through inhibition of apoptosis in the cerebellum of valproic acid-induced autistic rat pups.

    Science.gov (United States)

    Kim, Ji-Eun; Shin, Mal-Soon; Seo, Tae-Beom; Ji, Eun-Sang; Baek, Seong-Soo; Lee, Sam-Jun; Park, Joon-Ki; Kim, Chang-Ju

    2013-08-01

    Autism is a neurological disorder that occurs during childhood and is characterized by impairments in social interaction and communication, as well as restricted and repetitive behaviors. Abnormalities of the cerebellum in autism include Purkinje cell loss and motor disturbance. In the present study, we evaluated the effect of treadmill exercise on motor coordination and balance in correlation with reelin expression and the rate of apoptosis in the cerebellum of autistic rat pups. For the induction of the autism-like animal models, 400 mg/kg valproic acid was subcutaneously injected into rat pups on postnatal day 14. Rat pups in the exercise groups were forced to run on a treadmill for 30 min, once a day, five times a week for 4 weeks, starting on postnatal day 28. Motor coordination and balance, as measured using the rotarod test and vertical pole test, were affected by the induction of autism. By contrast, treadmill exercise ameliorated motor dysfunction in the autistic rat pups. The expression levels of reelin, GAD67 and cyclin D1 in the cerebellum of the autistic rat pups were decreased, while the expression levels of these molecules were increased in autistic rat pups who engaged in treadmill exercise. In the cerebellum of the autistic rat pups, Bcl-2 expression was decreased and Bax expression was increased. By contrast, treadmill exercise enhanced Bcl-2 expression and suppressed Bax expression. The therapeutic effect of treadmill exercise on motor deficits may be due to the reelin-mediated anti-apoptotic effect on cerebellar Purkinje neurons.

  5. Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

    Science.gov (United States)

    Yu, Liming; Gong, Bing; Duan, Weixun; Fan, Chongxi; Zhang, Jian; Li, Zhi; Xue, Xiaodong; Xu, Yinli; Meng, Dandan; Li, Buying; Zhang, Meng; Bin Zhang; Jin, Zhenxiao; Yu, Shiqiang; Yang, Yang; Wang, Huishan

    2017-01-01

    Enhancing mitochondrial biogenesis and reducing mitochondrial oxidative stress have emerged as crucial therapeutic strategies to ameliorate diabetic myocardial ischemia/reperfusion (MI/R) injury. Melatonin has been reported to be a safe and potent cardioprotective agent. However, its role on mitochondrial biogenesis or reactive oxygen species (ROS) production in type 1 diabetic myocardium and the underlying mechanisms remain unknown. We hypothesize that melatonin ameliorates MI/R injury in type 1 diabetic rats by preserving mitochondrial function via AMPK-PGC-1α-SIRT3 signaling pathway. Both our in vivo and in vitro data showed that melatonin reduced MI/R injury by improving cardiac function, enhancing mitochondrial SOD activity, ATP production and oxidative phosphorylation complex (II, III and IV), reducing myocardial apoptosis and mitochondrial MDA, H2O2 generation. Importantly, melatonin also activated AMPK-PGC-1α-SIRT3 signaling and increased SOD2, NRF1 and TFAM expressions. However, these effects were abolished by Compound C (a specific AMPK signaling blocker) administration. Additionally, our cellular experiment showed that SIRT3 siRNA inhibited the cytoprotective effect of melatonin without affecting p-AMPK/AMPK ratio and PGC-1α expression. Taken together, we concluded that melatonin preserves mitochondrial function by reducing mitochondrial oxidative stress and enhancing its biogenesis, thus ameliorating MI/R injury in type 1 diabetic state. AMPK-PGC1α-SIRT3 axis plays an essential role in this process. PMID:28120943

  6. Saline-alkali land in the Yellow River Delta:amelioration zonation based on GIS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Soil salinization is one of the major land degradation types andhas greatly influenced sustainable agricultural development. Zonation of saline-alkali land is the precondition for effective amelioration. The present situation of saline-alkali land is monitored by remote sensing image processing. Causes for land salinization are analyzed, especially the two key factors, ground water depth and its mineralization degree, are analyzed by using long-term observation data. Previously,zonation of saline-alkali soil was made descriptively and artificially. Based on the present situation of saline-alkali land, ground water depth and ground water mineralization degree, the zonation of salinealkali land for amelioration in the Yellow River Delta was completed quantitatively. Four different ypes of saline-alkali land amelioration zones are delineated, namely, easy ameliorated zone,elatively difficult ameliorated zone, difficult ameliorated zone and unfavorable ameliorated zone.Countermeasures for ameliorating saline-alkali soils are put forward according to ecological conditions of different saline-alkali land zones.

  7. 27 CFR 24.304 - Chaptalization (Brix adjustment) and amelioration record.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Chaptalization (Brix adjustment) and amelioration record. 24.304 Section 24.304 Alcohol, Tobacco Products and Firearms ALCOHOL AND... Chaptalization (Brix adjustment) and amelioration record. (a) General. A proprietor who chaptalizes juice...

  8. Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases.

    Science.gov (United States)

    Pitiyage, Gayani Nadika; Slijepcevic, Predrag; Gabrani, Aliya; Chianea, Yaghoub Gozaly; Lim, Kue Peng; Prime, Stephen Stewart; Tilakaratne, Wanninayake Mudiyanselage; Fortune, Farida; Parkinson, Eric Kenneth

    2011-04-01

    ameliorate the condition by the increased expression of MMPs prior to clearance by the immune system.

  9. Telmisartan Ameliorates Fibrocystic Liver Disease in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

    Science.gov (United States)

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M.; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  10. Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK.

    Science.gov (United States)

    Kim, Yong Deuk; Lee, Kwang Min; Hwang, Seung-Lark; Chang, Hyeun Wook; Kim, Keuk-Jun; Harris, Robert A; Choi, Hueng-Sik; Choi, Won-Sik; Lee, Sung-Eun; Park, Chul-Seung

    2015-12-01

    Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity. Wild-type, CRBN and PPARα null mice were fed an alcohol-containing liquid diet and administered with fenofibrate. Gene expression profiles and metabolic changes were measured in the liver and blood of these mice. Expression of CRBN, cytochrome P450 2E1 (CYP2E1), lipogenic genes, pro-inflammatory cytokines, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were increased in the Lieber-DeCarli alcohol-challenged mice. Fenofibrate attenuated the induction of CRBN and reduced hepatic steatosis and pro-inflammatory markers in these mice. Ablation of the gene encoding CRBN produced the same effect as fenofibrate. The increase in CRBN gene expression by alcohol and the reduction of CRBN expression by fenofibrate were negated in PPARα null mice. Fenofibrate increased the recruitment of PPARα on CRBN gene promoter in WT mice but not in PPARα null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPARα by fenofibrate alleviates alcohol-induced hepatic steatosis and inflammation by reducing the inhibition of AMPK by CRBN. CRBN is a potential therapeutic target for the alcoholic liver disease.

  11. Docosahexaenoic Acid Ameliorates Fructose-Induced Hepatic Steatosis Involving ER Stress Response in Primary Mouse Hepatocytes

    Directory of Open Access Journals (Sweden)

    Jinying Zheng

    2016-01-01

    Full Text Available The increase in fructose consumption is considered to be a risk factor for developing nonalcoholic fatty liver disease (NAFLD. We investigated the effects of docosahexaenoic acid (DHA on hepatic lipid metabolism in fructose-treated primary mouse hepatocytes, and the changes of Endoplasmic reticulum (ER stress pathways in response to DHA treatment. The hepatocytes were treated with fructose, DHA, fructose plus DHA, tunicamycin (TM or fructose plus 4-phenylbutyric acid (PBA for 24 h. Intracellular triglyceride (TG accumulation was assessed by Oil Red O staining. The mRNA expression levels and protein levels related to lipid metabolism and ER stress response were determined by real-time PCR and Western blot. Fructose treatment led to obvious TG accumulation in primary hepatocytes through increasing expression of fatty acid synthase (FAS and acetyl-CoA carboxylase (ACC, two key enzymes in hepatic de novo lipogenesis. DHA ameliorates fructose-induced TG accumulation by upregulating the expression of carnitine palmitoyltransferase 1A (CPT-1α and acyl-CoA oxidase 1 (ACOX1. DHA treatment or pretreatment with the ER stress inhibitor PBA significantly decreased TG accumulation and reduced the expression of glucose-regulated protein 78 (GRP78, total inositol-requiring kinase 1 (IRE1α and p-IRE1α. The present results suggest that DHA protects against high fructose-induced hepatocellular lipid accumulation. The current findings also suggest that alleviating the ER stress response seems to play a role in the prevention of fructose-induced hepatic steatosis by DHA.

  12. Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model.

    Science.gov (United States)

    Fukunaga, Yutaka; Izawa-Ishizawa, Yuki; Horinouchi, Yuya; Sairyo, Eriko; Ikeda, Yasumasa; Ishizawa, Keisuke; Tsuchiya, Koichiro; Abe, Yoshiro; Hashimoto, Ichiro; Tamaki, Toshiaki

    2017-01-16

    Ischemic skin flap necrosis can occur in random pattern flaps. An excess amount of reactive oxygen species is generated and causes necrosis in the ischemic tissue. Nitrosonifedipine (NO-NIF) has been demonstrated to possess potent radical scavenging ability. However, there has been no study on the effects of NO-NIF on ischemic skin flap necrosis. Therefore, they evaluated the potential of NO-NIF in ameliorating ischemic skin flap necrosis in a mouse model. A random pattern skin flap (1.0 × 3.0 cm) was elevated on the dorsum of C57BL/6 mice. NO-NIF was administered by topical injection immediately after surgery and every 24 hours thereafter. Flap survival was evaluated on postoperative day 7. Tissue samples from the skin flaps were harvested on postoperative days 1 and 3 to analyze oxidative stress, apoptosis and endothelial dysfunction. The viable area of the flap in the NO-NIF group was significantly increased (78.30 ± 7.041%) compared with that of the control group (47.77 ± 6.549%, p NIF reduced oxidative stress, apoptosis and endothelial dysfunction, which were evidenced by the decrease of malondialdehyde, p22phox protein expression, number of apoptotic cells, phosphorylated p38 MAPK protein expression, and vascular cell adhesion molecule-1 protein expression while endothelial nitric oxide synthase protein expression was increased. In conclusion, they demonstrated that NO-NIF ameliorated ischemic skin flap necrosis by reducing oxidative stress, apoptosis, and endothelial dysfunction. NO-NIF is considered to be a candidate for the treatment of ischemic flap necrosis.

  13. Flemingia macrophylla Extract Ameliorates Experimental Osteoporosis in Ovariectomized Rats

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    Hui-Ya Ho

    2011-01-01

    Full Text Available Flemingia macrophylla (Leguminosae, a native plant of Taiwan, is used as folk medicine. An in vitro study showed that a 75% ethanolic extract of F. macrophylla (FME inhibited osteoclast differentiation of cultured rat bone marrow cells, and the active component, lespedezaflavanone A (LDF-A, was isolated. It was found that oral administration of FME for 13 weeks suppressed bone loss in ovariectomized rats, an experimental model of osteoporosis. In addition, FME decreased urinary deoxypyridinoline concentrations but did not inhibit serum alkaline phosphatase activities, indicating that it ameliorated bone loss via inhibition of bone resorption. These results suggest that FME may represent a useful remedy for the treatment of bone resorption diseases, such as osteoporosis. In addition, LDF-A could be used as a marker compound to control the quality of FME.

  14. Quercetin Treatment Ameliorates Systemic Oxidative Stress in Cirrhotic Rats

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    Vieira, Emanuelle Kerber; Bona, Silvia; Di Naso, Fábio Cangeri; Porawski, Marilene; Tieppo, Juliana; Marroni, Norma Possa

    2011-01-01

    Our aim was to investigate whether the antioxidant quercetin protects against liver injury and ameliorates the systemic oxidative stress in rats with common bile duct ligation. Secondary biliary cirrhosis was induced through 28 days of bile duct obstruction. Animals received quercetin (Q) after 14 days of obstruction. Groups of control (CO) and cirrhotic (CBDL) animals received a daily 50 mg/kg body weight i.p. injection of quercetin (CO + Q; CBDL + Q) or vehicle (CO; CBDL). Quercetin corrected the reduction in superoxide dismutase (SOD), catalase CAT, and glutathione peroxidase GPx activities and prevented the increase of thiobarbituric acid reactive substances (TBARS), aminotransferases, and alkaline phosphatase in cirrhotic animals. Quercetin administration also corrected the reduced total nitrate concentration in the liver and prevented liver fibrosis and necrosis. These effects suggest that quercetin might be a useful agent to preserve liver function and prevent systemic oxidative stress. PMID:21991520

  15. Calcitonin, as SMS 201-995, ameliorates the VIPoma syndrome.

    Science.gov (United States)

    Antonelli, A; Gambuzza, C; Bertoni, F; Baschieri, L

    1993-01-01

    A 72-year-old woman was referred to our hospital for diarrhea, abdominal and back pain, weight loss, low serum potassium level. Pathological findings and high circulating Vasoactive Intestinal Peptide (VIP) levels allowed us to diagnose "VIPoma syndrome". The patient underwent a treatment with SMS 201-995 with improvement of symptomatology and reduction of circulating VIP levels. After a wash-out period the patient was treated with salmon calcitonin with a net improvement of diarrhea, normalization of potassium serum level and reduction of VIP level. The symptomatology recurred after calcitonin withdrawal. These data confirm the effectiveness of SMS 201-995 in the VIPoma syndrome and suggest that calcitonin may ameliorate symptomatology and reduce circulating VIP level in patients with VIPoma tumor.

  16. Pleurotus eryngii Ameliorates Lipopolysaccharide-Induced Lung Inflammation in Mice

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    Junya Kawai

    2014-01-01

    Full Text Available Pleurotus eryngii (P. eryngii is consumed as a fresh cultivated mushroom worldwide and demonstrated to have multiple beneficial effects. We investigated the anti-inflammatory effect of P. eryngii in mice with acute lung injury (ALI. Intranasal instillation of lipopolysaccharide (LPS (10 μg/site/mouse induced marked lung inflammation (increase in the number of inflammatory cells, protein leakage, and production of nitric oxide in bronchoalveolar lavage fluid as well as histopathological damage in the lung, 6 h after treatment. Mice administered heat-treated P. eryngii (0.3–1 g/kg, p.o. (HTPE 1 h before LPS challenge showed decreased pulmonary inflammation and ameliorated histopathological damage. These results suggest that HTPE has anti-inflammatory effects against ALI. Thus, P. eryngii itself may also have anti-inflammatory effects and could be a beneficial food for the prevention of ALI induced by bacterial infection.

  17. Association of Rev-erbα in adipose tissues with Type 2 diabetes mellitus amelioration after gastric bypass surgery in Goto-Kakizaki rats.

    Science.gov (United States)

    Zhang, Rui; Yan, Caifeng; Zhou, Xinrong; Qian, Bangguo; Li, Fuqiang; Sun, Yidan; Shi, Chen; Li, Bing; Saito, Shigeru; Horimoto, Katsuhisa; Zhou, Huarong

    2013-07-15

    We estimated the key molecules related to Type 2 diabetes mellitus (T2DM) in adipose, liver, and muscle tissues, from nonobese diabetic Goto-Kakizaki (GK) rats and their Wistar controls, by computationally analyzing the expression profiles in open source data. With the aid of information from previous reports, Rev-erbα in adipose tissue emerged as one of the most plausible candidates. Here, in animal models, including GK rats surgically treated to ameliorate T2DM, we examined the association of Rev-erbα in adipose tissue with T2DM progression. After analyses of the Rev-erbα mRNA expression in the adipose tissue of our animal models, we compared the Rev-erbα protein expression levels in the adipose, liver, and muscle tissues of GK and Wistar controls at the ages of 1 mo (M), 3M, and 6M. The Rev-erbα protein levels in adipose tissue showed a distinctive pattern, with the negative correlation of an increasing trend in GK rats, and a decreasing trend in Wistar rats during aging, from those in liver and muscle tissues. Moreover, dysregulation of the circadian Rev-erbα expression in the adipose tissue of 6-mo-old GK rats was also observed. In particular, we ameliorated T2DM in GK rats by gastric bypass surgery, and revealed that T2DM amelioration in diabetic GK rats was associated with improved circadian Rev-erbα expression, in a comparison between the surgically treated and untreated GK rats. The roles of Rev-erbα in adipose tissue were further investigated by observations of Rev-erbα-related molecules, with reference to previous reports.

  18. Amelioration of arsenic toxicity by phosphate salts in mungbean seedlings.

    Science.gov (United States)

    Swarnakar, Arpita; Mukherji, Subhendu

    2005-07-01

    Sodium arsenate (Na2HAsO4.7H2O) is a potent inhibitor of mungbean seed germination and seedling growth. Germination is totally stopped at or above 50 microM Na2HAsO4.7H2O. Inhibition of seedling elongation started at a lower concentration of 5 microM As(V) and was drastically reduced at 20 microM As(V). Nutrients like salts of macroelements viz., NaH2PO4.2H2O, KH2PO4, K2SO4, MgSO4.7H2O, CaCl2.2H2O, (NH4)2SO4 NH4NO3 solutions at a concentration of 10mM and microelements viz., ZnSO4, CuSO4.5H2O, Na2MoO4.2H2O, MnCl2.4H2O, CoCl2.6H2O, FeSO4.7H2O solutions at a concentration of 1mM could help to ameliorate the toxic effects of As(V) to different degrees. Amelioration of As(V) toxicity was possible only when the mungbean seeds were pretreated with the above mentioned nutrients for 24 hr and then transferred to sodium arsenate. Simultaneous treatment of nutrients with As(V) or using nutrient solutions following As(V) treatment were of no help to reverse the toxic effects of sodium arsenate.

  19. Propofol ameliorates electroconvulsive shock-induced learning and memory impairment by regulation of synaptic metaplasticity via autophosphorylation of CaMKIIa at Thr 305 in stressed rats.

    Science.gov (United States)

    Ren, Li; Zhang, Fan; Min, Su; Hao, Xuechao; Qin, Peipei; Zhu, Xianlin

    2016-06-30

    Electroconvulsive therapy (ECT) is an effective treatment for depression, but it can induce learning and memory impairment. Our previous study found propofol (γ-aminobutyric acid (GABA) receptor agonist) could ameliorate electroconvulsive shock (ECS, an analog of ECT to animals)-induced cognitive impairment, however, the underlying molecular mechanisms remain unclear. This study aimed to investigate the effects of propofol on metaplasticity and autophosphorylation of CaMKIIa in stressed rats receiving ECS. Depressive-like behavior and learning and memory function were assessed by sucrose preference test and Morris water test respectively. LTP were tested by electrophysiological experiment, the expression of CaMKIIa, p-T305-CaMKII in hippocampus and CaMKIIα in hippocampal PSD fraction were evaluated by western blot. Results suggested ECS raised the baseline fEPSP and impaired the subsequent LTP, increased the expression of p-T305-CaMKII and decreased the expression of CaMKIIα in hippocampal PSD fraction, leading to cognitive dysfunction in stressed rats. Propofol could down-regulate the baseline fEPSP and reversed the impairment of LTP partly, decreased the expression of p-T305-CaMKII and increased the expression of CaMKIIα in hippocampal PSD fraction and alleviated ECS-induced learning and memory impairment. In conclusion, propofol ameliorates ECS-induced learning and memory impairment, possibly by regulation of synaptic metaplasticity via p-T305-CaMKII.

  20. Blockade of Angiotensin II type-1 receptor reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation.

    Science.gov (United States)

    Kurata, A; Nishizawa, H; Kihara, S; Maeda, N; Sonoda, M; Okada, T; Ohashi, K; Hibuse, T; Fujita, K; Yasui, A; Hiuge, A; Kumada, M; Kuriyama, H; Shimomura, I; Funahashi, T

    2006-11-01

    Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease (CKD) associated with metabolic syndrome. The aim of this study was to determine the effects of treatment with angiotensin II (Ang II) type-1 receptor blocker (ARB) on the regulation of adipocytokines. Olmesartan, an ARB, significantly blunted the age- and body weight-associated falls in plasma adiponectin both in genetically and diet-induced obese mice, without affecting body weight, but had no effect on plasma adiponectin levels in lean mice. Olmesartan also ameliorated dysregulation of adipocytokines in obesity, such as tumor necrosis factor-alpha, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, and serum amyloid A3. Olmesartan significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue. In cultured adipocytes, olmesartan acted as an antioxidant and improved adipocytokine dysregulation. Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated, at least in part, by targeting oxidative stress in obese adipose tissue. Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome-based CKD.

