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Sample records for cisplatin-induced stress responses

  1. Cellular Responses to Cisplatin-Induced DNA Damage

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    Alakananda Basu

    2010-01-01

    Full Text Available Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

  2. Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses

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    Fritz, Gerhard; Issinger, Olaf-Georg; Olsen, Birgitte Brinkmann

    2009-01-01

    Targeting protein kinases as a therapeutic approach to treat various diseases, especially cancer is currently a fast growing business. Although many inhibitors are available, exhibiting remarkable potency, the major challenge is their selectivity. Here we show that the protein kinase CK2 inhibitors...... viability and inhibition of endogenous CK2 activity in the absence and presence of the anti-cancer drug cisplatin. The strongest effect on viability was observed with resorufin. In contrast to resorufin, TBB protected cells from cisplatin-induced cell killing. Furthermore, the inhibition of endogenous CK2...

  3. Protocatechuic aldehyde attenuates cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation

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    Li Gao

    2016-12-01

    Full Text Available Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress and programmed cell death of renal tubular epithelial cells. All of which lead to higher mortality rates in patients. In this study we examined the protective effect of protocatechuic aldehyde (PA in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza. Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA largely blocked cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients with cisplatin treatment.

  4. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats

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    Ko, Je-Won; Lee,In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-01-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological al...

  5. Role of ellagic acid against cisplatin-induced nephrotoxicity and oxidative stress in rats.

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    Ateşşahín, Ahmet; Ceríbaşi, Ali Osman; Yuce, Abdurrauf; Bulmus, Ozgür; Cikim, Gürkan

    2007-02-01

    The aim of this study was to investigate the possible protective role of antioxidant treatment with ellagic acid on cisplatin-induced nephrotoxicity using biochemical and histopatological approaches. Adult male Sprague-Dawley rats were randomly divided into four groups. The control group received 0.9% saline; animals in the ellagic acid group received only ellagic acid (10 mg/kg); animals in the cisplatin group received only cisplatin (7 mg/kg); animals in the cisplatin + ellagic acid group received ellagic acid for 10 days after cisplatin. The effects of ellagic acid on cisplatin-induced nephrotoxicity were evaluated by plasma creatinine, urea, sodium and calcium concentrations; kidney tissue malondialdehyde, reduced glutathione (GSH), glutathione peroxidase (GSH peroxidase) and catalase activities and histopatological examinations. Administration of cisplatin to rats induced a marked renal failure, characterized by significant increases in plasma creatinine, urea and calcium concentrations. Cisplatin also induced oxidative stress, as indicated by increased kidney tissue concentrations of malondialdehyde, and reduced activities of GSH peroxidase and catalase. Furthermore, treatment with cisplatin caused a marked tubular necrosis, degeneration and desquamation, luminal cast formation, karyomegaly, tubular dilatation, interstitial mononuclear cell infiltration and inter-tubular haemorrhagia. Ellagic acid markedly reduced elevated plasma creatinine, urea and calcium levels and counteracted the deleterious effects of cisplatin on oxidative stress markers. In the same way, ellagic acid ameliorated cisplatin-induced pathological changes including tubular necrosis, degeneration, karyomegaly, tubular dilatation when compared to the cisplatin alone group. These results indicate that the antioxidant ellagic acid might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat, but not enough to inhibit cisplatin-induced renal dysfunction.

  6. P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3

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    Zhang, Yuanyuan; Yuan, Fahuan; Cao, Xuejiao [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Zhai, Zhifang [Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Gang Huang [Department of Medical Genetics, Third Military Medical University, Chongqing 430038 (China); Du, Xiang; Wang, Yiqin; Zhang, Jingbo; Huang, Yunjian; Zhao, Jinghong [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Hou, Weiping, E-mail: hwp0518@aliyun.com [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China)

    2014-11-15

    Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease. - Highlights: • The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity. • P2X7R blockade significantly attenuated the cisplatin-induced renal injury. • P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue. • P2X7R blockade

  7. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats.

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    Ko, Je-Won; Lee, In-Chul; Park, Sung-Hyuk; Moon, Changjong; Kang, Seong-Soo; Kim, Sung-Ho; Kim, Jong-Choon

    2014-12-01

    We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity.

  8. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

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    Laila Ziko

    2015-01-01

    Full Text Available Cisplatin (CisPt is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2 cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death. Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death.

  9. Azadirachta indica Attenuates Cisplatin-Induced Nephrotoxicity and Oxidative Stress

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    Ahmed E. Abdel Moneim

    2014-01-01

    Full Text Available We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt on cisplatin- (CP- induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i as histopathological damage of the renal tissue, (ii as increases in serum uric acid, urea, and creatinine, (iii as increases in malondialdehyde (MDA and nitric oxide (NO, (iv as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

  10. Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats.

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    Yüce, Abdurrauf; Ateşşahin, Ahmet; Ceribaşi, Ali Osman; Aksakal, Mesut

    2007-11-01

    Cisplatin is one of the most active cytotoxic agents in the treatment of cancer. High doses of cisplatin have also been known to produce hepatotoxicity, and several studies suggest that supplemental antioxidants can reduce cisplatin-induced hepatotoxicity. The present study was designed to determine the effects on the liver and heart oxidant/antioxidant system and the possible protective effects of ellagic acid on liver and heart toxicity induced by cisplatin. The control group received 0.9% saline; animals in the ellagic acid group received only ellagic acid (10 mg/kg); animals in the cisplatin group received only cisplatin (7 mg/kg); animals in cisplatin + ellagic acid group received ellagic acid for 10 days after cisplatin. The rats were killed at the end of the treatment period. Malondialdehyde (MDA) and glutathione (GSH) levels, glutathione-peroxidase (GSH-Px) and catalase (CAT) activities were determined in liver and heart tissue. While administration of cisplatin increased the MDA levels in liver and heart tissues, it decreased the GSH, GSH-Px and CAT in these samples when compared to the control group. The administration of ellagic acid to cisplatin-treated rats decreased the MDA levels, and increased GSH, GSH-Px and CAT in these samples. Cisplatin caused marked damages in the histopathological status of liver and heart tissues. These damages were ameliorated by ellagic acid administration. In conclusion, ellagic acid may be used in combination with cisplatin in chemotherapy to improve cisplatin-induced oxidative stress parameters.

  11. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity.

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    Rubera, I; Duranton, C; Melis, N; Cougnon, M; Mograbi, B; Tauc, M

    2013-10-03

    The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl(-) channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR(inh)-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR(inh)-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR(inh)-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR(inh)-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR(inh)-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.

  12. D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs.

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    Cheng, Po-Wen; Liu, Shing-Hwa; Young, Yi-Ho; Lin-Shiau, Shoei-Yn

    2006-09-01

    Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na(+), K(+)-ATPase and Ca(2+)-ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na(+), K(+)-ATPase and Ca(2+)-ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property.

  13. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

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    Wei Li

    2016-09-01

    Full Text Available Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE and blood urea nitrogen (BUN levels. In addition, cisplatin increased the level of malondialdehyde (MDA and 4-hydroxynonenal (4-HNE, the makers of lipid peroxidation, and depleted glutathione (GSH content and superoxide dismutase (SOD activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1, 4-hydroxynonenal (4-HNE, tumor necrosis factor (TNF-α, interleukin (IL-1β, nuclear factor-kappa B (NF-κB p65, and cyclooxygenase-2 (COX-2 in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

  14. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

    OpenAIRE

    Rubera, I.; Duranton, C; Melis, N; Cougnon, M; Mograbi, B.; Tauc, M

    2013-01-01

    The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl− channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whe...

  15. Abrogation of cisplatin-induced nephrotoxicity in rats by Berne date extract through ameliorating oxidative stress, inflammation and apoptosis

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    El-Sayed M. El-Sayed

    2015-09-01

    Full Text Available Our study aimed to investigate the possible protective effect of Berne date extract on cisplatin-induced nephrotoxicity. A single dose of cisplatin (6 mg/kg was given intraperitoneally (i.p to male rats produced significant elevation in serum urea, creatinine and TNF-α levels with significant reduction in serum albumin. It also increased kidney contents of lipid peroxides measured as malondialdehyde (MDA and caspase-3 contents accompanied by a significant decrease in kidney contents of reduced glutathione (GSH as well as enzymatic activities of catalase (CAT and superoxide dismutase (SOD compared to that of the control group. On the other hand, administrations of Berne date extract and vitamin E (a standard reference antioxidant drug given per os (p.o in doses of 300 mg/kg and 1g/kg, respectively for 14 days before cisplatin and 7 consecutive days after cisplatin injection ameliorated the cisplatin-induced nephrotoxicity as indicated by the restoration of kidney function and oxidative stress parameters. Furthermore, they reduced the histopathological changes induced by cisplatin. In conclusion, Berne date extract showed protective effect against cisplatin-induced nephrotoxicity; effects that may be attributed to antioxidant, anti-inflammatory and antiapoptotic activities.

  16. Morin Hydrate Mitigates Cisplatin-Induced Renal and Hepatic Injury by Impeding Oxidative/Nitrosative Stress and Inflammation in Mice.

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    K V, Athira; Madhana, Rajaram Mohanrao; Kasala, Eshvendar Reddy; Samudrala, Pavan Kumar; Lahkar, Mangala; Gogoi, Ranadeep

    2016-12-01

    Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti-inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin-induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin-induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin-induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.

  17. Suramin protects from cisplatin-induced acute kidney injury.

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    Dupre, Tess V; Doll, Mark A; Shah, Parag P; Sharp, Cierra N; Kiefer, Alex; Scherzer, Michael T; Saurabh, Kumar; Saforo, Doug; Siow, Deanna; Casson, Lavona; Arteel, Gavin E; Jenson, Alfred Bennett; Megyesi, Judit; Schnellmann, Rick G; Beverly, Levi J; Siskind, Leah J

    2016-02-01

    Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer.

  18. Nephroprotective effect of gelsemine against cisplatin-induced toxicity is mediated via attenuation of oxidative stress.

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    Lin, Lin; Zheng, Jing; Zhu, Weiping; Jia, Ning

    2015-03-01

    Cisplatin-induced generation of reactive oxygen species leads to acute nephrotoxicity limiting its use in the treatment of various cancers. Gelsemine, an alkaloid isolated from Gelsemium elegans, is known to possess anti-inflammatory and anti-cancer activities. This study was aimed to investigate as to whether gelsemine can serve as a protective agent against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into 6 groups, each with 6 rats. Group 1 served as control and received the vehicles (peanut oil for 14 days and 0.9 % saline on day 14 for gelsemine and cisplatin respectively). Group 2 received a single intraperitoneal injection of cisplatin on day 14. Group 3 and 4 were pretreated with two different doses of gelsemine in addition to cisplatin, and group 5 and 6 received only gelsemine. The effects of gelsemine on cisplatin-induced nephrotoxicity were examined by measuring anti-oxidant enzymes activities, lipid peroxidation, and DNA damage in the kidneys, a well-established model of oxidative damage. Pretreatment of rats with gelsemine caused a significant attenuation of cisplatin-induced DNA and oxidative damages. The blockade of lipid peroxidation and xanthine oxidase activity was accompanied by increased production and/or activity of anti-oxidants, both enzymatic (catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase) and non-enzymatic (GSH). The biomarkers of kidney malfunctioning, creatinine, and blood urea nitrogen were ameliorated. The results of the present study suggest that gelsemine effectively suppressed cisplatin-induced renal injury by improving redox status.

  19. Beneficial Effects of Hesperidin against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats

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    Wafaa R Mohamed; Arafa, El-Shaimaa A.; Basim A. Shehata; Gamal A. El Sherbiny; Abdel Nasser A.M. Elgendy

    2015-01-01

    Cisplatin has been frequently used for treatment of wide variety of tumors. The use of cisplatin is associated with severe cytotoxicity such as nephrotoxicity, hepatotoxicity and spermiotoxicity which radically limits its clinical use. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced nephrotoxicity induced by single i.p injection of cisplatin (7.5 mg/kg). Hesperidin was given to rats at two different doses (100 an...

  20. Mitochondrial modulation by Epigallocatechin 3-Gallate ameliorates cisplatin induced renal injury through decreasing oxidative/nitrative stress, inflammation and NF-kB in mice.

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    Hao Pan

    Full Text Available Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN. EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX and manganese superoxide dismutase (MnSOD in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β, increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation. Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct

  1. Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

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    Ademiluyi, Adedayo O; Oboh, Ganiyu; Agbebi, Oluwaseun J; Boligon, Aline A; Athayde, Margareth L

    2014-12-01

    This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (Pinduced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

  2. MutS homologue hMSH5: role in cisplatin-induced DNA damage response

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    Tompkins Joshua D; Wu Xiling; Her Chengtao

    2012-01-01

    Abstract Background Cisplatin (cis-diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; however, its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage. These observations necessitate a need for a better understanding of the molecular events governing cellular sensitivity to cisplatin. Results Here, we show that hMSH5 mediat...

  3. The potential role of Azadirachta indica treatment on cisplatin-induced hepatotoxicity and oxidative stress in female rats.

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    Dkhil, Mohamed A; Al-Quraishy, Saleh; Aref, Ahmed M; Othman, Mohamed S; El-Deib, Kamal M; Abdel Moneim, Ahmed E

    2013-01-01

    Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a) histological changes, (b) tissue biochemical oxidant and antioxidant parameters, and (c) investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver.

  4. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

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    Mohamed A. Dkhil

    2013-01-01

    Full Text Available Azadirachta indica A. Juss. (neem, family: Meliaceae is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt on rats treated with cisplatin (CDDP-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a histological changes, (b tissue biochemical oxidant and antioxidant parameters, and (c investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver.

  5. Rutin ameliorates cisplatin-induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats.

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    Aksu, E H; Kandemir, F M; Özkaraca, M; Ömür, A D; Küçükler, S; Çomaklı, S

    2017-02-01

    Cisplatin (CP) treatment causes damage in the male reproductive system. Rutin (RUT) is a naturally occurring flavonoid glycoside that has antioxidant and anti-inflammatory properties. This study aimed to investigate effects of RUT against cisplatin-induced reproductive toxicity in male rats. Twenty-one adult male Sprague Dawley rats were used. The control group received physiological saline with oral gavage during 14 days, and physiological saline was injected intraperitoneally (IP) in 10th days of study. CP Group received physiological saline during 14 days, and 10 mg kg(-1) CP was injected IP in 10th day. RUT + CP group received RUT (150 mg kg(-1) ) during 14 days, and 10 mg kg(-1) CP was injected IP in 10th day. Spermatological parameters (including motility, cauda epididymal sperm density, dead sperm percentage and morphological sperm abnormalities), biochemical (MDA, GSH, GSH-px, SOD and CAT), histological (H&E dye) and immunochemistry evaluations of testicles were evaluated. CP treatment caused damage on some spermatological parameters, increased the oxidative stress and induced testicular degeneration and apoptosis when compared to the control group. However, RUT treatment mitigates these side effects when compared to the CP alone group. IT is concluded that RUT treatment may reduce CP-induced reproductive toxicity as a potential antioxidant compound.

  6. Chrysin protects against cisplatin-induced colon. toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38MAPK and p53

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    Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Lateef, Abdul; Tahir, Mir; Rehman, Muneeb U; Ali, Farrah; Sultana, Sarwat, E-mail: sarwat786@rediffmail.com

    2012-02-01

    Cisplatin, an antineoplastic drug, is widely used as a foremost therapy against numerous forms of cancer but it has pronounced adverse effects viz., nephrotoxicity, ototoxicity etc. CDDP-induced emesis and diarrhea are also marked toxicities that may be due to intestinal injury. Chrysin (5,7-dihydroxyflavone), a natural flavone commonly found in many plants possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer effects. In the present study, we investigated the protective effect of chrysin against CDDP-induced colon toxicity. The plausible mechanism of CDDP-induced colon toxicity and damage includes oxidative stress, activation of p38MAPK and p53, and colonic epithelial cell apoptosis via upregulating the expression of Bak and cleaved caspase-3. Chrysin was administered to Wistar rats once daily for 14 consecutive days at the doses of 25 and 50 mg/kg body weight orally in corn oil. On day 14, a single intraperitoneal injection of cisplatin was given at the dose of 7.5 mg/kg body weight and animals were euthanized after 24 h of cisplatin injection. Chrysin ameliorated CDDP-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated goblet cell disintegration, expression of phospho-p38MAPK and p53, and apoptotic tissue damage which were induced by CDDP. Histological findings further supported the protective effects of chrysin against CDDP-induced colonic damage. The results of the present study suggest that the protective effect of chrysin against CDDP-induced colon toxicity was related with attenuation of oxidative stress, activation of p38MAPK and p53, and apoptotic tissue damage. Highlights: ► Cisplatin-induced colon toxicity is associated with oxidative stress and

  7. Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.

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    Santos, N A G; Bezerra, C S Catão; Martins, N M; Curti, C; Bianchi, M L P; Santos, A C

    2008-01-01

    Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in

  8. Cisplatin Induced Nephrotoxicity

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    Seyed Seifollah Beladi Mousavi

    2014-02-01

    The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of lower doses of cisplatin in combination with the administration of full intravenous isotonic saline before and after cisplatin administration. Although a number of pharmacologic agents including sodium thiosulfate, N-acetylcysteine, theophylline and glycine have been evaluated for prevention of nephrotoxicity, none have proved to have an established role, thus, additional clinical studies will be required to confirm their probable effects.

  9. Cisplatin-induced apoptosis inhibits autophagy, which acts as a pro-survival mechanism in human melanoma cells.

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    Barbara Del Bello

    Full Text Available The interplay between a non-lethal autophagic response and apoptotic cell death is still a matter of debate in cancer cell biology. In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatin-induced cytotoxicity, as well as the contribution of cisplatin-induced activation of caspases 3/7 and conventional calpains. The results show that, while down-regulating Beclin-1, Atg14 and LC3-II, cisplatin treatment inhibits the basal autophagic response, impairing a physiological pro-survival response. Consistently, exogenously stimulated autophagy, obtained with trehalose or calpains inhibitors (MDL-28170 and calpeptin, protects from cisplatin-induced apoptosis, and such a protection is reverted by inhibiting autophagy with 3-methyladenine or ATG5 silencing. In addition, during trehalose-stimulated autophagy, the cisplatin-induced activation of calpains is abrogated, suggesting the existence of a feedback loop between the autophagic process and calpains. On the whole, our results demonstrate that in human melanoma cells autophagy may function as a beneficial stress response, hindered by cisplatin-induced death mechanisms. In a therapeutic perspective, these findings suggest that the efficacy of cisplatin-based polychemotherapies for melanoma could be potentiated by inhibitors of autophagy.

  10. Protective effect of metalloporphyrins against cisplatin-induced kidney injury in mice.

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    Hao Pan

    Full Text Available Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP, water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1 also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.

  11. Inhibition of PARP activation by enalapril is crucial for its renoprotective effect in cisplatin-induced nephrotoxicity in rats.

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    Rani, Neha; Bharti, Saurabh; Tomar, Ameesha; Dinda, Amit Kumar; Arya, D S; Bhatia, Jagriti

    2016-01-01

    Oxidative stress-induced PARP activation has been recognized to be a main factor in the pathogenesis of cisplatin-induced nephrotoxicity. Accumulating literature has revealed that ACE inhibitors may exert beneficial effect in several disease models via preventing PARP activation. Based on this hypothesis, we have evaluated the renoprotective effect of enalapril, an ACE inhibitor, and its underlying mechanism(s) in cisplatin-induced renal injury in rats. Male Albino Wistar rats were orally administered normal saline or enalapril (10, 20 and 40 mg/kg) for 10 days. Nephrotoxicity was induced by a single dose of cisplatin (8 mg/kg; i.p.) on the 7th day. The animals were thereafter sacrificed on the 11th day and both the kidneys were excised and processed for biochemical, histopathological, molecular, and immunohistochemical studies. Enalapril (40 mg/kg) significantly prevented cisplatin-induced renal dysfunction. In comparison to cisplatin-treated group, the elevation of BUN and creatinine levels was significantly less in this group. This improvement in kidney injury markers was well substantiated with reduced PARP expression along with phosphorylation of MAPKs including JNK/ERK/p38. Enalapril, in a dose-dependent fashion, attenuated cisplatin-induced oxidative stress as evidenced by augmented GSH, SOD and catalase activities, reduced TBARS and oxidative DNA damage (8-OHDG), and Nox-4 protein expression. Moreover, enalapril dose dependently inhibited cisplatin-induced inflammation (NF-κB/IKK-β/IL-6/Cox-2/TNF-α expressions), apoptosis (increased Bcl-2 and reduced p53, cytochrome c, Bax and caspase-3 expressions, and TUNEL/DAPI positivity) and preserved the structural integrity of the kidney. Thus, enalapril attenuated cisplatin-induced renal injury via inhibiting PARP activation and subsequent MAPKs/TNF-α/NF-κB mediated inflammatory and apoptotic response.

  12. Cisplatin-Induced Eosinophilic Pneumonia

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    Hideharu Ideguchi

    2014-01-01

    Full Text Available A 67-year-old man suffering from esophageal cancer was admitted to our hospital complaining of dyspnea and hypoxemia. He had been treated with cisplatin, docetaxel, and fluorouracil combined with radiotherapy. Chest computed tomography revealed bilateral ground-glass opacity, and bronchoalveolar lavage fluid showed increased eosinophils. Two episodes of transient eosinophilia in peripheral blood were observed after serial administration of anticancer drugs before the admission, and drug-induced lymphocyte stimulation test to cisplatin was positive. Thus cisplatin-induced eosinophilic pneumonia was suspected, and corticosteroid was effectively administered. To our knowledge, this is the first reported case of cisplatin-induced eosinophilic pneumonia.

  13. Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats.

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    Hagar, Hanan; Medany, Azza El; Salam, Reem; Medany, Gamila El; Nayal, Omina A

    2015-02-01

    Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. This study aims to investigate the effect of betaine supplementation on cisplatin-induced nephrotoxicity. A single intraperitoneal injection of cisplatin (5mg/kg) deteriorated the kidney functions as reflected by elevated blood urea nitrogen and serum creatinine levels. Oxidative/nitrosative stress was evident in cisplatin group by increased renal thiobarbituric acid-reactive substances (TBARS), an indicator of lipid peroxidation, reduced renal total antioxidant status and increased renal nitrite concentration. Cisplatin resulted in a decline in the concentrations of reduced glutathione, glutathione peroxidase, catalase, and superoxide dismutase in renal tissues. Renal tumor necrosis factor-α (TNF-α) was also elevated. Expressions of nuclear factor-kappa B (NF-κB) and caspase-3 were up-regulated in renal tissues as indicated by immunohistochemical analysis. Histopathological changes were observed in cisplatin group. Betaine supplementation (250 mg/kg/day) orally via gavage for 21 days prior to cisplatin injection was able to protect against deterioration in kidney function, abrogate the decline in antioxidants enzymes and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, betaine inhibited NF-κB and caspase-3 activation and improved the histological changes induced by cisplatin. Thus, the present study demonstrated the renoprotective nature of betaine by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in kidney tissues of cisplatin treated rats. Betaine could be a beneficial dietary supplement to attenuate cisplatin nephrotoxicity.

  14. Hepatoprotective effects of vitamin C, DPPD, and L-cysteine against cisplatin-induced oxidative stress in male rats

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    Hossam El-Din Mohamed Omar

    2012-01-01

    Full Text Available Cisplatin (CP is considered as a major antineoplastic drug against a broad spectrum of malignancies. CP acts on cancer cells by releasing free radicals which at the same time damage liver and kidney cells. The tissue specific toxicity of cisplatin to the kidneys is well documented. However, at higher doses less common toxic effects such as hepatotoxicity may arise. Strategies to protect tissues against CP toxicity are of clinical interest. In this study, we aimed to investigate the hepatotoxicity of CP which it may be mediated by oxidative stress and to establish whether some antioxidants, namely vitamin C, N,N-diphenyl-р-phenylenediamine (DPPD and L-cysteine, may provide protection against CP hepatotoxicity. Forty adult male albino rats (120-150 g were divided into 5 groups (8 rats each. CP was injected once a week (2 mg/kg for four weeks. The antioxidants DPPD (125 mg/kg b.w., vitamin C (100 mg/kg and L-cysteine (100 mg/kg were also injected once a week 24 hour prior to CP injection. The control group was injected with saline. All doses were injected intraperitoneally. Rats of different groups were killed by cervical dislocation, 24 hours after the last injection and blood was collected into a sterilized tube containing EDTA to separate plasma. The livers was taken for histological and biochemical examinations. CP-induced oxidative stress was indicated by increased level of LPO and superoxide anion in hepatic tissue and plasma. Also, CP induced decline of antioxidant enzymes such as SOD, CAT, GST and GGT and a decreased level of GSH, Vit. C and Vit. E in hepatic tissue and plasma. Treatment with Vit. C, DPPD and L-cysteine in combination with CP restored LPO and superoxide anion, the activities of SOD, GST, CAT and GGT and the content of GSH, Vit. C and Vit. E to about normal control levels. in conclusion treatment with Vit. C, DPPD or L-cysteine in combination with CP may be effective to protect from oxidative hepatic injury that induced by

  15. Short-term exposure to 50 Hz ELF-EMF alters the cisplatin-induced oxidative response in AT478 murine squamous cell carcinoma cells.

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    Bułdak, Rafał Jakub; Polaniak, Renata; Bułdak, Lukasz; Zwirska-Korczala, Krystyna; Skonieczna, Magdalena; Monsiol, Aleksandra; Kukla, Michał; Duława-Bułdak, Anna; Birkner, Ewa

    2012-12-01

    The aim of this study was to assess the influence of cisplatin and an extremely low frequency electromagnetic field (ELF-EMF) on antioxidant enzyme activity and the lipid peroxidation ratio, as well as the level of DNA damage and reactive oxygen species (ROS) production in AT478 carcinoma cells. Cells were cultured for 24 and 72 h in culture medium with cisplatin. Additionally, the cells were irradiated with 50 Hz/1 mT ELF-EMF for 16 min using a solenoid as a source of the ELF-EMF. The amount of ROS, superoxide dismutase (SOD) isoenzyme activity, glutathione peroxidase (GSH-Px) activity, DNA damage, and malondialdehyde (MDA) levels were assessed. Cells that were exposed to cisplatin exhibited a significant increase in ROS and antioxidant enzyme activity. The addition of ELF-EMF exposure to cisplatin treatment resulted in decreased ROS levels and antioxidant enzyme activity. A significant reduction in MDA concentrations was observed in all of the study groups, with the greatest decrease associated with treatment by both cisplatin and ELF-EMF. Cisplatin induced the most severe DNA damage; however, when cells were also irradiated with ELF-EMF, less DNA damage occurred. Exposure to ELF-EMF alone resulted in an increase in DNA damage compared to control cells. ELF-EMF lessened the effects of oxidative stress and DNA damage that were induced by cisplatin; however, ELF-EMF alone was a mild oxidative stressor and DNA damage inducer. We speculate that ELF-EMF exerts differential effects depending on the exogenous conditions. This information may be of value for appraising the pathophysiologic consequences of exposure to ELF-EMF.

  16. Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells.

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    Krüger, Katharina; Ziegler, Verena; Hartmann, Christina; Henninger, Christian; Thomale, Jürgen; Schupp, Nicole; Fritz, Gerhard

    2016-02-01

    The platinating agent cisplatin (CisPt) is commonly used in the therapy of various types of solid tumors. The anticancer efficacy of CisPt largely depends on the formation of bivalent DNA intrastrand crosslinks, which stimulate mechanisms of the DNA damage response (DDR), thereby triggering checkpoint activation, gene expression and cell death. The clinically most relevant adverse effect associated with CisPt treatment is nephrotoxicity that results from damage to renal tubular epithelial cells. Here, we addressed the question whether the HMG-CoA-reductase inhibitor lovastatin affects the DDR of renal cells by employing rat renal proximal tubular epithelial (NRK-52E) cells as in vitro model. The data show that lovastatin has extensive inhibitory effects on CisPt-stimulated DDR of NRK-52E cells as reflected on the levels of phosphorylated ATM, Chk1, Chk2, p53 and Kap1. Mitigation of CisPt-induced DDR by lovastatin was independent of the formation of DNA damage as demonstrated by (i) the analysis of Pt-(GpG) intrastrand crosslink formation by Southwestern blot analyses and (ii) the generation of DNA strand breaks as analyzed on the level of nuclear γH2AX foci and employing the alkaline comet assay. Lovastatin protected NRK-52E cells from the cytotoxicity of high CisPt doses as shown by measuring cell viability, cellular impedance and flow cytometry-based analyses of cell death. Importantly, the statin also reduced the level of kidney DNA damage and apoptosis triggered by CisPt treatment of mice. The data show that the lipid-lowering drug lovastatin extensively counteracts pro-apoptotic signal mechanisms of the DDR of tubular epithelial cells following CisPt injury.

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

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    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.

  18. Pathophysiology of Cisplatin-Induced Acute Kidney Injury

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    Abdullah Ozkok

    2014-01-01

    Full Text Available Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI. The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

  19. Protective effects of 6-hydroxy-1-methylindole-3-acetonitrile on cisplatin-induced oxidative nephrotoxicity via Nrf2 inactivation.

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    Moon, Ji Hee; Shin, Ji-Sun; Kim, Jong-Bin; Baek, Nam-In; Cho, Young-Wuk; Lee, Yong Sup; Kay, Hee Yeon; Kim, Soo-dong; Lee, Kyung-Tae

    2013-12-01

    We previously demonstrated the ethanol extract of the roots of Brassica rapa protects against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Here, we investigated the nephroprotective effects of 6-hydroxy-1-methylindole-3-acetonitrile (6-HMA), which was isolated from the roots of B. rapa, on cisplatin-induced toxicity in renal epithelial LLC-PK1 cells and in rats with acute renal injury. Pretreatment of LLC-PK1 cells with 6-HMA ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased levels of glutathione (GSH). In addition, 6-HMA inhibited cisplatin-induced heme oxygenase-1 (HO-1) expression, possibly due to the suppression of the nuclear translocation and binding activity of NF-E2-related factor 2 (Nrf2). Furthermore, 6-HMA administered rats showed lower levels of blood urea nitrogen (BUN), creatinine, and urinary lactate dehydrogenase (LDH) than cisplatin alone-treated rats in cisplatin-induced renal injury model. Moreover, 6-HMA inhibited the cisplatin-induced formation of MDA and GSH depletion and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). Taken together, these findings indicate 6-HMA is a major active constituent from the roots of B. rapa to have a protective effect against cisplatin-induced nephrotoxicity by attenuating oxidative stress.

  20. Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3.

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    St Germain, Carly; Niknejad, Nima; Ma, Laurie; Garbuio, Kyla; Hai, Tsonwin; Dimitroulakos, Jim

    2010-07-01

    The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.

  1. Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng.

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    Yousef, Mokhtar I; Hussien, Hend M

    2015-04-01

    Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage, including DNA fragmentation, upregulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidant enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes.

  2. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis.

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    Omar, Hany A; Mohamed, Wafaa R; Arab, Hany H; Arafa, El-Shaimaa A

    2016-01-01

    Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

  3. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis.

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    Hany A Omar

    Full Text Available Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST, inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α and enhancement of interleukin-10 (IL-10. Meanwhile, it lowered malondialdehyde (MDA, nitric oxide (NO and nuclear factor erythroid 2-related factor 2 (NRF-2 levels with restoration of glutathione (GSH, and glutathione peroxidase (GPx. Regarding mitogen-activated protein kinase (MAPK pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK and phospho-extracellular signal-regulated kinase (p-ERK1/2 in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

  4. Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

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    Sahu, Bidya Dhar; Rentam, Kiran Kumar Reddy; Putcha, Uday Kumar; Kuncha, Madhusudana; Vegi, Ganga Modi Naidu; Sistla, Ramakrishna

    2011-12-01

    Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (PGSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (PGSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties.

  5. An Extract of Rhodobacter sphaeroides Reduces Cisplatin-Induced Nephrotoxicity in Mice

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    Wen-Wei Chang

    2013-11-01

    Full Text Available Cisplatin is used as a treatment for various types of solid tumors. Renal injury severely limits the use of cisplatin. Renal cell apoptosis, oxidative stress, and inflammation contribute to cisplatin-induced nephrotoxicity. Previously, we found that an extract of Rhodobacter sphaeroides (Lycogen™ inhibited proinflammatory cytokines and the production of nitric oxide in activated macrophages in a dextran sodium sulfate (DSS-induced colitis model. Here, we evaluated the effect of Lycogen™, a potent anti-inflammatory agent, in mice with cisplatin-induced renal injury. We found that attenuated renal injury correlated with decreased apoptosis due to a reduction in caspase-3 expression in renal cells. Oral administration of Lycogen™ significantly reduced the expression of tumor necrosis factor-α and interleukin-1β in mice with renal injury. Lycogen™ reduces renal dysfunction in mice with cisplatin-induced renal injury. The protective effects of the treatment included blockage of the cisplatin-induced elevation in serum urea nitrogen and creatinine. Meanwhile, Lycogen™ attenuated body weight loss and significantly prolonged the survival of mice with renal injury. We propose that Lycogen™ exerts anti-inflammatory activities that represent a promising strategy for the treatment of cisplatin-induced renal injury.

  6. Preventive Effect of Dihydromyricetin against Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo

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    Fei Wu

    2016-01-01

    Full Text Available Nephrotoxicity is a frequent severe side effect of cisplatin chemotherapy, limiting its clinical use despite being one of the most potent chemotherapy drugs. Dihydromyricetin is a highly abundant compound purified from the leaves of Ampelopsis grossedentata. Previous studies have demonstrated the anti-inflammatory and antioxidative effects of Dihydromyricetin both in vitro and in vivo, but little is known about the effects of Dihydromyricetin on cisplatin-induced nephrotoxicity and its underlying mechanisms. In the present study, we investigated its potential renoprotective effect and found that Dihydromyricetin ameliorated the renal functional impairment and structural damage caused by cisplatin. Moreover, Dihydromyricetin markedly attenuated cisplatin-induced oxidative stress, as well as protecting against cisplatin-induced inflammation and apoptotic cell death in mouse kidney tissues. These results collectively highlight the potential of DMY as a rational renoprotective agent against cisplatin.

  7. Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

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    El-Naga, Reem N., E-mail: reemelnaga@hotmail.com

    2014-01-01

    Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is

  8. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

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    Aburto, Andrés [Program of M.Sc., Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Barría, Agustín [School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Cárdenas, Areli [Ph.D. Program, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Carpio, Daniel; Figueroa, Carlos D. [Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia (Chile); Burgos, Maria E. [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Ardiles, Leopoldo, E-mail: leopoldoardiles@gmail.com [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile)

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  9. Renoprotective mechanisms of morin in cisplatin-induced kidney injury.

    Science.gov (United States)

    Wei, Zhengkai; He, Xuexiu; Kou, Jinhua; Wang, Jingjing; Chen, Libin; Yao, Minjun; Zhou, Ershun; Fu, Yunhe; Guo, Changming; Yang, Zhengtao

    2015-09-01

    In this study, we investigated the renoprotective effects of morin on cisplatin-induced kidney injury in mice. Serum creatinine and blood urea nitrogen (BUN) levels, glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) activities were determined according to the corresponding kits. The mRNA levels of TNF-α and IL-1β in kidney tissues were measured by quantitative real-time PCR (qRT-PCR). The activities of cytochrome P450 2E1 (CYP2E1), nuclear factor kappa B (NF-κB) p65, P38 mitogen-activated protein kinase (MAPK), Bax, p53 and cleaved caspase 3 were evaluated by western blotting. The results showed that the model of cisplatin-induced kidney injury was successfully replicated, and morin significantly attenuated histopathological changes and decreased the levels of TNF-α and IL-1β in the kidneys. In addition, morin attenuated the activation of CYP2E1, phospho-NF-κB p65, phospho-P38 MAPK, Bax, phospho-p53 and cleaved caspase 3 in CP-induced kidney injury. In conclusion, these results indicated that the renoprotective mechanisms of morin may be attributed to the suppression of oxidative stress, inflammation and apoptosis in CP-induced kidney injury.

  10. Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

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    Carly St. Germain

    2010-07-01

    Full Text Available The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3 as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38 resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects.

  11. Hydrogen sulfide: A novel nephroprotectant against cisplatin-induced renal toxicity.

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    Dugbartey, George J; Bouma, Hjalmar R; Lobb, Ian; Sener, Alp

    2016-07-01

    Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury.

  12. Efficacy of safranal to cisplatin-induced nephrotoxicity.

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    Karafakıoğlu, Yasemin Sunucu; Bozkurt, Mehmet Fatih; Hazman, Ömer; Fıdan, A Fatih

    2017-03-20

    The aim of the present study was to investigate the effects of safranal on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague-Dawley rats were randomly divided into five groups. The control group received physiological saline; animals in Group 2 received only safranal and in Group 3 received only cisplatin; 5 days of safranal treatment was performed following administration of cisplatin for the animals in Group 4; 5 days of safranal pretreatment was applied to the animals in Group 5 before administration of cisplatin. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and safranal (200 mg/kg) was administered by gavage. Biochemical and histopathological methods were utilized for evaluation of the nephrotoxicity. The concentrations of creatinine and urea in plasma and levels of malondialdehyde (MDA) and glutathione (GSH) as well as total antioxidant status (TAS) and total oxidant status (TOS) were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. MDA and TOS levels of rats that received cisplatin alone were not significantly different compared with those of the control group, but GSH and TAS levels in the only cisplatin-administered group were significantly decreased. Safranal administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared with the only cisplatin-administered group, pretreatment with safranal being more effective. As a result, safranal treatment might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat.

  13. Cisplatin-induced anorexia and ghrelin.

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    Hattori, Tomohisa; Yakabi, Koji; Takeda, Hiroshi

    2013-01-01

    Cisplatin, a formidable anticancer treatment, is used for several varieties of cancer. There are, however, many cases in which treatment must be abandoned due to a decrease in the patient's quality of life from loss of appetite associated with vomiting and nausea. There is a moderate degree of improvement in prevention of cisplatin-induced nausea and vomiting when serotonin (5-HT) 3 receptor antagonists, neurokinin 1 receptor antagonists, and steroids-either alone or in combination-are administered. The mechanism of action for anorexia, which continues during or after treatment, is, however, still unclear. This anorexia is, similar to the onset of vomiting and nausea, caused by the action of large amounts of 5-HT released as a result of cisplatin administration on tissue 5-HT receptors. Among the 5-HT receptors, the activation of 5-HT2b and 5-HT2c receptors, in particular, seems to play a major role in cisplatin-induced anorexia. Following activation of these two receptors, there is reduced gastric and hypothalamic secretion of the appetite-stimulating hormone ghrelin. There is ample evidence of the usefulness of exogenous ghrelin, synthetic ghrelin agonists, and the endogenous ghrelin signal-enhancer rikkunshito, which are expected to play significant roles in the clinical treatment and prevention of anorexia in future.

  14. The effect of Thespesia populnea on cisplatin induced nephrotoxicity

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    Denish Mika

    2013-01-01

    Full Text Available Aim of the Study: To study the effect of Thespesia populnea on Cisplatin induced Nephrotoxicity. Materials and Methods: Experiments were conducted on Male Sprague Dawley Rats (4-6 weeks old weighing 100-120g B.Wt. The drug under study was cisplatin, which is an anticancer drug. Thespesia populnea extract was used to test its ability to alleviate the harmful effects of cisplatin. The animals were divided into three groups: Group I was considered as normal, Group II was given a single dose of cisplatin (6 mg/kg/b.wt., i.p and they constituted the control animals and Group III was treated with cisplatin along with Thespesia populnea (5 mg/kg/b.wt., i.p for 10 consecutive days. Results: Administration of cisplatin resulted in significant (P < 0.05 increase in the levels of serum urea (137 ± 1.6, creatinine (1.69 ± 0.14, ALT (96.18 ± 3.44, AST (80.84 ± 3.34 and bilirubin (4.57 ± 0.08 as compared to normal animals. On the other hand, introduction of Thespesia populnea extract caused a significant (P < 0.05 reduction in the levels of serum markers namely urea (112 ± 2.16, creatinine (0.54 ± 0.004, ALT (76.4 ± 1.45, AST (58.80 ± 1.6 and bilirubin (3.96 ± 0.85. Discussion: Increase in the levels of urea and creatinine in serum as well as ALT, AST and bilirubin is suggestive of both kidney and liver damage. Thespesia populnea extract ameliorated cisplatin induced kidney and liver damage as indicated by reduction in the levels of serum urea, creatinine, AST, ALT and bilirubin. Reduction in the levels of these biochemical markers is an indication of regeneration process. Thus it is concluded that the extract might contain nephroprotective compounds such as flavonoids, alkaloids, etc. which are responsible for alleviating cisplatin induced toxicity.

  15. Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies.

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    El-Awady, El-Sayed E; Moustafa, Yasser M; Abo-Elmatty, Dina M; Radwan, Asmaa

    2011-01-10

    Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500mg/kg, i.p.), DL-α-lipoic acid (100mg/kg, p.o.) and silymarin (100mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.

  16. A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

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    Mi Liu

    2016-01-01

    Full Text Available Accumulating evidence demonstrated that hydrogen sulfide (H2S is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

  17. Effect of Camel's Milk on Cisplatin-Induced Nephrotoxicity in Swiss Albino Mice

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    Mohamed M.E. Afifi

    2010-01-01

    Full Text Available Problem statement: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Camel's milk has good nutritive value, antigenotoxic and anticytotoxic effects. The aim of the present study was to assess the protective effect of camel's milk against Cisplatin-induced renal oxidative stress in mice. Approach: Forty mal Swiss albino mice were randomly divided into four groups (n = 10. Group I, control group. Group II was received cisplatin (12 mg kg-1 for 5 alternate days. Group III was received camel's milk (33 mL kg-1 for consecutive 30 days. Group IV was received camel's milk (33 mL kg-1 for consecutive 30 days before administration of Cisplatin. Results: Cisplatin-induced oxidative stress was indicated by increased level of tissue Malondialdehyde (MDA, serum creatinine and urea, decreased the concentration of reduced Glutathione (GSH, Vitamin C (Vit. C and Vitamin E (Vit. E and decreased both activities and gene expression of Superoxid Dismutase (SOD, Catalase (CAT, Glutathione Raductase (GR and Glutathione Peroxidase (GPx. Camel's milk reduced these biochemical changes and counteracted the deleterious effects of cisplatin Conclusion: The present study demonstrated the renoprotective potential of camel's milk against cisplatin-induced oxidative stress and renal dysfunction in mice. Hence, camel's milk has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.

  18. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

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    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-Sung

    2016-05-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

  19. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway

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    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-sung

    2016-01-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy-induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292] PMID:26728272

  20. Amelioration of cisplatin-induced nephrotoxicity by statins

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    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.

  1. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity.

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    Youn, Cha Kyung; Kim, Jun; Jo, Eu-Ri; Oh, Jeonghyun; Do, Nam Yong; Cho, Sung Il

    2016-11-18

    One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  2. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity

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    Cha Kyung Youn

    2016-11-01

    Full Text Available One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1. Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  3. The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

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    Kumar, Mukesh; Dahiya, Vicky; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Lahkar, Mangala

    2017-03-14

    Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin.

  4. Targeted amelioration of cisplatin-induced ototoxicity in guinea pigs.

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    Mohan, Shaulnie; Smyth, Brendan J; Namin, Arya; Phillips, Grady; Gratton, Michael Anne

    2014-11-01

    This pilot study compared otoprotection provided by trans-tympanic formulations and systemic intraperitoneal administration of L-N-acetylcysteine from cisplatin-induced cochlear oxidative stress. Protection was assessed by measures of hearing loss and cochlear glutathione levels. All groups received an equivalent single dose of L-N-acetylcysteine followed by cisplatin. Cisplatin was administered subcutaneously for 3 days (5.5 mg/kg/day). Two hours prior to day 1 cisplatin, L-N-acetylcysteine was administered either intraperitoneally (250 mg/kg), trans-tympanic as 2% L-N-acetylcysteine in gel, or trans-tympanic as L-N-acetylcysteine-loaded nanocapsules in gel. Hearing was assessed prior to and 3 days after cisplatin followed by microdissection of cochlear tissue. The levels of reduced (GSH) and oxidized (GSSG) glutathione in homogenized tissue supernatants were determined via luminometry. Intraperitoneal L-N-acetylcysteine administration preceding cisplatin resulted in less hearing loss and a higher GSH/GSSG ratio than either trans-tympanic formulation. This suggests that for equivalent doses of L-N-acetylcysteine, systemic rather than targeted cochlear delivery provides increased otoprotection from cisplatin ototoxicity.

  5. Calpain mediated cisplatin-induced ototoxicity in mice*

    Institute of Scientific and Technical Information of China (English)

    Liang Chang; Aimei Wang

    2013-01-01

    Ototoxic drug-induced apoptosis of inner ear cel s has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cel apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cel s. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin (2.5, 3.5, 4.5, 5.5 mg/kg). Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cel s, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an in-creased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cispla-tin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role.

  6. Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.

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    Bidya Dhar Sahu

    Full Text Available Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

  7. Baicalein, a Bioflavonoid, Prevents Cisplatin-Induced Acute Kidney Injury by Up-Regulating Antioxidant Defenses and Down-Regulating the MAPKs and NF-κB Pathways.

    Science.gov (United States)

    Sahu, Bidya Dhar; Mahesh Kumar, Jerald; Sistla, Ramakrishna

    2015-01-01

    Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatin-induced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

  8. The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries

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    Durdu Altuner; Mine Gulaboglu; Omer Erkan Yapca; Nihal Cetin

    2013-01-01

    Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After t...

  9. ROLE OF ERK1/2 KINASE IN CISPLATIN-INDUCED APOPTOSIS IN HUMAN OVARIAN CARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    Shu-qin Wei; Li-hua Sui; Jian-hua Zheng; Guang-mei Zhang; Yan-Lin Kao

    2004-01-01

    Objective To investigate the role of extracellular regulated kinase (ERK1/2) pathway in cisplatin-induced apoptosis in human ovarian carcinoma cells.Methods Cisplatin-induced apoptosis were stained with DAPI and was assessed microscopically in human epithelial adenocarcinoma ovarian cell line SKOV3 cells. ERK activation was determined by Western blotting using an anti-phosphoERK antibody to detect ERK activity. The effect of PD98059 on ERK activity induced by cisplatin was detected by MTT assay.Results Marked apoptosis of SKOV3 cells resulted from 48 hours treatment with 20 μg/mL cisplatin. Strong activation of ERK was led to by 15 μg/mL cisplatin. Dose response and time course of cisplatin induced apoptosis in SKOV3 cells.Cisplatin-induced ERK activation occurred at 12 hours and increased to highest induction at 24 hours by Western blotting.The effect of PD 98059 on ERK activity induced by cisplatin at the concentration of 100 μmol/L PD 98059. Statistically significant decreased in cell survival were observed with 100 μmol/L PD 98059 at 15 and 20 μg/mL cisplatin (P< 0.05).Conclusions Cisplatin activates the ERK signaling pathway in ovarian cancer cell line SKOV3. Inhibition of ERK activity enhances sensitivity to cisplatin cytotoxity in ovarian cancer cell line SKOV3. Evaluation of ERK activity could be useful in predicting which ovarian cancer will response most favorably to cisplatin therapy.

  10. Mechanisms of cisplatin-induced muscle atrophy

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    Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Sato, Ken [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Chiba, Yoshihiko [Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan); Yamazaki, Mitsuaki [Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan); Matoba, Motohiro [Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan); Narita, Minoru, E-mail: narita@hoshi.ac.jp [Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  11. P53 Contributes to Cisplatin Induced Renal Oxidative Damage via Regulating P66shc and MnSOD

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    Yanggang Yuan

    2015-10-01

    Full Text Available Background/Aims: Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear. Previous study demonstrated the central role of mitochondrial ROS (mtROS in the pathogenesis of cisplatin nephrotoxicity. The purpose of this study was to explore the mechanism of mtROS regulation in cisplatin nephrotoxicity. Methods: p53, MnSOD and p66shc were detected at mRNA and protein levels by qPCR and western blot in HK2 cells. mtROS levels were determined by DCFDA and MitoSOX staining. Cell viability and cell apoptosis were accessed by CCK-8 assay, TUNEL assay and flow cytometry, respectivesly. siRNAs were used to knock down p53 and p66shc expression and subsequent changes were observed. In vivo assays using a mouse model of cisplatin-induced acute kidney injury were used to validate the in vitro results. Results: In HK2 cells, cisplatin exposure decreased the MnSOD and increased the expression of p53 and p66shc. MnTBAP, a MnSOD mimic, blocked cisplatin-induced the generation of mtROS and cell injury. P66shc and p53 siRNAs rendered renal cells resistant to cisplatin-induced mtROS production and cell death. Furthermore, knockdown of p53 restored MnSOD and inhibiting p66shc. Consistent with these results, we revealed that p53 inhibitor reduced cisplatin-induced oxidative stress and apoptosis by regulating MnSOD and p66shc in the kidney of cisplatin-treated mice. Conclusion: Our study identifies activation of p53 signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent.

  12. Comment on: A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

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    Hamid Nasri

    2013-01-01

    Full Text Available Cisplatin (cis-diamminedichloroplatinum II, as one of the most applicable and potent anticancer medication, is used in the treatment of a various pediatric and adult malignancies. However, it gives side-effects such as renal toxicity which is dose-dependent, and thus limited its usage. Treatment with cisplatin induces the inflammatory mechanisms, which leads to a reduction in the antioxidant levels, leading to a failure of the antioxidant protection against free-radical damage generated by antitumor drugs. The oxidative stress, induced by cisplatin in the kidney was partially inhibited by antioxidant therapy using selenium, glutathione, flavonoids, and superoxide dismutase.

  13. Cisplatin-induced testicular toxicity in rats: the protective effect of arjunolic acid.

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    Sherif, Iman O; Abdel-Aziz, Azza; Sarhan, Osama M

    2014-11-01

    In the present study, the effect of arjunolic acid on testicular damage induced by intraperitoneal injection of rats with 7 mg/kg cisplatin was studied. Cisplatin induced a significant reduction in testicular weights, plasma testosterone, and testicular reduced glutathione levels in addition to a significant elevation of testicular malondialdehyde levels and testicular gene expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and p38 mitogen-activated protein kinase (MAPK) when compared with the control group (p testicular injury by attenuating oxidative stress parameters along with downregulation of iNOS, TNF-α, and p38-MAPK testicular expressions.

  14. Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa.

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    Karwasra, Ritu; Kalra, Prerna; Nag, T C; Gupta, Y K; Singh, Surender; Panwar, Anuj

    2016-11-01

    Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concentrations of reduced glutathione and superoxide dismutase, elevation in TNF-α level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boerhaavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg.

  15. Induction of heme oxygenase-1 with hemin alleviates cisplatin-induced reproductive toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line.

    Science.gov (United States)

    Heeba, Gehan Hussein; Hamza, Alaaeldin Ahmed; Hassanin, Soha Osama

    2016-12-15

    Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells.

  16. Effect of Matricaria chamomilla Hydroalcoholic Extract on Cisplatin-induced Neuropathy in Mice

    Institute of Scientific and Technical Information of China (English)

    A.Namvaran Abbas Abad; M.H.Kayate Nouri; A.Gharjanie; F.Tavakoli

    2011-01-01

    AIM: Cisplatin-based chemotherapy is a mainstay for the treatment of solid tumors, especially colorectal, ovarian,testicular, bladder, and lung cancer. Studies have shown that cisplatin could have painful effects on human and animal models. Matricaria chamomilla (MC) has analgesic and anti-inflammatory effects. The aim of this study was to investigate the effects of MC hydroalcoholic extract on cisplatin-induced peripheral neuropathy and to compare with morphine in mice. METHODS: Experiments were performed on 60 NMRI male mice weighed 25 g to 30 g which have been divided into 6 groups. The fast group received normal saline;the second group received MC hydroalcoholic extract; the third group received cisplatin; the fourth group received MC hydroalcoholic extract and cisplatin, 96 hours before formalin test; the fifth group received morphine and the sixth group received cisplatin and morphine. The time of injected hind paw biting and licking time were measured in 5-minute interval for an hour. RESULTS: Results showed that formalin induced significant (P<0.05) pain response (the first phase: 0-5 min and the second phase: 15-40 min after injection). Administration of MC extract before formalin injection showed significant (P<0.05) decrease of pain responses in the first and second phase. Administration of cisplatin produced significant (P<0.05) increase in pain response in both phases of formalin test.Injection of MC extract and cisplatin together have shown that MC is able to decrease the second phase of cisplatin-induced pain sig-nificantly (P<0.05). Morphine decreased cisplatin-induced pain in the first and second phase of formalin test significantly(P<0.05).In comparison morphine has analgesic effects in the first phase and MC extract has anti inflammatory effects in the second phase of formalin test significantly (P < 0.05). CONCLUSION: MC and cisplatin have analgesic and painful neuropathic respective effects, and MC hydroalcoholic extract is able to

  17. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway

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    Kilic Ulkan

    2013-01-01

    Full Text Available Abstract Background Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo. Methods Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days, cisplatin treatment (7 mg/kg b.w., i.p. and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis. Results Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin

  18. Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2- and Tr1-biased T-cell immunity

    Science.gov (United States)

    Kim, Hongmin; Kwon, Kee Woong; Im, Sin-Hyeog; Lee, Bo Ryeong; Ha, Sang-Jun; Shin, Sung Jae

    2016-01-01

    Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-κB signaling pathways without altering the levels of TNF-α and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10−/− mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3+CD4+LAG-3+CD49b+CD25−Foxp3− Tr1 cells, that was significantly increased without altering the Foxp3+ regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system. PMID:27172902

  19. Is intratympanic injection of erdosteine protective against cisplatin-induced ototoxicity?

    Science.gov (United States)

    Saliba, Issam; El Fata, Fouad

    2012-04-01

    Cisplatin induces ototoxicity in adult and pediatric population. Our aim was (1) to assess the protective effect of intratympanic injections of erdosteine in the prevention of cisplatin-induced ototoxicity and (2) to investigate inner ear protection using a scanning electron microscope. Ears of 20 Hartley guinea pigs were assigned to four subgroups and received an intratympanic injection of: E1-erdosteine 1.125 mg/cc, NS-normal saline, E2-erdosteine 2.25 mg/cc and E4-erdosteine 4.5 mg/cc. After 45 min, an intraperitoneal cisplatin injection of 3 mg/kg was performed and repeated 8 times, once a week to achieve 24 mg/kg. Auditory brainstem responses were recorded before any injection and after 24 mg/kg of cisplatin for the frequencies 1, 2, 4, 6 and 8 kHz. Cochleas were analyzed under scanning electron microscope. Average hearing loss in the NS subgroup was 29.8 dB which was lower than E1, E2 and E4 subgroups (40, 43.9, and 51.7 dB, respectively). Difference in the mean threshold increase was statistically significant between NS and the three erdosteine subgroups (P  0.05). However, difference was significant between E1 and E4 (P erdosteine showed a diffuse inflammatory reaction and osteitis of the middle ear. Low or high concentration of intratympanic erdosteine does not offer protection against cisplatin-induced ototoxicity as it causes a considerable inflammatory reaction.

  20. An investigation of the effect of thiamine pyrophosphate on cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine: thiamine and thiamine pyrophosphate effects on cisplatin neurotoxicity.

    Science.gov (United States)

    Turan, M I; Cayir, A; Cetin, N; Suleyman, H; Siltelioglu Turan, I; Tan, H

    2014-01-01

    This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant.

  1. Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis.

    Science.gov (United States)

    Malik, Salma; Suchal, Kapil; Gamad, Nanda; Dinda, Amit Kumar; Arya, Dharamvir Singh; Bhatia, Jagriti

    2015-02-05

    Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant-antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation.