  1. 8-Hydroxy-2-deoxyguanosine ameliorates high-fat diet-induced insulin resistance and adipocyte dysfunction in mice.

    Science.gov (United States)

    Huh, Joo Young; Jung, Inji; Piao, Lingjuan; Ha, Hunjoo; Chung, Myung-Hee

    2017-09-30

    8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, has been recently shown to exert anti-inflammatory effects through inhibition of Rac1. Inflammation in adipose tissue is a hallmark of obesity-induced insulin resistance, but the therapeutic potential of 8-OHdG in treatment of metabolic diseases has not been fully elucidated. The aim of this study was to examine the effect of exogenously administered 8-OHdG on adipose tissue and whole body metabolism. In cultured adipocytes, 8-OHdG inhibited adipogenesis and reversed TNFα-induced insulin resistance. In high-fat diet (HFD)-induced obese mice, 8-OHdG administration blunted the rise in body weight and fat mass. The decrease in adipose tissue mass by 8-OHdG was due to reduced adipocyte hypertrophy through induction of adipose triglyceride lipase and inhibition of fatty acid synthase expression. 8-OHdG also inhibited the infiltration of macrophages, resulting in amelioration of adipose tissue inflammation and adipokine dysregulation. Moreover, 8-OHdG administration ameliorated adipocyte as well as systemic insulin sensitivity. Both in vivo and in vitro results showed that 8-OHdG induces AMPK activation and reduces JNK activation in adipocytes. In conclusion, our results show that orally administered 8-OHdG protects against HFD-induced metabolic disorders by regulating adipocyte metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4(+) T Cells.

    Science.gov (United States)

    Zou, Ying; Li, Wen-Yang; Wan, Zheng; Zhao, Bing; He, Zhi-Wei; Wu, Zhu-Guo; Huang, Guo-Liang; Wang, Jian; Li, Bin-Bin; Lu, Yang-Jia; Ding, Cong-Cong; Chi, Hong-Gang; Zheng, Xue-Bao

    2015-01-01

    Huangqin-Tang decoction (HQT) is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS), we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4(+) T cells subsets.

  3. Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4+ T Cells

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    Ying Zou

    2015-01-01

    Full Text Available Huangqin-Tang decoction (HQT is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD. This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS, we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4+ T cells subsets.

  4. Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide.

    Science.gov (United States)

    Howell, Matthew D; Ottesen, Eric W; Singh, Natalia N; Anderson, Rachel L; Singh, Ravindra N

    2017-06-07

    Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  5. Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.

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    Young-Eun Yoo

    Full Text Available Amyotrophic lateral sclerosis (ALS is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT, which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

  6. Dihydrotestosterone Ameliorates Degeneration in Muscle, Axons and Motoneurons and Improves Motor Function in Amyotrophic Lateral Sclerosis Model Mice

    Science.gov (United States)

    Yoo, Young-Eun; Ko, Chien-Ping

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients. PMID:22606355

  7. Neuroprotective effect and mechanism of daucosterol palmitate in ameliorating learning and memory impairment in a rat model of Alzheimer's disease.

    Science.gov (United States)

    Ji, Zhi-Hong; Xu, Zhong-Qi; Zhao, Hong; Yu, Xin-Yu

    2017-03-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory decline and cognitive impairment. Amyloid beta (Aβ) has been proposed as the causative role for the pathogenesis of AD. Accumulating evidence demonstrates that Aβ neurotoxicity is mediated by glutamate excitotoxicity. Daucosterol palmitate (DSP), a plant steroid with anti-glutamate excitotoxicity effect, was isolated from the anti-aging traditional Chinese medicinal herb Alpinia oxyphylla Miq. in our previous study. Based on the anti-glutamate excitotoxicity effect of DSP, in this study we investigated potential benefit and mechanism of DSP in ameliorating learning and memory impairment in AD model rats. Results from this study showed that DSP administration effectively ameliorated Aβ-induced learning and memory impairment in rats, markedly inhibited Aβ-induced hippocampal ROS production, effectively prevented Aβ-induced hippocampal neuronal damage and significantly restored hippocampal synaptophysin expression level. This study suggests that DSP may be a potential candidate for development as a therapeutic agent for AD cognitive decline. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice.

    Science.gov (United States)

    Gao, Xiang; Xu, Jie; Jiang, Chengzi; Zhang, Yi; Xue, Yong; Li, Zhaojie; Wang, Jingfeng; Xue, Changhu; Wang, Yuming

    2015-04-01

    Trimethylamine N-oxide (TMAO), a component commonly present in seafood, has been found to have a harmful impact on glucose tolerance in high-fat diet (HFD)-fed mice. However, seafood also contains fish oil (FO), which has been shown to have beneficial effects on metabolism. Here, we investigated the effect of FO on TMAO-induced impaired glucose tolerance in HFD-fed mice. Male C57BL/6 mice were randomly assigned to the high fat (HF), TMAO, and fish oil groups. The HF group was fed a diet containing 25% fat, the TMAO group was fed the HFD plus 0.2% TMAO, and the FO group was fed the HFD plus 0.2% TMAO and 2% fish oil for 12 weeks. After 10 weeks of feeding, oral glucose tolerance tests were performed. Dietary FO improved the fasting glucose level, the fasting insulin level, HOMA-IR value, QUICKI score and ameliorated TMAO-induced exacerbated impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signalling pathway, glycogen synthesis, gluconeogenesis, and glucose transport in peripheral tissues. Dietary fish oil also decreased TMAO-aggravated adipose tissue inflammation. Our results suggested that dietary FO ameliorated TMAO-induced impaired glucose tolerance, insulin signal transduction in peripheral tissue, and adipose tissue inflammation in HFD-fed mice.

  9. Chinese Herbal Preparation Xuebijing Potently Inhibits Inflammasome Activation in Hepatocytes and Ameliorates Mouse Liver Ischemia-Reperfusion Injury.

    Directory of Open Access Journals (Sweden)

    Xiqiang Liu

    Full Text Available The Chinese herb preparation Xuebijing injection (XBJ has been widely used in the management of various septic disorders or inflammation-related conditions, however the molecular mechanism of its anti-inflammatory effect remains largely elusive. In the current study, we found that XBJ treatment potently ameliorated mouse hepatic ischemia-reperfusion (IR injury, manifested as decreased liver function tests (LDH, ALT, AST, improved inflammation and less hepatocyte apoptosis. Notably, XBJ markedly inhibited inflammasome activation and IL-1 production in mouse livers subjected to IRI, even in the absence of Kupffer cells, suggesting Kupffer cells are not necessary for hepatic inflammasome activation upon Redox-induced sterile inflammation. This finding led us to investigate the role of XBJ on hepatocyte apoptosis and inflammasome activation using an in vitro hydrogen peroxide (H2O2-triggered hepatocyte injury model. Our data clearly demonstrated that XBJ potently inhibited apoptosis, as well as caspase-1 cleavage and IL-1β production in a time- and dose-dependent manner in isolated hepatocytes, suggesting that in addition to its known modulatory effect on NF-κB-dependent inflammatory gene expression, it also has a direct impact on hepatocyte inflammasome activation. The current study not only deepens our understanding of how XBJ ameliorates inflammation and apoptosis, but also has immediate practical significance in many clinical situations such as partial hepatectomy, liver transplantation, etc.

  10. A fusion protein composed of IL-2 and caspase-3 ameliorates the outcome of experimental inflammatory colitis.

    Science.gov (United States)

    Sagiv, Yuval; Kaminitz, Ayelet; Lorberboum-Galski, Haya; Askenasy, Nadir; Yarkoni, Shai

    2009-09-01

    Targeted depletion of immune cells expressing the interleukin-2 (IL-2) receptor can exacerbate inflammatory bowel disease (IBD) through elimination of regulatory T (Treg) cells, or ameliorate its course by depletion of cytotoxic cells. To answer this question we used a fusion protein composed of IL-2 and caspase-3 (IL2-cas) in an experimental model of DSS-induced toxic colitis. In a preventive setting, co-administration of DSS with a daily therapeutic dose of IL2-cas for seven days improved all disease parameters. Although CD4(+)CD25(+) T cells were depleted in the mesenteric lymph nodes, a fractional increase in CD4(+)FoxP3(+) T cells was observed in the spleen. Likewise, IL2-cas therapy improved the outcome of established disease in a chronic model of colitis. These data demonstrate that therapies that use IL-2 as a targeting moiety exert a protective effect over the colon under conditions of inflammation. The efficacy of IL-2-targeted therapy is attributed to reduced activity of reactive T cells, which ameliorates the secondary inflammatory infiltration. IL2-cas evolves as a potential therapeutic tool in IBD.

  11. Lupeol acetate ameliorates collagen-induced arthritis and osteoclastogenesis of mice through improvement of microenvironment.

    Science.gov (United States)

    Wang, Wei-Hsun; Chuang, Hui-Yen; Chen, Chien-Hui; Chen, Wun-Ke; Hwang, Jeng-Jong

    2016-04-01

    Lupeol has been shown with anti-inflammation and antitumor capability, however, the poor bioavailability limiting its applications in living subjects. Lupeol acetate (LA), a derivative of lupeol, shows similar biological activities as lupeol but with better bioavailability. Here RAW 264.7 cells and bone marrow-derived macrophages (BMDMs) stimulated by lipopolysaccharide (LPS) were treated with 0-80μM of LA, and assayed for TNF-α, IL-1β, COX-2, MCP-1 using Western blotting. Moreover, osteoclatogenesis was examined with reverse transcription PCR (RT-PCR) and tartrate-resistant acid phosphatase (TRAP) staining. For in vivo study, collagen-induced arthritis (CIA)-bearing DBA/1J mice were randomly separated into three groups: vehicle, LA-treated (50mg/kg) and curcumin-treated (100mg/kg). Therapeutic efficacies were assayed by the clinical score, expression levels of serum cytokines including TNF-α and IL-1β, (18)F-fluorodeoxyglucose ((18)F-FDG) microPET/CT and histopathology. The results showed that LA could inhibit the activation, migration, and formation of osteoclastogenesis of macrophages in a dose-dependent manner. In RA-bearing mice, the expressions of inflammation-related cytokines were suppressed, and clinical symptoms and bone erosion were ameliorated by LA. The accumulation of (18)F-FDG in the joints of RA-bearing mice was also significantly decreased by LA. The results indicate that LA significantly improves the symptoms of RA by down-regulating expressions of inflammatory cytokines and osteoclastogenesis.

  12. Extracts from two ubiquitous Mediterranean plants ameliorate cellular and animal models of neurodegenerative proteinopathies.

    Science.gov (United States)

    Briffa, Michelle; Ghio, Stephanie; Neuner, Johanna; Gauci, Alison J; Cacciottolo, Rebecca; Marchal, Christelle; Caruana, Mario; Cullin, Christophe; Vassallo, Neville; Cauchi, Ruben J

    2017-01-18

    A signature feature of age-related neurodegenerative proteinopathies is the misfolding and aggregation of proteins, typically amyloid-β (Aβ) in Alzheimer's disease (AD) and α-synuclein (α-syn) in Parkinson's disease (PD), into soluble oligomeric structures that are highly neurotoxic. Cellular and animal models that faithfully replicate the hallmark features of these disorders are being increasing exploited to identify disease-modifying compounds. Natural compounds have been identified as a useful source of bioactive molecules with promising neuroprotective capabilities. In the present report, we investigated whether extracts derived from two ubiquitous Mediterranean plants namely, the prickly pear Opuntia ficus-indica (EOFI) and the brown alga Padina pavonica (EPP) alleviate neurodegenerative phenotypes in yeast (Saccharomyces cerevisiae) and fly (Drosophila melanogaster) models of AD and PD. Pre-treatment with EPP or EOFI in the culture medium significantly improved the viability of yeast expressing the Arctic Aβ42 (E22G) mutant. Supplementing food with EOFI or EPP dramatically ameliorated lifespan and behavioural signs of flies with brain-specific expression of wild-type Aβ42 (model of late-onset AD) or the Arctic Aβ42 variant (model of early-onset AD). Additionally, we show that either extract prolonged the survival of a PD fly model based on transgenic expression of the human α-syn A53T mutant. Taken together, our findings suggest that the plant-derived extracts interfere with shared mechanisms of neurodegeneration in AD and PD. This notion is strengthened by evidence demonstrating that EOFI and to a greater extent EPP, while strongly inhibiting the fibrillogenesis of both Aβ42 and α-syn, accumulate remodelled oligomeric aggregates that are less effective at disrupting lipid membrane integrity. Our work therefore opens new avenues for developing therapeutic applications of these natural plant extracts in the treatment of amyloidogenic

  13. Elemol from Chamaecyparis obtusa ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis.

    Science.gov (United States)

    Yang, Hyun; Jung, Eui-Man; Ahn, Changhwan; Lee, Geun-Shik; Lee, Su-Yeon; Kim, Seon-Hong; Choi, In-Gyu; Park, Mi-Jin; Lee, Sung-Suk; Choi, Don-Ha; Jeung, Eui-Bae

    2015-08-01

    Chamaecyparis obtusa has been traditionally used as an antibiotic agent and in cosmetics for the prevention of microorganism infection and skin troubles. Atopic dermatitis (AD) is a chronic inflammatory skin disease that encompasses immunologic responses, susceptibility factors and compromised skin-barrier function. Use of plant medicines in therapeutic treatment of AD has recently been suggested as an alternative therapeutic option. The present study examined the effect of elemol, an active component of Chamaecyparis obtusa, on AD using in vivo and in vitro models. RBL-2H3 cells were stimulated with concanavalin A and dinitrophenyl human serum albumin, and atopic dermatitis was induced in BALB/c mice by topical application of 2,4-dinitrochlorobenzene (DNCB) prior to elemol treatment. The mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction, and the levels of β-hexosaminidase and serum immunoglobulin E (IgE) were examined by ELISA. Histological changes were also performed by microscopy. Elemol attenuated the onset of AD-like skin lesions, reduced serum IgE levels and decreased mast cell infiltration into the dermis and hypodermis. In addition, elemol downregulated the transcriptional expression of several pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IκBα, in the skin of the DNCB-induced animal models of AD. In the RBL-2H3 mast cell line, elemol significantly inhibited the mRNA expression of IL-4 and IL-13, and further attenuated the release of β-hexosaminidase from mast cells. Histological examination revealed that elemol significantly ameliorated the DNCB-induced dermal destruction in mice. The results of the present study suggested that elemol may have therapeutic potential in the treatment of AD due to its immunosuppressive effects.

  14. Epigenetic intervention with a BET inhibitor ameliorates acute retinal ganglion cell death in mice

    Science.gov (United States)

    Li, Jun; Zhao, Lei; Urabe, Go; Fu, Yingmei

    2017-01-01

    Purpose The bromo and extraterminal (BET) epigenetic “reader” family is becoming an appealing new therapeutic target for several common diseases, yet little is known of its role in retinal neurodegeneration. We explored the potential of BET inhibition in the protection of retinal ganglion cells (RGCs). Methods To test the therapeutic effect of JQ1, an inhibitor highly selective for the BET family of proteins, we used an acute RGC damage model induced by N-methyl-D-aspartic acid (NMDA) excitotoxicity. Adult C57BL/6 mice received an intravitreal injection of NMDA with (or without) JQ1 in one eye and vehicle control in the contralateral eye; RGC loss was assessed on retinal sections and whole mounts. Gene expression and apoptosis were analyzed by quantitative real time (RT)-PCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), respectively. For counting RGCs, immunostaining of the marker protein BRN3A was performed on whole mounts. Results NMDA treatment eliminated RGCs (day 7 and day 14 post injection) and diminished the expression (mRNAs) of RGC-selective genes, including Thy1, Nrn1, Sncg, and Nfl (day 3 and day 7). In contrast, co-injection with JQ1 maintained the number and gene expression of RGCs at ~2 fold of the control (NMDA only, no JQ1), and it decreased NMDA-induced TUNEL-positive cells in the RGC layer by 35%. While NMDA treatment dramatically upregulated mRNAs of inflammatory cytokines (TNFα, IL-1β, MCP-1, RANTES) in retinal homogenates, co-injection with JQ1 suppressed their upregulation by ~50%. Conclusions Intravitreal injection of a BET inhibitor (JQ1) ameliorates NMDA-induced RGC death, revealing the RGC-protective potential of pharmacological blockage of the BET family. This new strategy of epigenetic intervention may be extended to other retinal degenerative conditions. PMID:28356707

  15. Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: Possible mechanism of nephroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Sahu, Bidya Dhar [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Tatireddy, Srujana [National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037 (India); Koneru, Meghana [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Borkar, Roshan M. [National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Kumar, Jerald Mahesh [CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500 007 (India); Kuncha, Madhusudana [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Srinivas, R. [National Centre for Mass Spectrometry, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India); Shyam Sunder, R. [Faculty of Pharmacy, Osmania University, Hyderabad 500 007 (India); Sistla, Ramakrishna, E-mail: sistla@iict.res.in [Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500 007 (India)

    2014-05-15

    Gentamicin-induced nephrotoxicity has been well documented, although its underlying mechanisms and preventive strategies remain to be investigated. The present study was designed to investigate the protective effect of naringin, a bioflavonoid, on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific renal function parameters (blood urea nitrogen and creatinine) and histopathology of kidney tissues were evaluated to assess the gentamicin-induced nephrotoxicity. Renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic and non-enzymatic antioxidants), inflammatory (NF-kB [p65], TNF-α, IL-6 and MPO) and apoptotic (caspase 3, caspase 9, Bax, Bcl-2, p53 and DNA fragmentation) markers were also evaluated. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicated the gentamicin-induced mitochondrial dysfunction. Naringin (100 mg/kg) treatment along with gentamicin restored the mitochondrial function and increased the renal endogenous antioxidant status. Gentamicin induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65) and NF-κB-DNA binding activity and myeloperoxidase (MPO) activity were significantly decreased upon naringin treatment. In addition, naringin treatment significantly decreased the amount of cleaved caspase 3, Bax, and p53 protein expression and increased the Bcl-2 protein expression. Naringin treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. U-HPLS-MS data revealed that naringin co-administration along with gentamicin did not alter the renal uptake and/or accumulation of gentamicin in kidney tissues. These findings suggest that naringin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction, inflammation and apoptosis in

  16. Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism.

    Science.gov (United States)

    Tyler, Christina R; Solomon, Benjamin R; Ulibarri, Adam L; Allan, Andrea M

    2014-09-01

    Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism.

  17. Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets

    Directory of Open Access Journals (Sweden)

    Lee Yun

    2012-08-01

    Full Text Available Abstract Background Arctium lappa L. (Asteraceae, burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD. Method EAL-I (100 mg·kg−1/day, EAL-II (200 mg·kg−1/day, and fluvastatin (3 mg·kg−1/day groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Results Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM-1, vascular cell adhesion molecule (VCAM-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. Conclusion The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.

  18. Vulnerability of Gastric Mucosa in Diabetic Rats, Its Pathogenesis and Amelioration by Cuminum cyminum.

    Science.gov (United States)

    Vador, N; Jagtap, Aarti G; Damle, Archana

    2012-09-01

    Various studies have indicated that peptic ulcers occurring during the course of diabetic state are more severe and often associated with complications such as gastrointestinal bleeding. This study is the first attempt to understand the pathogenesis of gastric ulcers occurring during the diabetic state considering alternate biochemical pathways using suitable markers and its amelioration by Cuminum cyminum. In this study, diabetic rats showed a progressive increase in the stomach advanced glycated end products formation, gastric mucosal tumour necrosis factor-α and Thiobarbituric acid reactive substances levels as compared to normal control (nondiabetic) rats. There was decrease in gastric mucosal content, antioxidant enzymes and cellular ATPase enzyme levels of diabetic gastric mucosa when compared to the normal control group. mRNA expression of epidermal growth factor was found to be significantly higher as compared to normal control animals. Further methanol extract of Cuminum cyminum treatment to diabetic animals caused a reduction in blood glucose, and ulcer score when compared to diabetic control rats. It significantly increased gastric mucus content, antioxidant status and cellular ATPase enzyme levels as compared to diabetic control animals. Methanol extract of Cuminum cyminum inhibited advanced glycated end products formation in vitro as well as in vivo.