  2. The Preventive Effect of Oxytocin to Cisplatin-Induced Neurotoxicity: An Experimental Rat Model

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    Tulay Akman

    2015-01-01

    Full Text Available Peripheral neurotoxicity is a frequent dose-limiting side effect of the chemotherapeutic agent cisplatin. This study was conducted to investigate the preventive effect of oxytocin (OT on cisplatin-induced neurotoxicity in rats. Forty-four adult female rats were included in the study. Thirty-six rats were administered intraperitoneally (i.p. single dose cisplatin 10 mg/kg and divided in to 3 groups. The first group (n=12 received saline i.p., whereas the second group (n=12 and the third group (n=12 were injected with 80 µg/kg and 160 µg/kg OT, respectively, for 10 days. The remaining 8 rats served as the control group. Electromyography (EMG studies were recorded and blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA, tumor necrosis factor (TNF-α, and glutathione (GSH levels. EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the nontreated cisplatin-injected rats compared with the control group (P<0.005. Also, nontreated cisplatin-injected rats showed significantly higher TNF-α and MDA levels and lower GSH level than control group. The administration of OT significantly ameliorated the EMG alterations, suppressed oxidative stress and inflammatory parameters, and increased antioxidative capacity. We suggest that oxytocin may have beneficial effects against cisplatin-induced neurotoxicity.

  3. The preventive effect of oxytocin to Cisplatin-induced neurotoxicity: an experimental rat model.

    Science.gov (United States)

    Akman, Tulay; Akman, Levent; Erbas, Oytun; Terek, Mustafa Cosan; Taskiran, Dilek; Ozsaran, Aydin

    2015-01-01

    Peripheral neurotoxicity is a frequent dose-limiting side effect of the chemotherapeutic agent cisplatin. This study was conducted to investigate the preventive effect of oxytocin (OT) on cisplatin-induced neurotoxicity in rats. Forty-four adult female rats were included in the study. Thirty-six rats were administered intraperitoneally (i.p.) single dose cisplatin 10 mg/kg and divided in to 3 groups. The first group (n=12) received saline i.p., whereas the second group (n=12) and the third group (n=12) were injected with 80 µg/kg and 160 µg/kg OT, respectively, for 10 days. The remaining 8 rats served as the control group. Electromyography (EMG) studies were recorded and blood samples were collected for the measurement of plasma lipid peroxidation (malondialdehyde; MDA), tumor necrosis factor (TNF)-α, and glutathione (GSH) levels. EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the nontreated cisplatin-injected rats compared with the control group (Pcisplatin-injected rats showed significantly higher TNF-α and MDA levels and lower GSH level than control group. The administration of OT significantly ameliorated the EMG alterations, suppressed oxidative stress and inflammatory parameters, and increased antioxidative capacity. We suggest that oxytocin may have beneficial effects against cisplatin-induced neurotoxicity.

  4. Mitochondria-Targeted Antioxidant Mitoquinone Reduces Cisplatin-Induced Ototoxicity in Guinea Pigs.

    Science.gov (United States)

    Tate, Alan D; Antonelli, Patrick J; Hannabass, Kyle R; Dirain, Carolyn O

    2017-03-01

    Objective To determine if mitoquinone (MitoQ) attenuates cisplatin-induced hearing loss in guinea pigs. Study Design Prospective and controlled animal study. Setting Academic, tertiary medical center. Subjects and Methods Guinea pigs were injected subcutaneously with either 5 mg/kg MitoQ (n = 9) or normal saline (control, n = 9) for 7 days and 1 hour before receiving a single dose of 10 mg/kg cisplatin. Auditory brainstem response thresholds were measured before MitoQ or saline administration and 3 to 4 days after cisplatin administration. Results Auditory brainstem response threshold shifts after cisplatin treatment were smaller by 28 to 47 dB in guinea pigs injected with MitoQ compared with those in the control group at all tested frequencies (4, 8, 16, and 24 kHz, P = .0002 to .04). Scanning electron microscopy of cochlear hair cells showed less outer hair cell loss and damage in the MitoQ group. Conclusion MitoQ reduced cisplatin-induced hearing loss in guinea pigs. MitoQ appears worthy of further investigation as a means of preventing cisplatin ototoxicity in humans.

  5. Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.

    Science.gov (United States)

    Kim, Se-Jin; Ho Hur, Joon; Park, Channy; Kim, Hyung-Jin; Oh, Gi-Su; Lee, Joon No; Yoo, Su-Jin; Choe, Seong-Kyu; So, Hong-Seob; Lim, David J; Moon, Sung K; Park, Raekil

    2015-02-20

    Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.

  6. Evidence for different mechanisms of ‘unhooking’ for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples

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    Spanswick Victoria J

    2012-09-01

    Full Text Available Abstract Background DNA interstrand cross-links (ICLs are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma and solid tumours (ovarian cancer that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Methods Using a modification of the single cell gel electrophoresis (Comet assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Results Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The

  7. Melatonin prevents cisplatin-induced primordial follicle loss via suppression of PTEN/AKT/FOXO3a pathway activation in the mouse ovary.

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    Jang, Hoon; Lee, Ok-Hee; Lee, Youngeun; Yoon, Hyemin; Chang, Eun Mi; Park, Miseon; Lee, Jeong-Woong; Hong, Kwonho; Kim, Jung Oh; Kim, Nam Keun; Ko, Jung Jae; Lee, Dong Ryul; Yoon, Tae Ki; Lee, Woo Sik; Choi, Youngsok

    2016-04-01

    Premature ovarian failure (POF) is a major side effect of chemotherapy in young cancer patients. To develop pharmaceutical agents for preserving fertility, it is necessary to understand the mechanisms responsible for chemotherapy-induced follicle loss. Here, we show that treatment with cisplatin, a widely used anticancer drug, depleted the dormant follicle pool in mouse ovaries by excessive activation of the primordial follicles, without inducing follicular apoptosis. Moreover, we show that co-treatment with the antioxidant melatonin prevented cisplatin-induced disruption of the follicle reserve. We quantified the various stages of growing follicles, including primordial, primary, secondary, and antral, to demonstrate that cisplatin treatment alone significantly decreased, whereas melatonin co-treatment preserved, the number of primordial follicles in the ovary. Importantly, analysis of the PTEN/AKT/FOXO3a pathway demonstrated that melatonin significantly decreased the cisplatin-mediated inhibitory phosphorylation of PTEN, a key negative regulator of dormant follicle activation. Moreover, melatonin prevented the cisplatin-induced activating phosphorylation of AKT, GSK3β, and FOXO3a, all of which trigger follicle activation. Additionally, we show that melatonin inhibited the cisplatin-induced inhibitory phosphorylation and nuclear export of FOXO3a, which is required in the nucleus to maintain dormancy of the primordial follicles. These findings demonstrate that melatonin attenuates cisplatin-induced follicle loss by preventing the phosphorylation of PTEN/AKT/FOXO3a pathway members; thus, melatonin is a potential therapeutic agent for ovarian protection and fertility preservation during chemotherapy in female cancer patients.

  8. Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice.

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    Lamiaa A Ahmed

    Full Text Available Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg with or without oral administration of tempol (100 mg/kg/day. Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma.This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.

  9. Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice

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    Carlton Susan M

    2010-03-01

    Full Text Available Abstract Background Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. Results In this study, using real-time, reverse transcriptase, polymerase chain reaction (RT-PCR, we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. Conclusion These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo.

  10. Tropisetron attenuates cisplatin-induced nephrotoxicity in mice.

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    Zirak, Mohammad Reza; Rahimian, Reza; Ghazi-Khansari, Mahmoud; Abbasi, Ata; Razmi, Ali; Mehr, Shahram Ejtemaei; Mousavizadeh, Kazem; Dehpour, Ahmad Reza

    2014-09-05

    Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.

  11. Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin.

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    Yalcin, Suayib; Müftüoğlu, Sevda; Cetin, Eren; Sarer, Banu; Yildirim, Berna Akkuş; Zeybek, Dilara; Orhan, Bülent

    2003-01-01

    Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.

  12. The Effect of Reduced Glutathione on Oxidative Stress in the Rodent Model of Cisplatin Induced Acute Kidney Injury%还原型谷胱甘肽对顺铂致大鼠急性肾损伤氧化应激的影响

    Institute of Scientific and Technical Information of China (English)

    孟晓燕; 黄向阳; 王英; 刘倩

    2013-01-01

    Objective:To observe the effect of reduced glutathione on oxidative stress in the rodent model of cisplatin induced acute kidney injury(AKI). Method:66 male wistar rats were randomly assigned to three groups.The rats of CP group(n=30) were injected once intraperitoneal with cisplatin at 10 mg/kg, the rats of CN group were injected intraperitoneal with same volume of normal saline vehicle,the GI group were injected intraperitoneal with reduced glutathione at 800 mg/kg before cisplatin injection.Rats were euthanized at 12,24,48,96 and 144 hours(n=6 in the CP group at each time point and n=6 in the GI group at each time point).The blood and kidney samples were analyzed at each time point.Result:A significant increase in serum creatinine was noted by 48 hours in the CP group versus CN group,peak levels of serum creatinine were seen on 144 hours(P<0.05).The levels of MDA in renal tissues were significantly higher by 48 hours in the CP group than in the CN group(P<0.05).The levels of SOD in renal tissues were significantly lower by 48 hours in the CP group than in the CN group(P<0.05).Compared with CP group,the levels of SOD in renal tissues increase significantly in GI 48 hours group,while the levels of MDA in renal tissues decreased significantly in GI 48 hours group.Conclusion:Reduced glutathione can attenuate the cisplatin induced AKI in rodent model,which may be associated with anti-oxidative stress effect.%目的::研究还原型谷胱甘肽对顺铂致大鼠急性肾损伤氧化应激的影响。方法:66只健康雄性Wistar大鼠为研究对象,随机数字法分为盐水对照组(CN组),顺铂模型组(CP组)及还原型谷胱甘肽干预组(GI组),CP组为腹腔单次注射顺铂10 mg/kg,据给药后各时间点不同分为CP 12 h组、CP 24 h组、CP 48 h组、CP 96 h组、CP 144 h组;GI组为应用顺铂前腹腔注射还原型谷胱甘肽800 mg/kg,同样据给药时间不同分为GI 12 h组、GI 24 h组、GI 48 h组、GI 96 h组、GI 144

  13. Disparity in actions of rosiglitazone against cisplatin-induced nephrotoxicity in female Sprague-Dawley rats.

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    Kumar, Parveen; Prashanth, Krishna Shastrula; Gaikwad, Anil Bhanudas; Vij, Mohit; Barua, Chandana C; Bezbaruah, Babul

    2013-11-01

    Cisplatin is one of the most common chemotherapeutic drugs used against various solid, tumours. Despite of its therapeutic benefits, its use in clinical practice is often limited because of dose, related toxicity. The nephrotoxic potential of cisplatin has been ascribed to its accumulation in the, renal tubular cells generating reactive oxygen species (ROS), activation of Bax, increased secretion of, TNFα and activation of certain inflammatory mediators like cytokines. The present investigation was, undertaken with an objective to study the effect of rosiglitazone against cisplatin induced, nephrotoxicity. Pretreatment of rosiglitazone prevents cisplatin induced nephrotoxicity which was, clearly evident from the renal biochemical parameters like reduced BUN, creatinine and TNFα levels, and increased albumin levels, which was also supported by histopathological studies of the kidneys. In contrast, posttreatment of rosiglitazone was not able to protect the renal damage in cisplatin induced, renal toxicity. These results showed the variation of pre & posttreatment effects of rosiglitazone, against the cisplatin induced nephrotoxicity.

  14. The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries

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    Durdu Altuner

    2013-01-01

    Full Text Available Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p. and mirtazapine (15 mg/kg p.o. or mirtazapine (30 mg/kg p.o. for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA, myeloperoxidase (MPO, nitric oxide (NO, total gluthatione (tGSH, gluthatione peroxidase (GPx, superoxide dismutase (SOD, and 8-hydroxy-2 deoxyguanine (8-OH Gua levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. The infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner.

  15. The effect of mirtazapine on cisplatin-induced oxidative damage and infertility in rat ovaries.

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    Altuner, Durdu; Gulaboglu, Mine; Yapca, Omer Erkan; Cetin, Nihal

    2013-01-01

    Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), total gluthatione (tGSH), gluthatione peroxidase (GPx), superoxide dismutase (SOD), and 8-hydroxy-2 deoxyguanine (8-OH Gua) levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. The infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner.

  16. Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death.

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    Shin, Yoo Seob; Song, Suk Jin; Kang, Sungun; Hwang, Hye Sook; Jung, Young-Sik; Kim, Chul-Ho

    2014-02-01

    Cisplatin [cis-diammine-dichloroplatinum (II)] is a widely used chemotherapeutic agent, and one of its most severe side effects is ototoxicity. In the course of developing a new protective agent against cisplatin-induced ototoxicity, we have been interested in a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335). We evaluated the effectiveness of KR-22335 as an otoprotective agent against cisplatin-induced toxicity. The otoprotective effect of KR-22335 against cisplatin was tested in vitro in cochlear organs of Corti-derived cell lines, HEI-OC1, and in vivo in a zebrafish (Danio rerio) model. Cisplatin-induced apoptosis, cell cycle arrest and an increase in intracellular reactive oxygen species (ROS) generation were demonstrated in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced apoptosis and mitochondrial injury in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. Scanning and transmission electron micrographs showed that KR-22335 prevented cisplatin-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. Tissue TUNEL of neuromasts in zebrafish demonstrated that KR-22335 blocked cisplatin-induced TUNEL positive hair cells in neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation. KR-22335 may be considered as a potential candidate for protective agents against cisplatin-induced ototoxicity.

  17. Protective role of turmeric on histological, ultrastructural and serobiochemical changes in cisplatin-induced nephrotoxicity in female rats

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    B. Ramya

    2013-10-01

    Full Text Available Aim: Protective role of turmeric was assessed against cisplatin-induced histological and ultra-structural changes in kidney.Materials and Methods: A total of 48 rats were divided into 4 groups of 12 rats in each. Group 1 was kept as sham control,group 2 was treated with cisplatin (@ 2 mg/kg b.wt, intraperitoneally on day 1, 7, 14 and 21, group 3 with turmeric (@ 0.05mg/kg b.wt. p.o. once daily for 28 days and group 4 with cisplatin + turmeric (as per above schedule. Blood was collected atfortnight intervals and serum was separated for estimation of kidney biomarkers. Six rats in each group were then euthanizedon day 14 and 28 for histopathology, and tissue parameters were assayed on day 28.Results: Thibarbituric acid reacting substances (TBARS, protein carbonyls, serum creatinine, blood urea nitrogen (BUNwere significantly (P < 0.05 increased, while GSH was significantly (P < 0.05 decreased in group 2 as compared to othergroups. Histological sections of kidney from group 2 rats showed marked inter-tubular haemorrhages, congestion, markeddilation of tubules, and other lesions of pathological significance. Ultrastructural changes of pathological significance werealso recorded in group 2. Kidney sections of group 4 showed nucleus with uniform size with well differentiated nuclearmembrane and nucleolus, and prominent inter tubular and inter cellular junctions.Conclusion: The study revealed that cisplatin induces nephrotoxicity due to oxidative stress and turmeric was foundbeneficial in countering the adverse effects.

  18. CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion

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    Johnson Erica L

    2010-06-01

    Full Text Available Abstract Background Cisplatin is more often used to treat ovarian cancer (OvCa, which provides modest survival advantage primarily due to chemo-resistance and up regulated anti-apoptotic machineries in OvCa cells. Therefore, targeting the mechanisms responsible for cisplatin resistance in OvCa cell may improve therapeutic outcomes. We have shown that ovarian cancer cells express CC chemokine receptor-9 (CCR9. Others have also shown that CCL25, the only natural ligand for CCR9, up regulates anti-apoptotic proteins in immature T lymphocytes. Hence, it is plausible that CCR9-mediated cell signals might be involved in OvCa cell survival and inhibition of cisplatin-induced apoptosis. In this study, we investigated the potential role and molecular mechanisms of CCR9-mediated inhibition of cisplatin-induced apoptosis in OvCa cells. Methods Cell proliferation, vibrant apoptosis, and TUNEL assays were performed with or without cisplatin treatment in presence or absence of CCL25 to determine the role of the CCR9-CCL25 axis in cisplatin resistance. In situ Fast Activated cell-based ELISA (FACE assays were performed to determine anti-apoptotic signaling molecules responsible for CCL25-CCR9 mediated survival. Results Our results show interactions between CCR9 and CCL25 increased anti-apoptotic signaling cascades in OvCa cells, which rescued cells from cisplatin-induced cell death. Specifically, CCL25-CCR9 interactions mediated Akt, activation as well as GSK-3β and FKHR phosphorylation in a PI3K-dependent and FAK-independent fashion. Conclusions Our results suggest the CCR9-CCL25 axis plays an important role in reducing cisplatin-induced apoptosis of OvCa cells.

  19. Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

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    Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C

    2017-01-11

    Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment.

  20. A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats

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    Mehdi Nematbakhsh

    2013-01-01

    Full Text Available Background: Cisplatin (cis-diamminedichloroplatinum II; CP is used widely as an antitumor drug in clinics, but is accompanied with renal toxicity. Cisplatin induced nephrotoxicity consists of change in kidney weight, histological changes in kidney and increase in serum creatinine (Cr and blood urea nitrogen (BUN. This study was designed to find out a model for prediction of cisplatin induced nephrotoxicity. Materials and Methods: Pathological damage score, kidney weight, BUN, and Cr of 227 rats that were involved in different projects were determined. A total of 187 rats were treated with 7 mg/kg cisplatin and sacrificed 1 week later. Results: There was a good significant correlation between normalized kidney weight and logarithmic scale of BUN and Cr. Relationship between BUN, Cr or normalized kidney weight and pathology damage score was significant. Conclusion: Normalized kidney weight and pathology damage score is a good predictor of renal function in cisplatin induced nephrotoxicity in experimental rats.

  1. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

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    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy.

  2. Ameliorating effect of DL-α-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals.

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    Hussein, Asmma; Ahmed, Amany A E; Shouman, Samia A; Sharawy, Sabry

    2012-06-01

    Cisplatin is a potent chemotherapeutic agent with a wide range of activities. Nephrotoxicity and cardiotoxicity represent it's major complication upon clinical use. The present study was carried out to evaluate the possible protective effect of DL-α-lipoic acid (LA) against cisplatin-induced nephrotoxicity and cardiotoxicity. Different groups of rats (n = 10) were administered either saline (control), cisplatin (10 mg/kg, i.p.), LA (100 mg/kg, i.p.) or their combination (LA 30 min prior to cisplatin administration). Twenty-four hours later all animals were decapitated and sera were used for estimation of activities of urea (BUN), creatinine (Cr), lactate dehydrogenase (LDH), and creatine kinase (CK). Homogenates of the kidney and heart were used for estimation of oxidative stress markers (reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO)). Additionally, caspase-3 activities and DNA-fragmentation were investigated in renal tissues. The results showed that cisplatin produced significant elevation in serum activities of LDH, CK, BUN, and Cr and also induced significant elevation in the oxidative stress makers (MDA and NO) accompanied by significant reduction in GSH and SOD in both kidney and heart. The integrity of DNA was heavily damaged and caspase-3 was activated in renal tissues. The results emphasized nephrotoxicty and cardiotoxicity of cisplatin. On the other hand, prior administration of LA significantly attenuated the cisplatin-evoked disturbances in the above mentioned parameters and protected both kidney and heart tissues. The histopathological examination emphasized the obtained results. In conclusion, LA is suggested to be a potential candidate to ameliorate cisplatin-induced nephrotoxicity and cardiotoxicity without altering the antitumor efficacy of cisplatin.

  3. Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination.

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    Cortina, Gerard; Hansford, Jordan R; Duke, Trevor

    2016-05-01

    We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury.

  4. Chronic low vitamin intake potentiates cisplatin-induced intestinal epithelial cell apoptosis in WNIN rats

    Institute of Scientific and Technical Information of China (English)

    Bodiga Vijayalakshmi; Boindala Sesikeran; Putcha Udaykumar; Subramaniam Kalyanasundaram; Manchala Raghunath

    2006-01-01

    AIM: To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN (WNIN) male rats.METHODS: Weanling, WNIN male rats (n = 12 per group) received adlibitum for 17 wk: control diet (20%protein) or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin (2.61 mg/kg bodyweight)once a week for three wk or PBS (vehicle control).Intestinal epithelial cell (IEC) apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height /crypt depth ratio and activities of alkaline phosphatase,lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism(s) of altered apoptosis,oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined.RESULTS: Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS,protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression,unaffected by VR was increased on cisplatin treatment.Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.CONCLUSION: Low intake of vitamins increases the sensitivity of rats to cisplatin and promotes intestinal epithelial cell apoptosis.

  5. Antiemetic role of thalidomide in a rat model of cisplatin-induced emesis.

    Science.gov (United States)

    Han, Zheng-xiang; Xu, Jie; Wang, Hong-mei; Ma, Jan; Sun, Xuan; Du, Xiu-ping

    2014-09-01

    The efficacy of thalidomide to attenuate cisplatin-induced emesis was evaluated in a rat model. Four groups were utilized: control group (peritoneal injection and gastric lavage with normal saline), cisplatin group (peritoneal injection of cisplatin at 10 mg/kg and gastric lavage with normal saline), thalidomide group (cisplatin as above and gastric lavage with thalidomide at 10 mg/kg), and granisetron group (positive control for antiemetic effects; cisplatin given as above and gastric lavage done with granisetron at 0.5 mg/kg). The cisplatin-induced kaolin consumption (pica behavior) was used as a model of emesis in patients. The animals' kaolin and food intakes were measured. Further, medulla and gastric tissues were obtained 5 and 33 h after peritoneal injections to quantify the levels of Substance P and Neurokinin-1 receptor (NK-1R). The cisplatin-induced kaolin consumption was significantly (p thalidomide 72 h after the injection. The levels of Substance P in the medulla and gastric tissue were increased 5 h after the injection in both cisplatin and thalidomide groups, however, returned faster to normal levels in the thalidomide group (p thalidomide, and granisetron group were significantly increased at both 5 and 33 h (p thalidomide attenuates animal equivalent of cisplatin-induced emesis, and this beneficial effect is associated with decreased levels of Substance P levels in the medulla and gastric tissue.

  6. Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy.

    Science.gov (United States)

    Bobylev, Ilja; Joshi, Abhijeet R; Barham, Mohammed; Neiss, Wolfram F; Lehmann, Helmar C

    2017-01-21

    Sensory neuropathy is a relevant side effect of the antineoplastic agent cisplatin. Mitochondrial damage is assumed to play a critical role in cisplatin-induced peripheral neuropathy, but the pathomechanisms underlying cisplatin-induced mitotoxicity and neurodegeneration are incompletely understood. In an animal model of cisplatin-induced neuropathy, we determined in detail the extent and spatial distribution of mitochondrial damage during cisplatin treatment. Changes in the total number of axonal mitochondria during cisplatin treatment were assessed in intercostal nerves from transgenic mice that express cyan fluorescent protein. Further, we explored the impact of cisplatin on the expression of nuclear encoded molecules of mitochondrial fusion and fission, including mitofusin-2 (MFN2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1). Cisplatin treatment resulted in a loss of total mitochondrial mass in axons and in an abnormal mitochondrial morphology including atypical enlargement, increased vacuolization, and loss of cristae. These changes were observed in distal and proximal nerve segments and were more prominent in axons than in Schwann cells. Transcripts of fusion and fission proteins were reduced in distal nerve segments. Significant reduced expression levels of the fusion protein MFN2 was detected in nerves of cisplatin-exposed animals. In summary, we provide for the first time an evidence that cisplatin alters mitochondrial dynamics in peripheral nerves. Loss of MFN2, previously implicated in the pathogenesis of other neurodegenerative diseases, also contributes to the pathogenesis in cisplatin-induced neuropathy.

  7. Protective Activity of Dendropanax Morbifera Against Cisplatin-Induced Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Eun-Sun Kim

    2015-01-01

    Full Text Available Background/Aims: Drug-induced acute kidney injury (AKI has been a severe threat to hospitalized patients, raising the urgent needs to develop strategies to reduce AKI. We investigated the protective activity of Dendropanax morbifera (DP, a medicinal plant which has been widely used to treat infectious and pain diseases, on acute kidney injury (AKI using cisplatin-induced nephropathic models. Methods: Both in vitro renal tubular cells (NRK-52E and in vivo rat models were used to demonstrate the nephroprotective effect of DP. Results: Methanolic extract from DP significantly reduced cisplatin-induced toxicity in renal tubular cells. Through successive liquid extraction, the extract of DP was separated into n-hexane, CHCl3, EtOAc, n-BuOH, and H2O fractions. Among these, the CHCl3 fraction (DPCF was found to be most potent. The protective activity of DPCF was found to be mediated through anti-oxidant, mitochondrial protective, and anti-apoptotic activities. In in vivo rat models of AKI, treatment with DPCF significantly reversed the cisplatin-induced increase in blood urea nitrogen and serum creatinine and histopathologic damage, recovered the level of anti-oxidant enzymes, and inhibited renal apoptosis. Conclusion: We demonstrated that DP extracts decreased cisplatin-induced renal toxicity, indicating its potential to ameliorate drug-associated acute kidney damage.

  8. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

    Science.gov (United States)

    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  9. Long Term Study of Protective Mechanisms of Human Adipose Derived Mesenchymal Stem Cells on Cisplatin Induced Kidney injury in Sprague-Daweley Rats

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    Elhusseini FM

    2016-05-01

    Full Text Available Background/Aims: Long-term evaluation of cisplatin induced nephrotoxicity and the probable renal protective activities of stem cells are lacking up until now. We evaluated the early and long-term role of human adipose derived mesenchymal stem cells (ADMSCs in prevention or amelioration of cisplatin induced acute kidney injury (AKI in Sprague-Dawley rats. For this, we determined the kidney tissue level of oxidative stress markers in conjugation with a renal histopathological scoring system of both acute and chronic renal changes. Methods: This study used eighty Sprague-Dawley (SD rats weighing 250-300g. They were assigned into four equal groups (each group n=20: (I Negative control group, rats injected with single dose of 1 ml normal saline. (II Positive control cisplatin, rats injected with a single dose of 5 mg/kg I.P in 1 ml saline. (III Cisplatin and culture media group, rats injected with 0.5 ml of culture media single dose into the tail vein and (IV Cisplatin and ADMSCs group, rats injected with a single dose of 0.5 ml of culture media containing 5 x106ADMSCs into the tail vein one day after cisplatin administration. Each main group was further divided according to the timing of sacrifice into four subgroups (each subgroup n=5. Rats in the subgroup A were sacrificed after 4 days; subgroup B were sacrificed after 7 days; subgroup C were sacrificed after 11 days; and subgroup D were sacrificed after 30 days. Before sacrifice, 24 hrs.-urine was collected using a metabolic cage. Renal function was evaluated through blood urea nitrogen (BUN, serum creatinine and creatinine clearance. Kidney tissue homogenate oxidative stress parameters, Malondialdehyde (MDA, Superoxide dismutase (SOD and Glutathione (GSH were determined. In addition, histopathological analysis for active injury, regenerative and chronic changes was performed. Results: ADMSCs were characterized and their capability of differentiation was proved. Cisplatin induced a significant

  10. Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence.

    Science.gov (United States)

    Sahu, Bidya Dhar; Kalvala, Anil Kumar; Koneru, Meghana; Mahesh Kumar, Jerald; Kuncha, Madhusudana; Rachamalla, Shyam Sunder; Sistla, Ramakrishna

    2014-01-01

    Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

  11. Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence.

    Directory of Open Access Journals (Sweden)

    Bidya Dhar Sahu

    Full Text Available Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine; degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65 nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.

  12. Total Coumarins from Hydrangea paniculata Protect against Cisplatin-Induced Acute Kidney Damage in Mice by Suppressing Renal Inflammation and Apoptosis

    Science.gov (United States)

    Jie, Ma; Jingzhi, Yang; Dongjie, Wang; Dongming, Zhang

    2017-01-01

    Aim. Hydrangea paniculata (HP) Sieb. is a medical herb which is widely distributed in southern China, and current study is to evaluate renal protective effect of aqueous extract of HP by cisplatin-induced acute kidney injury (AKI) in animal model and its underlying mechanisms. Materials and Methods. HP extract was prepared and the major ingredients were coumarin glycosides. AKI mouse models were established by single i.p. injection of 20 mg/kg cisplatin, and HP was orally administrated for total five times. The renal biochemical functions, pathological staining, kidney oxidative stress, and inflammatory status were measured. Apoptosis of tubular cells and infiltration of macrophages and neutrophils were also tested. Results. HP administration could improve the renal function by decreasing concentration of blood urea nitrogen (BUN) and creatinine and attenuates renal oxidative stress and tubular pathological injury and apoptosis; further research demonstrated that HP could inhibit the overproduction of proinflammatory cytokines and regulate caspase and BCL-2 family proteins. HP also reduced renal infiltration of macrophages and neutrophils, and its effect might be by downregulating phosphorylation of ERK1/2 and stat3 signaling pathway. Conclusions. This present study suggests that HP could ameliorate cisplatin induced kidney damage by antioxidation and suppressing renal inflammation and tubular cell apoptosis.

  13. Geraniin ameliorates cisplatin-induced nephrotoxicity in mice.

    Science.gov (United States)

    Jiang, Lei; Liu, Yong; He, Pengcheng; Chen, Jiyan; Liu, Shuangxin; Tan, Ning

    2016-08-01

    Geraniin, an active compound isolated from Geranium sibiricum, has been reported to have antioxidant and anti-inflammatory activities. The aim of this study was to investigate the protective effects of geraniin against cisplatin (CP)-induced kidney injury in mice. Geraniin was administrated for three consecutive days following CP (20 mg/kg) injection. The results showed that geraniin inhibited CP-induced kidney histopathologic changes, MDA, inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production in kidney tissues. Geraniin also inhibited CP-induced blood urea nitrogen (BUN) and creatinine production. Meanwhile, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) decreased by CP were reversed by the treatment of geraniin. In addition, geraniin significantly inhibited CP-induced NF-κB activation in kidney tissues. Treatment of geraniin dosedependently upregulated the expression of Nrf2 and HO-1. The anticancer effects of CP were not affected by the treatment of geraniin. In conclusion, these results indicated that geraniin protected against CP-induced nephrotoxicity by inhibiting oxidative stress and inflammatory response.

  14. Pinpointing differences in cisplatin-induced apoptosis in adherent and non-adherent cancer cells

    DEFF Research Database (Denmark)

    Tastesen, Hanne Sørup; Holm, Jacob Bak; Poulsen, Kristian Arild

    2010-01-01

    Platinum compounds are used in the treatment of cancer. We demonstrate that cisplatin-induced (10 µM) apoptosis (caspase-3 activity) is pronounced within 18 hours in non-adherent Ehrlich ascites tumour cells (EATC), whereas there is no increase in caspase-3 activity in the adherent Ehrlich Lettré...... ascites tumour cells (ELA). Loss of KCl and cell shrinkage are hallmarks in apoptosis and has been shown in EATC. However, we find no reduction in cell volume and only a minor loss of K(+) which is accompanied by net uptake of Na(+) following 18 hours cisplatin exposure in ELA. Glutathione and taurine...... have previously been demonstrated to protect cells from apoptosis. We find, however, that increase or decrease in the cellular content of glutathione and taurine has no effect on cisplatin-induced cell death in EATC and ELA. Nevertheless, knock-down of the taurine transporter TauT leads...

  15. Decursin Mediated Protection on Cisplatin-induced Nephrotoxicity in SD Rats and BDF1 Mice

    Institute of Scientific and Technical Information of China (English)

    Jiang Cheng-zhe; Han Ilhyun; Choung Seyoung

    2012-01-01

    Tisplatin is one of the valuable icancer agents against several types of neoplasm. However, nephrotoxicity is the major adverse effect representing in cisplatin therapy. In this study, the animal tests detecting protective effects of a natural compound, Decursin, on cisplatin-induced nephrotoxicity were examined by using in vivo model. Pretreatment Decursin 10, 20 and 40 mg · kg^-1 at 48, 24 and 6 h, and administration of a single dose of Cisplatin 5.2 mg · kg^-1. Nephrotoxicity was evaluated by serum BUN and creatinine examination. There was significant difference in body weights, serum BUN and creatinine levels of the normal group. Based on the new understanding of the protective mechanisms of cisplatin-induced nephrotocivity, new strategies can be developed to prevent renal injury or to enhance recovery after cisplatin treatment.

  16. Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats.

    Science.gov (United States)

    Yildirim, Zeki; Sogut, Sadik; Odaci, Ersan; Iraz, Mustafa; Ozyurt, Huseyin; Kotuk, Mahir; Akyol, Omer

    2003-02-01

    The effect of oral erdosteine on tissue malondialdehyde (MDA) and nitric oxide (NO) levels, and catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities are investigated in the cisplatin model of acute renal failure in rats. A single dose of cisplatin caused kidney damage manifested by kidney histology as well as increases in plasma creatinine and blood urea nitrogen (BUN) levels. Treatment with free radical scavenger erdosteine attenuated increases in plasma creatinine and BUN, and tissue MDA and NO levels, and provided a histologically-proven protection against cisplatin-induced acute renal failure. Erdosteine also reduced depletion in the tissue CAT, GSH-Px, and SOD activities. These results show that erdosteine may be a promising drug for protection against cisplatin-induced nephrotoxicity. However, further studies with different doses of erdosteine are warranted for clarifying the issue.

  17. Nephroprotective effect of Bauhinia variegata (Linn.) whole stem extract against cisplatin-induced nephropathy in rats.

    Science.gov (United States)

    Pani, Saumya R; Mishra, Satyaranjan; Sahoo, Sabuj; Panda, Prasana K

    2011-04-01

    The nephroprotective activity of the ethanolic extract of Bauhinia variegata (Linn.) whole stem against cisplatin-induced nephropathy was investigated by an in vivo method in rats. Acute nephrotoxicity was induced by i.p. injection of cisplatin (7 mg/kg of body weight (b.w.)). Administration of ethanol extract at dose levels of 400 and 200 mg/kg (b.w.) to cisplatin-intoxicated rats for 14 days attenuated the biochemical and histological signs of nephrotoxicity of cisplatin in a dose-dependent fashion. Ethanol extract at 400 mg/kg decreased the serum level of creatinine (0.65 ± 0.09; Pvariegata at 400 mg/kg (b.w.) exhibited significant and comparable nephroprotective potential to that of the standard polyherbal drug cystone. The statistically (one-way-ANOVA followed by Tukey-Kramer multiple comparison) processed results suggested the protective action of B. variegate whole stem against cisplatin-induced nephropathy.

  18. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    Science.gov (United States)

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  19. The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats

    OpenAIRE

    Li, Xiaohuan; Yang, Shu; Lv,Xiangyang; Sun, Haimei; Weng, Jing; Liang, Yuanjing; Zhou, Deshan

    2013-01-01

    Objective Cisplatin is a widely used chemotherapeutic agent in the treatment of cancers in clinic; but it often induces adverse effects on ovarian functions such as reduced fertility and premature menopause. Mesna could attenuate the cisplatin-induced ovarian damages; however, the underlying mechanism is still unknown. This study aimed to figure out the underlying mechanism of the protection of mesna for ovaries against cisplatin therapy in cancers. Methods We performed female adult Sprague-D...

  20. Changes in the Mucus Barrier during Cisplatin-Induced Intestinal Mucositis in Rats

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    Hajime Yamamoto

    2013-01-01

    Full Text Available Aim. Gastrointestinal mucositis is a frequent complication of antineoplastic chemotherapy, but the effects of chemotherapy on mucosal defense mechanisms remain poorly understood. We studied the effects of cisplatin on mucin, one of the principal defense factors of the gastrointestinal mucosa, and evaluated the efficacy of two different types of H2-receptor antagonists against cisplatin-induced mucositis. Methods. Cisplatin (6 mg/kg was administered intravenously to rats (day 0. The rats were sacrificed 1, 3, 7, and 11 days after treatment, and their stomach, jejunum, ileum, and colon were removed. Immunoreactivity of the mucosa was compared with the use of anti-mucin monoclonal antibody. To evaluate the efficacy of H2-receptor antagonists, either famotidine (3 mg/kg or lafutidine (30 mg/kg was given orally once daily on days 0, 1, and 2. Histological and biochemical findings were compared among the groups to assess effects on cisplatin-induced injury. Results. Cisplatin significantly altered the immunoreactivity and content of mucin in the small intestinal mucosa, especially in the ileum. Lafutidine protected against cisplatin-induced mucosal injury and attenuated decreased mucin accumulation. Conclusion. Cisplatin appears to alter the mucus barrier function in the intestinal mucosa. Lafutidine might effectively prevent chemotherapy-induced mucositis by activating intestinal mucus cells.

  1. Antiemetic and Myeloprotective Effects of Rhus verniciflua Stoke in a Cisplatin-Induced Rat Model

    Science.gov (United States)

    Kim, Hyo-Seon; Kim, Hyeong-Geug; Im, Hwi-Jin; Lee, Jin-Seok; Lee, Sung-Bae; Kim, Won-Yong; Lee, Hye-Won; Lee, Sam-Keun; Byun, Chang Kyu

    2017-01-01

    Rhus verniciflua Stoke has been commonly used in traditional medicine to treat gastrointestinal (GI) dysfunction diseases. In order to investigate pharmacological properties of Rhus verniciflua Stoke water extract (RVX) on cisplatin-induced amnesia, RVX (0, 25, 50, or 100 mg/kg) was orally administrated for five consecutive days after a single intraperitoneal injection of cisplatin (6 mg/kg) to SD rat. Cisplatin injection significantly increased the kaolin intake (emesis) but reduced the normal diet intake (anorexia) whereas the RVX treatment significantly improved these abnormal diet behaviors at both the acute and delayed phase. The serotonin concentration and the related gene expressions (5-HT3 receptors and SERT) in small intestine tissue were abnormally altered by cisplatin injection, which were significantly attenuated by the RVX treatment. Histological findings of gastrointestinal tracts, as well as the proteins level of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), revealed the beneficial effect of RVX on cisplatin-induced gastrointestinal inflammation. In addition, RVX significantly improved cisplatin-induced myelosuppression, as evidenced by the observation of leukopenia and by histological examinations in bone marrow. Our findings collectively indicated Rhus verniciflua Stoke improved the resistance of rats to chemotherapy-related adverse effects in the gastrointestinal track and bone marrow.

  2. Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats.

    Science.gov (United States)

    Taskin, Mine Islimye; Yay, Arzu; Adali, Ertan; Balcioglu, Esra; Inceboz, Umit

    2015-04-01

    The aim of this study is to evaluate the effects of sildenafil citrate on cisplatin-induced ovarian toxicity. Thirty-two female rats were divided into four groups. Group 1: saline control; group 2: cisplatin; group 3: sildenafil citrate; and group 4: cisplatin plus sildenafil citrate group. In groups 2 and 4, the rats were injected with 5 mg/kg cisplatin intraperitoneally (i.p.). In groups 3 and 4, the rats were injected with 1.4 mg/kg sildenafil citrate i.p. The ovaries were removed two weeks later in all groups. Histopathologic examination, follicle counting and classification were performed. The expression of anti-Müllerian hormone (AMH) was detected immunohistochemically in the ovarian tissues. Sildenafil alleviated cisplatin-induced histopathological changes in the ovarian tissue. Primordial, secondary and tertiary follicles were diminished in group 2 compared with group 1 (p sildenafil citrate preserved primordial follicle count in group 4 compared with group 2, and the difference was statistically significant (p sildenafil citrate is beneficial for protecting the ovaries from cisplatin-induced damage. Sildenafil citrate can be a choice for fertility preservation.

  3. Improved Protective Effect of Umbilical Cord Stem Cell Transplantation on Cisplatin-Induced Kidney Injury in Mice Pretreated with Antithymocyte Globulin

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    Željka Večerić-Haler

    2016-01-01

    Full Text Available Mesenchymal stem cells (MSCs are recognised as a promising tool to improve renal recovery in experimental models of cisplatin-induced acute kidney injury. However, these preclinical studies were performed on severely immunodeficient animals. Here, we investigated whether human umbilical cord derived MSC treatment could equally ameliorate acute kidney injury induced by cisplatin and prolong survival in mice with a normal immune system and those with a suppressed immune system by polyclonal antithymocyte globulin (ATG. We demonstrated that ATG pretreatment, when followed by MSC transplantation, significantly improved injured renal function parameters, as evidenced by decreased blood urea nitrogen and serum creatinine concentration, as well as improved renal morphology. This tissue restoration was also supported by increased survival of mice. The beneficial effects of ATG were associated with reduced level of inflammatory protein serum amyloid A3 and induced antioxidative expression of superoxide dismutase-1 (SOD-1, glutathione peroxidase (GPx, and hem oxygenase-1 (HO-1. Infused MSCs became localised predominantly in peritubular areas and acted to reduce renal cell death. In conclusion, these results show that ATG diminished in situ inflammation and oxidative stress associated with cisplatin-induced acute kidney injury, the effects that may provide more favourable microenvironment for MSC action, with consequential synergistic improvements in renal injury and animal survival as compared to MSC treatment alone.

  4. Stress Responses in Staphylococcus aureus

    DEFF Research Database (Denmark)

    Frees, Dorte; Ingmer, Hanne

    2016-01-01

    stress responses allowing it to sense and adapt to its very different niches. The stress responses often involve dramatic cellular reprogramming, and the technological advances provided by the access to whole genome sequences have let to an unprecedented insight into the global reorganization of gene...... and protein expression following stress-exposure. Characterization of global gene responses has been very helpful both in identifying regulators sensing specific environmental stress signals and overlaps between different stress responses. In this chapter we review the recent progress in our understanding...... of the specific and general S. aureusstress responses, with a special emphasis on how stress responses contribute to virulence and antibiotic resistance in this important human pathogen....

  5. Staphylococcal response to oxidative stress

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    Rosmarie eGaupp

    2012-03-01

    Full Text Available Staphylococci are a versatile genus of bacteria that are capable of causing acute and chronic infections in diverse host species. The success of staphylococci as pathogens is due in part to their ability to mitigate endogenous and exogenous oxidative and nitrosative stress. Endogenous oxidative stress is a consequence of life in an aerobic environment; whereas, exogenous oxidative and nitrosative stress are often due to the bacteria’s interaction with host immune systems. To overcome the deleterious effects of oxidative and nitrosative stress, staphylococci have evolved protection, detoxification, and repair mechanisms that are controlled by a network of regulators. In this review, we summarize the cellular targets of oxidative stress, the mechanisms by which staphylococci sense oxidative stress and damage, oxidative stress protection and repair mechanisms, and regulation of the oxidative stress response. When possible, special attention is given to how the oxidative stress defense mechanisms help staphylococci control oxidative stress in the host.

  6. The role of apoptosis in cisplatin-induced ototoxicity in rats Papel da apoptose na ototoxicidade por cisplatina em ratos

    Directory of Open Access Journals (Sweden)

    Marcos Rabelo De Freitas

    2009-10-01

    Full Text Available Cisplatin is a chemotherapy agent frequently used to treat different types of neoplasia. Ototoxicity is one of the side-effects which cause significant morbidity and limits its use. This study aimed at assessing the role of apoptosis in cisplatin-induced ototoxicity. DESIGN: experimental study. MATERIALS AND METHODS: male Wistar rats were treated with intraperitoneal cisplatin, in the doses of 24 and 16 mg/kg. The animals were assessed by means of distortion product evoked otoacoustic emissions (DPEOAE or brainstem evoked auditory potentials (BEAP in the third (D3 and fourth (D4 days after drug infusion onset. Following that, their cochleas were removed for immunohistochemical studies of apoptosis - TUNEL method. RESULTS: the group treated with 24 mg/kg showed a significant reduction in DPEOAE amplitude, and such fact was not seen with the 16 mg/kg. Both doses caused an increase in BEAP electrophysiological threshold in D3 and D4. Apoptosis was the injury mechanism responsible for the cisplatin-induced ototoxicity - 16 mg/kg dose, when the animals were assessed on D3. CONCLUSION: apoptosis may be involved in the cisplatin-induced ototoxicity, depending on the dose and time of injury assessment.Cisplatina é um agente quimioterápico frequentemente usado para o tratamento de várias linhagens de neoplasias. A ototoxicidade é um dos efeitos colaterais causadores de significativa morbidade e que limita sua utilização. Este estudo teve por objetivo avaliar o papel da apoptose na ototoxicidade por cisplatina. DESENHO DO ESTUDO: Estudo experimental. MATERIAL E MÉTODO: Ratos Wistar machos foram tratados com cisplatina, via intraperitoneal, nas doses de 24 e 16 mg/kg. Os animais foram avaliados através de emissões otoacústicas evocadas produtos de distorção (EOAPD ou potenciais auditivos evocados de tronco encefálico (PAETE no terceiro (D3 e quarto (D4 dias após o início da infusão das drogas. Em seguida suas cócleas foram removidas para

  7. Protective role of apigenin in cisplatin-induced renal injury.

    Science.gov (United States)

    He, Xuexiu; Li, Chunmei; Wei, Zhengkai; Wang, Jingjing; Kou, Jinhua; Liu, Weijian; Shi, Mingyu; Yang, Zhengtao; Fu, Yunhe

    2016-10-15

    This study aimed to investigate the effects and molecular mechanisms of the effects of apigenin on cisplatin (CP)-induced kidney injury in mice. Apigenin was intraperitoneally administered for 3 consecutive days before CP treatment. We found that apigenin pretreatment significantly attenuated the damage to the kidneys and decreased the levels of serum creatinine, blood urea nitrogen (BUN), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD), which were increased by CP. Apigenin significantly decreased the levels of TNF-α, IL-1β and TGFβ in the kidneys. Additionally, apigenin inhibited the activations of CYP2E1, phospho-NF-κB p65 and phospho-P38 MAPK in CP-induced renal injury. These results suggest that the renoprotective effects of apigenin may be related to the suppressions of oxidative stress and inflammation in CP-induced renal injury in mice.

  8. Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity

    Science.gov (United States)

    Venkataraman, Balaji; Kurdi, Amani; Mahgoub, Eglal; Sadek, Bassem

    2016-01-01

    Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals) to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage.

  9. Effect of tunicamycin on cisplatin induced apoptosis of HeLa cells

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    Ye XU

    2013-04-01

    Full Text Available Objective  To investigate the effect of endoplasmic reticulum stress (ER stress in cisplatin-induced apoptosis of human cervical cancer HeLa cells. Methods  HeLa cells were used as the study object which were divided into four groups: TUNI (5mg/L group, cisplatin (6mg/L group, TUNI(5mg/L+cisplatin(6mg/L group, and negative control group (no drug treatment. MTT assay was employed to examine the growth status of the cells. Hoechst staining was used to observe the morphological change in the nucleus. Immunoblotting was used to detect the activation of apoptotic proteins, caspase-3 and caspase-4. Indirect immunofluorescence was used to assess the expression of the protein disulfide isomerase (PDI and phosphorylated histone H2AX (γ-H2AX. Results  MTT assay showed that the growth inhibition rates were 2.65%±2.71%, 19.60%±4.34%, 44.69%±7.07% and 0% in TUNI group, cisplatin group, TUNI+cisplatin group and control group, respectively (P<0.05. Cisplatin showed a significant inhibitory effect on the growth of HeLa cells, and TUNI enhanced the effect of cisplatin. Statistical significance was found between TUNI+cisplatin group and cisplatin group (P<0.05. Hoechst staining showed that the fluorescence of the nucleus in control group was weak and well-distributed. At 12h after treatment, the nuclei in some HeLa cells in cisplatin group and TUNI+cisplatin group diminished in size, thus showing dense hyperfluorescence, and some of them were broken. The proportion of karyorrhexis cells in TUNI+cisplatin group (44.5%±5.1% was significantly higher than that in cisplatin group (22.7%±3.9%, P<0.05. Immunoblotting showed the expressions of activated caspase-3 and caspase-4 were up-regulated obviously in cisplatin group. Compared to cisplatin group, the expressions of those proteins significantly increased in TUNI+cisplatin group (P<0.05. Indirect immunofluorescence staining showed no PDI expression and weak fluorescence was found in control group. PDI

  10. Metformin Protects Against Cisplatin-Induced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKα-regulated Autophagy Induction.

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    Li, Jianzhong; Gui, Yuan; Ren, Jiafa; Liu, Xin; Feng, Ye; Zeng, Zhifeng; He, Weichun; Yang, Junwei; Dai, Chunsun

    2016-04-07

    Metformin, one of the most common prescriptions for patients with type 2 diabetes, is reported to protect the kidney from gentamicin-induced nephrotoxicity. However, the role and mechanisms for metformin in preventing cisplatin-induced nephrotoxicity remains largely unknown. In this study, a single intraperitoneal injection of cisplatin was employed to induce acute kidney injury (AKI) in CD1 mice. The mice exhibited severe kidney dysfunction and histological damage at day 2 after cisplatin injection. Pretreatment of metformin could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis and inflammatory cell accumulation in the kidneys. Additionally, pretreatment of metformin could enhance both AMPKα phosphorylation and autophagy induction in the kidneys after cisplatin injection. In cultured NRK-52E cells, a rat kidney tubular cell line, metformin could stimulate AMPKα phosphorylation, induce autophagy and inhibit cisplatin-induced cell apoptosis. Blockade of either AMPKα activation or autophagy induction could largely abolish the protective effect of metformin in cisplatin-induced cell death. Together, this study demonstrated that metformin may protect against cisplatin-induced tubular cell apoptosis and AKI through stimulating AMPKα activation and autophagy induction in the tubular cells.

  11. Real-time monitoring of cisplatin-induced cell death.

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    Hamed Alborzinia

    Full Text Available Since the discovery of cisplatin more than 40 years ago and its clinical introduction in the 1970s an enormous amount of research has gone into elucidating the mechanism of action of cisplatin on tumor cells. With a novel cell biosensor chip system allowing continuous monitoring of respiration, glycolysis, and impedance we followed cisplatin treatment of different cancer cell lines in real-time. Our measurements reveal a first effect on respiration, in all cisplatin treated cell lines, followed with a significant delay by interference with glycolysis in HT-29, HCT-116, HepG2, and MCF-7 cells but not in the cisplatin-resistant cell line MDA-MB-231. Most strikingly, cell death started in all cisplatin-sensitive cell lines within 8 to 11 h of treatment, indicating a clear time frame from exposure, first response to cisplatin lesions, to cell fate decision. The time points of most significant changes were selected for more detailed analysis of cisplatin response in the breast cancer cell line MCF-7. Phosphorylation of selected signal transduction mediators connected with cellular proliferation, as well as changes in gene expression, were analyzed in samples obtained directly from sensor chips at the time points when changes in glycolysis and impedance occurred. Our online cell biosensor measurements reveal for the first time the time scale of metabolic response until onset of cell death under cisplatin treatment, which is in good agreement with models of p53-mediated cell fate decision.

  12. Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity

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    Shreesh Ojha

    2016-01-01

    Full Text Available Cisplatin (CSP is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage.

  13. The protective effect of Nigella sativa against cisplatin-induced nephrotoxicity in rats

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    Sara Hosseinian

    2016-01-01

    Full Text Available Objective: The clinical use of cisplatin is highly restricted, because of its nephrotoxicity.In this study the protective effect of Nigella sativa (N. sativa against cisplatin-induced nephrotoxicity was investigated in rats. Materials and Methods: In the current study, the effects of the administration of aqueous-ethanolic extract of N. sativa (100 and 200 mg/kg, BW and vitamin E (100 mg/kg, BW against blood and urine biochemical alterations and kidney function in rats treated with cisplatin were investigated. Cisplatin was injected at a dose of 6 mg/kg, BW, on the sixth day of the experiment. Results: The results indicated significant changes in serum urea and creatinine concentration, urine glucose concentration, and urine output in cisplatin group compared with control group. Serum urea and creatinine concentration in preventive and preventive+treatment vitamin E and preventive+treatment N. sativa (200 mg/kg, BW groups and also serum creatinine concentration in preventive+treatment N. sativa (100 mg/kg, BW group significantly decreased compared with cisplatin group. Urine glucose concentration in preventive and preventive+treatment N. sativa groups and urine output in preventive and preventive+treatment N. sativa (200 mg/kg, BW groups significantly decreased compared with cisplatin group.Osmolarity excretion rate in preventive and preventive+treatment vitamin E and preventive N. sativa groups was significantly higher than control group. Conclusions: The current study suggests that N. sativa extract and vitamin E in a dose- and time-dependent manner improved the serum and urine biochemical parameters and kidney function in cisplatin-induced nephrotoxicity in rats. However, it needs more investigations to determine the mechanism of N. sativa action on cisplatin-induced kidney toxicity.

  14. Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection.

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    Yasuhiro Kidera

    Full Text Available Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity.We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m2 of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%.Cisplatin-induced nephrotoxicity was observed in 127 patients (32%. Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004 and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs (risk ratio, 1.357; P = 0.047 were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004. The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025. Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012.A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further

  15. Neuronal responses to physiological stress

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    Konstantinos eKagias

    2012-10-01

    Full Text Available Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. Physiological stress can be divided into three different aspects: environmental stress, intrinsic developmental stress and aging. Throughout life all living organisms are challenged by changes in the environment. Fluctuations in oxygen levels, temperature and redox state for example, trigger molecular events that enable an organism to adapt, survive and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner chemistry during normal development. For example, conditions such as intrinsic hypoxia and oxidative stress, which result from an increase in tissue mass, have to be confronted by developing embryos in order to complete their development. Finally, organisms face the challenge of stochastic accumulation of molecular damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review the responses of neurons to various physiological stressors at the molecular and cellular level.

  16. Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation.

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    Sahu, Bidya Dhar; Kuncha, Madhusudana; Putcha, Uday Kumar; Sistla, Ramakrishna

    2013-09-01

    Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy.

  17. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia.

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    Yakabi, Koji; Sadakane, Chiharu; Noguchi, Masamichi; Ohno, Shino; Ro, Shoki; Chinen, Katsuya; Aoyama, Toru; Sakurada, Tomoya; Takabayashi, Hideaki; Hattori, Tomohisa

    2010-08-01

    Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.

  18. The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1.

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    Li, Yi; Chen, Xi; Wang, Zehua; Zhao, Dong; Chen, Hui; Chen, Wenlin; Zhou, Zhongmei; Zhang, Junran; Zhang, Jing; Li, Hongmin; Chen, Ceshi

    2013-01-01

    Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase with unknown functions. Here, we show that HECTD3 confers cancer cell resistance to cisplatin. To understand the molecular mechanisms, we performed a yeast two-hybrid analysis and identified mucosa-associated lymphoid tissue 1 (MALT1) as an HECTD3-interacting protein. HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. HECTD3 depletion dramatically decreases the levels of MALT1 in MCF7 and HeLa cells treated with cisplatin, which is correlated to an increase in apoptosis. Knockdown of MALT1 likewise increases cisplatin-induced apoptosis in these cancer cells. However, HECTD3 over-expression leads to a decreased cisplatin-induced apoptosis, whereas overexpression of MALT1 partially rescues HECTD3 depletion-induced apoptosis. These findings suggest that HECTD3 promotes cell survival through stabilizing MALT1. Our data have important implications in cancer therapy by providing novel molecular targets.

  19. The HECTD3 E3 Ubiquitin Ligase Suppresses Cisplatin-Induced Apoptosis via Stabilizing MALT1

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    Yi Li

    2013-01-01

    Full Text Available Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3 is an E3 ubiquitin ligase with unknown functions. Here, we show that HECTD3 confers cancer cell resistance to cisplatin. To understand the molecular mechanisms, we performed a yeast two-hybrid analysis and identified mucosa-associated lymphoid tissue 1 (MALT1 as an HECTD3-interacting protein. HECTD3 promotes MALT1 ubiquitination with non-degradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. HECTD3 depletion dramatically decreases the levels of MALT1 in MCF7 and HeLa cells treated with cisplatin, which is correlated to an increase in apoptosis. Knockdown of MALT1 likewise increases cisplatin-induced apoptosis in these cancer cells. However, HECTD3 overexpression leads to a decreased cisplatin-induced apoptosis, whereas overexpression of MALT1 partially rescues HECTD3 depletion–induced apoptosis. These findings suggest that HECTD3 promotes cell survival through stabilizing MALT1. Our data have important implications in cancer therapy by providing novel molecular targets.