  19. Vulnerability of gastric mucosa in diabetic rats, its pathogenesis and amelioration by Cuminum cyminum

    Directory of Open Access Journals (Sweden)

    N Vador

    2012-01-01

    Full Text Available Various studies have indicated that peptic ulcers occurring during the course of diabetic state are more severe and often associated with complications such as gastrointestinal bleeding. This study is the first attempt to understand the pathogenesis of gastric ulcers occurring during the diabetic state considering alternate biochemical pathways using suitable markers and its amelioration by Cuminum cyminum. In this study, diabetic rats showed a progressive increase in the stomach advanced glycated end products formation, gastric mucosal tumour necrosis factor-α and Thiobarbituric acid reactive substances levels as compared to normal control (nondiabetic rats. There was decrease in gastric mucosal content, antioxidant enzymes and cellular ATPase enzyme levels of diabetic gastric mucosa when compared to the normal control group. mRNA expression of epidermal growth factor was found to be significantly higher as compared to normal control animals. Further methanol extract of Cuminum cyminum treatment to diabetic animals caused a reduction in blood glucose, and ulcer score when compared to diabetic control rats. It significantly increased gastric mucus content, antioxidant status and cellular ATPase enzyme levels as compared to diabetic control animals. Methanol extract of Cuminum cyminum inhibited advanced glycated end products formation in vitro as well as in vivo.

  20. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1

    Science.gov (United States)

    Yu, Bo; Shao, Hui; Su, Chang; Jiang, Yuanfeng; Chen, Xiteng; Bai, Lingling; Zhang, Yan; Li, Qiutang; Zhang, Xiaomin; Li, Xiaorong

    2016-01-01

    Although accumulated evidence supports the notion that mesenchymal stem cells (MSCs) act in a paracrine manner, the mechanisms are still not fully understood. Recently, MSC-derived exosomes (MSC-Exos), a type of microvesicle released from MSCs, were thought to carry functional proteins and RNAs to recipient cells and play therapeutic roles. In the present study, we intravitreally injected MSCs derived from either mouse adipose tissue or human umbilical cord, and their exosomes to observe and compare their functions in a mouse model of laser-induced retinal injury. We found that both MSCs and their exosomes reduced damage, inhibited apoptosis, and suppressed inflammatory responses to obtain better visual function to nearly the same extent in vivo. Obvious down-regulation of monocyte chemotactic protein (MCP)-1 in the retina was found after MSC-Exos injection. In vitro, MSC-Exos also down-regulated MCP-1 mRNA expression in primarily cultured retinal cells after thermal injury. It was further demonstrated that intravitreal injection of an MCP-1-neutralizing antibody promoted the recovery of retinal laser injury, whereas the therapeutic effect of exosomes was abolished when MSC-Exos and MCP-1 were administrated simultaneously. Collectively, these results suggest that MSC-Exos ameliorate laser-induced retinal injury partially through down-regulation of MCP-1. PMID:27686625

  1. Paeoniflorin ameliorates acute necrotizing pancreatitis and pancreatitis‑induced acute renal injury.

    Science.gov (United States)

    Wang, Peng; Wang, Weixing; Shi, Qiao; Zhao, Liang; Mei, Fangchao; Li, Chen; Zuo, Teng; He, Xiaobo

    2016-08-01

    Acute renal injury caused by acute necrotizing pancreatitis (ANP) is a common complication that is associated with a high rate of mortality. Paeoniflorin is the active ingredient of paeonia radix and exhibits a number of pharmacological effects, such as anti‑inflammatory, anticancer, analgesic and immunomodulatory effects. The present study detected the potential treatment effects of paeoniflorin on acute renal injury induced by ANP in a rat model. The optimal dose of paeoniflorin for preventing acute renal injury induced by ANP was determined. Then, the possible protective mechanism of paeoniflorin was investigated. The serum levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β and IL‑6 were measured with enzyme‑linked immunosorbent assay kits. Renal inflammation and apoptosis were measured by immunohistochemistry and terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling assay. The expression of nitric oxide in kidney tissues was also evaluated. The p38 mitogen‑activated protein kinases (MAPKs) were measured by western blotting. The results shown that paeoniflorin may ameliorate acute renal injury following ANP in rats by inhibiting inflammatory responses and renal cell apoptosis. These effects may be associated with the p38MAPK and nuclear factor‑κB signal pathway.

  2. Periploca forrestii Saponin Ameliorates Murine CFA-Induced Arthritis by Suppressing Cytokine Production.

    Science.gov (United States)

    Liu, Yingqin; Li, Minghui; He, Qiuhong; Yang, Xinping; Ruan, Fang; Sun, Guangchen

    2016-01-01

    Periploca forrestii Schltr. has been used as a Chinese folk medicine due to its versatile pharmacological effects such as promoting wounds and rheumatoid arthritis. However, the antiarthritic activity of Periploca forrestii saponin (PFS) and its active compound Periplocin has still not been demonstrated. Here, we evaluated the antiarthritic effects of PFS in adjuvant-induced arthritis (AIA) rats by intragastric administration at a dose of 50 mg/kg. The anti-inflammatory activities of Periplocin were also examined in LPS-induced AIA splenocytes and synoviocytes. PFS significantly ameliorated joint swelling; inhibited bone erosion in joints; lowered levels of IL-6 and TGF-β1 in AIA rat splenocyte; and reduced joint protein expression levels of phospho-STAT3 and IKKα. Using LPS-induced AIA splenocytes, we demonstrate that Periplocin suppressed the key proinflammatory cytokines levels of IL-6, IFN-γ, TGF-β1, and IL-13 and IL-22 and transcription factor levels of T-bet, GATA3, and C-Jun genes. Periplocin also suppressed LPS-induced cytokine secretion from synoviocytes. Our study highlights the antiarthritic activity of PFS and its derived Periplocin and the underlying mechanisms. These results provide a strong rationale for further testing and validation of the use of Periploca forrestii Schltr. as an alternative modality for the treatment of RA.

  3. C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes.

    Science.gov (United States)

    Khan, Mahmood; Varadharaj, Saradhadevi; Shobha, Jagdish C; Naidu, Madireddi U; Parinandi, Narasimham L; Kutala, Vijay Kumar; Kuppusamy, Periannan

    2006-01-01

    Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.

  4. Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice.

    Science.gov (United States)

    Li, Zhigui; Hao, Shuang; Yin, Hongqiang; Gao, Jing; Yang, Zhuo

    2016-05-15

    The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3-MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1-mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms.

  5. Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets.

    Science.gov (United States)

    Lee, Yun Jung; Choi, Deok Ho; Cho, Guk Hyun; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

    2012-08-06

    Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). EAL-I (100 mg·kg-1/day), EAL-II (200 mg·kg-1/day), and fluvastatin (3 mg·kg-1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.

  6. Ac-SDKP ameliorates the progression of lupus nephritis in MRL/lpr mice.

    Science.gov (United States)

    Tan, Hechang; Zhao, Jijun; Wang, Shuang; Zhang, Lili; Wang, Hongyue; Huang, Bin; Liang, Yingjie; Yu, Xueqing; Yang, Niansheng

    2012-12-01

    N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is an endogenous tetrapeptide which can inhibit the differentiation, migration and activation of macrophages and suppress the proliferation of fibroblast. This study examined the effects of Ac-SDKP on the progression of lupus nephritis (LN). MRL/lpr mice received subcutaneous infusion of Ac-SDKP (1.0 mg kg(-1) d(-1)) or vehicle through implanted osmotic mini-pumps from 12 to 20 weeks until being euthanized. MRL/MpJ mice served as normal controls. The data indicative of renal inflammation and fibrosis were evaluated before and after treatment. Ac-SDKP-treated MRL/lpr mice showed reduced proteinuria and improved renal function compared with vehicle-treated controls. Ac-SDKP-treated mice demonstrated decreased inflammatory infiltrates of T cells and macrophages in the kidneys as compared to vehicle-treated animals. The treatment also inhibited the activation of NF-κB and production of TNF-α. Despite this, immune complex deposition and plasma anti-dsDNA levels were not statistically different between the two groups. In addition, the treatment inhibited renal expression of TGF-β1, α-SMA and fibronectin as well as the phosphorylation of Smad2/3. Ac-SDKP treatment ameliorated LN through exerting anti-inflammatory and anti-fibrotic effects on MRL/lpr mice, providing therapeutic potential for halting the progression of LN.

  7. Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver.

    Science.gov (United States)

    Shimada, Shingo; Wakayama, Kenji; Fukai, Moto; Shimamura, Tsuyoshi; Ishikawa, Takahisa; Fukumori, Daisuke; Shibata, Maki; Yamashita, Kenichiro; Kimura, Taichi; Todo, Satoru; Ohsawa, Ikuroh; Taketomi, Akinobu

    2016-12-01

    Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H2 (+) and H2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H2 (+) group, these harmful changes were significantly suppressed [vs. H2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter. Copyright © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  8. Paeoniflorin Ameliorates Experimental Autoimmune Encephalomyelitis via Inhibition of Dendritic Cell Function and Th17 Cell Differentiation

    Science.gov (United States)

    Zhang, Han; Qi, Yuanyuan; Yuan, Yuanyang; Cai, Li; Xu, Haiyan; Zhang, Lili; Su, Bing; Nie, Hong

    2017-01-01

    Paeoniflorin (PF) is a monoterpene glycoside and exhibits multiple effects, including anti-inflammation and immunoregulation. To date, the effect of PF on multiple sclerosis (MS) has not been investigated. In this study, we investigated the effect of PF in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. After administered with PF, the onset and clinical symptoms of EAE mice were significantly ameliorated, and the number of Th17 cells infiltrated in central nervous system (CNS) and spleen was also dramatically decreased. Instead of inhibiting the differentiation of Th17 cells directly, PF influenced Th17 cells via suppressing the expression of costimulatory molecules and the production of interlukin-6 (IL-6) of dendritic cells (DCs) in vivo and in vitro, which may be attributable to the inhibition of IKK/NF-κB and JNK signaling pathway. When naïve CD4+ T cells were co-cultured with PF-treated dendritic cells under Th17-polarizing condition, the percentage of Th17 cells and the phosphorylation of STAT3 were decreased, as well as the mRNA levels of IL-17, RORα, and RORγt. Our study provided insights into the role of PF as a unique therapeutic agent for the treatment of multiple sclerosis and illustrated the underlying mechanism of PF from a new perspective. PMID:28165507

  9. Apoptotic signaling through Fas and TNF receptors ameliorates GVHD in mobilized peripheral blood grafts.

    Science.gov (United States)

    Mizrahi, K; Yaniv, I; Ash, S; Stein, J; Askenasy, N

    2014-05-01

    Mobilized peripheral blood (mPB) is a prevalent source of hematopoietic progenitors for transplantation; however, allogeneic and haploidentical transplants are often accompanied by severe GVHD. Following the observation that murine GVHD is ameliorated by pretransplant donor cell exposure to Fas-ligand (FasL) without host-specific sensitization, we assessed the susceptibility of mPB cells to spontaneous and receptor-induced apoptosis as a possible approach to GVHD prophylaxis. Short incubation for 4 h resulted in spontaneous apoptosis of 50% of the T and B lymphocytes and 60% myeloid cells. Although expression of Fas and TNF-R1 was proportionate to fractional apoptosis, cell death was dominated by spontaneous apoptosis. Functional assays revealed that the death receptors modulated mPB graft composition as compared with incubation in medium, without detectable quantitative variations. Removal of dead cells increased the frequency of mPB myeloid progenitors (P<0.001 vs medium), and recipients of mPB exposed to death ligands displayed reduced GVHD (P<0.01 vs medium) and improved survival following lipopolysacharide stimulation. mPB grafts exposed to the apoptotic challenge retained SCID reconstituting potential and graft versus tumor activity. These data emphasize that short-term exposure of mPB grafts to an apoptotic challenge is effective in reduction of GVHD effector activity.

  10. The wnt/β-catenin signaling pathway participates in rhein ameliorating kidney injury in DN mice.

    Science.gov (United States)

    Duan, Suyan; Wu, Yingyi; Zhao, Chuanyan; Chen, Mingyu; Yuan, Yanggang; Xing, Changying; Zhang, Bo

    2016-01-01

    The present study aimed to investigate the relationship between wnt/β-catenin signaling pathway and kidney impairment in diabetic nephropathy (DN) mice as well as the renoprotective effect of rhein (RH). Mice were randomly divided into four groups (n = 6): db/db mice treated with RH (DN + RH), db/db mice (DN), db/m mice treated with RH (NC + RH) and db/m mice (NC). RH-treated groups were administered orally at a daily dose 120 mg/kg. Mice were sacrificed after 12 weeks of treatments. In our study, increased albuminuria, together with weight gain and hyperglycemia was observed in the beginning of the study and continued to increase throughout the length of the study (12 weeks). Histopathologic changes were observed in the DN group. Expectedly, mice receiving the treatment with RH were protected from this injury. Meanwhile, the expression of nephrin, a podocyte-specific marker, was significantly reduced while wnt1, p-GSK-3β/tGSK-3β, p-β-catenin/tβ-catenin were higher in the DN group mice when analyzed by immunofluorescence and Western blotting. RH reversed these above changes. wnt/β-catenin signaling pathway participates in RH ameliorating kidney injury in DN mice. The manipulation of RH might act as a promising therapeutic intervention for DN.

  11. Curcuma oil ameliorates insulin resistance & associated thrombotic complications in hamster & rat

    Directory of Open Access Journals (Sweden)

    Vishal Singh

    2015-01-01

    Full Text Available Background & objectives: Curcuma oil (C. oil isolated from turmeric (Curcuma longa L. has been shown to have neuro-protective, anti-cancer, antioxidant and anti-hyperlipidaemic effects in experimental animal models. However, its effect in insulin resistant animals remains unclear. The present study was carried out to investigate the disease modifying potential and underlying mechanisms of the C. oil in animal models of diet induced insulin resistance and associated thrombotic complications. Methods: Male Golden Syrian hamsters on high fructose diet (HFr for 12 wk were treated orally with vehicle, fenofibrate (30 mg/kg or C. oil (300 mg/kg in the last four weeks. Wistar rats fed HFr for 12 wk were treated orally with C. oil (300 mg/kg in the last two weeks. To examine the protective effect of C. oil, blood glucose, serum insulin, platelet aggregation, thrombosis and inflammatory markers were assessed in these animals. Results: Animals fed with HFr diet for 12 wk demonstrated hyperlipidaemia, hyperglycaemia, hyperinsulinaemia, alteration in insulin sensitivity indices, increased lipid peroxidation, inflammation, endothelial dysfunction, platelet free radical generation, tyrosine phosphorylation, aggregation, adhesion and intravascular thrombosis. Curcuma oil treatment for the last four weeks in hamsters ameliorated HFr-induced hyperlipidaemia, hyperglycaemia, insulin resistance, oxidative stress, inflammation, endothelial dysfunction, platelet activation, and thrombosis. In HFr fed hamsters, the effect of C. oil at 300 mg/kg [ ] was comparable with the standard drug fenofibrate. Curcuma oil treatment in the last two weeks in rats ameliorated HFr-induced hyperglycaemia and hyperinsulinaemia by modulating hepatic expression of sterol regulatory element binding protein 1c (SREBP-1c, peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α and PGC-1β genes known to be involved in lipid and glucose metabolism. Interpretation

  12. Curcuma oil ameliorates insulin resistance & associated thrombotic complications in hamster & rat.

    Science.gov (United States)

    Singh, Vishal; Jain, Manish; Misra, Ankita; Khanna, Vivek; Prakash, Prem; Malasoni, Richa; Dwivedi, Anil Kumar; Dikshit, Madhu; Barthwal, Manoj Kumar

    2015-06-01

    Curcuma oil (C. oil) isolated from turmeric (Curcuma longa L.) has been shown to have neuro-protective, anti-cancer, antioxidant and anti-hyperlipidaemic effects in experimental animal models. However, its effect in insulin resistant animals remains unclear. The present study was carried out to investigate the disease modifying potential and underlying mechanisms of the C. oil in animal models of diet induced insulin resistance and associated thrombotic complications. Male Golden Syrian hamsters on high fructose diet (HFr) for 12 wk were treated orally with vehicle, fenofibrate (30 mg/kg) or C. oil (300 mg/kg) in the last four weeks. Wistar rats fed HFr for 12 wk were treated orally with C. oil (300 mg/kg) in the last two weeks. To examine the protective effect of C. oil, blood glucose, serum insulin, platelet aggregation, thrombosis and inflammatory markers were assessed in these animals. Animals fed with HFr diet for 12 wk demonstrated hyperlipidaemia, hyperglycaemia, hyperinsulinaemia, alteration in insulin sensitivity indices, increased lipid peroxidation, inflammation, endothelial dysfunction, platelet free radical generation, tyrosine phosphorylation, aggregation, adhesion and intravascular thrombosis. Curcuma oil treatment for the last four weeks in hamsters ameliorated HFr-induced hyperlipidaemia, hyperglycaemia, insulin resistance, oxidative stress, inflammation, endothelial dysfunction, platelet activation, and thrombosis. In HFr fed hamsters, the effect of C. oil at 300 mg/kg [ ] was comparable with the standard drug fenofibrate. Curcuma oil treatment in the last two weeks in rats ameliorated HFr-induced hyperglycaemia and hyperinsulinaemia by modulating hepatic expression of sterol regulatory element binding protein 1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1)α and PGC-1β genes known to be involved in lipid and glucose metabolism. High fructose feeding to rats and hamsters led to the development of insulin

  13. Biologically Synthesized Gold Nanoparticles Ameliorate Cold and Heat Stress-Induced Oxidative Stress in Escherichia coli

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    Xi-Feng Zhang

    2016-06-01

    Full Text Available Due to their unique physical, chemical, and optical properties, gold nanoparticles (AuNPs have recently attracted much interest in the field of nanomedicine, especially in the areas of cancer diagnosis and photothermal therapy. Because of the enormous potential of these nanoparticles, various physical, chemical, and biological methods have been adopted for their synthesis. Synthetic antioxidants are dangerous to human health. Thus, the search for effective, nontoxic natural compounds with effective antioxidative properties is essential. Although AuNPs have been studied for use in various biological applications, exploration of AuNPs as antioxidants capable of inhibiting oxidative stress induced by heat and cold stress is still warranted. Therefore, one goal of our study was to produce biocompatible AuNPs using biological methods that are simple, nontoxic, biocompatible, and environmentally friendly. Next, we aimed to assess the antioxidative effect of AuNPs against oxidative stress induced by cold and heat in Escherichia coli, which is a suitable model for stress responses involving AuNPs. The response of aerobically grown E. coli cells to cold and heat stress was found to be similar to the oxidative stress response. Upon exposure to cold and heat stress, the viability and metabolic activity of E. coli was significantly reduced compared to the control. In addition, levels of reactive oxygen species (ROS and malondialdehyde (MDA and leakage of proteins and sugars were significantly elevated, and the levels of lactate dehydrogenase activity (LDH and adenosine triphosphate (ATP significantly lowered compared to in the control. Concomitantly, AuNPs ameliorated cold and heat-induced oxidative stress responses by increasing the expression of antioxidants, including glutathione (GSH, glutathione S-transferase (GST, super oxide dismutase (SOD, and catalase (CAT. These consistent physiology and biochemical data suggest that AuNPs can ameliorate cold and

  14. Paroxetine ameliorates changes in hippocampal energy metabolism in chronic mild stress-exposed rats

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    Khedr LH

    2015-11-01

    Full Text Available Lobna H Khedr, Noha N Nassar, Ezzeldin S El-Denshary, Ahmed M Abdel-tawab 1Department of Pharmacology, Faculty of Pharmacy, Misr International University, 2Department of Pharmacology, Faculty of Pharmacy, Cairo University, 3Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt Abstract: The molecular mechanisms underlying stress-induced depression have not been fully outlined. Hence, the current study aimed at testing the link between behavioral changes in chronic mild stress (CMS model and changes in hippocampal energy metabolism and the role of paroxetine (PAROX in ameliorating these changes. Male Wistar rats were divided into three groups: vehicle control, CMS-exposed rats, and CMS-exposed rats receiving PAROX (10 mg/kg/day intraperitoneally. Sucrose preference, open-field, and forced swimming tests were carried out. Corticosterone (CORT was measured in serum, while adenosine triphosphate and its metabolites, cytosolic cytochrome-c (Cyt-c, caspase-3 (Casp-3, as well as nitric oxide metabolites (NOx were measured in hippocampal tissue homogenates. CMS-exposed rats showed a decrease in sucrose preference as well as body weight compared to control, which was reversed by PAROX. The latter further ameliorated the CMS-induced elevation of CORT in serum (91.71±1.77 ng/mL vs 124.5±4.44 ng/mL, P<0.001 as well as the changes in adenosine triphosphate/adenosine diphosphate (3.76±0.02 nmol/mg protein vs 1.07±0.01 nmol/mg protein, P<0.001. Furthermore, PAROX reduced the expression of Cyt-c and Casp-3, as well as restoring NOx levels. This study highlights the role of PAROX in reversing depressive behavior associated with stress-induced apoptosis and changes in hippocampal energy metabolism in the CMS model of depression. Keywords: rats, CMS, hippocampus, paroxetine, apoptosis, adenine nucleotides, cytochrome-c, caspase-3

  15. Mesenchymal stem cells transplantation mildly ameliorates experimental diabetic nephropathy in rats

    Institute of Scientific and Technical Information of China (English)

    ZHOU Hong; TIAN Hao-ming; LONG Yang; ZHANG Xiang-xun; ZHONG Li; DENG Li; CHEN Xiao-he; LI Xiu-qun

    2009-01-01

    Background Diabetic nephropathy is a common complication of diabetes mellitus.This study aimed to explore whether mesenchymal stem cells(MSCs)transplantation could attenuate diabetic nephropathy in experimental diabetic rats.Methods Sprague-Dawley rats received a single intraperitoneal injection of streptozotocin(STZ)(60 mg/kg).Diabetic rats were randomized to four groups:diabetes control group(DC),ciclosporin A group(CsA),MSC group,and MSC+CsA group(MSCA).Bone marrow mesenchymal stern cells were cultured,identified and labeled by 5-bromo-2'-deoxyuridine(BrdU)in vitro.Then they were transplanted to diabetic rats via introcardiac infusion.Ciclosporin A was administered daily at 5 mg/kg.At 1,2,4,8 weeks after transplantation,random blood glucose,urine albumin/creatinine ratio(Alb/Cr),endogenous creatinine clearance rate and renal mass index were tested.Renal morphology and labeled cells were examined.Results Cultured MSCs expressed mesenchymal cell phenotype,and could be multidifferentiated to osteogenic and adipogenic cells.Labeled MSCs could be detected in the kidney of nephropathic rats,mainly in renal interstitium,but they did not propagate after engrafting in kidney.Over the course of the experiment,MSCA group showed a significant decrease in blood glucose compared with MSC group,CsA group and DC group(P<0.05,respectively).The Alb/Cr in MSCA group and MSC group were significantly lower than CsA group and DC group(P<0.05).And the Alb/Cr in MSCA group showed a significant decrease compared with MSC group(0.74 vs 0.84,P<0.05).There was a significant difference in renal mass index between the MSCA group and DC group(5.66 vs 6.37,P<0.05).No significant difference was found in creatinine clearance rate among 4 groups(P>0.05).Treatment with MSC+CsA significantly ameliorated the morphology of diabetic kidney.Conclusion MSC could mildly ameliorate diabetic nephropathy by decreasing blood glucose,Alb/Cr ratio and renal mass index.