  20. Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats.

    Science.gov (United States)

    Koc, Ahmet; Duru, Mehmet; Ciralik, Harun; Akcan, Ramazan; Sogut, Sadik

    2005-10-01

    Cisplatin, one of the most active cytotoxic agents against cancer, has several toxicities. Hepatotoxicity is one of them occurred during high doses treatment. The aim of this study was to determine the effects of erdosteine against cisplatin-induced liver injury through tissue oxidant/antioxidant parameters and light microscopic evaluation. The rats were randomly divided into three groups: control (n=5), cisplatin (10 mg/kg, n=6) and cisplatin+erdosteine (50 mg/kg/day oral erdosteine, n=8) groups. The rats were sacrificed at the 5th day of cisplatin treatment. The liver tissues were examined with light microscopy and oxidant/antioxidant biochemical parameters. The malondialdehyde (MDA) and nitric oxide (NO) levels were increased in the cisplatin group in comparison with the control and cisplatin+erdosteine groups (perdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in cisplatin+erdosteine group than cisplatin group (perdosteine group, a decrease in cytoplasmic changes with the hepatocytes and sinusoidal dilatations around cells of central vein were noticed in as compared to cisplatin group. In the light of microscopic and biochemical results, it was concluded that cisplatin-induced liver damage in high dose and erdosteine prevented this toxic side effect by the way of its antioxidant and radical scavenging effects.

  1. Cisplatin-induced acute renal failure is ameliorated by erdosteine in a dose-dependent manner.

    Science.gov (United States)

    Ozyurt, Hüseyin; Yildirim, Zeki; Kotuk, Mahir; Yilmaz, H Ramazan; Yağmurca, Murat; Iraz, Mustafa; Söğüt, Sad; Gergerlioglu, Serdar

    2004-01-01

    The aim of this study was to investigate the optimum dosage of erdosteine to ameliorate cisplatin-induced nephrotoxicity. Three different doses of erdosteine at 25, 50 and 75 mg kg(-1) were studied in rats. Intraperitoneal administration of 7 mg kg(-1) cisplatin led to acute renal failure, as indicated by kidney histology and increases in plasma creatinine and blood urea nitrogen (BUN) levels. At 5 days after cisplatin injection the BUN level was increased significantly from 15.1 +/- 4.3 to 126.7 +/- 152.6 mg dl(-1) and plasma creatinine levels increased from 0.37 +/- 0.005 to 1.68 +/- 1.9 mg dl(-1). When the rats were administered 50 and 75 mg kg(-1) erdosteine 24 h before cisplatin injection that was continued until sacrifice (total of 6 days), the BUN and creatinine levels remained similar to control levels and the grade of histology was similar. Erdosteine at doses of 50 and 75 mg kg(-1) ameliorates cisplatin-induced renal failure. The optimum dose of erdosteine may be 50 mg kg(-1) in this study.

  2. Nephroprotective effect of Bauhinia variegata (linn. whole stem extract against cisplatin-induced nephropathy in rats

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    Saumya R Pani

    2011-01-01

    Full Text Available The nephroprotective activity of the ethanolic extract of Bauhinia variegata (Linn. whole stem against cisplatin-induced nephropathy was investigated by an in vivo method in rats. Acute nephrotoxicity was induced by i.p. injection of cisplatin (7 mg/kg of body weight (b.w.. Administration of ethanol extract at dose levels of 400 and 200 mg/kg (b.w. to cisplatin-intoxicated rats for 14 days attenuated the biochemical and histological signs of nephrotoxicity of cisplatin in a dose-dependent fashion. Ethanol extract at 400 mg/kg decreased the serum level of creatinine (0.65 ± 0.09; P<0.001 and urea (32.86 ± 5.88; P<0.001 associated with a significant increase in body weight (7.16 ± 1.10; P<0.001 and urine volume output (11.95 ± 0.79; P<0.05 as compared to the toxic control group. The ethanol extract of B. variegata at 400 mg/kg (b.w. exhibited significant and comparable nephroprotective potential to that of the standard polyherbal drug cystone. The statistically (one-way-ANOVA followed by Tukey-Kramer multiple comparison processed results suggested the protective action of B. variegate whole stem against cisplatin-induced nephropathy.

  3. Protective Effect of Aqueous and Ethanolic Extracts of Portulaca Oleracea Against Cisplatin Induced Nephrotoxicity

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    Gholamreza Karimi

    2010-04-01

    Full Text Available Objective(sPortulaca oleracea L. is a herbaceous weed from portulacaceae family. It can be found in many parts of the world. Modern pharmacological studies have demonstrated that P. oleracea have antioxidant effects. The protective effect of aqueous and ethanolic extract of P. oleracea against cisplatin-induced renal toxicity was studied in rats.Materials and MethodsSingle intraperitoneal injection of 4 mg/kg cisplatin was administrated to rats. After 5 days, blood urea nitrogen (BUN and serum creatinine (Scr concentration were determined. Effect of aqueous and ethanolic extracts, before and after cisplatin injection on BUN and Scr, as well as morphological renal damage, was evaluated. ResultsIt was indicated that treatment with aqueous and ethanolic extracts of P. oleracea in the highest dose (0.8 and 2 g/ kg, 6 and 12 hr before cisplatin injection reduced BUN and Scr. Tubular necrotic damage was not observed either. ConclusionResults suggest that P. oleracea extract may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplan to limit renal injury.

  4. Effects of Roselle and Ginger on cisplatin-induced reproductive toxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Amr Amin; AlaaEldin A. Hamza

    2006-01-01

    Aim: To evaluate the protective effects of Hibiscus sabdariffa (Roselle) and Zingiber officinale (Ginger) against cisplatin-induced reproductive toxicity in rats and to study the mechanisms underlying these effects. Methods:which began 21 days before a single cisplatin I.p. Injection (10 mg/kg body weight). Results: Extracts of H. Sabdariffa and Z. Officinale reduced the extent of cisplatin-induced sperm abnormality and enhanced sperm motility. Both extracts restored the control level of malondialdehyde (MDA) (lipid peroxidation marker) in the cisplatin-treated testis.The cisplatin injection induced decline in the levels of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were significantly reversed to control levels in groups where cisplatin was preceded by the administration of either H. Sabdariffa or Z. Officinale. Conclusion: Both H. Sabdariffa and Z. Officinale treatment increased the activities of testicular antioxidant enzymes and restored sperm motility of cisplatin-treated rats. The protective effects of tested plants are, therefore, suggested to be mediated by their potent antioxidant activities.

  5. Protective effect of speman on cisplatin-induced testicular and epididymal toxicity in mice

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    S B Sainath

    2011-01-01

    Full Text Available Testicular cancer is the most common cancer affecting men of reproductive age. Advances in treatment of the disease, which includes the administration of cisplatin, have brought the 5-year survival rate to over 90%. This high cure rate, coupled with young age of patients, makes elucidation of the impact of the treatment on reproduction become increasingly important. The objective of the present study was to investigate the protective effect of speman, a non-hormonal herbal formulation, on cisplatin-induced suppressed male reproductive health in mice. Male mice were treated with cisplatin or speman alone or in combination and assessed for spermatogenesis and steroidogenesis. Significant decrease in the weights of testes and epididymis was observed in cisplatin treated animals. Injection of cisplatin significantly decreased epididymal sperm count, viable sperms, motile sperms and hypo-osmotic swelling (HOS-tail coiled sperms with a significant reduction in the testicular steroidogenic enzyme activities and serum testosterone levels, whereas co-administration of speman with cisplatin showed a significant improvement in the selected reproductive parameters over cisplatin alone treated mice indicating the beneficial effect of speman to combat cisplatin-induced suppressed reproduction in male mice.

  6. Comparison of Intracellular Stress Response of NCI-H526 Small Cell Lung Cancer (SCLC) Cells to Platinum(II) Cisplatin and Platinum(IV) Oxoplatin

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    Hamilton, Gerhard [Ludwig Boltzmann Cluster of Translational Oncology, A-1090 Vienna (Austria)

    2014-07-08

    In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the initial cellular stress response of the chemosensitive NCI-H526 small cell lung cancer (SCLC) cells by determination of the relative phosphorylation of 46 specific phosphorylation sites of 38 selected proteins in a six hours response to cisplatin (platinum(II)) or oxoplatin (platinum(IV)), respectively. Oxoplatin is considered as prodrug of cisplatin, although several findings point to differences in intracellular effects. Cisplatin induced hyperphosphorylation of p38α MAPK and AMPKα1, whereas oxoplatin treatment resulted in increased phosphorylation of a large number of signaling proteins involved in stress response/drug resistance, including JNK, GSK-3α, AMPKα1, src kinases, STATs, CHK-2 and especially focal adhesion kinase (FAK). Cisplatin exerts markedly higher cytotoxicity upon four hours short-term exposure in comparison to oxoplatin and, correspondingly, the extended initial stress response to the platinum(IV) drug oxoplatin thus is expected to increase clinical drug resistance. Induction of a substantial stress response to any prodrug of a platinum-based compound may likewise limit the effectivity of its active metabolite(s), such contributing to the failure of selected derivatized platinum complexes.

  7. Individual heat stress response

    NARCIS (Netherlands)

    Havenith, G.

    1997-01-01

    In 5 experiments, heterogeneous subject groups (large variations in _VO2 max, regular daily activity level, mass, body surface area (AD), % body fat, and AD/mass ratio) were tested for their physiological response while exercising on a cycle ergometer at a relative (45% _VO2 max; REL) or an absolute

  8. Auxin response under osmotic stress.

    Science.gov (United States)

    Naser, Victoria; Shani, Eilon

    2016-08-01

    The phytohormone auxin (indole-3-acetic acid, IAA) is a small organic molecule that coordinates many of the key processes in plant development and adaptive growth. Plants regulate the auxin response pathways at multiple levels including biosynthesis, metabolism, transport and perception. One of the most striking aspects of plant plasticity is the modulation of development in response to changing growth environments. In this review, we explore recent findings correlating auxin response-dependent growth and development with osmotic stresses. Studies of water deficit, dehydration, salt, and other osmotic stresses point towards direct and indirect molecular perturbations in the auxin pathway. Osmotic stress stimuli modulate auxin responses by affecting auxin biosynthesis (YUC, TAA1), transport (PIN), perception (TIR/AFB, Aux/IAA), and inactivation/conjugation (GH3, miR167, IAR3) to coordinate growth and patterning. In turn, stress-modulated auxin gradients drive physiological and developmental mechanisms such as stomata aperture, aquaporin and lateral root positioning. We conclude by arguing that auxin-mediated growth inhibition under abiotic stress conditions is one of the developmental and physiological strategies to acclimate to the changing environment.

  9. Stress disrupts response memory retrieval.

    Science.gov (United States)

    Guenzel, Friederike M; Wolf, Oliver T; Schwabe, Lars

    2013-08-01

    Stress effects on memory are well-known. Most studies, however, focused on the impact of stress on hippocampus-dependent 'declarative' memory processes. Less is known about whether stress influences also striatum-based memory processes, such as stimulus-response (S-R) memory. First evidence from rodent experiments shows that glucocorticoid stress hormones may enhance the consolidation of S-R memories. Whether stress affects also S-R memory retrieval remains largely elusive. Therefore, we tested in the present experiment in humans the effect of stress on the retrieval of S-R memories. Healthy men and women were trained to locate three objects in an S-R version of a virtual eight-arm radial maze. One week later, participants underwent a stressor or a control condition before their memory of the S-R task was tested. Our results showed that participants (n=43) who were exposed to the stressor before retention testing made significantly more errors in this test trial, suggesting that stress impaired S-R memory retrieval. Moreover, high cortisol concentrations were associated with reduced S-R memory. These findings indicate that stress may affect memory retrieval processes in humans beyond hippocampal 'declarative' memory.

  10. The Effects of Nifedipine on Renal Perfusion Pressure and Kidney During Cisplatin-Induced Nephrotoxicity in Rats

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    Meral Erdinç

    2007-01-01

    Full Text Available Cisplatin is one of the most effective cancer chemotherapeutic agent used against various solid tumors. Nephrotoxicity is one of the major dose-limiting side effects of cisplatin. It has been known that different mechanisms as oxidative stress may play an important role in cisplatin induced nephrotoxicity resulted with changes in renal haemodynamics. This study was performed to investigate the effect of nifedipine –one of the dihydropyridine calcium antagonist on changes in renal perfusion pressures and kidneys of rats with cisplatin nephrotoxicity. Male wistar albino rats were divided into 3 groups (n=8:1-Control group(1 ml saline. i.p 2-Cisplatin group (a single dose of cisplatin (5 mg/kg, i.p 3- A single dose of cisplatin (5 mg/kg, i.p + Nifedipine (2 mg/kg/day, i.p for five days. When those pre-treated groups compared with control group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels were found significantly higher in cisplatin group (p<0.001. Histopathological examination showed widespread tubular necrosis and dilatation in cisplatin-treated group versus other groups. In cisplatin + nifedipine pretreated group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels found significantly lower than cisplatin group (p<0. 001 and less tubular dilatation and necrosis was observed. As a result it was demonstrated that Nifedipine has protective effects against cisplatin nephrotoxicity. We suggest that this is partly provided by the beneficial effects of nifedipine on altered renal haemodynamics during cisplatin nephrotoxicity.

  11. The peroxisome proliferator-activated receptor-γ agonist pioglitazone protects against cisplatin-induced renal damage in mice.

    Science.gov (United States)

    Jesse, Cristiano R; Bortolatto, Cristiani F; Wilhelm, Ethel A; Roman, Silvane Souza; Prigol, Marina; Nogueira, Cristina W

    2014-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1)  day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity.

  12. The Protective Effect of mammalian Target of Rapamycin (mTOR in Cisplatin Induced Nephropathy

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    Kultigin Turkmen

    2009-05-01

    Full Text Available "nCisplatin, a simple inorganic compound, has been one of the leading antitumor drugs especially for solid tumors for near 30 years. The mechanisms of cisplatin include denaturation of DNA and cell mitochondria, arresting cell cycle in the G2 phase and eventually causing apoptosis, inflammation, necrosis and death in cells. Apoptosis is a process of programmed cell death through cystein proteases named ‘caspases'. Pathways of caspase-mediated apoptosis can classified as ‘mitochondrial' pathway and ‘death receptor' pathway Especially caspase-3 plays a crucial role in cisplatin-induced nephrotoxicity through the pathways of apoptosis. The mammalian target of rapamycin (mTOR, is a serine/threonine kinase that regulates both cell growth and cell cycle progression through the phosphotidyl 3 kinase (PI3K/protein kinase B (Akt signaling pathway. mTOR regulates both cell growth, cell cycle progression and angiogenesis. By targeting mTOR, the immunsuppressant and antiproliferative agent Rapamycin inhibits signals required for cell cycle progression, cell growth, cell proliferation and angiogenesis. Angiogenesis is extremely important in tumor progression and metastasis. Although rapamycin is proapoptotic agent especially in cancers, there is an evidence that rapamycin can also have antiapoptotic properties through pleiotropic function in the regulation of cell death depending on the cell type and activation state as well as downstream targets of antiapoptotic molecules such as p53 and Bcl-2 proteins. Activation of caspase signaling pathways and dysregulation of pro- and antiapoptotic Bcl-2 proteins have been described previously. So there are links between the mTOR and caspase signaling pathways. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity such as acute tubuler necrosis (ATN causing acute renal failure (ARF. Several agents have been tested to see whether they could

  13. Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.

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    He, Jun; Yu, Jing-Jie; Xu, Qing; Wang, Lin; Zheng, Jenny Z; Liu, Ling-Zhi; Jiang, Bing-Hua

    2015-01-01

    Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin-resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

  14. Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death

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    Yde, Christina Westmose; Gyrd-Hansen, Mads; Lykkesfeldt, Anne E

    2007-01-01

    for future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells...... with parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment.......Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor-positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance...

  15. NEPHROPROTECTIVE ACTIVITY OF CYANOTIS FASCICULATA VAR., FASCICULATA AGAINST CISPLATIN INDUCED NEPHROTOXICITY

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    Murthy R.L.N

    2011-09-01

    Full Text Available Cisplatin is quite effective against various neoplastic diseases, but its potential nephrotoxicity leads to increased morbidity, complications and hospitalization costs. Prevention of nephrotoxicity may allow clinicians to administer higher doses for added therapeutic benefits. So, the present investigation was designed to evaluate the ability of the 70% hydro-alcoholic extract of Cyanotis fasciculata Var., fasciculata (CFEE to combat Cisplatin induced nephrotoxicity. Where, CFEE demonstrated dose dependent decrement of elevated biochemical markers of nephrotoxicity along with significant restoration of protective-GSH levels and suppression of LPO levels in tissues. Further, the remarkable renal-cellular rejuvenation found in histopathological studies also enunciated the organ protective activity of CFEE. It was concluded that, in addition to polyphenolics, some of the phyto-fragments found during GC-MS analysis might also contributed to the protection offered by CFEE.

  16. Long-term aerobic exercise protects against cisplatin-induced nephrotoxicity by modulating the expression of IL-6 and HO-1.

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    Mariana Yasue Saito Miyagi

    Full Text Available Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI. In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX. The group submitted to exercise before cisplatin administration (CIS-EX exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS. Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney.

  17. Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats.

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    Adeneye, A A; Benebo, A S

    2016-08-30

    Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

  18. Selective Cyclooxygenase-2 Inhibitor Prevents Cisplatin-induced Tumorigenesis in A/J Mice

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    Okada,Toshiaki

    2012-06-01

    Full Text Available Cisplatin is used to treat lung cancer;however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2 inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups:group 1, no treatment;group 2, low-dose celecoxib (150mg/kg;group 3, high-dose celecoxib (1,500mg/kg;group 4, cisplatin alone;group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62mg/kg, i.p. once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p<0.05, group 4 vs. group 6. Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p<0.01, group 4 vs. group 6.

  19. Cisplatin Induces Bmi-1 and Enhances the Stem Cell Fraction in Head and Neck Cancer

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    Carolina Nör

    2014-02-01

    Full Text Available Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs. These unique cells, named here cancer stem cells (CSCs, proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B cells and observed that cisplatin treatment increased (P = .0013 the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1 and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3 phosphorylation (indicative of stemness was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK phosphorylation (indicative of differentiation processes was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs

  20. Neural regulation of the kidney function in rats with cisplatin induced renal failure

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    Niamh E Goulding

    2015-06-01

    Full Text Available Aim: Chronic kidney disease (CKD is often associated with a disturbed cardiovascular homeostasis. This investigation explored the role of the renal innervation in mediating deranged baroreflex control of renal sympathetic nerve activity (RSNA and renal excretory function in cisplatin-induced renal failure.Methods: Rats were either intact or bilaterally renally denervated four days prior to receiving cisplatin (5mg/kg i.p. and entered a chronic metabolic study for 8 days. At day 8, other groups of rats were prepared for acute measurement of RSNA or renal function with either intact or denervated kidneys.Results: Following the cisplatin challenge, creatinine clearance was 50% lower while fractional sodium excretion and renal cortical and medullary TGF-β1 concentrations were 3-4 fold higher in both intact and renally denervated rats compared to control rats. In cisplatin-treated rats, the maximal gain of the high-pressure baroreflex curve was only 20% that of control rats, but not different from that of renally denervated control rats. Volume expansion reduced RSNA by 50% in control and in cisplatin-treated rats but only following bilateral renal denervation. The volume expansion mediated natriuresis/diuresis was absent in the cisplatin-treated rats but was normalised following renal denervation. Conclusions: Cisplatin-induced renal injury impaired renal function and caused a sympatho-excitation with blunting of high and low pressure baroreflex regulation of RSNA, which was dependent on the renal innervation. It is suggested that in man with CKD there is a dysregulation of the neural control of the kidney mediated by its sensory innervation.

  1. The impact of erdosteine on cisplatin-induced ototoxicity: a proteomics approach.

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    Waissbluth, Sofia; Garnier, Delphine; Akinpelu, Olubunmi V; Salehi, Pezhman; Daniel, Sam J

    2017-03-01

    Cisplatin is a commonly used chemotherapeutic agent and causes serious side effects, including progressive and irreversible hearing loss. No treatment is currently available for cisplatin-induced ototoxicity. We have previously demonstrated that erdosteine, a potent antioxidant, partially protected the cochlea against cisplatin toxicity in vivo. The aims of this study were to (1) evaluate the protein profiles of the cochlea following cisplatin administration and (2) evaluate the impact of erdosteine on the protein profile using a proteomics-based approach. Thirty Sprague-Dawley rats were injected intraperitoneally with saline (n = 10), cisplatin (n = 10) or with cisplatin and erdosteine (n = 10). The cisplatin dosage was 14 mg/kg and for erdosteine, 500 mg/kg. Following euthanasia, protein lysates were obtained from fresh-frozen cochleae and were processed for mass spectrometry and western blotting. We detected 445 proteins that exhibited a twofold change or greater in the cisplatin group as compared to the control group. Of these, 18 proteins showed a fourfold or greater change in expression associated with cisplatin administration, including ras-related protein Rab-2A, Rab-6A, cd81, ribosomal protein S5, and myelin basic protein, which were downregulated, while Ba1-647 and fibrinogen (alpha chain), amongst others, were upregulated. Co-administration of erdosteine revealed a reversal of these changes in the expression of ras-related protein Rab-2A, ribosomal protein S5, myelin basic protein, and fibrinogen (alpha chain); erdosteine also upregulated glutathione reductase. In this study, we identified various proteins that may play a role in cisplatin-induced ototoxicity. We also observed the changes resulting from co-treatment with an antioxidant.

  2. Effect of aqueous extract of Rheum ribes on cisplatin-induced nephrotoxicity in rat

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    Mousa-Al-Reza Hadjzadeh

    2013-01-01

    Full Text Available Objective: The purpose of the present study was to examine whether Rheum ribes extract prevents cisplatin-induced nephrotoxicity. Materials and Methods: The animals were divided into three groups: Group A considered as control group, group B were treated with cisplatin (3 mg/kg B.W. for 3 alternative days, and group C further to cisplatin received the aqueous extract of Rheum ribes (150 mg/rat. Results: Blood urea nitrogen (BUN level increased in group B on days 14 and 42 compared to day 0 ( P < 0.001; it was also increased in group B vs. group A on day 14 ( P < 0.001. Rheum ribes extract decreased the serum BUN level on day 14 compared to group B ( P < 0.001. Serum creatinine level in group B had a similar profile as serum BUN level but Rheum ribes had no effect on blood creatinine level. Serum cholesterol level was increased in group B on days 14 and 42 compared to day 0 ( P < 0.001. Also, cholesterol level was significantly increased in group B when compared to group A on day 14 ( P < 0.001. Rheum ribes decreased the blood cholesterol level on day 42 in comparison to group B ( P < 0.001. Serum glucose level was increased in group B on days 14 and 42 vs. day 0 ( P < 0.001. Also, glucose level was significantly increased in group B when compared to group A on day 42 ( P < 0.001. Rheum ribes increased the serum glucose level on days 14 and 42 compared to day 0 ( P < 0.05. Histology of kidneys exposed to cisplatin showed renal injury, but Rheum ribes had no effect on the kidney architecture. Conclusion: Cisplatin-induced nephrotoxicity was confirmed in our study. Although Rheum ribes had some effects on biochemical parameters; its effect on renal histology in injured kidney was insignificant.

  3. Ameliorative effect of Apodytes dimidiata on cisplatin-induced nephrotoxicity in Wistar rats.

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    Divya, Menon Kunnathully; Lincy, Lawrence; Raghavamenon, Achuthan Chathrattil; Babu, Thekkekara Devassy

    2016-10-01

    Context Nutraceuticals possessing antioxidant potential have been used to alleviate side effects exerted by many chemotherapeutics, including cisplatin. Since Apodytes dimidiata E. Mey. Ex Arn. (Icacinaceae) shows antioxidant potential, it may possess significant chemoprotective effects. Objectives The study investigated whether A. dimidiata could attenuate cisplatin-induced renal damage. Materials and methods Nephrotoxicity was induced by cisplatin (single i.p., 16 mg/kg b wt.) in Wistar rats. Methanolic leaf extract of A. dimidiata (AMF) was administered at a dose of 250 mg/kg b. wt. orally for 5 consecutive days before/after cisplatin administration. Blood and renal parameters were analysed. Total phenolic and flavonoid content in AMF and its NO scavenging effect was determined. Results Significant protective effect of AMF on cisplatin-induced nephrotoxicity was observed in pre-treated animals. The reduction of urea, creatinine and lipid peroxidation was 58.31%, 42.19% and 60%, respectively, and the increase in haemoglobin and leucocyte count was 28.25% and 42.91%, respectively. The increase calculated for GSH, GPx, SOD and catalase was 35.64%, 18.14%, 74.42% and 35.46%, respectively. Tissue architecture of kidney was almost normal in AMF treated animals. The results were comparable to the standard drug, silymarin. AMF contained high level of polyphenols and flavonoids and was found to scavenge NO radicals (IC50 121.8 μg/mL). Discussion and conclusion AMF can effectively counteract cisplatin mediated renal acute toxicity possibly by scavenging reactive oxygen and nitrogen species. Accordingly, the study suggests that AMF can ameliorate free radical-induced damage associated with chemotherapeutic drugs.

  4. Plant Responses to Nanoparticle Stress

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    Zahed Hossain

    2015-11-01

    Full Text Available With the rapid advancement in nanotechnology, release of nanoscale materials into the environment is inevitable. Such contamination may negatively influence the functioning of the ecosystems. Many manufactured nanoparticles (NPs contain heavy metals, which can cause soil and water contamination. Proteomic techniques have contributed substantially in understanding the molecular mechanisms of plant responses against various stresses by providing a link between gene expression and cell metabolism. As the coding regions of genome are responsible for plant adaptation to adverse conditions, protein signatures provide insights into the phytotoxicity of NPs at proteome level. This review summarizes the recent contributions of plant proteomic research to elaborate the complex molecular pathways of plant response to NPs stress.

  5. Attenuation of cisplatin-induced emetogenesis by standardized Bacopa monnieri extracts in the pigeon: behavioral and neurochemical correlations.

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    Ullah, Ihsan; Subhan, Fazal; Rudd, John A; Rauf, Khalid; Alam, Javaid; Shahid, Muhammad; Sewell, Robert D E

    2014-11-01

    Nausea and vomiting are the most distressing and common side effects of cancer chemotherapy which often result in patient noncompliance. In the present study, standardized methanolic and n-butanolic fractions of Bacopa monnieri were evaluated against cisplatin-induced emesis in the pigeon in relation to their activity on central and intestinal neurotransmitters levels. Cisplatin (7.0 mg/kg, i. v.) induced reproducible emesis without lethality in healthy pigeons. The methanolic (10-40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5-20 mg/kg), as well as the antioxidant N-(2-mercaptopropionyl) glycine (10 mg/kg), attenuated cisplatin-induced emesis by 66.3% (p bacoside-rich n-butanolic fractions might be a valuable adjunct in the treatment of emetogenic chemotherapy, and this warrants further study in other models of emesis.

  6. Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats.

    Science.gov (United States)

    Koçak, Hasan Emre; Taşkın, Ümit; Aydın, Salih; Oktay, Mehmet Faruk; Altınay, Serdar; Çelik, Duygu Sultan; Yücebaş, Kadir; Altaş, Bengül

    2016-12-01

    The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations

  7. Protection by ozone preconditioning is mediated by the antioxidant system in cisplatin-induced nephrotoxicity in rats

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    Enys Rojas

    1992-01-01

    Full Text Available Background: Acute renal failure is a dose-limiting factor of cisplatin chemotherapy. Here, we show the protective effect of ozone oxidative preconditioning against cisplatin-induced renal dysfunction in rats. Ozone oxidative preconditioning is a prophylactic approach, which favors the antioxidant–pro-oxidant balance for preservation of the cell redox state by increasing antioxidant endogenous systems in various in vivo and in vitro experimental models.

  8. Nephroprotective effect of vanillic acid against cisplatin induced nephrotoxicity in wistar rats: a biochemical and molecular study.

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    Sindhu, Ganapathy; Nishanthi, Emayavaramban; Sharmila, Ramalingam

    2015-01-01

    Cisplatin is one of the extensively used anticancer drugs against various cancers. Dosage dependent nephrotoxicity is the major problem in cisplatin chemotherapy. Cisplatin induced nephrotoxicity results in the depletion of renal antioxidant defence system. Our present study is aimed to investigate the nephroprotective effect of vanilic acid to against cisplatin induced nephrotoxicity in male wistar rats. Elevated levels of serum creatinine, blood urea nitrogen, serum uric acid and reduced antioxidant status were observed as indicatives of nephrotoxicity in cisplatin (7mg/kg bw) alone administered rats. Animals which are pre-treated with vanillic acid (50mg/kg and 100mg/kg) restored the elevated levels of renal function markers and reduced antioxidant status to near normalcy when compared to cisplatin alone treated animals. Cisplatin induced lipid peroxidation was markedly reduced by oral administration of vanillic acid at a high dose. The findings in the present study suggest that vanillic acid is a potential antioxidant that reduce cisplatin nephrotoxicity and can be as a combinatorial regimen in cancer chemotherapy.

  9. Effects of Korean ginseng root extract on cisplatin-induced emesis in a rat-pica model.

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    Raghavendran, Hanumantha Rao Balaji; Rekha, Sathyanath; Shin, Jang-Woo; Kim, Hyeong-Geug; Wang, Jing-Hua; Park, Hye-Jung; Choi, Min-Kyung; Cho, Jung-Hyo; Son, Chang-Gue

    2011-01-01

    In the present study, we investigate the effect of Korean ginseng root extract (KG) on cisplatin-induced pica in a rat model. Rats were treated with KG before (25, 50, and 100 mg/kg) or after (12.5, 25, and 50 mg/kg) a single intraperitoneal injection of cisplatin (7 and 6 mg/kg, respectively). We examined intake of kaolin and normal food as an indicator of the emetic stimulus every 24 h for 120 h. Changes in body weight, haematology and histopathology were additionally assessed. Pre-treatment with KG (25 and 50 mg/kg) significantly attenuated cisplatin-induced kaolin intake (24, 48, and 72 h) and markedly improved intake of normal food by rats at 48, 72, 96, and 120 h. Cisplatin-induced kaolin intake was markedly decreased upon post-treatment of rats with KG (12.5, 25, and 50 mg/kg) at 24 h. Notably, post-treatment with the lowest KG dose resulted in a significant anti-pica effect and improved food intake until 72 h. The magnitude of body weight reduction was significantly diminished in rats pre-treated/post-treated with 25, 50, and 12.5 mg/kg KG. The anti-pica effects of KG were further confirmed with haematological and histopathological findings. Our findings collectively indicate that KG improves the resistance of rats against emesis.

  10. Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines.

    Science.gov (United States)

    Mahmoud, Mona F; El Shazly, Shimaa M

    2013-01-01

    Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated. Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.

  11. Syzygium Cumini (L. Seeds Extract Ameliorates Cisplatin Induced Hepatotoxicity in Male Wistar Rats

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    R.Maheswari

    2015-02-01

    Full Text Available The discovery of cisplatin, cis-[Pt(II(NH(3(2Cl(2] ([PtCl2(NH32] or CDDP, was a corner stone which triggered the interest in platinum(II-and other metal-containing compounds as potential anticancer drugs. Cisplatin, is one of the most potent chemotherapy drugs widely used for cancer treatment. In our present study, an attempt has been made to study the effect of Cisplatin on biochemical and histopathological parameters and ameliorating effects of the Syzygium cumini (L. aqueous seeds extract or Eugena Jambolana in male wistar rats. Adult male wistar rats were divided into four different groups. Group I Served as vehicle treated normal saline (Control, Group II Rats received single intra-peritoneal (Ip injection of cisplatin (7mg/kg bw, Group III received Syzygium cumini (L. aqueous seeds extract 400mg/kg/bw orally for 7 days beginning one day prior to cisplatin (CP injection. Group IV Rats received alone Syzygium cumini (L. aqueous seeds extract (400mg/kg bw treated. Cisplatin exposure leads to adverse effects on hematological, hepatotoxic parameters including Erythrocytes (RBCs. Cisplatin induction leads to reduction in the levels of Enzymic and Non-Enzymic antioxidants levels. However, on treatment with Syzygium cumini (L. aqueous seeds extract normalized the levels of all the biochemical and hematological parameters. These findings highlight the efficacy of Syzygium cumini (L. aqueous seeds extract as protective effects Cisplatin induced hepatotoxicity.

  12. The Mechanism of Cisplatin-induced Apoptosis in HeLa Cells

    Institute of Scientific and Technical Information of China (English)

    Youqing Liu; Hui Xing; Xiaobing Han; Xiaoyan Shi; Fengqi Liang; Gang Chen; Ding Ma

    2005-01-01

    OBJECTIVE To study the mechanism of apoptosis induced by cisplatin in vitro in HeLa cells cervical cancer cell line.METHODS The inhibitory effect of cisplatin on HeLa cell growth was analyzed by the MTT assay. Cell apoptosis was measured with flow cytometry and Hoechst 33258 staining following cisplatin treatment. The effect of cisplatin on transcription of HPV E6 was analyzed by RT-PCR and protein expression of E6, P53, p21, Bax and Bcl-2 was studied by Western blots.RESULTS Cisplatin inhibited cellular proliferation in a time and dosedependant manner. The sub-G1 peak by flow cytometry showed a higher apoptotic rate in the experimental group compared to the controls and Hoechst 33258 staining indicated that apoptosis was induced by cisplatin. Results of RT-PCR demonstrated that cisplatin decreased transcription of E6. Western Blots showed that cisplatin decreased protein expression of E6 and increased protein expression of P53, p21 and Bax but had no effect on protein expression of Bcl-2.CONCLUSION Cisplatin induces apoptosis and death of HeLa cells through the suppression of HPV E6 and restoration of p53 function.

  13. Cisplatin-induced premature senescence with concomitant reduction of gap junctions in human fibroblasts

    Institute of Scientific and Technical Information of China (English)

    Wei ZHAO; Zhong Xiang LIN; Zhi Qian ZHANG

    2004-01-01

    To examine the role of gap junctions in cell senescence,the changes of gap junctions in cisplatin-induced premature senescence of primary cultured fibroblasts were studied and compared with the replicative senescent human fibroblasts.Dye transfer assay for gap junction function and immunofluorescent staining for connexin 43 protein distribution were done respectively. Furthermore,cytofluorimetry and DAPI fluorescence staining were performed for cell cycle and apoptosis analysis. p53 gene expression level was detected with indirect immunofluorescence. We found that cisplatin (10 mM) treatment could block cell growth cycle at G1 and induced premature senescence. The premature senescence changes included high frequency of apoptosis,elevation of p53 expression,loss of membranous gap junctions and reduction of dye-transfer capacity. These changes were comparable to the changes of replicative senescence of human fibroblasts. It was also concluded that cisplatin could induce premature senescence concomitant with inhibition of gap junctions in the fibroblasts. Loss of functional gap junctions from the cell membrane may account for the reduced intercellular communication in the premature senescent fibroblasts. The cell system we used may provide a model useful for the study of the gap junction thus promoting agents against premature senescence.

  14. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice.

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    Pernille Hojman

    Full Text Available Loss of muscle mass related to anti-cancer therapy is a major concern in cancer patients, being associated with important clinical endpoints including survival, treatment toxicity and patient-related outcomes. We investigated effects of voluntary exercise during cisplatin treatment on body weight, food intake as well as muscle mass, strength and signalling. Mice were treated weekly with 4 mg/kg cisplatin or saline for 6 weeks, and randomized to voluntary wheel running or not. Cisplatin treatment induced loss of body weight (29.8%, P < 0.001, lean body mass (20.6%, P = 0.001, as well as anorexia, impaired muscle strength (22.5% decrease, P < 0.001 and decreased glucose tolerance. In addition, cisplatin impaired Akt-signalling, induced genes related to protein degradation and inflammation, and reduced muscle glycogen content. Voluntary wheel running during treatment attenuated body weight loss by 50% (P < 0.001, maintained lean body mass (P < 0.001 and muscle strength (P < 0.001, reversed anorexia and impairments in Akt and protein degradation signalling. Cisplatin-induced muscular inflammation was not prevented by voluntary wheel running, nor was glucose tolerance improved. Exercise training may preserve muscle mass in cancer patients receiving cisplatin treatment, potentially improving physical capacity, quality of life and overall survival.

  15. Effect of free creatine therapy on cisplatin-induced renal damage.

    Science.gov (United States)

    Genc, Gurkan; Okuyucu, Ali; Meydan, Bilge Can; Yavuz, Oguzhan; Nisbet, Ozlem; Hokelek, Murat; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Abstract Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague-Dawley rats were divided into three groups: Group I: Cisplatin (n=20) (7 mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin+creatine monohydrate (n=20) (7 mg/kg cisplatin i.p. single dose and 300 mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n=20) (Serum physiologic, 2.5 mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (pcreatine significantly reversed kidney functions and pathological findings, this improvement was not sufficient to reach normal control group's results at days 7 and 30. In conclusion, the present study demonstrates that creatine administration is a promising adjuvant protective drug for reducing nephrotoxic effect of cisplatin.

  16. Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation.

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    Yong-Min Choi

    Full Text Available The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player.

  17. Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice

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    Hyojung Lee

    2013-01-01

    Full Text Available Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug. In the present study, we examined whether paeonol, a major compound of Moutan Cortex, has protective effects on cisplatin-induced acute renal failure in mice. To accomplish this, Balb/c mice (6 to 8 wk of age, weighing 20 to 25 g were administered, Moutan Cortex (300 mg/kg or paeonol (20 mg/kg once a day. At day 4, mice received cisplatin (30, 20, or 10 mg/kg intraperitoneally. The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of proinflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin.

  18. Amelioration of cisplatin induced nephrotoxicity in Swiss albino mice by Rubia cordifolia extract

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    Joy Jisha

    2008-01-01

    Full Text Available Background: Cisplatin is one of the most effective chemotherapeutics against a wide range of cancers including head, neck, ovarian and lung cancers. But its usefulness is limited by its toxicity to normal tissues, including cells of the kidney proximal tubule. The purpose of the present study is to investigate whether the hydro-alcoholic extract of Rubia cordifolia could decrease the intensity of toxicity in Swiss albino mice. Materials and Methods: Cisplatin at a dose of 12 mg/kg body wt was administered intraperitoneally to Swiss albino mice. Another set of animals was given hydro-alcoholic extract of Rubia cordifolia at different doses along with cisplatin treatment. The antioxidant levels, serum creatinine, serum urea etc. were analyzed. Results: The extract could significantly decrease the cisplatin induced nephrotoxicity as inferred from the tissue antioxidant status in the drug administered animals. Remarkable change was observed in serum creatinine and urea levels. Lipid peroxidation in the kidney and liver tissues was also considerably reduced in Rubia cordifolia extract treated animals. Conclusion: Hydro-alcoholic extracts of Rubia cordifolia are effective in reducing the renal damage caused by the cancer chemotherapeutic drug cisplatin. Since Rubia cordifolia has been in use as an important ingredient in the traditional Ayurvedic system of medicine, it could be safe and beneficial to use this herbal extract as an adjuvant to ameliorate renal damage in patients undergoing cancer chemotherapy with cisplatin.

  19. Cisplatin-induced testicular dysfunction and its amelioration by Launaea taraxacifolia leaf extract.

    Science.gov (United States)

    Adejuwon, S A; Femi-Akinlosotu, O M; Omirinde, J O

    2015-06-01

    This study investigates the ameliorative potential of Launea taraxacifolia (LT) aqueous leaf extract on cisplatin-induced testicular dysfunction in Wistar rats. Thirty rats were randomly divided into six groups (A-F) of 5 rats each: Group A which served as control received water; Group B was intraperitoneally (ip) injected 10 mg kg(-1) body wt cisplatin on day 21; Groups C and D were given 100 and 400 mg of LT via oral administration, respectively, for 21 days while Groups E and F received similar treatment as Groups C and D, respectively, and then exposed to ip administration of 10 mg kg(-1) body weight cisplatin on the 21st day. Exclusively, Cisplatin-exposed Group B rats showed reduced sperm characteristics and increased sperm morphological abnormalities; distorted histological architecture of seminiferous tubules; significantly increased lipid peroxidation (LPO) and decreased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH)levels in the testes. These parameters in LT alone treated Groups C and D were not markedly different compared with the control group. The rats with the combined treatment in Groups E and F showed significantly improved sperm parameters, testicular histo-architecture and antioxidant enzymatic activities. Conclusively, aqueous extract of L. taraxacifolia has protective potential against cisplatin damage.

  20. Science behind cisplatin-induced nephrotoxicity in humans:A clinical study

    Institute of Scientific and Technical Information of China (English)

    Arunkumar PA; Viswanatha GL; Radheshyam N; Mukund H; Belliyappa MS

    2012-01-01

    Objective: To investigate the relationship between serum electrolyte changes and cisplatin induced nephrotoxicity. Methods: We collected data from 18 patients undergoing cisplatin chemotherapy including serum electrolytes, creatinine, blood urea nitrogen (BUN) and urine potassium, sodium and pH levels before and after the cisplatin chemotherapy. All the patients had cancer and were treated with 40-50 mg/day cisplatin. Renal injury was assessed by measuring serum electrolytes, creatinine, BUN levels and urine potassium, sodium and pH levels.Results:The five cycles of cisplatin based chemotherapy resulted in hypomagnesia (P=0.029), hypocalcaemia (P=0.001*), hypophosphatemia (P=0.003*), hypokalemia (P=0.001*) and increased serum creatinine (P=0.001*) and BUN (P=0.292*) levels. In urine analysis, decrease in potassium (P=0.024*) was found, except potassium there was no significant changes in sodium and urine pH.Conclusions:The present study demonstrates that, acute nephrotoxicity was observed in patients with different types of cancers undergoing cisplatin based chemotherapy due to electrolyte disturbances, when no corrective measures were initiated.

  1. Eriodictyol attenuates cisplatin-induced kidney injury by inhibiting oxidative stress and inflammation.

    Science.gov (United States)

    Li, Cheng-zhen; Jin, Hai-hong; Sun, Hong-xin; Zhang, Zhong-zhe; Zheng, Jia-xin; Li, Shu-hua; Han, Seong-ho

    2016-02-05

    Eriodictyol, a flavonoid present in citrus fruits, has been reported to have antioxidant and anti-inflammatory effects. In this study, the protective effects of eriodictyol on cisplatin (CP)-induced kidney injury were detected. CP-induced kidney injury model was established by administration of CP (20mg/kg). The results showed that treatment of eriodictyol inhibited the production of blood urea nitrogen (BUN), creatinine, MDA, TBARS, reactive oxygen species (ROS), as well as the production of TNF-α, and IL-1β in kidney tissues induced by CP. Eriodictyol also up-regulated the activities of SOD, CAT, and GSH-PX decreased by CP. Furthermore, eriodictyol was found to up-regulate the expression of Nrf2/HO-1 and inhibited CP-induced NF-κB activation in kidney tissues. In conclusion, eriodictyol protected against CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation.

  2. C-phycocyanin prevents cisplatin-induced mitochondrial dysfunction and oxidative stress.

    Science.gov (United States)

    Fernández-Rojas, Berenice; Rodríguez-Rangel, Daniela Sarai; Granados-Castro, Luis Fernando; Negrette-Guzmán, Mario; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; Molina-Jijón, Eduardo; Reyes, José L; Zazueta, Cecilia; Pedraza-Chaverri, José

    2015-08-01

    The potential of C-phycocyanin (C-PC) to prevent cisplatin (CP)-induced kidney mitochondrial dysfunction was determined in CD-1 male mice. The CP-induced mitochondrial dysfunction was characterized by ultrastructural abnormalities and by decrease in the following parameters in isolated kidney mitochondria: adenosine diphosphate (ADP)-induced oxygen consumption (state 3), respiratory control ratio, ADP/oxygen (ADP/O) ratio, adenosine triphosphate synthesis, membrane potential, calcium retention, glutathione (GSH) content, and activity of respiratory complex I, aconitase, catalase, and GSH peroxidase. These mitochondria also showed increase in hydrogen peroxide production, malondialdehyde, and 3-nitrotyrosine protein adducts content. The above-described changes, as well as CP-induced nephrotoxicity, were attenuated in mice pretreated with a single injection of C-PC. Our data suggest that the attenuation of mitochondrial abnormalities is involved in the protective effect of C-PC against CP-induced nephrotoxicity. This is the first demonstration that C-PC pretreatment prevents CP-induced mitochondrial dysfunction in mice.

  3. Subjective Stress, Salivary Cortisol, and Electrophysiological Responses to Psychological Stress

    OpenAIRE

    Qi, Mingming; Gao, Heming; Guan, Lili; Liu, Guangyuan; Yang, Juan

    2016-01-01

    The present study aimed to investigate the subjective stress, salivary cortisol, and electrophysiological responses to psychological stress induced by a modified version of a mental arithmetic task. Fifteen participants were asked to estimate whether the multiplication product of two-decimal numbers was above 10 or not either with a time limit (the stress condition) or without a time limit (the control condition). The results showed that participants reported higher levels of stress, anxiety,...

  4. Fetal kidney stem cells ameliorate cisplatin induced acuterenal failure and promote renal angiogenesis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    AIM To investigate whether fetal kidney stem cells(fKSC) ameliorate cisplatin induced acute renal failure(ARF) in rats and promote renal angiogenesis.METHODS: The fKSC were isolated from rat fetusesof gestation day 16 and expanded in vitro up to 3rdpassage. They were characterized for the expressionof mesenchymal and renal progenitor markers by flowcytometry and immunocytochemistry, respectively.The in vitro differentiation of fKSC towards epitheliallineage was evaluated by the treatment with specificinduction medium and their angiogenic potential bymatrigel induced tube formation assay. To study theeffect of fKSC in ARF, fKSC labeled with PKH26 wereinfused in rats with cisplatin induced ARF and, the bloodand renal tissues of the rats were collected at differenttime points. Blood biochemical parameters werestudied to evaluate renal function. Renal tissues wereevaluated for renal architecture, renal cell proliferationand angiogenesis by immunohistochemistry, renal cellapoptosis by terminal deoxynucleotidyl transferase nickendlabeling assay and early expression of angiogenicmolecules viz . vascular endothelial growth factor (VEGF),hypoxia-inducible factor (HIF)-1α and endothelial nitricoxide synthase (eNOS) by western blot.RESULTS: The fKSC expressed mesenchymal markersviz . CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz . Wt1, Pax2 and Six2. Theyexhibited a potential to form CD31 and Von Willebrandfactor expressing capillary-like structures and could bedifferentiated into cytokeratin (CK)18 and CK19 positiveepithelial cells. Administration of fKSC in rats with ARF ascompared to administration of saline alone, resulted in asignificant improvement in renal function and histology onday 3 (2.33 ± 0.33 vs 3.50 ± 0.34, P 〈 0.05) and on day7 (0.83 ± 0.16 vs 2.00 ± 0.25, P 〈 0.05). The infusedPKH26 labeled fKSC were observed to engraft in damagedrenal tubules and showed increased proliferation andreduced

  5. Rikkunshito, a traditional Japanese medicine, suppresses cisplatin-induced anorexia in humans

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    Ohno T

    2011-12-01

    Full Text Available Tetsuro Ohno, Mitsuhiro Yanai, Hiroyuki Ando, Yoshitaka Toyomasu, Atsushi Ogawa, Hiroki Morita, Kyoichi Ogata, Erito Mochiki, Takayuki Asao, Hiroyuki KuwanoDepartment of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, JapanBackground: The aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans.Methods: The study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5 was started on Rikkunshito (2.5 g three times daily, orally from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5. All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin.Results: In the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period.Conclusion: Rikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule.Keywords: Rikkunshito, cisplatin, ghrelin, anorexia, stomach cancer

  6. Modulation of Nrf2/HO-1 by Thymoquinone During Cisplatin-Induced Nephrotoxicity

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    Ramazan ULU

    2013-05-01

    Full Text Available OBJECTIVE: Side effects of cisplatin, such as nephrotoxicity, limit its use in chemotherapeutic regimens and indicate an agent that suppresses its toxicity. Thymoquinone (TQ, the predominant bioactive constituent present in black seed oil (Nigella sativa, has antiinfl ammatory, antioxidant and antitumor effects. We propose a protective mechanism of of TQ on cisplatin-nephrotoxicity in rats that is through modulation of Nrf2-mediated antioxidant induction and reduced inflammation. MATERIAL and METHODS: Twenty-eight male Wistar rats (8 weeks-old were divided into four groups; Control (vehicle; 0.9% saline, 1 ml/kg body wt., p.o., TQ (10 mg/kg body weight/day in drinking water for 5 days, cisplatin (a single injection of 7mg/kg body wt, i.p. and TQ for 5 days in drinking water then a single injection of cisplatin. On day 10, all rats were sacrificed by cervical dislocation, kidneys were removed, and serum urea and creatinine were collected. RESULTS: Serum urea and creatinine levels were significantly higher in cisplatin-treated rats compared with control rats. TQ-treatment significantly decreased serum urea and creatinine levels. Cisplatin-treatment caused significant downregulation of the nuclear NF-E2-related factor-2 (Nrf2, heme oxygenase-1(HO-1 and caused an increase in the levels of nuclear factor-kappa B (NF-κB. Interestingly, TQ supplementation significantly improved the changes associated with cisplatin nephrotoxicity by increasing the levels of Nrf-2 and HO-1 and decreasing the levels of NF-κB. CONCLUSION: This study demonstrates the TQ targets NRF2/HO-1 and can be used as a potential agent against cisplatin-induced nephrotoxicity.

  7. Hepatoprotective effect of Ficus religiosa latex on cisplatin induced liver injury in Wistar rats

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    Yogesh C. Yadav

    2015-06-01

    Full Text Available AbstractFicus religiosa L., Moraceae, is widely planted in the tropics. The chemical constituents of F. religiosa include tannin, saponin gluanol acetate, β-sitosterol, leucoanthocyanidin, and leucoanthocyanin. These are used for the treatment of pain, inflammation, impotence, menstrual disturbances, and urine related problems, and as uterine tonic. The present study aimed to evaluate hepatoprotective effects of F. religiosa latex on cisplatin induced liver injury in Wistar rats. In experimental protocol contained five groups of rats (n = 6. In which, group I (control was administered acacia (2%, w/v of 5 ml/kg throughout the experiment for 16 days. The group II (cisplatin treated was administered single dose of cisplatin (7.5 mg/kg i.p. on 1st day. Group III (extract control was administered 300 mg/kg p.o. of extract for 1stto 10th day. Group IV (Protective was administered extract (300 mg/kg p.o. of F. religiosa latex for 1st to 10th day and administered single dose of cisplatin (7.5 mg/kg i.p. on 11th day and group V (Curative received single dose of cisplatin (7.5 mg/kg i.p. on day 1st, and administered extract (300 mg/kg p.o. from 7th to 16thdays. On the 6th day in cisplatin treated, 10th day in extract control and 16th day in control, protective and curative, blood withdrawn from retro-orbital sinus of rats for biochemical estimation for serum and dissected out the livers for estimation of antioxidant enzymes and histopathological works. The cisplatin-treated group 2 showed a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and hepatocytes cells degeneration inflammatory infiltrate and necrosis it's were significantly (**p < 0.01 alleviates by protective groups.

  8. ATP sensitizes H460 lung carcinoma cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Swennen, Els L R; Ummels, Vanessa; Buss, Irina; Jaehde, Ulrich; Bast, Aalt; Dagnelie, Pieter C

    2010-03-30

    Platinum resistance of cancer cells may evolve due to a decrease in intracellular drug accumulation, decreased cell permeability or by an increased deactivation of the drug by glutathione (GSH). The aim of this study was (1) to investigate the effect of adenosine 5'-triphosphate (ATP) on the cytotoxicity of cisplatin in a large cell lung carcinoma cell line (H460), and (2) to examine the potential involvement of increased cisplatin uptake, GSH depletion and pyrimidine starvation by ATP in this effect. H460 cells were harvested and seeded (5% CO(2); 37 degrees C). Subsequently, cells were incubated with medium or ATP followed by an incubation with cisplatin. Cytotoxicity screening was analyzed by the sulforhodamine B (SRB) colorimetric assay, lactate dehydrogenase and caspase-3/7 activity. Pre-incubation for 72h with 0.3 and 3mM ATP strongly enhanced the anti-proliferative potency of cisplatin 2.9- and 7.6-fold, respectively. Moreover, after incubation of H460 cells with 0.3mM ATP the intracellular platinum concentration increased, indicating increased cisplatin uptake by ATP. ATP, despite lowering the LD(50) of cisplatin, did not modulate GSH levels in H460 cells. ATP itself showed a biphasic effect on H460 cell growth: 0.3mM inhibited H460 cell growth via the pyrimidine starvation effect, activation of caspase-3/7 and LDH leakage, while 3mM ATP showed no effect on cell growth. In conclusion, ATP sensitizes the H460 cells to cisplatin-induced apoptosis. The effect of 0.3mM ATP is not due to GSH depletion but involves increased cisplatin uptake and pyrimidine starvation due to ATP conversion to adenosine followed by cellular uptake.

  9. Protective effect of riboflavin on cisplatin induced toxicities: a gender-dependent study.

    Science.gov (United States)

    Naseem, Imrana; Hassan, Iftekhar; Alhazza, Ibrahim M; Chibber, Sandesh

    2015-01-01

    The toxicity exerted by the anticancer drug, cisplatin in vivo is functional to many factors such as dose, duration, gender and age etc. The present study is aimed to investigate if ameliorative potential of riboflavin on cisplatin induced toxicity is gender dependent. Eighty four adult mice from male and female sex were divided into seven groups (n=6) for both sexes. They were treated with riboflavin (2mg/kg), cisplatin (2mg/kg) and their two different combinations (cisplatin at 2mg/kg with 1mg/kg and 2mg/kg of riboflavin) under photoillumination with their respective controls for the combination groups without photoillumination. After treatment, all groups were sacrificed and their kidney, liver and serum were collected for biochemical estimations, comet assay and histopathology. In the present investigation, it was evident from antioxidant and detoxification studies (SOD, CAT, GSH, GST, MDA and carbonyl level) that the female mice exhibited better tolerance towards cisplatin inducted toxicity and the ameliorative effect of riboflavin against cisplatin toxicity was found stronger in their combination groups as compared to the male groups as the activity of all antioxidant enzymes were found better concomitant with lower level of MDA and carbonyl contents in the female combination groups than their male counterparts. Furthermore, single cell gel electrophoresis and histopathological examination confirmed that restoration of normal nuclear and cellular integrity was more prominent in female with respect to the males after treatment in the combination groups in a dose-dependent manner. Hence, this study reveals that cisplatin is more toxic in male mice and the ameliorative effect of riboflavin against cisplatin toxicity is stronger in female mice.

  10. Agreeableness, Extraversion, Stressor and Physiological Stress Response

    OpenAIRE

    Xiaoyuan Chu; Zhentao Ma; Yuan Li; Jing Han

    2015-01-01

    Based on the theoretical analysis, with first-hand data collection and using multiple regression models, this study explored the relationship between agreeableness, extraversion, stressor and stress response and figured out interactive effect of agreeableness, extraversion, and stressor on stress response. We draw on the following conclusions: (1) the interaction term of stressor (work) and agreeableness can negatively predict physiological stress response; (2) the interaction term of stresso...