  16. Sulforaphane Ameliorates Bladder Dysfunction through Activation of the Nrf2-ARE Pathway in a Rat Model of Partial Bladder Outlet Obstruction

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    Chong Liu

    2016-01-01

    Full Text Available Purpose. We evaluated the effect of sulforaphane (SFN treatment on the function and changes of expression of Nrf2-ARE pathway in the bladder of rats with bladder outlet obstruction (BOO. Materials and Methods. A total of 18 male Sprague-Dawley rats at age of 8 weeks were divided into 3 groups (6 of each: the sham operated group, the BOO group, and the BOO+SFN group. We examined histological alterations and the changes of oxidative stress markers and the protein expression of the Nrf2-ARE pathway. Results. We found that SFN treatment could prolong micturition interval and increase bladder capacity and bladder compliance. However, the peak voiding pressure was lower than BOO group. SFN treatment can ameliorate the increase of collagen fibers induced by obstruction. SFN treatment also increased the activity of SOD, GSH-Px, and CAT compared to the other groups. The level of bladder cell apoptosis was decreased in BOO rats with SFN treatment. Moreover, SFN could reduce the ratio of Bax/Bcl-2 expression. Furthermore, SFN could activate the Nrf2 expression with elevation of its target antioxidant proteins. Conclusions. The sulforaphane-mediated decrease of oxidative stress and activation of the Nrf2-ARE pathway may ameliorate bladder dysfunction caused by bladder outlet obstruction.

  17. The amelioration of renal damage in Skp2-deficient mice canceled by p27 Kip1 deficiency in Skp2-/- p27-/- mice.

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    Sayuri Suzuki

    Full Text Available SCF-Skp2 E3 ubiquitin ligase (Skp2 hereafter targets several cell cycle regulatory proteins for degradation via the ubiquitin-dependent pathway. However, the target-specific physiological functions of Skp2 have not been fully elucidated in kidney diseases. We previously reported an increase in Skp2 in progressive nephropathy and amelioration of unilateral ureteral obstruction (UUO renal injury associated with renal accumulation of p27 in Skp2(-/- mice. However, it remains unclear whether the amelioration of renal injury in Skp2(-/- mice is solely caused by p27 accumulation, since Skp2 targets several other proteins. Using Skp2(-/-p27(-/- mice, we investigated whether Skp2 specifically targets p27 in the progressive nephropathy mediated by UUO. In contrast to the marked suppression of UUO renal injury in Skp2(-/- mice, progression of tubular dilatation associated with tubular epithelial cell proliferation and tubulointerstitial fibrosis with increased expression of collagen and α-smooth muscle actin were observed in the obstructed kidneys in Skp2(-/-p27(-/- mice. No significant increases in other Skp2 target proteins including p57, p130, TOB1, cyclin A and cyclin D1 were noted in the UUO kidney in Skp2(-/- mice, while p21, c-Myc, b-Myb and cyclin E were slightly increased. Contrary to the ameliorated UUO renal injure by Skp2-deficiency, the amelioration was canceled by the additional p27-deficiency in Skp2(-/-p27(-/- mice. These findings suggest a pathogenic role of the reduction in p27 targeted by Skp2 in the progression of nephropathy in UUO mice.

  18. [Role of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice].

    Science.gov (United States)

    Peng, Yue; Jiang, Yu; Ou, Hao; Xing, Wei; Yang, Mingshi; Gao, Min

    2017-08-28

    To investigate roles of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice.
 Methods: A total of 152 male Balb/c mice (8-week old) were randomly divided into a sham group, a septic model group, an allicin treatment group, and an autophagy inhibition group. Septic mouse model was established by cecal ligation and puncture (CLP). Mice in the allicin treatment group were given allicin (30 mg/kg, intra-peritoneal injection) at 6 and 12 h, while those in the autophagy inhibition group were given autophagy inhibitor 3-MA (15 mg/kg, intra-peritoneal injection) at half an hour after allicin administration. Mice in the model and sham group were administered with the same amount of saline. Twenty mice in each group were randomly chosen to observe the 7 d survival rate. The other 12 mice were killed at 24 h, and the bronchoalveolar lavage fluid (BALF) (n=6) and lung tissues (n=6) were collected. ELISA was used to detect the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the BALF. Hematoxylin-eosin staining was preformed to show the morphological changes in the lung tissues. Malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) in the lung tissues were examined. The expression of LC3B and Beclin-1 was determined by immunohistochemical analysis.
 Results: Compared with the sham group, the 7 d survival rate and lung SOD activity were decreased in the CLP group (P<0.05); the lung morphological damage score, the levels of TNF-α and IL-6 in the BALF, MDA content in the lung, and expression of LC3B and Beclin-1 were increased greatly in the CLP group (P<0.05). Compared with the CLP group, the 7 d survival rate, lung SOD activity and the expressions of LC3B and Beclin-1 were increased significantly in the allicin treatment group (P<0.05); the lung morphological damage scores, the levels of TNF-α and IL-6 in the BALF and MDA content in the lung were decreased obviously in the allicin treatment group (P<0

  19. Undaria pinnatifida and Fucoxanthin Ameliorate Lipogenesis and Markers of Both Inflammation and Cardiovascular Dysfunction in an Animal Model of Diet-Induced Obesity

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    Ameyalli Grasa-López

    2016-08-01

    Full Text Available Brown algae and its carotenoids have been shown to have a positive influence on obesity and its comorbidities. This study evaluated the effect of Undaria pinnatifida and fucoxanthin on biochemical, physiological and inflammation markers related to obesity and on the expression of genes engaged on white adipose tissue lipid metabolism in a murine model of diet-induced obesity. The treatments improved energy expenditure, β-oxidation and adipogenesis by upregulating PPARα, PGC1α, PPARγ and UCP-1. Adipogenesis was also confirmed by image analysis of the retroperitoneal adipose tissue, by measuring cell area, perimeter and cellular density. Additionally, the treatments, ameliorated adipose tissue accumulation, insulin resistance, blood pressure, cholesterol and triglycerides concentration in serum, and reduced lipogenesis and inflammation by downregulating acetyl-CoA carboxylase (ACC gene expression, increasing serum concentration and expression of adiponectin as well as downregulating IL-6 expression. Both fucoxanthin and Undaria pinnatifida may be considered for treating obesity and other diseases related.

  20. Undaria pinnatifida and Fucoxanthin Ameliorate Lipogenesis and Markers of Both Inflammation and Cardiovascular Dysfunction in an Animal Model of Diet-Induced Obesity

    Science.gov (United States)

    Grasa-López, Ameyalli; Miliar-García, Ángel; Quevedo-Corona, Lucía; Paniagua-Castro, Norma; Escalona-Cardoso, Gerardo; Reyes-Maldonado, Elba; Jaramillo-Flores, María-Eugenia

    2016-01-01

    Brown algae and its carotenoids have been shown to have a positive influence on obesity and its comorbidities. This study evaluated the effect of Undaria pinnatifida and fucoxanthin on biochemical, physiological and inflammation markers related to obesity and on the expression of genes engaged on white adipose tissue lipid metabolism in a murine model of diet-induced obesity. The treatments improved energy expenditure, β-oxidation and adipogenesis by upregulating PPARα, PGC1α, PPARγ and UCP-1. Adipogenesis was also confirmed by image analysis of the retroperitoneal adipose tissue, by measuring cell area, perimeter and cellular density. Additionally, the treatments, ameliorated adipose tissue accumulation, insulin resistance, blood pressure, cholesterol and triglycerides concentration in serum, and reduced lipogenesis and inflammation by downregulating acetyl-CoA carboxylase (ACC) gene expression, increasing serum concentration and expression of adiponectin as well as downregulating IL-6 expression. Both fucoxanthin and Undaria pinnatifida may be considered for treating obesity and other diseases related. PMID:27527189

  1. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    Science.gov (United States)

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-07

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

  2. Carnitine administration reduces cytokine levels, improves food intake, and ameliorates body composition in tumor-bearing rats.

    Science.gov (United States)

    Laviano, Alessandro; Molfino, Alessio; Seelaender, Marilia; Frascaria, Teresa; Bertini, Giuseppe; Ramaccini, Cesarina; Bollea, Maria Rosa; Citro, Gennaro; Rossi Fanelli, Filippo

    2011-12-01

    Increased cytokine expression contributes to the pathogenesis of cancer anorexia?cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines? levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia?cachexia, via reduction of the inflammatory status.

  3. Oral probiotic microcapsule formulation ameliorates non-alcoholic fatty liver disease in Bio F1B Golden Syrian hamsters.

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    Jasmine Bhathena

    Full Text Available The beneficial effect of a microencapsulated feruloyl esterase producing Lactobacillus fermentum ATCC 11976 formulation for use in non-alcoholic fatty liver disease (NAFLD was investigated. For which Bio F1B Golden Syrian hamsters were fed a methionine deficient/choline devoid diet to induce non-alcoholic fatty liver disease. Results, for the first time, show significant clinical benefits in experimental animals. Examination of lipids show that concentrations of hepatic free cholesterol, esterified cholesterol, triglycerides and phospholipids were significantly lowered in treated animals. In addition, serum total cholesterol, triglycerides, uric acid and insulin resistance were found to decrease in treated animals. Liver histology evaluations showed reduced fat deposits. Western blot analysis shows significant differences in expression levels of key liver enzymes in treated animals. In conclusion, these findings suggest the excellent potential of using an oral probiotic formulation to ameliorate NAFLD.

  4. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com; Lv, Changjun, E-mail: Lucky_lcj@sina.com; Jiang, Wanglin, E-mail: jwl518@163.com

    2015-02-15

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  5. Erythropoietin ameliorates renal interstitial fibrosis via the inhibition of fibrocyte accumulation.

    Science.gov (United States)

    Geng, Xu Chang; Hu, Zhou Pang; Lian, Guo Yong

    2015-05-01

    Erythropoietin (EPO) is a hematopoietic hormone that protects against renal interstitial fibrosis in animal models; however, the mechanism underlying the anti‑fibrotic activity of EPO has remained elusive. The present study aimed to elucidate this mechanism. Twenty‑four male C57BL6 mice were randomly divided into four groups, each comprising six mice: (i) control group (Sh); (ii) unilateral ureteral obstruction (UUO) plus vehicle group (U+V); (ⅲ) UUO plus 300 U/kg body weight recombinant human (rh)EPO (U+E1) and (ⅳ) UUO plus 1,000 U/kg body weight rhEPO (U+E2). Seven days post‑surgery, the mice were sacrificed for examination. UUO induced significant deposition of extracellular matrix, detected by picro‑sirius red staining, which was decreased following rhEPO treatment. UUO also induced deposition of collagen I and fibronectin, rhEPO treatment was able to attenuate this effect at protein and mRNA levels. Compared with the control groups, UUO resulted in the accumulation of α‑smooth muscle actin‑positive cells in the interstitium, an effect which was ameliorated by rhEPO. Furthermore, rhEPO abrogated the UUO‑induced increase in the number of bone marrow‑derived myofibroblasts. Mechanistically, it was discovered that rhEPO decreased CXC chemokine ligand 16 (CXCL16) expression at protein level. However, treatment with rhEPO did not alter the protein expression of CC chemokine ligand 21 or CXCL12. These results suggested that rhEPO decreased fibrocyte accumulation via the suppression of renal CXCL16, which resulted in the attenuation of renal fibrosis.

  6. N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation.

    Science.gov (United States)

    Rashid, Mohammad Abdur; Kim, Hee-Yong

    2016-03-01

    Previous studies demonstrated that prenatal exposure to ethanol interferes with embryonic and fetal development, and causes abnormal neurodevelopment. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid highly enriched in the brain, was shown to be essential for proper brain development and function. Recently, we found that N-docosahexenoyethanolamine (synaptamide), an endogenous metabolite of DHA, is a potent PKA-dependent neurogenic factor for neural stem cell (NSC) differentiation. In this study, we demonstrate that ethanol at pharmacologically relevant concentrations downregulates cAMP signaling in NSC and impairs neurogenic differentiation. In contrast, synaptamide reverses ethanol-impaired NSC neurogenic differentiation through counter-acting on the cAMP production system. NSC exposure to ethanol (25-50 mM) for 4 days dose-dependently decreased the number of Tuj-1 positive neurons and PKA/CREB phosphorylation with a concomitant reduction of cellular cAMP. Ethanol-induced cAMP reduction was accompanied by the inhibition of G-protein activation and expression of adenylyl cyclase (AC) 7 and AC8, as well as PDE4 upregulation. In contrast to ethanol, synaptamide increased cAMP production, GTPγS binding, and expression of AC7 and AC8 isoforms in a cAMP-dependent manner, offsetting the ethanol-induced impairment in neurogenic differentiation. These results indicate that synaptamide can reduce ethanol-induced impairment of neuronal differentiation by counter-affecting shared targets in G-protein coupled receptor (GPCR)/cAMP signaling. The synaptamide-mediated mechanism observed in this study may offer a possible avenue for ameliorating the adverse impact of fetal alcohol exposure on neurodevelopment.

  7. Stem cell therapy ameliorates bladder dysfunction in an animal model of Parkinson disease.

    Science.gov (United States)

    Soler, Roberto; Füllhase, Claudius; Hanson, Ariel; Campeau, Lysanne; Santos, Cesar; Andersson, Karl-Erik

    2012-04-01

    Different cell based therapies have been tested, focusing on motor function. We evaluated the effect of human amniotic fluid stem cells and bone marrow derived mesenchymal stem cells (ALLCELLS, Emeryville, California) on bladder dysfunction in a rat model of Parkinson disease. A nigrostriatal lesion was induced by 6-hydroxydopamine in 96 athymic nude female rats divided into 3 treatment groups. After 2 weeks the groups were injected with human amniotic fluid stem cells, bone marrow derived mesenchymal stem cells and vehicle for sham treatment, respectively. At 3, 7, 14 and 28 days the bladder function of 8 rats per group was analyzed by conscious cystometry. Brains were extracted for immunostaining. The nigrostriatal lesion caused bladder dysfunction, which was consistent in sham treated animals throughout the study. Several cystometric parameters improved 14 days after human amniotic fluid stem cell or bone marrow derived mesenchymal stem cell injection, concomitant with the presence of human stem cells in the brain. At 14 days only a few cells were observed in a more caudal and lateral position. At 28 days the functional improvement subsided and human stem cells were no longer seen. Human stem cell injection improved the survival of dopaminergic neurons until 14 days. Human stem cells expressed superoxide dismutase-2 and seemed to modulate the expression of interleukin-6 and glial cell-derived neurotrophic factor by host cells. Cell therapy with human amniotic fluid stem cells and bone marrow derived mesenchymal stem cells temporarily ameliorated bladder dysfunction in a Parkinson disease model. In contrast to integration, cells may act on the injured environment via cell signaling. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  8. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Khames, Ali; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

    2017-02-28

    Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin.

  9. Barnidipine ameliorates the vascular and renal injury in L-NAME-induced hypertensive rats.

    Science.gov (United States)

    Alp Yildirim, F Ilkay; Eker Kizilay, Deniz; Ergin, Bülent; Balci Ekmekçi, Özlem; Topal, Gökçe; Kucur, Mine; Demirci Tansel, Cihan; Uydeş Doğan, B Sönmez

    2015-10-05

    The present study was aimed to investigate the influence of Barnidipine treatment on early stage hypertension by determining the function and morphology of the mesenteric and renal arteries as well as the kidney in N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Barnidipine (3 mg/kg/day p.o) was applied to rats after 2 weeks of L-NAME (60 mg/kg/day) administration, and continued for the next 3 weeks concomitantly with L-NAME. The systolic blood pressure (SBP) of rats was determined to decrease significantly in Barnidipine treated hypertensive group when compared to that of rats received L-NAME alone. Myograph studies demonstrated that the contractile reactivity to noradrenaline were significantly reduced in both of the resistance arteries while endothelium-dependent relaxations to acethylcholine were significantly diminished particularly in the mesenteric arteries of L-NAME-induced hypertensive rats. The impaired contractile and endothelial responses were completely restored by concomitant treatment of Barnidipine with L-NAME. Histopathological examinations verified structural alterations in the arteries as well as the kidney. Moreover, a decrease in endothelial nitric oxide synthase (eNOS) expression was presented both in the arteries and kidney of hypertensive rats which were increased following Barnidipine treatment. Elevated plasma levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were also reduced in Barnidipine treated hypertensive rats. In conclusion, besides to its efficacy in reducing the elevated SBP, amelioration of vascular function, modulation of arterial and renal eNOS expressions as well as reduction of the plasma levels of oxidative and inflammatory biomarkers are possible supportive mechanisms mediating the favorable implications of Barnidipine in L-NAME-induced hypertension model.

  10. Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway.

    Science.gov (United States)

    Gao, Feng; Yao, Min; Cao, Yanping; Liu, Shuxia; Liu, Qingjuan; Duan, Huijun

    2016-05-01

    The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ-induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice.

  11. Telmisartan ameliorates oxidative stress and subarachnoid haemorrhage-induced cerebral vasospasm.

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    Erdi, Fatih; Keskin, Fatih; Esen, Hasan; Kaya, Bulent; Feyzioglu, Bahadir; Kilinc, Ibrahim; Karatas, Yasar; Cuce, Gokhan; Kalkan, Erdal

    2016-03-01

    Growing evidence suggests that oxidative stress is one of the factors contributing to subarachnoid haemorrhage (SAH)-induced cerebral vasospasm. SAH-induced cerebral vasospam alters thioredoxin (Trx) cycle enzymes and thioredoxin-interacting protein (TXNIP) as an important endogenous antioxidant system. In this study, we have explored the effects of telmisartan on the vascular morphological changes, endothelial apoptosis, tissue oxidative stress status and the level of Trx cycle enzymes/ TXNIP in a rabbit SAH model. Forty male New Zealand rabbits were randomly divided into five groups of eight rabbits each: control group, sham group, SAH group, SAH + vehicle group and SAH + telmisartan group. SAH was created by a single cisterna magna blood injection. SAH + telmisartan group received telmisartan treatment (5 mg/kg intraperitoneal, once daily) for 72 h. The brainstem tissue Trx1, Trx2, Trx reductase (TrxR), TrxR1and TXNIP levels were investigated. Total oxidant status (TOS), total antioxidant status (TAS), malondialdehyde (MDA) levels and tumour necrosis factor alpha (TNF alpha) levels were investigated. Basilar artery segments were investigated for cross-sectional area, wall thickness measurements and endothelial apoptosis. Telmisartan treatment restored the lowered level of Trx1, TrxR, TAS and the expression of TrxR1 seen in SAH. Telmisartan treatment also decreased TXNIP expression, TOS, MDA and TNF alpha levels. Morphological changes of cerebral vasospasm were attenuated after treatment. Endothelial apoptosis significantly reduced. Treatment with telmisartan ameliorates oxidative stress and SAH-induced cerebral vasospasm in rabbits. These effects of telmisartan may be associated with downregulation of TXNIP and upregulation of Trx/TrxR.

  12. Interruption of Wnt signaling in Muller cells ameliorates ischemia-induced retinal neovascularization.

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    Kelu Kevin Zhou

    Full Text Available Retinal Müller cells are major producers of inflammatory and angiogenic cytokines which contribute to diabetic retinopathy (DR. Over-activation of the Wnt/β-catenin pathway has been shown to play an important pathogenic role in DR. However, the roles of Müller cell-derived Wnt/β-catenin signaling in retinal neovascularization (NV and DR remain undefined. In the present study, mice with conditional β-catenin knockout (KO in Müller cells were generated and subjected to oxygen-induced retinopathy (OIR and streptozotocin (STZ-induced diabetes. Wnt signaling was evaluated by measuring levels of β-catenin and expression of its target genes using immunoblotting. Retinal vascular permeability was measured using Evans blue as a tracer. Retinal NV was visualized by angiography and quantified by counting pre-retinal nuclei. Retinal pericyte loss was evaluated using retinal trypsin digestion. Electroretinography was performed to examine visual function. No abnormalities were detected in the β-catenin KO mice under normal conditions. In OIR, retinal levels of β-catenin and VEGF were significantly lower in the β-catenin KO mice than in littermate controls. The KO mice also had decreased retinal NV and vascular leakage in the OIR model. In the STZ-induced diabetic model, disruption of β-catenin in Müller cells attenuated over-expression of inflammatory cytokines and ameliorated pericyte dropout in the retina. These findings suggest that Wnt signaling activation in Müller cells contributes to retinal NV, vascular leakage and inflammation and represents a potential therapeutic target for DR.

  13. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling.

    Science.gov (United States)

    Lee, Hanbyeol; Park, Jeong-Ran; Kim, Woo Jin; Sundar, Isaac K; Rahman, Irfan; Park, Sung-Min; Yang, Se-Ran

    2017-05-01

    The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathway via Nrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2(+/+) , but not in Nrf2(-/-) mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.-Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling. © FASEB.

  14. Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice.

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    Kazuki Noda

    Full Text Available BACKGROUND: Metabolic disorders, caused by excessive calorie intake and low physical activity, are important cardiovascular risk factors. Rho-kinase, an effector protein of the small GTP-binding protein RhoA, is an important cardiovascular therapeutic target and its activity is increased in patients with metabolic syndrome. We aimed to examine whether Rho-kinase inhibition improves high-fat diet (HFD-induced metabolic disorders, and if so, to elucidate the involvement of AMP-activated kinase (AMPK, a key molecule of metabolic conditions. METHODS AND RESULTS: Mice were fed a high-fat diet, which induced metabolic phenotypes, such as obesity, hypercholesterolemia and glucose intolerance. These phenotypes are suppressed by treatment with selective Rho-kinase inhibitor, associated with increased whole body O2 consumption and AMPK activation in the skeletal muscle and liver. Moreover, Rho-kinase inhibition increased mRNA expression of the molecules linked to fatty acid oxidation, mitochondrial energy production and glucose metabolism, all of which are known as targets of AMPK in those tissues. In systemic overexpression of dominant-negative Rho-kinase mice, body weight, serum lipid levels and glucose metabolism were improved compared with littermate control mice. Furthermore, in AMPKα2-deficient mice, the beneficial effects of fasudil, a Rho-kinase inhibitor, on body weight, hypercholesterolemia, mRNA expression of the AMPK targets and increase of whole body O2 consumption were absent, whereas glucose metabolism was restored by fasudil to the level in wild-type mice. In cultured mouse myocytes, pharmacological and genetic inhibition of Rho-kinase increased AMPK activity through liver kinase b1 (LKB1, with up-regulation of its targets, which effects were abolished by an AMPK inhibitor, compound C. CONCLUSIONS: These results indicate that Rho-kinase inhibition ameliorates metabolic disorders through activation of the LKB1/AMPK pathway, suggesting that

  15. Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.

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    Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu

    2014-03-15

    High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury.

  16. Magnolol Ameliorates Ligature-Induced Periodontitis in Rats and Osteoclastogenesis: In Vivo and In Vitro Study

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    Sheng-Hua Lu

    2013-01-01

    Full Text Available Periodontal disease characterized by alveolar bone resorption and bacterial pathogen-evoked inflammatory response has been believed to have an important impact on human oral health. The aim of this study was to evaluate whether magnolol, a main constituent of Magnolia officinalis, could inhibit the pathological features in ligature-induced periodontitis in rats and osteoclastogenesis. The sterile, 3–0 (diameter; 0.2 mm black braided silk thread, was placed around the cervix of the upper second molars bilaterally and knotted medially to induce periodontitis. The morphological changes around the ligated molars and alveolar bone were examined by micro-CT. The distances between the amelocemental junction and the alveolar crest of the upper second molars bilaterally were measured to evaluate the alveolar bone loss. Administration of magnolol (100 mg/kg, p.o. significantly inhibited alveolar bone resorption, the number of osteoclasts on bony surface, and protein expression of receptor activator of nuclear factor-κB ligand (RANKL, a key mediator promoting osteoclast differentiation, in ligated rats. Moreover, the ligature-induced neutrophil infiltration, expression of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP-1 and MMP-9, superoxide formation, and nuclear factor-κB activation in inflamed gingival tissues were all attenuated by magnolol. In the in vitro study, magnolol also inhibited the growth of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans that are key pathogens initiating periodontal disease. Furthermore, magnolol dose dependently reduced RANKL-induced osteoclast differentiation from RAW264.7 macrophages, tartrate-resistant acid phosphatase (TRAP activity of differentiated cells accompanied by a significant attenuation of resorption pit area caused by osteoclasts. Collectively, we demonstrated for the first time that magnolol significantly ameliorates the alveolar bone loss in

  17. Mycophenolate mofetil ameliorates diabetic nephropathy through epithelial mesenchymal transition in rats.

    Science.gov (United States)

    Xiao, Xiaoyan; Wang, Jie; Chang, Xiangdi; Zhen, Junhui; Zhou, Gengyin; Hu, Zhao

    2015-09-01

    Recent studies in animal models have revealed that mycophenolate mofetil (MMF) has certain protective effects against experimental diabetic nephropathy. The present study therefore aimed to investigate the hypothesis that diabetic nephropathy may be ameliorated by mycophenolate mofetil and benazepril treatment alone or in combination, and identify the potential underlying mechanisms in a rat model. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin. Rats were subsequently treated with benazepril, MMF or a combination of the two drugs, and blood glucose, normalized kidney weight, urine protein and serum creatinine were determined. The pathological changes in renal tissue were also observed. In addition, indices of epithelial mesenchymal transition, including α‑smooth muscle actin (α‑SMA) and transforming growth factor (TGF)‑β1 expression, were examined. Normalized kidney weight, urine protein and serum creatinine levels were significantly improved in the diabetic rats treated with benazepril or mycophenolate mofetil, compared with those of rats in the untreated diabetic group. Pathological changes in the kidney were detected concurrently with increasing kidney weight and urinary albumin excretion, with a similar trend in variation among groups. In addition, the expression of epithelial mesenchymal transition indices, including α‑SMA and TGF‑β1, in the renal tubule interstitium were significantly decreased in the benazepril‑ and MMF‑treated groups compared with those of the diabetic group. As expected, the aforementioned indices were markedly lower in the benazepril and MMF combined treatment group than those in the single medication groups. These data suggested that MMF may have a protective role in diabetic nephropathy, and that the underlying mechanism may be partially dependent upon the suppression of the epithelial mesenchymal transition. Furthermore, the combination of benazepril and MMF conferred enhanced

  18. Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms.

    Science.gov (United States)

    Tian, Jihua; Wang, Yanhong; Liu, Xinyan; Zhou, Xiaoshuang; Li, Rongshan

    2015-07-01

    IgA nephropathy is the most frequent type of glomerulonephritis worldwide. The role of cell cycle regulation in the pathogenesis of IgA nephropathy has been studied. The present study was designed to explore whether rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. After establishing an IgA nephropathy model, rats were randomly divided into four groups. Coomassie Brilliant Blue was used to measure the 24-h urinary protein levels. Renal function was determined using an autoanalyzer. Proliferation was assayed via Proliferating Cell Nuclear Antigen (PCNA) immunohistochemistry. Rat mesangial cells were cultured and divided into the six groups. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and flow cytometry were used to detect cell proliferation and the cell cycle phase. Western blotting was performed to determine cyclin E, cyclin-dependent kinase 2, p27(Kip1), p70S6K/p-p70S6K, and extracellular signal-regulated kinase 1/2/p- extracellular signal-regulated kinase 1/2 protein expression. A low dose of the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented an additional increase in proteinuria, protected kidney function, and reduced IgA deposition in a model of IgA nephropathy. Rapamycin inhibited mesangial cell proliferation and arrested the cell cycle in the G1 phase. Rapamycin did not affect the expression of cyclin E and cyclin-dependent kinase 2. However, rapamycin upregulated p27(Kip1) at least in part via AKT (also known as protein kinase B)/mTOR. In conclusion, rapamycin can affect cell cycle regulation to inhibit mesangial cell proliferation, thereby reduce IgA deposition, and slow the progression of IgAN.

  19. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke.

    Science.gov (United States)

    Yang, Fan; Wang, Ziying; Wei, Xinbing; Han, Huirong; Meng, Xianfang; Zhang, Yan; Shi, Weichen; Li, Fengli; Xin, Tao; Pang, Qi; Yi, Fan

    2014-04-01

    Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1β (IL-1β) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.

  20. Brain microvascular endothelial cell transplantation ameliorates ischemic white matter damage.

    Science.gov (United States)

    Puentes, Sandra; Kurachi, Masashi; Shibasaki, Koji; Naruse, Masae; Yoshimoto, Yuhei; Mikuni, Masahiko; Imai, Hideaki; Ishizaki, Yasuki

    2012-08-21

    Ischemic insults affecting the internal capsule result in sensory-motor disabilities which adversely affect the patient's life. Cerebral endothelial cells have been reported to exert a protective effect against brain damage, so the transplantation of healthy endothelial cells might have a beneficial effect on the outcome of ischemic brain damage. In this study, endothelin-1 (ET-1) was injected into the rat internal capsule to induce lacunar infarction. Seven days after ET-1 injection, microvascular endothelial cells (MVECs) were transplanted into the internal capsule. Meningeal cells or 0.2% bovine serum albumin-Hank's balanced salt solution were injected as controls. Two weeks later, the footprint test and histochemical analysis were performed. We found that MVEC transplantation improved the behavioral outcome based on recovery of hind-limb rotation angle (P<0.01) and induced remyelination (P<0.01) compared with the control groups. Also the inflammatory response was repressed by MVEC transplantation, judging from fewer ED-1-positive activated microglial cells in the MVEC-transplanted group than in the other groups. Elucidation of the mechanisms by which MVECs ameliorate ischemic damage of the white matter may provide important information for the development of effective therapies for white matter ischemia.

  1. Astragaloside IV ameliorates renal injury in db/db mice

    Science.gov (United States)

    Sun, Huili; Wang, Wenjing; Han, Pengxun; Shao, Mumin; Song, Gaofeng; Du, Heng; Yi, Tiegang; Li, Shunmin

    2016-09-01

    Diabetic nephropathy is a lethal complication of diabetes mellitus and a major type of chronic kidney disease. Dysregulation of the Akt pathway and its downstream cascades, including mTOR, NFκB, and Erk1/2, play a critical role in the development of diabetic nephropathy. Astragaloside IV is a major component of Huangqi and exerts renal protection in a mouse model of type 1 diabetes. The current study was undertaken to investigate the protective effects of diet supplementation of AS-IV on renal injury in db/db mice, a type 2 diabetic mouse model. Results showed that administration of AS-IV reduced albuminuria, ameliorated changes in the glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-β1 in db/db mice. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity. Collectively, these findings showed AS-IV to be beneficial to type 2 diabetic nephropathy, which might be associated with the inhibition of Akt/mTOR, NFκB and Erk1/2 signaling pathways.

  2. Ameliorative Effect of Allopurinol on Vascular Complications of Insulin Resistance

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    Hany M. El-Bassossy

    2015-01-01

    Full Text Available The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo on experimentally induced insulin resistance (IR and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo, and allopurinol-treated control (Allo. IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion.

  3. Ozone therapy ameliorates paraquat-induced lung injury in rats.

    Science.gov (United States)

    Kaldirim, Umit; Uysal, Bulent; Yuksel, Ramazan; Macit, Enis; Eyi, Yusuf E; Toygar, Mehmet; Tuncer, Salim K; Ardic, Sukru; Arziman, Ibrahim; Aydin, Ibrahim; Oztas, Yesim; Karslioglu, Yildirim; Topal, Turgut

    2014-12-01

    Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (Ptherapy.

  4. Food Restriction Ameliorates the Development of Polycystic Kidney Disease.

    Science.gov (United States)

    Warner, Gina; Hein, Kyaw Zaw; Nin, Veronica; Edwards, Marika; Chini, Claudia C S; Hopp, Katharina; Harris, Peter C; Torres, Vicente E; Chini, Eduardo N

    2016-05-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the accumulation of kidney cysts that ultimately leads to loss of renal function and kidney failure. At present, the treatment for ADPKD is largely supportive. Multiple studies have focused on pharmacologic approaches to slow the development of the cystic disease; however, little is known about the role of nutrition and dietary manipulation in PKD. Here, we show that food restriction (FR) effectively slows the course of the disease in mouse models of ADPKD. Mild to moderate (10%-40%) FR reduced cyst area, renal fibrosis, inflammation, and injury in a dose-dependent manner. Molecular and biochemical studies in these mice indicate that FR ameliorates ADPKD through a mechanism involving suppression of the mammalian target of the rapamycin pathway and activation of the liver kinase B1/AMP-activated protein kinase pathway. Our data suggest that dietary interventions such as FR, or treatment that mimics the effects of such interventions, may be potential and novel preventive and therapeutic options for patients with ADPKD. Copyright © 2016 by the American Society of Nephrology.

  5. Transcranial amelioration of inflammation and cell death after brain injury

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    Roth, Theodore L.; Nayak, Debasis; Atanasijevic, Tatjana; Koretsky, Alan P.; Latour, Lawrence L.; McGavern, Dorian B.

    2014-01-01

    Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.

  6. Magnesium lithospermate B ameliorates renal cortical microperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Chun-guang CHEN; Yi-ping WANG

    2006-01-01

    Aim: To investigate the effects of magnesium lithospermate B (MLB) isolated from Salviae miltiorrhizae on renal microcirculation, and renal and systemic hemodynamics in Sprague-Dawley rats. Methods: MLB (10, 30, and 60 mg/kg) was injected intravenously and renal blood flow (RBF), renal cortical microperfusion (RCM), and systemic hemodynamic function parameters including heart rate (HR),mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximal velocity of pressure increase (dp/dtmax) were measured for 45 min after administration. Results: Intravenous MLB at doses of 10, 30, and 60 mg/kg increased RCM significantly, but had no obvious effects on RBF or systemic hemodynamics. The effect of MLB on RCM reached its peak 15 min after injection and returned to baseline after 45 min. Up to60 mg/kg MLB increased RCM by 62.4%±20.2% (changes from baseline, P<0.01),whereas RBF (3.7%±9.7% vs baseline) and renal vascular resistance (-1.4%±9.1%vs baseline) did not obviously change. Conclusion: These results indicate that MLB ameliorates renal microcirculation in a dose-dependent manner, which may be related to the renoprotective effects of MLB.

  7. Coniferyl Aldehyde Ameliorates Radiation Intestine Injury via Endothelial Cell Survival

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    Jeong, Ye Ji; Jung, Myung Gu; Lee, Yoonjin; Lee, Haejune [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Yunsil [Ewha Woman' s Univ., Seoul (Korea, Republic of); Ko, Younggyu [Korea Univ., Seoul (Korea, Republic of)

    2014-05-15

    Cancer treatments related gastrointestinal toxicity has also been recognized as a significant economic burden. Especially, extensive apoptosis of microvascular endothelial cell of the lamina propria is the primary lesion initiating intestinal radiation damage after abdominal radiation therapy. Coniferyl aldehyde (CA) is phenolic compounds isolated from cork stoppers, and one of the major pyrolysis products of lignin. Shi H. was support for the empirical use of CA as a medicinal food for cardiovascular diseases. CA has positive effect in broad way but there is no consequence in radiation induced intestine damage. Here, we investigate effect of CA on small intestine after abdominal IR to mice in this study. In this study, CA increased the survival rate in C3H mice against 13.5 Gy abdominal IR. We found CA protects small intestine via preventing endothelial cell apoptosis and enhancing their angiogenic activity. CA also showed protective effect on crypt cell survival. Endothelial cell survival may affect crypt cell protection against IR. From this data, we concluded that CA is effective for protection against abdominal radiation injury. CA could ameliorate side-effect of radiation therapy.

  8. Thiazolidinediones attenuate lipolysis and ameliorate dexamethasone-induced insulin resistance.

    Science.gov (United States)

    He, Jinhan; Xu, Chong; Kuang, Jiangying; Liu, Qinhui; Jiang, Hongfeng; Mo, Li; Geng, Bin; Xu, Guoheng

    2015-07-01

    Elevated levels of circulating free fatty acids induce insulin resistance and often occur in obese and diabetic conditions. One pharmacological basis for the antidiabetic effects of thiazolidinediones (TZDs) is that TZDs reduce levels of circulating FFAs by accelerating their uptake and reesterification from plasma into adipocytes. Here, we investigated whether TZDs affect adipose lipolysis, a process controlling triglyceride hydrolysis and FFA efflux to the bloodstream. The effects of TZDs on lipolysis were investigated in primary rat adipocytes in vitro and in rats in vivo. In rat primary adipocytes, the TZDs pioglitazone, rosiglitazone and troglitazone inhibited the lipolytic reaction dose- and time-dependently and in a post-receptor pathway by decreasing cAMP level and total lipase activity. TZDs increased the phosphorylation of Akt/protein kinase B, an action required for activating cyclic-nucleotide phosphodiesterase 3B, a major enzyme responsible for cAMP hydrolysis in adipocytes. Furthermore, rosiglitazone inhibited the lipolytic action in dexamethasone-stimulated adipocytes, thereby preventing the increased level of circulating FFAs, and ameliorated insulin resistance in vivo in dexamethasone-treated rats. TZDs may attenuate lipolysis and FFA efflux by activating Akt signaling to decrease cAMP level and hence reduce lipase activity in adipocytes. Inhibiting lipolysis and FFA efflux with TZDs could be a pharmacological basis by which TZDs antagonize diabetes, particularly in patients with hypercortisolemia or glucocorticoid challenge. Copyright © 2015. Published by Elsevier Inc.

  9. Ameliorative property of Teucrium polium on second degree burn

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    Ansari Roya

    2013-01-01

    Full Text Available Introduction: Traditionally, burn wound healing activities have been claimed for Teucrium polium. Teucrium polium possesses antioxidant and inflammatory activities and seems to ameliorate burn wound healing. This study was performed to evaluate the effects of Teucrium polium on burn healing in Balb/C mice. Materials and Methods: In this preclinical experimental study 56 mice were randomly designated into 4 equal groups. Burn wounds were made using a hot plate with a surface area of 1.5 cm2. Animals were treated with Teucrium 2%, Silver sulfadiazine or Vaseline 2 times per day for 21 days. The forth group received no treatment. Results: The percentage of burn wounds healing and total time required for complete healing were evaluated and compared in different groups. Data were analyzed using ANOVA test. Conclusion: Teucrium extract accelerated the burn wound healing more rapidly than control groups (p<0.01. Teucrium polium is effective on burn wounds healing and might be beneficial in these groups of patients.