  11. Neuronal responses to physiological stress

    DEFF Research Database (Denmark)

    Kagias, Konstantinos; Nehammer, Camilla; Pocock, Roger David John

    2012-01-01

    Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged ...

  12. The Effects of Pretreatment with Various Doses of L-Arginine on Cisplatin-Induced Nephropathy of Male Rats

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    B Rasoulian

    2016-09-01

    Full Text Available Introduction: Cisplatin is a widely used anti-cancer drug, which its application is limited by nephrotoxicity. In this study, the effect of pretreatment with different l-arginine doses on Cisplatin-induced renal functional injury was investigated. Methods: 63 male rats were divided into 7 groups: In groups 3, 4, 5 and 6, 60 min before the Cisplatin injection (5mg/kg; L-Arginine with doses of 50,100,200 or 400mg/kg was injected, respectively. In group7, normal saline was injected before Cisplatin administration. In groups 1 and 2, normal saline was injected instead of Cisplatin. In group 2, 60min before normal saline injection, 400mg/kg L-Arginine was administered and in group1, instead of L-arginine, normal saline was injected too. Injections were intraperitoneal. 72h after Cisplatin injection, blood sampling and plasma separation were done. Urine sample was collected 24 hours before blood sampling by metabolic cage. The mean of plasma urea and creatinine levels and creatinine clearance (ml/day.kg and fractional excretion of Na (FENa, % were compared among different groups as renal functional parameters. Results: In comparison to group 7, L-arginine injection in a dose of 400mg/kg led to significant amelioration of all parameters. 200 mg/kg L-arginine administration led to significant decrease in plasma urea level and FENa. 100mg/kg L-arginine caused significant improvement in fractional excretion of sodium. L-arginine injection with 50mg/kg dose, significantly ameliorate all renal function tests instead of creatinine clearance. Conclusion: Pretreatment with L-arginine administration with 400 or 50 mg/kg doses, respectively, had the highest effect on reducing Cisplatin-induced nephropathy. L-arginine injection with intermediate doses i.e. 200 or 100 mg/kg had less effect in reducing Cisplatin-induced nephropathy and it needs more investigations.

  13. Stress responses and pre-eclampsia.

    Science.gov (United States)

    Redman, C W G

    2013-04-01

    Biological stress may affect individual cells, tissues or whole organisms, arising from disturbed homoeostasis of any cause. Stress is rarely localised. Because biological systems are closely integrated, it spreads to involve other systems. Stress responses are highly integrated and work to restore homoeostasis. Different response pathways overlap and interlink. If the responses fail or decompensate, distress ensues, of which the end-stage is death. Pre-eclampsia results from a series of biological stresses, possibly from conception, which become established by abnormal placentation and affect the mother, her foetus and her placenta. The stresses involve dialogue between mother and placenta. Even a normal placenta imposes substantial stress on maternal systems. When placental growth and perfusion is abnormal (poor placentation) then the placenta, particularly its outer trophoblast layer, becomes stressed - loosely denoted hypoxic damage or oxidative stress. Signals from the placenta spread the stress to the mother, who develops signs of pre-eclampsia. Cellular stress sensors initiate stress responses. Different stresses may trigger similar responses in specific cell types. The first cell response is reduced protein synthesis. However some synthetic pathways are spared or activated to produce stress signals. In relation to pre-eclampsia and the placenta, an excessive release of sFlt-1 a soluble decoy receptor for vascular endothelial growth factor (VEGF) is a trophoblast related stress signal. SFlt1 perturbs the angiogenic balance in the maternal circulation and is considered to cause many of the specific features of the maternal syndrome in pre-eclampsia. Three key points will be emphasised. First, multiple stressors, not simply hypoxia, stimulate the release of sFlt-1 from trophoblast. Second, sFlt-1 is only one of the group of stress signals delivered by trophoblast to the mother. Third, sFlt-1 is not the only trophoblast derived factor to perturb the maternal

  14. Oxidative stress response in sugarcane

    Directory of Open Access Journals (Sweden)

    Luis Eduardo Soares Netto

    2001-12-01

    Full Text Available Oxidative stress response in plants is still poorly understood in comparison with the correspondent phenomenon in bacteria, yeast and mammals. For instance, nitric oxide is assumed to play various roles in plants although no nitric oxide synthase gene has yet been isolated. This research reports the results of a search of the sugarcane expressed sequence tag (SUCEST database for homologous sequences involved in the oxidative stress response. I have not found any gene similar to nitric oxide synthase in the SUCEST database although an alternative pathway for nitric oxide synthesis was proposed. I have also found several genes involved in antioxidant defense, e.g. metal chelators, low molecular weight compounds, antioxidant enzymes and repair systems. Ascorbate (vitamin C is a key antioxidant in plants because it reaches high concentrations in cells and is a substrate for ascorbate peroxidase, an enzyme that I found in different isoforms in the SUCEST database. I also found many enzymes involved in the biosynthesis of low molecular weight antioxidants, which may be potential targets for genetic manipulation. The engineering of plants for increased vitamin C and E production may lead to improvements in the nutritional value and stress tolerance of sugarcane. The components of the antioxidant defense system interact and their synthesis is probably closely regulated. Transcription factors involved in regulation of the oxidative stress response in bacteria, yeast and mammals differ considerably among themselves and when I used them to search the SUCEST database only genes with weak similarities were found, suggesting that these transcription regulators are not very conserved. The involvement of reactive oxygen species and antioxidants in plant defense against pathogens is also discussed.A resposta ao estresse oxidativo não é bem conhecida em plantas como em bactérias, leveduras e humanos. Por exemplo, assume-se que óxido nítrico tem várias fun

  15. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qing [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Guo, Dong [Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Dong, Zhongqi [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Zhang, Wei [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Institute of Clinical Pharmacology, Central South University, Hunan 410078 (China); Zhang, Lei; Huang, Shiew-Mei [Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD (United States); Polli, James E. [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States); Shu, Yan, E-mail: yshu@rx.umaryland.edu [Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)

    2013-11-15

    The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT{sub 3}) receptor antagonists, such as ondansetron, should be investigated in patients. - Highlights: • Nephrotoxicity significantly limits clinical use of the chemotherapeutic

  16. SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Sang Yong [Department of Diagnostic Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Han, Myung Kwan [Department of Microbiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kim, Duk Hoon [Division of Forensic Medicine, National Forensic Service, Seoul (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

  17. Assessment of the possible role of iron and copper in cisplatin-induced nephrotoxicity in the rat.

    Science.gov (United States)

    Goudie, J; Chandra, M; Lawrence, G D; Williams, P

    1994-01-01

    Nephrotoxic lesions induced by cisplatin in rats are characterized by acute tubular necrosis in the outer stripe of the medulla. The purpose of this study was to examine the potential role of changes in metal binding proteins, and iron and copper content in urine and renal tissue in cisplatin-induced nephrotoxicity. Cisplatin was administered intravenously to groups of 20 rats at single doses of 0, 1, 2.5, and 5 mg/kg and rats were sacrificed at 1, 2, 3 and 6 days after treatment. Increased serum BUN and creatinine were observed at a dose of 5 mg/kg cisplatin on day 2 through day 6. Increased urinary copper excretion coincided with necrosis and increased BUN and creatinine on day 3 in the high-dose group. Evidence of renal injury was apparent histologically as karyomegaly at all dose levels as early as 48 hours after injection of cisplatin, prior to increases in urinary copper levels. No change in the distribution of metal binding proteins (transferrin, ferritin, ceruloplasmin, and metallothionein) evaluated by immunohistochemical staining, was seen. Based upon these results, it is unlikely that changes in metal excretion play a primary role in cisplatin-induced nephrotoxicity however, changes in nuclear function indicated by karyomegaly may be involved in early renal injury.

  18. Bee Venom Mitigates Cisplatin-Induced Nephrotoxicity by Regulating CD4+CD25+Foxp3+ Regulatory T Cells in Mice

    Directory of Open Access Journals (Sweden)

    Hyunseong Kim

    2013-01-01

    Full Text Available Cisplatin is used as a potent anticancer drug, but it often causes nephrotoxicity. Bee venom (BV has been used for the treatment of various inflammatory diseases, and its renoprotective action was shown in NZB/W mice. However, little is known about whether BV has beneficial effects on cisplatin-induced nephrotoxicity and how such effects might be mediated. In the present study, the BV-injected group showed a significant increase in the population of Tregs in spleen. Although there was no significant difference in the numbers of Tregs 3 days after cisplatin injection between the BV- and PBS-injected groups, more migration of Tregs into the kidney was observed 6 hours after cisplatin administration in BV group than in PBS group. In addition, BV-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, proinflammatory cytokines, and macrophage infiltration into the kidney 3 days after cisplatin administration. These renoprotective effects were abolished by the depletion of Tregs. The anticancer effect of repeated administrations of cisplatin was not affected by BV injection. These results suggest that BV has protective effects on cisplatin-induced nephrotoxicity in mice, at least in part, through the regulation of Tregs without a big influence on the antitumor effects of cisplatin.

  19. miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer.

    Science.gov (United States)

    Lin, Jiong; Lin, Yao; Fan, Li; Kuang, Wei; Zheng, Liwei; Wu, Jiahua; Shang, Peng; Wang, Qiaofeng; Tan, Jiali

    2016-04-29

    Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3'UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR-203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC.

  20. Prevention of cisplatin induced nephrotoxicity by terpenes isolated from Ganoderma lucidum occurring in Southern Parts of India.

    Science.gov (United States)

    Pillai, Thulasi G; John, Mathew; Sara Thomas, Gifty

    2011-01-01

    Investigations were carried out to determine the protective effect of terpenes isolated from the fruiting bodies of Ganoderma lucidum (Fr) P.Karst against nephrotoxicity caused by the cisplatin, in mice. Intraperitoneal administration of cisplatin (16 mg/kg body wt) resulted in significant nephrotoxicity in mice. Serum urea, creatinine and ALP levels were drastically elevated indicating severe nephrotoxicity . The renal antioxidant defense system such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and concentration of reduced glutathione (GSH) were depleted by cisplatin injection. The oral administration of terpenes at a dose of 100mg/kg body weight prevented increase in urea, creatinine levels and ALP activity and also maintained the renal antioxidant defense. The Ganoderma terpenes also imparted protection against cisplatin induced renal tissue lipid peroxidation. The results indicated that the total terpenes isolated from G. lucidum possessed significant in vivo antioxidant activity and rendered protection against cisplatin induced nephrotoxicity. The results suggest the potential therapeutic use of Ganoderma terpenes to prevent nephrotoxicity caused during chemotherapy using cisplatin.

  1. Abiotic stressors and stress responses

    DEFF Research Database (Denmark)

    Sulmon, Cecile; Van Baaren, Joan; Cabello-Hurtado, Francisco

    2015-01-01

    Abstract Organisms are regularly subjected to abiotic stressors related to increasing anthropogenic activities, including chemicals and climatic changes that induce major stresses. Based on various key taxa involved in ecosystem functioning (photosynthetic microorganisms, plants, invertebrates), ...

  2. Process Control Minitoring by Stress Response

    Energy Technology Data Exchange (ETDEWEB)

    Hazen, Terry C.; Stahl, David A.

    2006-04-17

    Environmental contamination with a variety of pollutants hasprompted the development of effective bioremediation strategies. But howcan these processes be best monitored and controlled? One avenue underinvestigation is the development of stress response systems as tools foreffective and general process control. Although the microbial stressresponse has been the subject of intensive laboratory investigation, theenvironmental reflection of the laboratory response to specific stresseshas been little explored. However, it is only within an environmentalcontext, in which microorganisms are constantly exposed to multiplechanging environmental stresses, that there will be full understanding ofmicrobial adaptive resiliency. Knowledge of the stress response in theenvironment will facilitate the control of bioremediation and otherprocesses mediated by complex microbial communities.

  3. Stress, stress-induced cortisol responses, and eyewitness identification performance.

    Science.gov (United States)

    Sauerland, Melanie; Raymaekers, Linsey H C; Otgaar, Henry; Memon, Amina; Waltjen, Thijs T; Nivo, Maud; Slegers, Chiel; Broers, Nick J; Smeets, Tom

    2016-07-01

    In the eyewitness identification literature, stress and arousal at the time of encoding are considered to adversely influence identification performance. This assumption is in contrast with findings from the neurobiology field of learning and memory, showing that stress and stress hormones are critically involved in forming enduring memories. This discrepancy may be related to methodological differences between the two fields of research, such as the tendency for immediate testing or the use of very short (1-2 hours) retention intervals in eyewitness research, while neurobiology studies insert at least 24 hours. Other differences refer to the extent to which stress-responsive systems (i.e., the hypothalamic-pituitary-adrenal axis) are stimulated effectively under laboratory conditions. The aim of the current study was to conduct an experiment that accounts for the contemporary state of knowledge in both fields. In all, 123 participants witnessed a live staged theft while being exposed to a laboratory stressor that reliably elicits autonomic and glucocorticoid stress responses or while performing a control task. Salivary cortisol levels were measured to control for the effectiveness of the stress induction. One week later, participants attempted to identify the thief from target-present and target-absent line-ups. According to regression and receiver operating characteristic analyses, stress did not have robust detrimental effects on identification performance. Copyright © 2016 John Wiley & Sons, Ltd. © 2016 The Authors Behavioral Sciences & the Law Published by John Wiley & Sons Ltd.

  4. Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects.

    NARCIS (Netherlands)

    Verschraagen, M.; Boven, E.; Torun, E; Hausheer, FH; Vijgh, van der WJ

    2004-01-01

    Disodium 2,2'-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo intracellul

  5. Post-treatment effects of erythropoietin and nordihydroguaiaretic acid on recovery from cisplatin-induced acute renal failure in the rat.

    Science.gov (United States)

    Lee, Dong Won; Kwak, Ihm Soo; Lee, Soo Bong; Song, Sang Heon; Seong, Eun Young; Yang, Byeong Yun; Lee, Min Young; Sol, Mee Young

    2009-01-01

    5-lipoxygenase inhibitor and human recombinant erythropoietin might accelerate renal recovery in cisplatin-induced acute renal failure rats. Male Sprague-Dawley rats were randomized into four groups: 1) normal controls; 2) Cisplatin group-cisplatin induced acute renal failure (ARF) plus vehicle treatment; 3) Cisplatin+nordihydroguaiaretic acid (NDGA) group-cisplatin induced ARF plus 5-lipoxygenase inhibitor treatment; 4) Cisplatin+erythropoietin (EPO) group-cisplatin induced ARF plus erythropoietin treatment. On day 10 (after 7 daily injections of NDGA or EPO), urea nitrogen and serum Cr concentrations were significantly lower in the Cisplatin+NDGA and Cisplatin+EPO groups than in the Cisplatin group, and 24 hr urine Cr clearances were significantly higher in the Cisplatin+EPO group than in the Cisplatin group. Semi-quantitative assessments of histological lesions did not produce any significant differences between the three treatment groups. Numbers of PCNA(+) cells were significantly higher in Cisplatin, Cisplatin+NDGA, and Cisplatin+EPO groups than in normal controls. Those PCNA(+) cells were significantly increased in Cisplatin+NDGA group. These results suggest that EPO and also NDGA accelerate renal function recovery by stimulating tubular epithelial cell regeneration.

  6. Antrodia cinnamomea alleviates cisplatin-induced hepatotoxicity and enhances chemo-sensitivity of line-1 lung carcinoma xenografted in BALB/cByJ mice.

    Science.gov (United States)

    Huang, Tse-Hung; Chiu, Yi-Han; Chan, Yi-Lin; Wang, Hang; Li, Tsung-Lin; Liu, Chien-Yin; Yang, Cheng-Ta; Lee, Tzung-Yan; You, Jyh-Sheng; Hsu, Kuang-Hung; Wu, Chang-Jer

    2015-09-22

    Whereas cisplatin (cis-diamminedichloroplatinum II) is a first-line medicine to treat solid cancerous tumors, it often causes serious side effects. New medicines that have an equivalent or even better therapeutic effect but with free or less side effects than cisplatin are highly anticipated in cancer therapy. Recent reports revealed that Antrodia cinnamomea (AC) possesses hepatoprotective activity in addition to anticancer. In this study, we wanted to know whether AC enhances chemo-sensitivity of cisplatin and/or alleviates cisplatin-induced hepatotoxicity, as well as the underlying mechanisms thereof. Our results indicated that AC inhibited proliferation of line-1 lung carcinoma cells and rescued hepatic HepG2 cells from cisplatin-induced cell death in vitro. The fact is that AC and cisplatin synergized to constrain growth of line-1 lung carcinoma cells in BALB/cByJ mice. Quantitative real-time PCR further revealed that AC promoted expression of apoptosis-related genes, while it decreased expression of NF-κB and VEGF in tumor tissues. In liver, AC reduced cisplatin-induced liver dysfunctions, liver inflammation and hepatic apoptosis in addition to body weight restoration. In summary, AC is able to increase cisplatin efficacy by triggering expression of apoptosis-related genes in line-1 lung cancer cells as well as to protect liver from tissue damage by avoiding cisplatin-induced hepatic inflammation and cell death.

  7. Protective effect of curcumin and vitamin C each alone and in combination on cisplatin-induced sperm abnormalities in male albino rats

    Directory of Open Access Journals (Sweden)

    Sabha Elsayed Elballat

    2016-08-01

    The results of the present investigation concluded that the combination between curcumin and vitamin C in cisplatin treatment afforded the best ameliorative effect on cisplatin induced sperm shape abnormalities. This may be due to the synergistic effect between curcumin and vitamin C as both of them have antioxidant properties which in turn lead to repairing of sperm abnormalities.

  8. Protective efficacy of antioxidants on cisplatin-induced tissue damage caused in Leishmania donovani infected BALB/c mice against murine visceral leishmaniasis

    Directory of Open Access Journals (Sweden)

    Meenakshi Sharma

    2013-06-01

    Full Text Available Objective: Therapeutic interventions against visceral leishmaniasis (VL are limited and facing serious concerns of toxicity, high cost and emerging resistance, there is a greater interest in new drug developments which are cost effective, efficient and easily available to people suffering from leishmaniasis. Cisplatin (cis-diamminedichloroplatinum II; CDDP has been found to have antileishmanial activity in vitro and in vivo which lead towards an apoptosis like cell death of both promastigotes and amastigotes and a significant reduction in parasite load and enhanced DTH responses which suggested the generation of protective cell-mediated immune responses. But, at higher doses it causes nephrotoxicity-a major side effect. The present study was designed to evaluate the protective efficacy of antioxidants on cisplatin induced tissue damage in Leishmania donovani infected BALB/c mice. Materials and methods: L. donovani infected and uninfected animals were treated with higher doses (5 and 2.5 mg/kg body weight of cisplatin alone and in combination with antioxidants (vitamin C, vitamin E and silibinin for 5 days. Mice were examined for the protective effects of antioxidants on cisplatin indiced tissue damage by DNA fragmentation and histological studies of kidneys, liver and spleen. Results: The damage caused by cisplatin was ameliorated after the supplementation of antioxidants showing a marked reduction in the extent of tubular damage, the focal reaction changes in liver were reversed and no signs of toxicity in the spleen were reported. Moreover, no DNA damage was observed in animals treated with cisplatin along with various antioxidants. Conclusion: The present results showed that antioxidants helped in the amelioration of drug induced toxic effects against murine visceral leishmaniasis, making the combination a potential anti-leishmanial therapy. [J Interdiscipl Histopathol 2013; 1(3.000: 121-136

  9. Amelioration of cisplatin-induced nephrotoxicity by ethanolic extract of Bauhinia purpurea: An in vivo study in rats.

    Science.gov (United States)

    Rana, Md Azmat; Khan, Rahat Ali; Nasiruddin, Mohammad; Khan, Aijaz Ahmed

    2016-01-01

    Our objective is to study the nephroprotective activity and antioxidant potential of Bauhinia purpurea unripe pods and bark against cisplatin-induced nephrotoxicity. Healthy adult albino rats of either sex (150-200 g) were randomly divided into six groups of six animals each Group I (vehicle control) and Group II (negative control). Group III (BBE200) and Group IV (BBE400) were administered the ethanolic extract of Bauhinia purpurea bark in doses of 200 and 400 mg/kg/day p.o., respectively, and Group V (BPE200) and Group VI (BPE400) were administered the ethanolic extract of Bauhinia purpurea unripe pods at doses of 200 and 400 mg/kg/day p.o., respectively. All the treatments were given for nine days. Cisplatin in a single dose of 6 mg/kg i.p. was given on the 4 th day to all groups, except the vehicle control group. On the 10 th day, blood and urine were collected for biochemical tests and the rats were sacrificed. The kidney was removed for histology and lipid peroxidation-antioxidant test. Cisplatin caused nephrotoxicity as evidenced by elevated blood urea, serum creatinine and urine glucose, and there was decreased creatinine clearance in Group II as compared with Group I. Administration of BBE and BPE at doses of 200 and 400 mg/kg in Group III and Group VI caused a dose-dependant reduction in the rise of blood urea, serum creatinine and urine glucose, and there was a dose-dependant increase in creatinine clearance compared with Group II. There was increased catalase and glutathione and decreased malondialdehyde levels in Group II, while BBE 400 (Group IV) and BPE 400 (Group VI) treatments significantly reversed the changes toward normal values. Histological examination of the kidney revealed protection in Group IV and Group VI compared with Group II. The ethanolic extract of Bauhinia purpurea unripe pods and bark has a nephroprotective activity against cisplatin-induced nephrotoxicity in rats.

  10. Response of Desulfovibrio vulgaris to Alkaline Stress

    Energy Technology Data Exchange (ETDEWEB)

    Stolyar, S.; He, Q.; He, Z.; Yang, Z.; Borglin, S.E.; Joyner, D.; Huang, K.; Alm, E.; Hazen, T.C.; Zhou, J.; Wall, J.D.; Arkin, A.P.; Stahl, D.A.

    2007-11-30

    The response of exponentially growing Desulfovibrio vulgarisHildenborough to pH 10 stress was studied using oligonucleotidemicroarrays and a study set of mutants with genes suggested by microarraydata to be involved in the alkaline stress response deleted. The datashowed that the response of D. vulgaris to increased pH is generallysimilar to that of Escherichia coli but is apparently controlled byunique regulatory circuits since the alternative sigma factors (sigma Sand sigma E) contributing to this stress response in E. coli appear to beabsent in D. vulgaris. Genes previously reported to be up-regulated in E.coli were up-regulated in D. vulgaris; these genes included three ATPasegenes and a tryptophan synthase gene. Transcription of chaperone andprotease genes (encoding ATP-dependent Clp and La proteases and DnaK) wasalso elevated in D. vulgaris. As in E. coli, genes involved in flagellumsynthesis were down-regulated. The transcriptional data also identifiedregulators, distinct from sigma S and sigma E, that are likely part of aD. vulgaris Hildenborough-specific stress response system.Characterization of a study set of mutants with genes implicated inalkaline stress response deleted confirmed that there was protectiveinvolvement of the sodium/proton antiporter NhaC-2, tryptophanase A, andtwo putative regulators/histidine kinases (DVU0331 andDVU2580).

  11. Changes in expression of renal Oat1, Oat3 and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Tao, E-mail: liutaomedical@qq.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Meng, Qiang, E-mail: mengq531@yahoo.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Wang, Changyuan, E-mail: wangcyuan@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Liu, Qi, E-mail: llaqii@yahoo.com.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Guo, Xinjin, E-mail: guo.xinjin@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Sun, Huijun, E-mail: sunhuijun@hotmail.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); Peng, Jinyong, E-mail: jinyongpeng2005@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University (China); and others

    2012-11-01

    The purpose of this study is to investigate whether the effect of cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) on acute renal failure (ARF) induced by cisplatin is related to change in expression of renal Oat1, Oat3 and Mrp2 in rats. JBP485 reduced creatinine, blood urea nitrogen (BUN) and indoxyl sulfate (IS) in plasma and malondialdehyde (MDA) in kidney, and recovered the glomerular filtration rate (GFR) and the activity of superoxide dismutase (SOD) in cisplatin-treated rats. The plasma concentration of PAH (para-aminohippurate) determined by LC–MS/MS was increased markedly after intravenous administration of cisplatin, whereas cumulative urinary excretion of PAH and the uptake of PAH in kidney slices were significantly decreased. qRT-PCR and Western-blot showed a decrease in mRNA and protein of Oat1 and Oat3, an increase in mRNA and protein of Mrp2 in cisplatin-treated rats, and an increase in IS (a uremic toxin) after co-treatment with JBP485. It indicated that JBP485 promoted urinary excretion of toxins by upregulating renal Mrp2. This therefore gives in part the explanation about the mechanism by which JBP485 improves ARF induced by cisplatin in rats. -- Highlights: ► Cisplatin induces acute renal failure (ARF). ► The expression of Oat1, Oat3 and Mrp2 were changed during ARF. ► The regulated expression of Oat1, Oat3 and Mrp2 is an adaptive protected response. ► JBP485 could facilitate the adaptive protective action.

  12. Endocannabinoids and the cardiovascular response to stress.

    Science.gov (United States)

    O'Sullivan, Saoirse E; Kendall, Patrick J; Kendall, David A

    2012-01-01

    Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), resulting in cardiovascular responses. The endocannabinoid system (ECS), a ubiquitously expressed lipid signalling system, modulates both HPA and SNS activity. The purpose of this review is to explore the possible involvement/role of the ECS in the cardiovascular response to stress. The ECS has numerous cardiovascular effects including modulation of blood pressure, heart rate, the baroreflex, and direct vascular actions. It is also involved in a protective manner in response to stressors in cardiac preconditioning, and various stressors (for example, pain, orthostasis and social stress) increase plasma levels of endocannabinoids. Given the multitude of vascular effects of endocannabinoids, this is bound to have consequences. Beneficial effects of ECS upregulation could include cardioprotection, vasodilatation, CB(2)-mediated anti-inflammatory effects and activation of peroxisome proliferator-activated receptors. Negative effects of endocannabinoids could include mediation of the effects of glucocorticoids, CB(1)-mediated metabolic changes, and metabolism to vasoconstrictor products. It is also likely that there is a central role for the ECS in modulating cardiovascular activity via the HPA and SNS. However, much more work is required to fully integrate the role of the ECS in mediating many of the physiological responses to stress, including cardiovascular responses.

  13. Dynamics of active cellular response under stress

    Science.gov (United States)

    de, Rumi; Zemel, Assaf; Safran, Samuel

    2008-03-01

    Forces exerted by and on adherent cells are important for many physiological processes such as wound healing and tissue formation. In addition, recent experiments have shown that stem cell differentiation is controlled, at least in part, by the elasticity of the surrounding matrix. Using a simple theoretical model that includes the forces due to both the mechanosensitive nature of cells and the elastic response of the matrix, we predict the dynamics of orientation of cells. The model predicts many features observed in measurements of cellular forces and orientation including the increase with time of the forces generated by cells in the absence of applied stress and the consequent decrease of the force in the presence of quasi-static stresses. We also explain the puzzling observation of parallel alignment of cells for static and quasi-static stresses and of nearly perpendicular alignment for dynamically varying stresses. In addition, we predict the response of the cellular orientation to a sinusoidally varying applied stress as a function of frequency. The dependence of the cell orientation angle on the Poisson ratio of the surrounding material can be used to distinguish systems in which cell activity is controlled by stress from those where cell activity is controlled by strain. Reference: Nature Physics, vol. 3, pp 655 (2007).

  14. In vivo evidence suggesting a role for purine-catabolizing enzymes in the pathogenesis of cisplatin-induced nephrotoxicity in rats and effect of erdosteine against this toxicity.