  10. Olmesartan ameliorates urinary dysfunction in the spontaneously hypertensive rat via recovering bladder blood flow and decreasing oxidative stress.

    Science.gov (United States)

    Shimizu, Shogo; Saito, Motoaki; Oiwa, Harunori; Ohmasa, Fumiya; Tsounapi, Panagiota; Oikawa, Ryo; Dimitriadis, Fotios; Martin, Darryl T; Satoh, Itaru; Kinoshita, Yukako; Tomita, Shuhei

    2014-03-01

    As hypertension (HT) is one of the risk factors for lower urinary tract symptoms, we investigated the effect of an angiotensin II type I receptor blocker, olmesartan, on bladder dysfunction in the spontaneously hypertensive rat (SHR). Twelve-week-old male SHRs were administered perorally with olmesartan (0, 1, or 3 mg/kg/day) or nifedipine (30 mg/kg/day) for 6 weeks. Wistar rats were used as normotensive controls. The effects of olmesartan or nifedipine on blood pressure (BP), bladder blood flow (BBF), urodynamic parameters, tissue levels of malondialdehyde (MDA), nuclear factor erythroid 2-related factor 2 (Nrf2), and nerve growth factor (NGF) were measured in the bladder. Localization of 4-hydroxy-2-nonenal (4-HNE), Nrf2, and NGF in the bladder was shown by immunohistochemistry. The SHRs showed significant increase in BP, micturition frequency, and expression of MDA, 4-HNE, Nrf2, and NGF when compared to the control Wistar rats. Conversely, there was a decrease in BBF and single voided volume in SHRs when compared to Wistar rats. Treatment with olmesartan and nifedipine significantly improved BP. However, only olmesartan significantly ameliorated urodynamic parameters and oxidative damage compared to the non-treated SHR. The immunoreactivities of 4-HNE, Nrf2, and NGF in SHR urothelium and blood vessels were increased compared to the control. Treatment with a high dose of olmesartan decreased the expressions of 4-HNE, Nrf2, and NGF in the bladder. Our data suggest that BP, BBF, and oxidative stress may be responsible for the functional changes in HT-related bladder dysfunction. Olmesartan significantly ameliorated this bladder dysfunction. © 2013 Wiley Periodicals, Inc.

  11. Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase

    Institute of Scientific and Technical Information of China (English)

    LIU Wei-hua; HUANG Wen-ge; CHEN Feng-ying; LIU Pei-qing; HEI Zi-qing; NIE Hong; TANG Fu-tian; HUANG He-qing; LI Xue-juan; DENG Yan-hui; CHEN Shao-rui; GUO Fen-fen

    2008-01-01

    Background Berberine is one of the main constituents of Coptidis rhizoma (CR) and Cortex phellodendri, In this study, we investigated the beneficial effects of berberine on renal function and its possible mechanisms in rats with diabetic nephropathy(DN). Methods Male Wistar rats were divided into three groups: normal, diabetic model, and berberine treatment groups. Rats in the diabetic model and berberine treatment groups were induced to diabetes by intraperitonal injection with streptozotocin(STZ). Glomerular area, glomerular volume, fasting blood glucose(FBG), blood urea nitrogen(BUN), serum creatinine (Cr)and urine protein for 24 hours(UP24h) were measured using commercially available kits. Meanwhile, the activity of superoxide dismutase (SOD), content of malondialdehyde (MDA) in serum, activity of aldose reductase (AR)and the expression of AR mRNA and protein in kidney were detected by different methods. Results The result showed that oral administration of berberine (200mg·kg-1·d-1) significantly ameliorated the ratio of kidney weight to body weight. Glomerular area, glomerular volume, FBG, BUN, Cr and UP24h were significantly decreased in the berberine treatment group compared with the diabetic model group(P<0.05). Berberine treatment significantly increased serum SOD activity and decreased the content of MDA compared with diabetic model group(P<0.05). AR activity as well as the expression of AR mRNA and protein in the kidney was markedly decreased in the berberine treatment group compared with diabetic model group (P<0.05). Conclusion These results suggested that berberine could ameliorate renal dysfunction in DN rats through controlling blood glucose, reduction of oxidative stress and inhibition of the activation of the polyol pathway.

  12. Norisoboldine ameliorates DSS-induced ulcerative colitis in mice through induction of regulatory T cells in colons.

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    Lv, Qi; Qiao, Si-miao; Xia, Ying; Shi, Can; Xia, Yu-feng; Chou, Gui-xin; Wang, Zheng-tao; Dai, Yue; Wei, Zhi-feng

    2015-12-01

    Norisoboldine (NOR), the main active constituent of Radix Linderae, was previously demonstrated to ameliorate collagen-induced arthritis in rats through regulating the imbalance of T cells in intestines, which implied its therapeutic potential in inflammatory bowel disease. Here, we investigated the effect of NOR on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice. Results showed that NOR (20, 40mg/kg) markedly reduced the symptoms of colitis, the levels of IL-1β and TNF-α, and the activation of ERK, p38 MAPK and NF-κB-p65. NOR only slightly decreased the levels of IFN-γ and IL-17A in mouse colons, but it dramatically increased the level of IL-10 at both protein and mRNA grades. Consistently, NOR increased the number of CD4(+)CD25(+)Foxp3(+) Treg cells more obviously than it decreased that of CD4(+)IL-17(+) Th17 cells in mesenteric lymph nodes (MLNs) and colonic lamina proprias (LPs) of colitis mice, and promoted the expression of Foxp3 mRNA in colon tissues. It could facilitate the in vitro differentiation of Treg cells from naive T cells and promote the phosphorylations of Smad2/3 in colon tissues of colitis mice. On the other hand, NOR did not affect the expressions of homing receptors CCR9 and α4β7 in SPs, and homing ligands CCL25 and Madcam-1 in MLNs and colonic LPs, suggesting that the increase of Treg cells in colons by NOR was not due to gut homing. In conclusion, NOR can ameliorate DSS-induced UC in mice, and the mechanisms involve reduction of pro-inflammatory cytokines and selective induction of Treg cells in colons.

  13. Growth hormone ameliorates adipose dysfunction during oxidative stress and inflammation and improves glucose tolerance in obese mice.

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    Fukushima, M; Okamoto, Y; Katsumata, H; Ishikawa, M; Ishii, S; Okamoto, M; Minami, S

    2014-08-01

    Patients with adult growth hormone deficiency exhibit visceral fat accumulation, which gives rise to a cluster of metabolic disorders such as impaired glucose tolerance and dyslipidemia. Plasma growth hormone levels are lower in obese patients with metabolic syndrome than in healthy subjects. Here we examined the hypothesis that exogenous growth hormone administration regulates function of adipose tissue to improve glucose tolerance in diet-induced obese mice. Twelve-week-old obese male C57BL/6 J mice received bovine growth hormone daily for 6 weeks. In epididymal fat, growth hormone treatment antagonized diet-induced changes in the gene expression of adiponectin, leptin, and monocyte chemoattractant protein-1, and significantly increased the gene expression of interleukin-10 and CD206. Growth hormone also suppressed the accumulation of oxidative stress marker, thiobarbituric acid-reactive substances, in the epididymal fat and enhanced the gene expression of anti-oxidant enzymes. Moreover, growth hormone significantly restored glucose tolerance in obese mice. In cultured 3T3-L1 adipocytes, growth hormone prevented the decline in adiponectin gene expression in the presence of hydrogen peroxide. These results suggest that growth hormone administration ameliorates glucose intolerance in obese mice presumably by decreasing adipose mass, oxidative stress, and chronic inflammation in the visceral fat.

  14. Xiangshao Granule Exerts Antidepressive Effects in a Depression Mouse Model by Ameliorating Deficits in Hippocampal BDNF and TrkB

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    Yi Chen

    2013-01-01

    Full Text Available This study explores the therapeutic effects of Xiangshao granules in a mouse depression model and examines the potential molecular mechanisms involved. After 21 consecutive days of chronic stress challenge, all mice were divided into three groups: control group, depression group, and Xiangshao granule treatment group. On the 22nd day, rats in the Xiangshao granule treatment group received Xiangshao granules via gastrogavage for 3 consecutive weeks. Depression group mice showed a significant reduction of crossings (P<0.01 but not rearings (P<0.05. Serum CRH, CORT, and ACTH levels were significantly increased in depression mice compared with control (P<0.05 and the expression levels of hippocampal BDNF and TrkB were reduced in the model group (P<0.05. However, Xiangshao granule treatment remarkably rescued the decrease in the body weight (P<0.05, increased crossings in the open field test (P<0.05, upregulated the expression of hippocampal BDNF and TrkB expression, and reduced the serum CRH, CORT, and ACTH concentrations compared with the depression group (P<0.05. Collectively, these results demonstrated that Xiangshao granule could effectively induce antidepressive effects in the depression mouse model by ameliorating the expression of hippocampal BDNF and TrkB.

  15. Ameliorative effect of melatonin against increased intestinal permeability in diabetic rats: possible involvement of MLCK-dependent MLC phosphorylation.

    Science.gov (United States)

    Yang, Xiaoping; Zou, Duobing; Tang, Songtao; Fan, Tingting; Su, Huan; Hu, Ruolei; Zhou, Qing; Gui, Shuyu; Zuo, Li; Wang, Yuan

    2016-05-01

    The increased intestinal permeability and functional impairment play an important role in type 2 diabetes (T2D), and melatonin may possess enteroprotection properties. Therefore, we used streptozotocin-induced diabetic rat model to investigate the regulation of intestinal permeability by melatonin. Rats were randomly divided into three groups, including control, diabetes mellitus (DM), and DM rats treated with melatonin. Melatonin was administered (10 mg/kg/day) by gavage for 24 weeks. The DM rats significantly increased the serum fasting blood glucose and lipid levels, which were alleviated by melatonin treatment. Importantly, the intestinal epithelial permeability was significantly increased in DM rats but was ameliorated following treatment with melatonin. These findings also indicated the expression of myosin light chain kinase (MLCK) and phosphorylation of MLC targeting subunit (MYPT) induced myosin light chain (MLC) phosphorylation level was markedly elevated in hyperglycemic and hyperlipidemic status. They were partly associated with down-regulated membrane type 1 and 2 (MT1 and MT2) expression, and up-regulated Rho-associated protein kinase (ROCK) expression and increased extracellular signal-regulated kinase (ERK) phosphorylation. However, the changes in target protein expression were reversed by melatonin. In conclusion, our results show melatonin beneficial effects on impaired intestinal epithelial permeability in T2D by suppressing ERK/MLCK- and ROCK/MCLP-dependent MLC phosphorylation.

  16. Hypoglycemic effects of Zanthoxylum alkylamides by enhancing glucose metabolism and ameliorating pancreatic dysfunction in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    You, Yuming; Ren, Ting; Zhang, Shiqi; Shirima, Gerald Gasper; Cheng, YaJiao; Liu, Xiong

    2015-09-01

    This study aimed to evaluate the hypoglycemic effect of Zanthoxylum alkylamides and explore the potential mechanism in streptozotocin (STZ)-induced diabetic rats. Diabetic rats were orally treated with 3, 6, and 9 mg per kg bw alkylamides daily for 28 days. As the alkylamide dose increased, the relative weights of the liver and kidney, fasting blood glucose, and fructosamine levels were significantly decreased. The alkylamides also significantly increased the body weight and improved the oral glucose tolerance of the rats. Likewise, the alkylamides significantly increased the levels of liver and muscle glycogen and plasma insulin. These substances further alleviated the histopathological changes in the pancreas of the diabetic rats. The beneficial effects of high-dose alkylamides showed a comparable activity to the anti-diabetic drug glibenclamide. Western blot and real-time PCR results revealed that the alkylamide treatment significantly decreased the expression levels of the key enzymes (phosphoenolpyruvate caboxykinase and glucose-6-phosphatase) involved in gluconeogenesis and increased the glycolysis enzyme (glucokinase) in the liver, and enhanced the expression levels of pancreatic duodenal homeobox-1, glucokinase, and glucose transporter 2 in the pancreas. In addition, it was also observed that the alkylamides, unlike glibenclamide, increased the transient receptor potential cation channel subfamily V member 1 and decreased cannabinoid receptor 1 expressions in the liver and pancreas. Therefore, alkylamides can prevent STZ-induced hyperglycemia by altering the expression levels of the genes related to glucose metabolism and by ameliorating pancreatic dysfunction.

  17. Hydrogen sulfide ameliorates vascular calcification induced by vitamin D3 plus nicotine in rats

    Institute of Scientific and Technical Information of China (English)

    Sheng-ying WU; Chun-shui PAN; Bin GENG; Jing ZHAO; Fang YU; Yong-zheng PANG; Chao-shu TANG; Yong-fen QI

    2006-01-01

    Aim:To investigate the role of the endogenous cystathionine γ-synthase(CSE)/hydrogen sulfide(H2S)pathway in vascular calcification in vivo.Methods:A rat vascular calcitication model was established by administration of vitamin D3 plus nicotine(VDN).The amount of CSE and osteopontin(OPN)mRNA was determined by using semi-quantitative reverse-transcription polymerase chain reaction.The calcium content,45Ca2+ accumulation and alkaline phosphatase(ALP)activity were measured.H2S production and CSE activity were measured.Results:von Kossa staining produced strong positive black/brown staining in areas among the elastic fibers of the medial layer in the calcified aorta.The calcium content,45Ca2+ accumulation and ALP activity in calcified arteries increased by 6.77-,1.42-,and 1.87-fold,respectively,compared with controls.The expression of the OPN gene was upregulated(P<0.01).Expression of the CSE gene was downregulated.However,calcium content.45Ca2+ uptake and ALP activity in the VDN plus NaHS group was lower than that in the VDN group.The content of calcium and 45Ca2+ accumulation and activity of ALP in the aorta were 34.8%,40.75%and 63.5%lower in the low-dosage NaHS group than in the VDN group,respectively(P<0.01),and the calcium content and deposition of 45Ca2+ and activity of ALP was 83.9%,37.8%and 46.2% lower in the aorta in the high-dosage NaHS group than in the VDN group,respectively(P<0.01).The expression of the OPN gene was downregulated.Conclusion:The production of H2S,and CSE activity were decreased and CSE gene expression was downregulated in rats with vascular catcification.H2S can ameliorate vascular calcification,suggesting that the H2S/CSE pathway plays a regulatory role in the pathogenesis of vascular calcification.

  18. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats.

    Science.gov (United States)

    Zhu, Zeng-Yan; Gao, Tian; Huang, Yan; Xue, Jie; Xie, Mei-Lin

    2016-04-01

    Apigenin is a natural flavonoid compound that can inhibit hypoxia-inducible factor (HIF)-1α expression in cultured tumor cells under hypoxic conditions. Hypertension-induced cardiac hypertrophy is always accompanied by abnormal myocardial glucolipid metabolism due to an increase of HIF-1α. However, whether or not apigenin may ameliorate the cardiac hypertrophy and abnormal myocardial glucolipid metabolism remains unknown. This study aimed to examine the effects of apigenin. Rats with cardiac hypertrophy induced by renovascular hypertension were treated with apigenin 50-100 mg kg(-1) (the doses can be achieved by pharmacological or dietary supplementation for an adult person) by gavage for 4 weeks. The results showed that after treatment with apigenin, the blood pressure, heart weight, heart weight index, cardiomyocyte cross-sectional area, serum angiotensin II, and serum and myocardial free fatty acids were reduced. It is important to note that apigenin decreased the expression level of myocardial HIF-1α protein. Moreover, apigenin simultaneously increased the expression levels of myocardial peroxisome proliferator-activated receptor (PPAR) α, carnitine palmitoyltransferase (CPT)-1, and pyruvate dehydrogenase kinase (PDK)-4 proteins and decreased the expression levels of myocardial PPARγ, glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter (GLUT)-4 proteins. These findings demonstrated that apigenin could improve hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism in rats, and its mechanisms might be associated with the down-regulation of myocardial HIF-1α expression and, subsequently increasing the expressions of myocardial PPARα and its target genes CPT-1 and PDK-4, and decreasing the expressions of myocardial PPARγ and its target genes GPAT and GLUT-4.

  19. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

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    Jin-Hang Gao

    Full Text Available BACKGROUND: Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2 in the cirrhotic liver might be a potential target to ameliorate portal hypertension. OBJECTIVE: To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA. 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF, VEGF receptor-2 (VEGFR-2 and related signal molecules were quantitated. RESULTS: Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2, phosphorylated extracellular signal-regulated kinase (p-ERK, hypoxia-inducible factor-1α (HIF-1α, and c-fos were also down-regulated after celecoxib treatment. CONCLUSIONS: Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its

  20. Gadolinium chloride ameliorates acute lung injury associated with severe acute pancreatitis in rats by regulating CYLD/NF-κB signaling.

    Science.gov (United States)

    Zhao, Xiuhao; Jin, Bei; Yang, Bin; Yan, Wenmao; Wu, Xianjia; Jiang, Cuinan; Cheng, Shi

    2017-10-14

    The present study was embarked on an investigation of the mechanisms behind the effects of Gadolinium chloride (GdCl3) on lung injury associated with severe acute pancreatitis (SAP) in rats. Rats were randomly distributed into three groups: sham operation group (SO), SAP group and SAP treated with GdCl3 group (SAP + GdCl3). Retrograde injection of 5% sodium taurocholate into the biliopancreatic duct was adopted to induce SAP. Lung tissue specimens were harvested for histological study, wet-to-dry weight ratio calculation and myeloperoxidase examination. Meanwhile, bronchoalveolar lavage fluid was analyzed for TNF-α and IL-1β activity and proteins content. Then the apoptosis ratio of alveolar macrophages (AMs) was detected. NF-κB activation and cylindromatosis (CYLD) expression in AMs were measured respectively. Results showed that GdCl3 treatment notably ameliorated lung injury induced by SAP, and simultaneously, the apoptosis ratio of AMs was significantly promoted. The NF-κB activation was obviously inhibited when CYLD expression was markedly up-regulated in AMs of SAP + GdCl3. Negative correlation was analyzed between CYLD and NF-κB in both SAP and SAP + GdCl3. These data demonstrate that GdCl3 ameliorates lung injury secondary to SAP in rats mainly by up-regulating CYLD expression and inhibiting NF-κB activation in AMs, which may play a vital role in lung injury. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Orally administered lactoperoxidase ameliorates dextran sulfate sodium-induced colitis in mice by up-regulating colonic interleukin-10 and maintaining peripheral regulatory T cells.

    Science.gov (United States)

    Shin, Kouichirou; Horigome, Ayako; Yamauchi, Koji; Yaeshima, Tomoko; Iwatsuki, Keiji

    2009-11-01

    We previously demonstrated orally administered bovine lactoperoxidase (LPO) ameliorated dextran sulfate sodium-induced colitis in mice. Here, we examine the mechanism of action of LPO. Three days after colitis induction, expression of interferon-gamma mRNA in colonic tissue was significantly decreased in mice administered LPO; while mRNA expression of interleukin (IL)-10 and regulatory T cell (Treg) marker, Foxp3, were significantly increased. The proportion of CD4+CD25+ Tregs in peripheral CD4+ T cells was also significantly elevated when LPO was administered. Nine days after colitis induction, the severity of colitis symptoms, including body weight loss and colon shortening, was reduced and expression of IL-10 mRNA was increased in mice administered LPO. The proportion of CD4+CD25+ Tregs in peripheral leukocytes was also significantly elevated when LPO was administered. These results suggest LPO ameliorates colitis by up-regulating colonic anti-inflammatory cytokines and maintaining peripheral regulatory T cells.

  2. 副溶血弧菌VopS效应子基因的克隆与原核表达%Cloning and Prokaryotic Expression of VopS Gene of Vibrio parahaemolyticus

    Institute of Scientific and Technical Information of China (English)

    袁军; 倪丹; 方遂; 王荣智

    2012-01-01

    Vibrio parahaemolyticus can secrete a virulence protein and thus lead to the lysis and apoptosis of the eukaryotic cells by its type Ⅲ secretion system. VopS is one of virulence factors from the type Ⅲ secretion system. It can inhibit the activity of NF-KB, which mediates the death of macrophage cells. In this study, the gene encoding VopS was cloned onto to the vector pET28a( + ) and the recombined vector pET28a(+)-vopS was constructed successfully and expressed in E. coli BL2KDE3). SDS-PAGE analysis showed that the recombinant produced a target protein with a corresponding molecular weight of 43 kDa. The concentration of the protein purified by Ni2+-NTA was 175 mg/L. These results will provide materials for the further research of the pathogenic mechanism of type Ⅲ secretion system in V. parahaemolyticus.%副溶血弧菌可通过Ⅲ型分泌系统分泌效应毒力蛋白导致真核靶细胞的细胞溶解及细胞凋亡.VopS是Ⅲ型分泌系统中的一个效应毒力因子,能通过抑制NF-κB的活性介导巨噬细胞死亡.实验将效应因子VopS的编码基因克隆到pET28a(+)载体上,成功构建了pET28a(+)-vopS重组质粒,将该质粒转入大肠杆菌BL21 (DE3)中诱导表达,经SDS-PAGE分析,发现在分子量约为43 kDa处有一明显蛋白表达条带.用Ni2+-NTA柱亲和层析获得纯化蛋白,浓度为175 mg/L.为进一步研究副溶血弧菌Ⅲ型分泌系统致病机制提供了材料.

  3. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

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    J Pedro Fernández-Murray

    2016-01-01

    Full Text Available Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

  4. Aedes aegypti salivary gland extract ameliorates experimental inflammatory bowel disease.

    Science.gov (United States)

    Sales-Campos, Helioswilton; de Souza, Patricia Reis; Basso, Paulo José; Ramos, Anderson Daniel; Nardini, Viviani; Chica, Javier Emílio Lazo; Capurro, Margareth Lara; Sá-Nunes, Anderson; de Barros Cardoso, Cristina Ribeiro

    2015-05-01

    Current therapies for inflammatory bowel disease (IBD) are not totally effective, resulting in persistent and recurrent disease for many patients. Mosquito saliva contains immunomodulatory molecules and therein could represent a novel therapy for IBD. Here, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Aedes aegypti on dextran sulfate sodium (DSS)-induced colitis. For this purpose, C57BL/6 male mice were exposed to 3% DSS in drinking water and treated with SGE at early (days 3-5) or late (days 5-8) time points, followed by euthanasia on days 6 and 9, respectively, for sample collection. The results showed an improvement in clinical disease outcome and postmortem scores after SGE treatment, accompanied by the systemic reduction in peripheral blood lymphocytes, with no impact on bone marrow and mesenteric lymph nodes cellularity or macrophages toxicity. Moreover, a local diminishment of IFN-γ, TNF-α, IL-1β and IL-5 cytokines together with a reduction in the inflammatory area were observed in the colon of SGE-treated mice. Strikingly, early treatment with SGE led to mice protection from a late DSS re-challenging, as observed by decreased clinical and postmortem scores, besides reduced circulating lymphocytes, indicating that the mosquito saliva may present components able to prevent disease relapse. Indeed, high performance liquid chromatography (HPLC) experiments pointed to a major SGE pool fraction (F3) able to ameliorate disease signs. In conclusion, SGE and its components might represent a source of important immunomodulatory molecules with promising therapeutic activity for IBD.

  5. Economic recession and suicidal behaviour: Possible mechanisms and ameliorating factors.

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    Haw, Camilla; Hawton, Keith; Gunnell, David; Platt, Stephen

    2015-02-01

    A growing body of research evidence from countries around the world indicates that economic recession is associated with increases in suicide, particularly in males of working age. To explore contributory and ameliorating factors associated with economic recession and suicide and thereby stimulate further research in this area and encourage policy makers to consider how best to reduce the impact of recession on mental health and suicidal behaviour. We conducted a selective review of the worldwide literature focusing on possible risk factors, mechanisms and preventative strategies for suicidal behaviour linked to economic recession. A model of how recession might affect suicide rates is presented. A major and often prolonged effect of recession is on unemployment and job insecurity. Other important effects include those exerted by financial loss, bankruptcy and home repossession. It is proposed these factors may lead directly or indirectly to mental health problems such as depression, anxiety and binge drinking and then to suicidal behaviour. Countries with active labour market programmes and sustained welfare spending during recessions have less marked increases in suicide rates than those that cut spending on welfare and job-search initiatives for the unemployed. Other measures likely to help include targeted interventions for unemployed people, membership of social organisations and responsible media reporting. Good primary care and mental health services are needed to cope with increased demand in times of economic recession but some governments have in fact reduced healthcare spending as an austerity measure. The research evidence linking recession, unemployment and suicide is substantial, but the evidence for the other mechanisms we have investigated is much more tentative. We describe the limitations of the existing body of research as well as make suggestions for future research into the effects of economic recession on suicidal behaviour. © The Author

  6. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Michelle F Goody

    Full Text Available Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction

  7. Amelioration of acidic soil using various renewable waste resources.

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    Moon, Deok Hyun; Chang, Yoon-Young; Ok, Yong Sik; Cheong, Kyung Hoon; Koutsospyros, Agamemnon; Park, Jeong-Hun

    2014-01-01

    In this study, improvement of acidic soil with respect to soil pH and exchangeable cations was attempted for sample with an initial pH of approximately 5. Acidic soil was amended with various waste resources in the range of 1 to 5 wt.% including waste oyster shells (WOS), calcined oyster shells (COS), Class C fly ash (FA), and cement kiln dust (CKD) to improve soil pH and exchangeable cations. Upon treatment, the soil pH was monitored for periods up to 3 months. The exchangeable cations were measured after 1 month of curing. After a curing period of 1 month, a maize growth experiment was conducted with selected-treated samples to evaluate the effectiveness of treatment. The treatment results indicate that in order to increase the soil pH to a value of 7, 1 wt.% of WOS, 3 wt.% of FA, and 1 wt.% of CKD are required. In the case of COS, 1 wt.% was more than enough to increase the soil pH value to 7 because of COS's strong alkalinity. Moreover, the soil pH increases after a curing period of 7 days and remains virtually unchanged thereafter up to 1 month of curing. Upon treatment, the summation of cations (Ca, Mg, K, and Na) significantly increased. The growth of maize is superior in the treated samples rather than the untreated one, indicating that the amelioration of acidic soil is beneficial to plant growth, since soil pH was improved and nutrients were replenished.

  8. Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

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    Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

    2016-02-10

    This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus.

  9. Glucosamine-induced Sp1 O-GlcNAcylation ameliorates hypoxia-induced SGLT dysfunction in primary cultured renal proximal tubule cells.

    Science.gov (United States)

    Suh, Han Na; Lee, Yu Jin; Kim, Mi Ok; Ryu, Jung Min; Han, Ho Jae

    2014-10-01

    The aim of this study is to determine whether GlcN could recover the endoplasmic reticulum (ER) stress-induced dysfunction of Na(+) /glucose cotransporter (SGLT) in renal proximal tubule cells (PTCs) under hypoxia. With the rabbit model, the renal ischemia induced tubulointerstitial abnormalities and decreased SGLTs expression in tubular brush-border, which were recovered by GlcN. Thus, the protective mechanism of GlcN against renal ischemia was being examined by using PTCs. Hypoxia decreased the level of protein O-GlcNAc and the expression of O-GlcNAc transferase (OGT) while increased O-GlcNAcase (OGA) and these were reversed by GlcN. Hypoxia also decreased the expression of SGLTs (SGLT1 and 2) and [(14) C]-α-methyl-D-glucopyranoside (α-MG) uptake which were recovered by GlcN and PUGNAc (OGA inhibitor). Hypoxia enhanced reactive oxygen species (ROS) and then ER stress proteins, glucose-regulated protein 78 (GRP78), and C/EBP-homologous protein (CHOP). However, the expression of GRP78 increased till 6 h and then decreased whereas CHOP increased gradually. Moreover, decreased GRP78 and increased CHOP were reversed by NAC (antioxidant) and GlcN. GlcN ameliorated hypoxia-induced decrease of O-GlcNAc modification of Sp1 but OGT or Sp1 siRNAs blocked the recovery effect of GlcN on SGLT expression and α-MG uptake. In addition, hypoxia-decreased GRP78 and HIF-1α expression was reversed by GlcN but OGT siRNA or Sp1 siRNA ameliorated the effect of GlcN. When PTCs were transfected with GRP78 siRNA or HIF-1α siRNA, SGLT expression and α-MG uptake was decreased. Taken together, these data suggest that GlcN-induced O-GlcNAc modified Sp1 with stimulating GRP78 and HIF-1α activity ameliorate hypoxia-induced SGLT dysfunction in renal PTCs. J. Cell. Physiol. 229: 1557-1568, 2014. © 2014 Wiley Periodicals, Inc.

  10. Gypenosides ameliorate memory deficits in MPTP-lesioned mouse model of Parkinson's disease treated with L-DOPA.

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    Zhao, Ting Ting; Kim, Kyung Sook; Shin, Keon Sung; Park, Hyun Jin; Kim, Hyun Jeong; Lee, Kyung Eun; Lee, Myung Koo

    2017-09-06

    Previous studies have revealed that gypenosides (GPS) improve the symptoms of anxiety disorders in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rat model of Parkinson's disease (PD). The present study aimed to investigate the effects of GPS on memory deficits in an MPTP-lesioned mouse model of PD treated with L-3,4-dihydroxyphenylalanine (L-DOPA). MPTP (30 mg/kg/day, 5 days)-lesioned mice were treated with GPS (50 mg/kg) and/or L-DOPA (10 and 25 mg/kg) for 21 days. After the final treatments, behavioral changes were assessed in all mice using passive avoidance and elevated plus-maze tests. We then evaluated the biochemical influences of GPS treatment on levels of tyrosine hydroxylase (TH), dopamine, N-methyl-D-aspartate (NMDA) receptors, extracellular signal-regulated kinase (ERK1/2), and cyclic AMP-response element binding protein (CREB) phosphorylation. MPTP-lesioned mice exhibited deficits associated with habit learning and spatial memory, which were further aggravated by treatment with L-DOPA (25 mg/kg). However, treatment with GPS (50 mg/kg) ameliorated memory deficits. Treatment with GPS (50 mg/kg) also improved L-DOPA (25 mg/kg)-treated MPTP lesion-induced decreases in retention latency on the passive avoidance test, as well as levels of TH-immunopositive cells and dopamine in the substantia nigra and striatum. GPS treatment also attenuated increases in retention transfer latency on the elevated plus-maze test and in NMDA receptor expression, as well as decreases in the phosphorylation of ERK1/2 and CREB in the hippocampus. Treatment with L-DOPA (10 mg/kg) also ameliorated deficits in habit learning and spatial memory in MPTP-lesioned mice, and this effect was further enhanced by treatment with GPS (50 mg/kg). GPS ameliorate deficits in habit learning and spatial memory by modulating the dopaminergic neuronal and N-methyl-D-aspartate receptor-mediated signaling systems in MPTP-lesioned mice treated with L-DOPA. GPS may serve as an adjuvant

  11. Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways

    Directory of Open Access Journals (Sweden)

    Yang Yao-Jong

    2012-03-01

    Full Text Available Abstract Background H. pylori infection may trigger Smad7 and NFκB expression in the stomach, whereas probiotics promote gastrointestinal health and improve intestinal inflammation caused by pathogens. This study examines if probiotics can improve H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways. Results Challenge with H. pylori increased IL-8 and TNF-α expressions but not TGF-β1 in MKN45 cells. The RNA levels of Smad7 in AGS cells increased after H. pylori infection in a dose-dependent manner. A higher dose (MOI 100 of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-β1. Such anti-inflammatory effect was mediated via increased cytoplasmic IκBα and depletion of nuclear NFκB. L. acidophilus also inhibited H. pylori-induced Smad7 transcription by inactivating the Jak1 and Stat1 pathways, which might activate the TGF-β1/Smad pathway. L. acidophilus pre-treatment ameliorated IFN-γ-induced Smad7 translation level and subsequently reduced nuclear NF-κB production, as detected by western blotting. Conclusions H. pylori infection induces Smad7, NFκB, IL-8, and TNF-α production in vitro. Higher doses of L. acidophilus pre-treatment reduce H. pylori-induced inflammation through the inactivation of the Smad7 and NFκB pathways.

  12. Treadmill exercise during pregnancy ameliorates post‑traumatic stress disorder‑induced anxiety‑like responses in maternal rats.

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    Seo, Jin-Hee; Kim, Tae-Woon; Kim, Chang-Ju; Sung, Yun-Hee; Lee, Sam-Jun

    2013-02-01

    Post‑traumatic stress disorder (PTSD) is an anxiety disorder triggered by life‑threatening events that cause intense fear. Exercise is known to have protective effects on neuropsychiatric diseases. The present study investigated whether treadmill exercise during pregnancy reduced or alleviated symptoms of PTSD in maternal rats. To induce predator stress in pregnant rats, rats were exposed to a hunting dog in an enclosed room. Exposure time was three 10‑min daily sessions separated by 1 h, starting at week 1 of pregnancy until delivery. Pregnant rats in the exercise group were forced to run on a treadmill for 30 min once a day, starting one week following pregnancy until delivery. Rats receiving predator stress during pregnancy exhibited PTSD anxiety‑like behaviors following delivery. Expression of 5‑hydroxytryptamine (5‑HT) and its synthesizing enzyme tryptophan hydroxylase (TPH) in the dorsal raphe was increased compared with unstressed rats. Expression of c‑Fos and neuronal nitric oxide synthases (nNOS) in the hypothalamus and locus coeruleus were higher in the rats receiving stress during pregnancy compared with unstressed rats. By contrast, treadmill exercise during pregnancy ameliorated anxiety‑like behaviors and reduced the expression of 5‑HT, TPH, c‑Fos and nNOS in the PTSD maternal rats. The results of the present study indicate that exercise during pregnancy is suitable for use as a therapeutic strategy to reduce anxiety‑related disorders, including PTSD.

  13. Beetroot (Beta vulgaris L. Extract Ameliorates Gentamicin-Induced Nephrotoxicity Associated Oxidative Stress, Inflammation, and Apoptosis in Rodent Model

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    Ali A. El Gamal

    2014-01-01

    Full Text Available The present investigation was designed to investigate the protective effect of (Beta vulgaris L. beat root ethanolic extract (BVEE on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific kidney function parameters (urea, uric acid, total protein, creatinine, and histopathology of kidney tissue were evaluated to access gentamicin-induced nephrotoxicity. The oxidative/nitrosative stress (Lipid peroxidation, MDA, NP-SH, Catalase, and nitric oxide levels was assessed. The inflammatory response (TNF-α, IL-6, MPO, NF-κB (p65, and NF-κB (p65 DNA binding and apoptotic marker (Caspase-3, Bax, and Bcl-2 were also evaluated. BVEE (250 and 500 mg/kg treatment along with gentamicin restored/increased the renal endogenous antioxidant status. Gentamicin-induced increased renal inflammatory cytokines (TNF-α and IL-6, nuclear protein expression of NF-κB (p65, NF-κB-DNA binding activity, myeloperoxidase (MPO activity, and nitric oxide level were significantly down regulated upon BVEE treatment. In addition, BVEE treatment significantly reduced the amount of cleaved caspase 3 and Bax, protein expression and increased the Bcl-2 protein expression. BVEE treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. These findings suggest that BVEE treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, inflammation, and apoptosis in the kidney.

  14. Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress.

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    Yajuan Li

    Full Text Available Previously we have shown that kallikreins (klks play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1 gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 10(6 hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis.

  15. Ameliorative effects of a combination of baicalin, jasminoidin and cholic acid on ibotenic acid-induced dementia model in rats.

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    Junying Zhang

    Full Text Available AIMS: To investigate the therapeutic effects and acting mechanism of a combination of Chinese herb active components, i.e., a combination of baicalin, jasminoidin and cholic acid (CBJC on Alzheimer's disease (AD. METHODS: Male rats were intracerebroventricularly injected with ibotenic acid (IBO, and CBJC was orally administered. Therapeutic effect was evaluated with the Morris water maze test, FDG-PET examination, and histological examination, and the acting mechanism was studied with DNA microarrays and western blotting. RESULTS: CBJC treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Additionally, the expression levels of 19 genes in the forebrain were significantly influenced by CBJC; approximately 60% of these genes were related to neuroprotection and neurogenesis, whereas others were related to anti-oxidation, protein degradation, cholesterol metabolism, stress response, angiogenesis, and apoptosis. Expression of these genes was increased, except for the gene related to apoptosis. Changes in expression for 5 of these genes were confirmed by western blotting. CONCLUSION: CBJC can ameliorate the IBO-induced dementia in rats and may be significant in the treatment of AD. The therapeutic mechanism may be related to CBJC's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc.

  16. Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1.

    Science.gov (United States)

    Matsuishi, Yujiro; Jesmin, Subrina; Kawano, Satoru; Hideaki, Sakuramoto; Shimojo, Nobutake; Mowa, Chishimba Nathan; Akhtar, Shila; Zaedi, Sohel; Khatun, Tanzila; Tsunoda, Yoshiya; Kiwamoto, Takumi; Hizawa, Nobuyuki; Inoue, Yoshiaki; Mizutani, Taro

    2016-12-01

    Among the dysfunctions and pathologies associated with sepsis, the underlying molecular mechanisms of sepsis-induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-inflammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting β-blocker, plays a crucial role in ameliorating and attenuating LPS-induced ALI through modulation of the ET-1 system. Male Wistar rats at 8weeks of age were administered with either saline or lipopolysaccharide (LPS) for three hours (3h) and some of the LPS-administered rats were continuously treated with landiolol for 3h. ALI was induced by LPS, including levels of both circulatory and pulmonary TNF-α and IL-6 but [PaO2] was significantly decreased. LPS also induced a significant increase in levels of pulmonary ET-1 and ET-A receptor, but levels of ET-B receptor, which has vasodilating effects, were remarkably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1α. Finally, the treatment of LPS-administered rats with landiolol for 3h ameliorated and prevented ALI, normalized the altered levels of pulmonary ET-1 and ET-A receptors. Landiolol also induced significant down-regulation of ET-B receptor in lung tissues in the early hours (phase) of sepsis. However, Landiolol treatment had no effect on the up-regulated inflammatory mediators (TNF-α, IL-6) in both plasma and lung tissues during sepsis, and expression of pulmonary HIF-1α also remained unchanged after landiolol treatment. Collectively, these data led us to conclude that landiolol may ameliorate sepsis-induced ALI via the pulmonary ET system. Copyright © 2016. Published by Elsevier Inc.

  17. St. John's wort may ameliorate 2,4,6-trinitrobenzenesulfonic acid colitis off rats through the induction of pregnane X receptors and/or P-glycoproteins.

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    Sehirli, A O; Cetinel, S; Ozkan, N; Selman, S; Tetik, S; Yuksel, M; Dulger, F G A

    2015-04-01

    It is reported that deficiencies of the pregnane X receptor (PXR) and P-glycoprotein (P-gp), the latter of which is encoded by the MDR1 gene, are important factors in the pathogenesis of inflammatory bowel disease (IBD). It is also known that the activation of PXR is protective of IBD due to the mutual repression between PXR and nuclear factor kappa B (NF-κB) expression and because NF-κB was reported to play a pivotal role in the pathogenesis of ulcerative colitis. The goal of this study was to investigate whether St. John's wort (SJW) and spironolactone (SPL), both known to have strong inducing effects on cytochrome P 450 (CYP) enzymes as well as PXR and P-gp, have ameliorating effects on 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis of rats through induction of PXR and/or P-gp. Wistar albino rats (250 - 300 g) were divided into control and TNBS-colitis groups. Each group was then divided into a) control (saline), b) SJW (300 mg/kg p.o. bid), and c) SPL (80 mg/kg p.o.) groups. Drugs were given for 7 days. Both treatments ameliorated the clinical hallmarks of colitis, as determined by body weight loss and assessment of diarrhea, colon length, and bowel histology. Plasma levels of NF-κB, tumour necrosis factor-alpha (TNF-α) and tissue myeloperoxidase (MPO) activity, as well as the oxidative stress markers that increased during colitis, decreased significantly after both treatments. The PXR and P-gp expression in the intestinal tissues was diminished in the colitis group but increased after drug treatments. Both drugs appeared to have significant antioxidant and anti-inflammatory effects and ameliorated the TNBS colitis of the rats, most likely through their PXR- and P-gp-inducing properties.

  18. Carbon monoxide inhalation ameliorates conditions of lung grafts from rat brain death donors

    Institute of Scientific and Technical Information of China (English)

    ZHOU Hua-cheng; DING Wen-gang; CUI Xiao-guang; PAN Peng; ZHANG Bing; LI Wen-zhi

    2008-01-01

    Background Successful lung transplantation has been limited by the scarcity of donors. Brain death (BD) donors are major source of lung transplantation. Whereas BD process induces acute lung injury and aggravates lung ischemia reperfusion injury. Carbon monoxide (CO) inhalation at 50-500 parts per million (ppm) can ameliorate lung injury in several models. We examined in rats whether CO inhalation in BD donor would show favorable effects on lung grafts.Methods Rats were randomly divided into 4 groups. In sham group, donor rats received insertion of a balloon catheter into the cranial cavity, but the balloon was not inflated. In BD-only group, donor rats were ventilated with 40% oxygen after BD confirmation. In BD+CO250 and BD+CO500 groups, donor rats inhaled, after BD confirmation, 250 ppm or 500 ppm CO for 120 minutes prior to lung procurement, and orthotopic lung transplantation was performed. The rats were sacrificed 120 minutes after the lung transplantation by exsanguination, and their blood and lung graft samples were obtained. A total of 8 rats fulfilling the criteria were included in each group.Results The inhalation decreased the severity of lung injury in grafts from BD donors checked by histological examination. CO pretreatment reversed the aggravation of PaO2/FiO2 in recipients from BD donors. The CO inhalation down-regulated pro-inflammatory cytokines (TNF-α, IL-6) along with the increase of anti-inflammatory cytokine (IL-10) in recipient serum, and inhibited the activity of myeloperoxidase in grafts tissue. The inhalation significantly decreased cell apoptosis in lung grafts, inhibiting mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1) and caspase-3 in lung grafts. Further, the inhalation activated phosphorylation of p38 expression and inhibited phosphorylation of anti-extraceUular signal-regulated kinase (ERK) expression in lung grafts. The effects of CO at 500 ppm were greater than those at 250 ppm.Conclusions CO exerts

  19. Epigallocatechin-3-Gallate Ameliorates Alcohol-Induced Liver Injury in Rats

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    Xi Li

    2006-07-01

    Full Text Available Endotoxemia is a common event in alcoholic liver disease. Elevated intestinalpermeability is the major factor involved in the mechanism of alcoholic endotoxemia andthe pathogenesis of alcoholic liver disease. This study examined the effect ofepigallocatechin-3-gallate (EGCG on alcohol-induced gut leakiness, and explored therelated mechanisms involved in its protection against alcohol-induced liver injury in rats.Four groups of female Sprague-Dawley rats were studied. Alcohol and alcohol/EGCGgroups rats received fish oil along with alcohol daily via gastrogavage for 6 weeks, anddextrose and dextrose/EGCG groups rats were given fish oil along with isocaloric dextroseinstead of alcohol. The dextrose/EGCG and alcohol/EGCG groups received additionaltreatment of EGCG (100mg.kg-1 body weight daily intragastrically by gavage. Intestinalpermeability was assessed by urinary excretion of lactulose and mannitol (L/M ratio. Liverinjury was evaluated histologically and by serum alanine aminotransferase (ALT. Plasmaendotoxin and serum tumor necrosis factor-α (TNF-α levels were assayed; livermalondialdehyde (MDA contents determined. CD14 and inflammatory factors, such asTNF-α, cyclooxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS mRNAs inthe liver were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR. Ratsgiven fish oil plus alcohol had gut leakiness (L/M ratio was increased, which wasassociated with both endotoxemia and liver injury. The above responses were accompaniedby increased CD14, TNF-α, COX-2 and iNOS mRNA expressions in the liver. EGCGsupplementation partly blocked the gut leakiness, reduced endotoxemia and lipidperoxidation, and blunted the elevated expressions of CD14, TNF-α, COX-2 and iNOS, allof which were associated with improved liver injury. These results show that EGCG can block alcohol-induced gut leakiness, reduce endotoxemia, and inhibit inflammatory factors expressions in

  20. Lysine acetylsalicylate ameliorates lung injury in rats acutely exposed to paraquat

    Institute of Scientific and Technical Information of China (English)

    HUANG Wei-dong; WANG Jie-zan; LU Yuan-qiang; DI Ya-min; JIANG Jiu-kun; ZHANG Qin

    2011-01-01

    Background Paraquat (PQ), an effective and widely used herbicide, has been proven to be safe when appropriately applied to eliminate weeds. However, PQ poisoning is an extremely frustrating clinical condition with a high mortality and with a lack of effective treatments in humans. PQ mainly accumulates in the lung, and the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. The aim of this study was to evaluate whether lysine acetylsalicylate (LAS) could protect the lung from the damage of PQ poisoning and to study the mechanisms of protection.Methods A model of PQ poisoning was established in 75 Sprague-Dawley rats by intragastric administration of 50 mg/kg PQ, followed by treatment with 200 mg/kg of LAS. The rats were randomly divided into sham, PQ, and PQ+LAS groups, with 25 in each group. We assessed and compared the malonaldehyde (MDA) content, superoxide dismutase activity (SOD), glutathion peroxidase (GSH-Px), and catalase (CAT) in serum and lung and the hydroxyproline (HYP)content, pathological changes, apoptosis and expression of Bcl-2/Bax protein in lung of rats on days 1, 3, 7, 14 and 21after PQ poisoning and LAS treatment.Results Compared to the PQ group rats, early treatment with LAS reduced the MDA and HYP contents, and increased the SOD, GSH-Px, and CAT activities in the serum and lung on days 1, 3, 7, 14, and 21 after PQ poisoning (all P<0.05).After early LAS treatment, the apoptotic rate and Bax expression of lung decreased, the Bcl-2 expression increased, and the Bcl-2/Bax ratio increased, compared to the PQ group rats. Furthermore, the pathological results of lungs revealed that after LAS treatment, early manifestations of PQ poisoning, such as hemorrhage, edema and inflammatory-cell infiltration, were improved to some degree, and collagen fibers in the pulmonary interstitium were also obviously reduced.Conclusion In this rat model of PQ poisoning, LAS effectively ameliorated the lung

  1. Amygdalin ameliorates the progression of atherosclerosis in LDL receptor‑deficient mice.

    Science.gov (United States)

    Lv, Jianzhen; Xiong, Wen; Lei, Tiantian; Wang, Hailian; Sun, Minghan; Hao, Erwei; Wang, Zhiping; Huang, Xiaoqi; Deng, Shaoping; Deng, Jiagang; Wang, Yi

    2017-09-25

    Previous studies have demonstrated that regulatory T cells (Tregs) are pivotal in the regulation of T cell‑mediated immune responses in atherosclerosis, a chronic autoimmune‑like disease. In the authors' previous studies, it was demonstrated that amygdalin ameliorated atherosclerosis by the regulation of Tregs in apolipoprotein E‑deficient (ApoE‑/‑) mice. Therefore, the aim of the present study was to investigate the therapeutic effect of amygdalin on low‑density lipoprotein (LDL) receptor deficient (LDLR‑/‑) mice, and to examine its immune regulatory function by the stimulation of Tregs. To establish an atherosclerosis mouse model, the LDLR‑/‑ mice were fed a high fat and high cholesterol diet then the total plasma cholesterol, triglyceride, LDL and chemokines levels were measured by an ELISA. Following sacrificing the mice, the upper sections of the aorta were stained by hematoxylin and eosin, and Oil red O to assess the plaque area. Then western blotting and reverse transcription polymerase chain reactions were performed to analysis the expression levels of cluster of differentiation 68, monocyte chemoattractant protein‑1, matrix metalloproteinase (MMP)‑2, MMP‑9 and forkhead box P3 (Foxp3). To further confirm the activation of FOXP3 by amygdalin, lentiviruses carrying Foxp3 shRNA were injected into the mice, and the serum cytokines levels were measured by ELISA. Following feeding of the mice with a high‑fat/high‑cholesterol diet, the LDLR‑/‑ mice demonstrated comparatively higher levels of triglyceride, total cholesterol and LDL, compared with levels in the amygdalin‑treated mice. By comparing the vessel area, lumen area, plaque area, and percentage aortic plaque coverage, the effects of amygdalin on pre‑existing lesions were assessed. In addition, the levels of CD68, monocyte chemoattractant protein‑1, MMP‑2 and MMP‑9 were analyzed, and analysis of the expression of interleukin (IL)‑1β, IL‑6 and tumor necrosis

  2. Tripterygium Glycosides Tablet Ameliorates Renal Tubulointerstitial Fibrosis via the Toll-Like Receptor 4/Nuclear Factor Kappa B Signaling Pathway in High-Fat Diet Fed and Streptozotocin-Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Ze-jun Ma

    2015-01-01

    Full Text Available Tripterygium glycosides tablet (TGT is a Chinese traditional medicine that has been shown to protect podocytes from injury and reduce the proteinuria. The aim of this study was to assess the effect of TGT on renal tubulointerstitial fibrosis and its potential mechanism in high-fat diet fed and STZ-induced diabetic rats. Rats were randomly divided into normal control rats (NC group, diabetic rats without drug treatment (DM group, and diabetic rats treated with TGT (1, 3, or 6 mg/kg/day, respectively for 8 weeks. The results showed that 24 h proteinuria and urinary N-acetyl-glucosaminidase (NAG in diabetic rats were decreased by TGT treatment without affecting blood glucose. Masson’s trichrome stains showed that apparent renal tubulointerstitial fibrosis was found in DM group, which was ameliorated by TGT treatment. The expression of α-SMA was significantly decreased, accompanied by increased expression of E-cadherin in TGT-treated rats, but not in untreated DM rats. Further studies showed that TGT administration markedly reduced expression of TLR4, NF-κB, IL-1β, and MCP-1 in TGT-treated diabetic rats. These results showed that TGT could ameliorate renal tubulointerstitial fibrosis, the mechanism which may be at least partly associated with the amelioration of EMT through suppression of the TLR4/NF-κB pathway.

  3. Course of psychopathology, cognition and neurobiological abnormality in schizophrenia: developmental origins and amelioration by antipsychotics?

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    Waddington, J L; Buckley, P F; Scully, P J; Lane, A; O'Callaghan, E; Larkin, C

    1998-01-01

    It is argued that schizophrenia has origins in events occurring during the first or early second trimester that are reflected in minor physical anomalies and which may at least in part predispose to later obstetric complications. This neurodevelopmental basis underlies certain neuromotor and psychosocial abnormalities of infancy and childhood, which are the early manifestations of what will be reconceptualised later as negative symptoms and (particularly frontal) cognitive dysfunction, but gives rise to positive symptoms only on the maturation of other systems necessary for their expression. This later emergence of psychosis may reflect an active morbid process that is associated with increased accrual of negative symptoms and of general (but not frontal) cognitive impairment that may be ameliorated by effective antipsychotic treatment. The psychological or biological basis of this heuristic process is poorly understood. Contemporary re-appraisal of any impact of antipsychotics on the long-term course of schizophrenia must take into account what is known of the origins of the disease process with which such drugs might interact. Much recent work continues to indicate that very early events, during the embryonic/fetal period, are important in, if not fundamental to, the genesis of schizophrenia; i.e. that there is a neurodevelopmental basis to the disorder. The present article seeks to establish a time-line relating early intrauterine adversity and dysmorphogenesis, through the onset of psychosis, to the chronic phase of the illness over adulthood; from this time-line, a schema is elaborated for a beneficial impact of antipsychotics on the course of psychopathology, cognition and, less clearly, neurobiological abnormality.

  4. Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy

    Directory of Open Access Journals (Sweden)

    Miao Shen

    2013-01-01

    Full Text Available Background. Hepatic ischemia-reperfusion (I/R injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy. Methods. Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg were administered 1 h before a model of segmental (70% hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h. Results. Alanine aminotransferase (ALT, aspartate aminotransferase (AST, and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg. The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg. Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6. Conclusion. Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.

  5. Preischemic exercise reduces brain damage by ameliorating metabolic disorder in ischemia/reperfusion injury.

    Science.gov (United States)

    Dornbos, David; Zwagerman, Nathan; Guo, Miao; Ding, Jamie Y; Peng, Changya; Esmail, Fatema; Sikharam, Chaitanya; Geng, Xiaokun; Guthikonda, Murali; Ding, Yuchuan

    2013-06-01

    Physical exercise preconditioning is known to ameliorate stroke-induced injury. In addition to several other mechanisms, the beneficial effect of preischemic exercise following stroke is due to an upregulated capacity to maintain energy supplies. Adult male Sprague-Dawley rats were used in exercise and control groups. After 1-3 weeks of exercise, several enzymes were analyzed as a gauge of the direct effect of physical exercise on cerebral metabolism. As a measure of metabolic capacity, an ADP/ATP ratio was obtained. Glucose transporters (GLUT1 and GLUT3) were monitored to assess glucose influx, and phosphofructokinase (PFK) was measured to determine the rate of glycolysis. Hypoxia-induced factor-1α (HIF-1α) and 5'AMP-activated protein kinase (AMPK) levels were also determined. These same analyses were performed on preconditioned and control rats following an ischemic/reperfusion (I/R) insult. Our results show that GLUT1, GLUT3, PFK, AMPK, and HIF-1α were all increased following 3 weeks of exercise training. In addition, the ADP/ATP ratio was chronically elevated during these 3 weeks. After I/R injury, HIF-1α and AMPK were significantly higher in exercised rats. The ADP/ATP ratio was reduced in preconditioned rats in the acute phase after stroke, suggesting a lower level of metabolic disorder. GLUT1 and GLUT3 were also increased in the acute phase in exercise rats, indicating that these rats were better able to increase rates of metabolism immediately after ischemic injury. In addition, PFK expression was increased in exercise rats showing an enhanced glycolysis resulting from exercise preconditioning. Altogether, exercise preconditioning increased the rates of glucose metabolism, allowing a more rapid and more substantial increase in ATP production following stroke.

  6. Hydrogen-rich saline ameliorates the severity of L-arginine-induced acute pancreatitis in rats

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    Chen, Han; Sun, Yan Ping; Li, Yang [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Liu, Wen Wu [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Xiang, Hong Gang [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Fan, Lie Ying [Department of Clinical Laboratory, Shanghai East Hospital, Tong Ji University, Shanghai 200120 (China); Sun, Qiang [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Xu, Xin Yun [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Cai, Jian Mei [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Ruan, Can Ping; Su, Ning; Yan, Rong Lin [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Sun, Xue Jun, E-mail: sunxjk@hotmail.com [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Wang, Qiang, E-mail: wang2929@hotmail.com [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China)

    2010-03-05

    Molecular hydrogen, which reacts with the hydroxyl radical, has been considered as a novel antioxidant. Here, we evaluated the protective effects of hydrogen-rich saline on the L-arginine (L-Arg)-induced acute pancreatitis (AP). AP was induced in Sprague-Dawley rats by giving two intraperitoneal injections of L-Arg, each at concentrations of 250 mg/100 g body weight, with an interval of 1 h. Hydrogen-rich saline (>0.6 mM, 6 ml/kg) or saline (6 ml/kg) was administered, respectively, via tail vein 15 min after each L-Arg administration. Severity of AP was assessed by analysis of serum amylase activity, pancreatic water content and histology. Samples of pancreas were taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in pancreatic acinar cell was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa B (NF-{kappa}B) were detected with immunohistochemistry. Hydrogen-rich saline treatment significantly attenuated the severity of L-Arg-induced AP by ameliorating the increased serum amylase activity, inhibiting neutrophil infiltration, lipid oxidation and pancreatic tissue edema. Moreover, hydrogen-rich saline treatment could promote acinar cell proliferation, inhibit apoptosis and NF-{kappa}B activation. These results indicate that hydrogen treatment has a protective effect against AP, and the effect is possibly due to its ability to inhibit oxidative stress, apoptosis, NF-{kappa}B activation and to promote acinar cell proliferation.

  7. Ginkgo biloba extract ameliorates oxidative phosphorylation performance and rescues abeta-induced failure.

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    Rhein, Virginie; Giese, Maria; Baysang, Ginette; Meier, Fides; Rao, Stefania; Schulz, Kathrin L; Hamburger, Matthias; Eckert, Anne

    2010-08-24

    Energy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism. We used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Abeta-induced disturbance in the activity of mitochondrial complexes III and IV restoring impaired ATP levels possibly through decreasing Abeta and oxidative stress level. Although the underlying molecular mechanisms of the mode of action of GBE remain to be

  8. Moringa oleifera from Cambodia Ameliorates Oxidative Stress, Hyperglycemia, and Kidney Dysfunction in Type 2 Diabetic Mice.

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    Tang, Yujiao; Choi, Eun-Ju; Han, Weon Cheol; Oh, Mirae; Kim, Jin; Hwang, Ji-Young; Park, Pyo-Jam; Moon, Sang-Ho; Kim, Yon-Suk; Kim, Eun-Kyung

    2017-05-01

    Recent reports have shown the antidiabetic effect of Moringa oleifera from various parts of the world. However, M. oleifera from Cambodia has never determined. Therefore, the aim of this study was to assess the antidiabetic effect of M. oleifera extract from Cambodia. The leaf ethanolic extract contained flavonoids (31.90 mg/mL), polyphenols (53.03 mg/mL), lycopene (0.042 mg/mL), and ß-carotene (0.170 mg/mL), and possessed 2,2-diphenyl-1-picrylhydrazyl, hydrogen peroxide, and hydroxyl radical scavenging activities of 92.40, 99.25, and 83.57 TE/μM at 1 mg/mL, respectively. Db/db mice were orally administered the leaf extract (150 mg/kg/day) for 5 weeks. M. oleifera treatment significantly ameliorated the altered fasting plasma glucose (from 483 to 312 mg/dL), triglyceride (from 42.12 to 23.00 mg/dL), and low-density lipoprotein cholesterol (from 107.21 to 64.25 mg/dL) compared to control group, and increased the insulin levels from 946 ± 92 to 1678 ± 268 pg/mL. The histopathological damage and expression levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase in renal tissue decreased. These results indicate the potential antidiabetic benefits of M. oleifera ethanolic leaf extract.

  9. Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.

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    Josep Bassaganya-Riera

    Full Text Available BACKGROUND: There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(- strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM and increased adipose tissue regulatory T cells (Treg cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4 in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. CONCLUSIONS/SIGNIFICANCE: Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.

  10. Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice.

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    Moriguchi, Shigeki; Sakagami, Hiroyuki; Yabuki, Yasushi; Sasaki, Yuzuru; Izumi, Hisanao; Zhang, Chen; Han, Feng; Fukunaga, Kohji

    2015-12-01

    Sigma-1 receptor (Sig-1R) is a molecular chaperone regulating calcium efflux from the neuronal endoplasmic reticulum to the mitochondria. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice exhibit depressive-like behaviors and impaired neurogenesis as assessed by bromodeoxyuridine (BrdU) incorporation into newborn cells of the hippocampal dentate gyrus (DG). Here, we demonstrate that chronic stimulation of Sig-1R by treatment with the agonist SA4503 or the SSRI fluvoxamine for 14 days improves depressive-like behaviors in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig-1R, did not alter these behaviors. Reduced numbers of BrdU-positive cells and decreased brain-derived neurotrophic factor (BDNF) mRNA expression and protein kinase B (Akt; Ser-473) phosphorylation seen in the DG of CaMKIV null mice were significantly rescued by chronic Sig-1R stimulation. Interestingly, reduced ATP production observed in the DG of CaMKIV null mice was improved by chronic Sig-1R stimulation. Such stimulation also improved hippocampal long-term potentiation (LTP) induction and maintenance, which are impaired in the DG of CaMKIV null mice. LTP rescue was closely associated with both increases in calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and GluA1 (Ser-831) phosphorylation. Taken together, Sig-1R stimulation by SA4503 or fluvoxamine treatment increased hippocampal neurogenesis, which is closely associated with amelioration of depressive-like behaviors in CaMKIV null mice.

  11. Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

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    Nakamura, Masuo; Wada, Hiroo; Honda, Kojiro; Nakamoto, Keitaro; Inui, Toshiya; Sada, Mitsuru; Watanabe, Masato; Takata, Saori; Yokoyama, Takuma; Saraya, Takeshi; Kurai, Daisuke; Ishii, Haruyuki; Goto, Hajime; Kamma, Hiroshi; Takizawa, Hajime

    2015-12-01

    Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. The antiprotozoal drug pentamidine ameliorates experimentally induced acute colitis in mice

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    Esposito Giuseppe

    2012-12-01

    Full Text Available Abstract Background Intestinal inflammation is partly driven by enteroglial-derived S100B protein. The antiprotozoal drug pentamidine directly blocks S100B activity. We aimed to investigate the effect of pentamidine on intestinal inflammation