    Science.gov (United States)

    Söğüt, Sadik; Kotuk, Mahir; Yilmaz, H Ramazan; Ulu, Ramazan; Ozyurt, Hüseyin; Yildirim, Zeki

    2004-01-01

    The aim of this experimental study was to investigate the possible role of adenosine deaminase (AD) and xanthine oxidase (XO) in the pathogenesis of cisplatin-induced nephrotoxicity and the effect of erdosteine in decreasing the toxicity. The intraperitoneal injection of cisplatin (7 mg kg(-1) body weight) induced a significant increase in plasma creatinine level and blood urea nitrogen (BUN), and plasma and damaged renal tissue activities of AD and XO in rats. Co-treatment with erdosteine (10 mg kg(-1)day(-1)) attenuated the increase in the plasma creatinine and BUN levels, and significantly prevented the increase in tissue and plasma AD and XO activities (Perdosteine may have protective potential in this process and it will become a promising drug in the prevention of this undesired side-effect of cisplatin, but further studies are needed to illuminate the exact protection mechanism of erdosteine against cisplatin-induced nephrotoxicity.

  15. Amelioration of cisplatin-induced nephrotoxicity by ethanolic extract of Bauhinia purpurea: An in vivo study in rats

    Directory of Open Access Journals (Sweden)

    Md Azmat Rana

    2016-01-01

    Full Text Available Our objective is to study the nephroprotective activity and antioxidant potential of Bauhinia purpurea unripe pods and bark against cisplatin-induced nephrotoxicity. Healthy adult albino rats of either sex (150-200 g were randomly divided into six groups of six animals each Group I (vehicle control and Group II (negative control. Group III (BBE200 and Group IV (BBE400 were administered the ethanolic extract of Bauhinia purpurea bark in doses of 200 and 400 mg/kg/day p.o., respectively, and Group V (BPE200 and Group VI (BPE400 were administered the ethanolic extract of Bauhinia purpurea unripe pods at doses of 200 and 400 mg/kg/day p.o., respectively. All the treatments were given for nine days. Cisplatin in a single dose of 6 mg/kg i.p. was given on the 4 th day to all groups, except the vehicle control group. On the 10 th day, blood and urine were collected for biochemical tests and the rats were sacrificed. The kidney was removed for histology and lipid peroxidation-antioxidant test. Cisplatin caused nephrotoxicity as evidenced by elevated blood urea, serum creatinine and urine glucose, and there was decreased creatinine clearance in Group II as compared with Group I. Administration of BBE and BPE at doses of 200 and 400 mg/kg in Group III and Group VI caused a dose-dependant reduction in the rise of blood urea, serum creatinine and urine glucose, and there was a dosedependant increase in creatinine clearance compared with Group II. There was increased catalase and glutathione and decreased malondialdehyde levels in Group II, while BBE 400 (Group IV and BPE 400 (Group VI treatments significantly reversed the changes toward normal values. Histological examination of the kidney revealed protection in Group IV and Group VI compared with Group II. The ethanolic extract of Bauhinia purpurea unripe pods and bark has a nephroprotective activity against cisplatin-induced nephrotoxicity in rats.

  16. Antioxidantes da dieta como inibidores da nefrotoxicidade induzida pelo antitumoral cisplatina Dietary antioxidants as inhibitors of cisplatin-induced nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Lusânia Maria Greggi Antunes

    2004-03-01

    Full Text Available A cisplatina é uma droga antineoplásica altamente efetiva contra vários tipos de cânceres humanos, tais como tumores do testículo e ovário, câncer da cabeça e pescoço e câncer do pulmão. Entretanto, a nefrotoxicidade é um dos principais efeitos colaterais da terapia com a cisplatina. A gravidade da nefrotoxicidade induzida pela cisplatina está relacionada com a concentração de platina nos rins. As evidências mostram que a nefrotoxicidade induzida pela cisplatina é atribuída ao dano oxidativo resultante da geração de radicais livres, e que a administração de antioxidantes é eficiente na inibição destes efeitos colaterais. Uma abordagem alternativa para proteger os roedores dos efeitos colaterais da cisplatina é o uso de conhecidos antioxidantes da dieta. Alguns estudos têm sido realizados para diminuir a peroxidação lipídica e os efeitos citotóxicos induzidos pela cisplatina, com o emprego de antioxidantes da dieta, tais como, selenito de sódio, vitaminas C e E, curcumina e o carotenóide bixina. Nós sugerimos que aqueles antioxidantes da dieta têm efeito nefroprotetor, e que os mecanismos antioxidantes destes compostos deveriam ser explorados durante a quimioterapia com a cisplatina.Cisplatin is a highly effective antineoplastic drug used against several types of human cancers, such as testicular and ovarian tumors; head and neck; and lung cancer. However, nephrotoxicity is one of the most important side-effects of cisplatin therapy. The severity of cisplatin nephrotoxicity is related to platinum concentration in the kidneys. There is a growing amount of evidence that cisplatin-induced nephrotoxicity is ascribed to oxidative damage resulting from free radical generation and that the administration of antioxidants is efficient in inhibiting these side effects. An alternative approach aiming to protect rodents against cisplatin side-effects is the introduction of known dietary antioxidants. Some studies have been

  17. Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats.

    Science.gov (United States)

    el Daly, E S

    1998-01-01

    Cisplatin [cis-dichlorodiammineplatinum (II)] is a widely used chemotherapeutic drug that is toxic to the kidney. Concurrent administration of cysteine together with vitamin E, Crocus sativus and Nigella sativa reduced the toxicity of cisplatin in rats. When administered i.p. for 5 alternate days with 3 mg/kg cisplatin, cysteine (20 mg/kg) together with vitamin E (2 mg/rat) an extract of Crocus sativus stigmas (50 mg/kg) and Nigella sativa seed (50 mg/kg) significantly reduced blood urea nitrogen (BUN) and serum creatinine levels as well as cisplatin-induced serum total lipids increases. In contrast, the protective agents given together with cisplatin led to an even greater decrease in blood glucose than that seen with cisplatin alone. The serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase and alanine aminotransferase of cisplatin-treated rats were significantly decreased, whereas the activities of glutathione reductase and isocitrate dehydrogenase were significantly increased. Addition of cysteine and vitamin E, Crocus sativus and Nigella sativa in combination with cisplatin partially prevented many changes in the activities of serum enzymes. In cisplatin-treated rats, the liver activities of isocitrate dehydrogenase and aspartate aminotransferase were significantly increased, whereas much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of alkaline phosphatase, isocitrate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase and gamma-glutamyl transferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Also, administration of cysteine and vitamin E, Crocus sativus and Nigella sativa together with cisplatin partially reversed many of the kidney enzymes changes induced by cisplatin

  18. Biochemical changes associated with ascorbic acid–cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Amenla Longchar

    2015-01-01

    Full Text Available Cisplatin is one of the well-established anticancer drugs being used against a wide spectrum of cancers. However, full therapeutic efficacy of the drug is limited due to development of various toxicities in the host. This study examines the comparative therapeutic effectiveness and toxicities of cisplatin alone and in combination of dietary ascorbic acid (AA in ascites Dalton's lymphoma-bearing mice. The findings show that the combination treatment of mice with ascorbic acid plus cisplatin has much better therapeutic efficacy against murine ascites Dalton's lymphoma (DL in comparison to cisplatin alone and this may involve a decrease in reduced glutathione (GSH, catalase activity and increased lipid peroxidation (LPO in Dalton's lymphoma tumor cells. At the same time, combination treatment indicates a protective role of ascorbic acid against cisplatin-induced tissue toxicities (side effects in the hosts. Cisplatin-induced histopathological changes in liver, kidney and testes were decreased after combination treatment. The analysis of renal function test (RFT, liver function test (LFT and sperm abnormalities also suggest an improvement in these parameters after combination treatment. Therefore, it may be concluded that the increased GSH level, catalase activity and decreased LPO in the tissues, i.e., liver, kidney and testes after combination treatment may be involved in its protective ability against cisplatin-induced tissue toxicities in the host.

  19. The Effect of Vitamin E on Cisplatin Induced Nephrotoxicity in Mice and its Mechanism%维生素E对顺铂所致的小鼠肾毒性的影响及其机制研究

    Institute of Scientific and Technical Information of China (English)

    张林; 刘伏友; 彭佑铭; 李大伟; 曾妮; 武蓉; 刘沧桑

    2012-01-01

      目的观察维生素E对抗癌药物顺铂致小鼠肾毒性的影响及其可能机制.方法采用10 mg·kg-1顺铂腹腔注射诱导小鼠肾脏损伤,48小时后分别予维生素E 250 mg·kg-1和500 mg·kg-1口服灌胃,顺铂诱导72小时后通过检测小鼠血清尿素氮和肌酐水平评价肾功能的变化,检测肾组织中丙二醛(malonaldehyde,MDA)含量,过氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)、还原型谷胱甘肽(reduced glutathione,GSH)和谷胱甘肽过氧化物酶(glutathion peroxidase,GPX)活性的变化,以评价小鼠肾组织氧化应激水平.结果与正常小鼠相比,10 mg·kg-1顺铂诱导的小鼠血清尿素氮、肌酐水平和肾组织MDA水平均显著升高(P0.05).结论高剂量的维生素E可以有效改善顺铂诱导的小鼠肾功能,可能与其降低肾组织的氧化应激有关.%  Objective To investigate the effects of vitamin E on cisplatin induced nephrotoxicity in mice and its mechanism. Methods 10 mg·kg-1 cisplatin was used to induce nephrotoxicity in mice by intraperitoneal injection, and 48 h later, 250 mg·kg-1 and 500 mg·kg-1 vitamin E were respectively used. Then at 72 h after cisplatin treatment, the serum level of urea nitrogen and creatinine were detected to evaluate the change of renal function, and the activities of malonaldehyde (MDA), superoxide dis-mutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathion peroxidase (GPX) in renal tissue were detected to evaluate the change of oxidative stress. Results Compared with normal mice, the serum level of urea nitrogen and creatinine as well as MDA in renal tissue significantly increased in 10 mg·kg-1 cisplatin-induced mice (P0.05). Conclusions High dose of vitamin E was effective to improve the renal function of cisplatin induced mice, and the decrease of oxidative stress may be involved.

  20. Oxidative stress response in Paracoccidioides brasiliensis.

    Science.gov (United States)

    Campos, Elida G; Jesuino, Rosália Santos Amorim; Dantas, Alessandra da Silva; Brígido, Marcelo de Macedo; Felipe, Maria Sueli S

    2005-06-30

    Survival of pathogenic fungi inside human hosts depends on evasion from the host immune system and adaptation to the host environment. Among different insults that Paracoccidioides brasiliensis has to handle are reactive oxygen and nitrogen species produced by the human host cells, and by its own metabolism. Knowing how the parasite deals with reactive species is important to understand how it establishes infection and survives within humans. The initiative to describe the P. brasiliensis transcriptome fostered new approaches to study oxidative stress response in this organism. By examining genes related to oxidative stress response, one can evaluate the parasite's ability to face this condition and infer about possible ways to overcome this ability. We report the results of a search of the P. brasiliensis assembled expressed sequence tag database for homologous sequences involved in oxidative stress response. We described several genes coding proteins involved in antioxidant defense, for example, catalase and superoxide dismutase isoenzymes, peroxiredoxin, cytochrome c peroxidase, glutathione synthesis enzymes, thioredoxin, and the transcription factors Yap1 and Skn7. The transcriptome analysis of P. brasiliensis reveals a pathogen that has many resources to combat reactive species. Besides characterizing the antioxidant defense system in P. brasiliensis, we also compared the ways in which different fungi respond to oxidative damage, and we identified the basic features of this response.

  1. Effects of Rhus tripartitum fruit extract on CCl4-induced hepatotoxicity and cisplatin-induced nephrotoxicity in rats.

    Science.gov (United States)

    Tlili, Nizar; Feriani, Anouar; Allagui, Mohamed Salah; Saadoui, Ezzeddine; Khaldi, Abdelhamid; Nasri, Nizar

    2016-08-01

    Rhus tripartitum D.C., Anacardiaceae, has traditionally been used in Tunisia against many illnesses. The present study investigates, for the first time, the protective effects of the methanol extract of Rhus tripartitum fruit (MERT) against CCl4-induced hepatotoxicity and cisplatin-induced nephrotoxicty in Wistar rats. ALT, AST, LDH, GGT, creatinin, urea, and uric acid levels were studied. The changes in antioxidant parameters such as malondialdehyde (MDA) and protein carbonyl contents were also determined. The increased levels of MDA (30.97 and 11.50 nmol MDA/mg protein in liver and kidney, respectively) and protein carbonyls (13.4 and 17.95 nmol/mg protein in liver and kidney, respectively) were attenuated by MERT pretreatment (19.35 and 6.1 nmol MDA/mg protein and 9.15 and 12 nmol/mg protein in liver and kidney, respectively). The MERT pretreatment significantly reduced the increased biochemical parameters of liver and kidney caused by CCl4 and cisplatin treatment. The histopathologic observation showed that MERT pretreatment restores the altered tissues. The observed results could be due to the high phenolic content and to MERT's important antioxidant potential. This study supports the hepatoprotective and nephroprotective effects of R. tripartitum.

  2. Cisplatin-Induced Non-Oliguric Acute Kidney Injury in a Pediatric Experimental Animal Model in Piglets.

    Directory of Open Access Journals (Sweden)

    Maria José Santiago

    Full Text Available To design an experimental pediatric animal model of acute kidney injury induced by cisplatin.Prospective comparative observational animal study in two different phases. Acute kidney injury was induced using three different doses of cisplatin (2, 3 and 5 mg/kg. The development of nephrotoxicity was assessed 2 to 4 days after cisplatin administration by estimating biochemical parameters, diuresis and renal morphology. Analytical values and renal morphology were compared between 15 piglets treated with cisplatin 3 mg/kg and 15 control piglets in the second phase of the study.41 piglets were studied. The dose of 3 mg/kg administered 48 hours before the experience induced a significant increase in serum creatinine and urea without an increase in potassium levels. Piglets treated with cisplatin 3 mg/kg had significantly higher values of creatinine, urea, phosphate and amylase, less diuresis and lower values of potassium, sodium and bicarbonate than control piglets. Histological findings showed evidence of a dose-dependent increase in renal damage.a dose of 3 mg/kg of cisplatin induces a significant alteration in renal function 48 hours after its administration, so it can be used as a pediatric animal model of non-oliguric acute kidney injury.

  3. Protective effects of the aqueous leaf extract of Aloe barbadensis on gentamicin and cisplatin-induced nephrotoxic rats

    Institute of Scientific and Technical Information of China (English)

    Paoulomi Chatterjee﹡; Aniruddha Mukherjee; Subhangkar Nandy

    2012-01-01

    Objective: To study the protective effects of the aqueous leaf extract of Aloe barbadensis (AEAB) on gentamicin and Cisplatin-induced nephrotoxic Wistar rats. Methods: In each model of nephrotoxicity, thirty adult male Wistar rats were evenly divided into 5 groups. Groups I and II served as untreated and model controls, respectively while groups III-V were the treatment groups which were pretreated with 100-200 mg/kg bodyweight per day of AEAB 1 h before each dose of the nephrotoxicants. On the 8th day(in case of gentamicin) and on 6th day(in case of Cisplatin), blood samples for serum urea, total protein and creatinine as well as some ions like sodium, potassium, chloride and uric acid while the rat kidneys for histology were obtained under inhaled diethyl ether anesthesia. Results: In the gentamicin nephrotoxic rats, 100-200 mg/kg bodyweight per day significantly attenuated elevations in the serum creatinine, total protein and blood urea nitrogen levels in dose related fashion and no treatment related effect on uric acid and ions, and attenuated the gentamicin-induced tubulonephrosis. Similar effects were also recorded in the Cisplatin model of acute renal injury. Conclusions:The nephroprotective effect of AEAB could be due to the inherent antioxidant and free-radical-scavenging principle(s) contained in the extract.In the near future, AEAB could constitute a lead to discovery of a novel drug for the treatment of drug-induced nephrotoxicity.

  4. EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis.

    Science.gov (United States)

    Liu, Haidan; Li, Wei; Yu, Xinfang; Gao, Feng; Duan, Zhi; Ma, Xiaolong; Tan, Shiming; Yuan, Yunchang; Liu, Lijun; Wang, Jian; Zhou, Xinmin; Yang, Yifeng

    2016-08-30

    Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non-small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2-regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers.

  5. Andrographolide sensitizes cisplatin-induced apoptosis via suppression of autophagosome-lysosome fusion in human cancer cells.

    Science.gov (United States)

    Zhou, Jing; Hu, Shuai-Er; Tan, Shi-Hao; Cao, Ruoxi; Chen, Yiyang; Xia, Dajing; Zhu, Xinqiang; Yang, Xing-Fen; Ong, Choon-Nam; Shen, Han-Ming

    2012-03-01

    Suppression of autophagy has been increasingly recognized as a novel cancer therapeutic approach. Andrographolide (Andro), a diterpenoid lactone isolated from an herbal plant Andrographis paniculata, is known to possess anti-inflammatory and anticancer activity. In this study, we sought to examine the effect of Andro on autophagy, and to evaluate whether such effect is relevant to the sensitization effect of Andro on apoptosis induced by DNA damage agents in cancer cells. First, we found that Andro is able to significantly enhance autophagic markers in various cancer cell lines, including GFP-LC3 puncta and LC3-II level. Interestingly, Andro treatment also led to marked increase of p62 protein level and addition of chloroquine (CQ) failed to further enhance either LC3-II or p62 level, indicating that Andro is likely to suppress autophagic flux at the maturation and degradation stage. Next, we provided evidence that Andro inhibits autophagosome maturation not by affecting the lysosomal function, but by impairing autophagosome-lysosome fusion. Lastly, we demonstrated that treatment with cisplatin, a DNA damage agent, induces autophagy in cancer cells. Importantly, Andro is capable of sensitizing cisplatin-induced cell killing determined with both short-term apoptosis assays and long-term clonogenic test, via suppression of autophagy, a process independent of p53. In summary, these observations collectively suggest that Andro could be a promising anti-cancer agent in combination therapy via its potent inhibitory effect on autophagy by disrupting autophagosome-lysosome fusion.

  6. Physiological Responses to Thermal Stress and Exercise

    Science.gov (United States)

    Iyota, Hiroyuki; Ohya, Akira; Yamagata, Junko; Suzuki, Takashi; Miyagawa, Toshiaki; Kawabata, Takashi

    The simple and noninvasive measuring methods of bioinstrumentation in humans is required for optimization of air conditioning and management of thermal environments, taking into consideration the individual specificity of the human body as well as the stress conditions affecting each. Changes in human blood circulation were induced with environmental factors such as heat, cold, exercise, mental stress, and so on. In this study, the physiological responses of human body to heat stress and exercise were investigated in the initial phase of the developmental research. We measured the body core and skin temperatures, skin blood flow, and pulse wave as the indices of the adaptation of the cardiovascular system. A laser Doppler skin blood flowmetry using an optical-sensor with a small portable data logger was employed for the measurement. These results reveal the heat-stress and exercise-induced circulatory responses, which are under the control of the sympathetic nerve system. Furthermore, it was suggested that the activity of the sympathetic nervous system could be evaluated from the signals of the pulse wave included in the signals derived from skin blood flow by means of heart rate variability assessments and detecting peak heights of velocity-plethysmogram.

  7. The terminal basal mitosis of chicken retinal Lim1 horizontal cells is not sensitive to cisplatin-induced cell cycle arrest.

    Science.gov (United States)

    Shirazi Fard, Shahrzad; Thyselius, Malin; All-Ericsson, Charlotta; Hallböök, Finn

    2014-01-01

    For proper development, cells need to coordinate proliferation and cell cycle-exit. This is mediated by a cascade of proteins making sure that each phase of the cell cycle is controlled before the initiation of the next. Retinal progenitor cells divide during the process of interkinetic nuclear migration, where they undergo S-phase on the basal side, followed by mitoses on the apical side of the neuroepithelium. The final cell cycle of chicken retinal horizontal cells (HCs) is an exception to this general cell cycle behavior. Lim1 expressing (+) horizontal progenitor cells (HPCs) have a heterogenic final cell cycle, with some cells undergoing a terminal mitosis on the basal side of the retina. The results in this study show that this terminal basal mitosis of Lim1+ HPCs is not dependent on Chk1/2 for its regulation compared to retinal cells undergoing interkinetic nuclear migration. Neither activating nor blocking Chk1 had an effect on the basal mitosis of Lim1+ HPCs. Furthermore, the Lim1+ HPCs were not sensitive to cisplatin-induced DNA damage and were able to continue into mitosis in the presence of γ-H2AX without activation of caspase-3. However, Nutlin3a-induced expression of p21 did reduce the mitoses, suggesting the presence of a functional p53/p21 response in HPCs. In contrast, the apical mitoses were blocked upon activation of either Chk1/2 or p21, indicating the importance of these proteins during the process of interkinetic nuclear migration. Inhibiting Cdk1 blocked M-phase transition both for apical and basal mitoses. This confirmed that the cyclin B1-Cdk1 complex was active and functional during the basal mitosis of Lim1+ HPCs. The regulation of the final cell cycle of Lim1+ HPCs is of particular interest since it has been shown that the HCs are able to sustain persistent DNA damage, remain in the cell cycle for an extended period of time and, consequently, survive for months.

  8. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles

    Energy Technology Data Exchange (ETDEWEB)

    Rezvanfar, Mohammad Amin; Rezvanfar, Mohammad Ali [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of); Shahverdi, Ahmad Reza [Department of Pharmaceutical Biotechnology and Biotechnology Research Centre, Faculty of Pharmacy, TUMS, Tehran (Iran, Islamic Republic of); Ahmadi, Abbas [Department of Histology and Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia (Iran, Islamic Republic of); Baeeri, Maryam; Mohammadirad, Azadeh [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of); Abdollahi, Mohammad, E-mail: mohammad.abdollahi@utoronto.ca [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran (Iran, Islamic Republic of)

    2013-02-01

    Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential. Highlights: ► Cisplatin (CIS) affects spermatozoa as a male reproductive toxicant. ► Effect of Nano-Se on CIS-induced spermatotoxicity was investigated. ► CIS-exposure induces oxidative sperm DNA damage

  9. Stress response and apoptosis in pro- and antiinflammatory macrophages.

    Science.gov (United States)

    Malyshev, I Yu; Kruglov, S V; Bakhtina, L Yu; Malysheva, E V; Zubin, M; Norkin, M

    2004-08-01

    We showed that stress response and apoptosis in macrophages depend on the phenotype of their secretory activity and specific biological and physical characteristics of the factor inducing stress-response or apoptosis.

  10. Response to temperature stress in rhizobia.

    Science.gov (United States)

    Alexandre, Ana; Oliveira, Solange

    2013-08-01

    It is well established that soil is a challenging environment for bacteria, where conditions may change rapidly and bacteria have to acclimate and adapt in order to survive. Rhizobia are an important group of soil bacteria due to their ability to establish atmospheric nitrogen-fixing symbioses with many legume species. Some of these legumes are used to feed either humans or cattle and therefore the use of rhizobia can reduce the need for synthetic N-fertilizers. Several environmental factors shape the composition and the activity of rhizobia populations in the rhizosphere. Soil pH and temperature are often considered to be the major abiotic factors in determining the bacterial community diversity. The present review focuses on the current knowledge on the molecular bases of temperature stress response in rhizobia. The effects of temperature stress in the legume-rhizobia symbioses are also addressed.

  11. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles.

    Science.gov (United States)

    Rezvanfar, Mohammad Amin; Rezvanfar, Mohammad Ali; Shahverdi, Ahmad Reza; Ahmadi, Abbas; Baeeri, Maryam; Mohammadirad, Azadeh; Abdollahi, Mohammad

    2013-02-01

    Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential.

  12. The early stress responses in fish larvae.

    Science.gov (United States)

    Pederzoli, Aurora; Mola, Lucrezia

    2016-05-01

    During the life cycle of fish the larval stages are the most interesting and variable. Teleost larvae undergo a daily increase in adaptability and many organs differentiate and become active. These processes are concerted and require an early neuro-immune-endocrine integration. In larvae communication among the nervous, endocrine and immune systems utilizes several known signal molecule families which could be different from those of the adult fish. The immune-neuroendocrine system was studied in several fish species, among which in particular the sea bass (Dicentrarchus labrax), that is a species of great commercial interest, very important in aquaculture and thus highly studied. Indeed the immune system of this species is the best known among marine teleosts. In this review the data on main signal molecules of stress carried out on larvae of fish are considered and discussed. For sea bass active roles in the early immunological responses of some well-known molecules involved in the stress, such as ACTH, nitric oxide, CRF, HSP-70 and cortisol have been proposed. These molecules and/or their receptors are biologically active mainly in the gut before complete differentiation of gut-associated lymphoid tissue (GALT), probably acting in an autocrine/paracrine way. An intriguing idea emerges from all results of these researches; the molecules involved in stress responses, expressed in the adult cells of the hypothalamic-pituitary axis, during the larval life of fish are present in several other localizations, where they perform probably the same role. It may be hypothesized that the functions performed by hypothalamic-pituitary system are particularly important for the survival of the larva and therefore they comprises several other localizations of body. Indeed the larval stages of fish are very crucial phases that include many physiological changes and several possible stress both internal and environmental.

  13. Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference

    Directory of Open Access Journals (Sweden)

    Zohreh Zamani

    2016-01-01

    Conclusion: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.

  14. Lifestyle, stress and cortisol response: Review I: Mental stress

    OpenAIRE

    Fukuda, Sanae; Morimoto, Kanehisa

    2001-01-01

    The incidences of diseases related to mental stress are increasing in Japan. Mental stress, unacknowledged for long periods, has been shown to lead to the development of a number of diseases. Thus, an index for mental stress is important to induce awareness of its presence. We focused on the relationship between cortisol and mental stress in this review. We will discuss both the usefulness and problems of cortisol as a mental stress index by summarizing the relationship between cortisol and m...

  15. The protective effect of trimetazidine against cisplatin-induced nephrotoxicity in rats.

    Science.gov (United States)

    El-Sherbeeny, Nagla A; Attia, Ghalia M

    2016-07-01

    Nephrotoxicity is a dose-limiting side effect of cisplatin (CSP). The study investigated the possible protective role of trimetazidine (TMZ) against CSP-induced nephrotoxicity in rats. Rats were divided into four groups; control, TMZ, CSP, and CSP + TMZ. The CSP group showed significant deterioration in kidney function with structural changes in the form of interstitial hemorrhage, glomeruli shrinkage and peritublar capillary congestion, tubular cells vacuolation, pyknosis, shedding and necrosis, and inflammatory cell infiltrates, all indicating renal damage. CSP also caused a significant increase in the lipid peroxidation marker malondialdehyde (MDA) levels, renal nuclear factor kappa B (NF-κB) DNA-binding activity and protein expression, and tumor necrosis factor alpha (TNF-α) and IL-6 levels. Treatment with TMZ before and after CSP injection produced significant improvement of kidney function and histopathology. TMZ treatment also significantly attenuated CSP-induced oxidative stress and suppressed elevated levels of TNF-α and IL-6 and NF-κB expression and its DNA-binding activity caused by CSP administration. TMZ has a protective effect against CSP-induced nephrotoxicity mediated by reduction of oxidative stress and attenuation of CSP-induced inflammation.

  16. Taurine Rescues Cisplatin-Induced Muscle Atrophy In Vitro: A Morphological Study

    Directory of Open Access Journals (Sweden)

    Alessandra Stacchiotti

    2014-01-01

    Full Text Available Cisplatin (CisPt is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 μM CisPt challenged myotubes (4 h–8 h before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Differently, 25 mM taurine pretreatment rescues the majority of myotubes size upon 50 μM CisPt at 24 h. Taurine appears to counteract atrophy by restoring regular microtubular apparatus and mitochondria and reducing the overload and the localization of autophagolysosomes. Such a promising taurine action in preventing atrophy needs further molecular and biochemical studies to best define its impact on muscle homeostasis and the maintenance of an adequate skeletal mass in vivo.

  17. Combinatorial stress responses: direct coupling of two major stress responses in Escherichia coli

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    Daniel R. Brown

    2014-09-01

    Full Text Available Nitrogen is an essential element for all life, and this is no different for the bacterial cell. Numerous cellular macromolecules contain nitrogen, including proteins, nucleic acids and cell wall components. In Escherichia coli and related bacteria, the nitrogen stress (Ntr response allows cells to rapidly sense and adapt to nitrogen limitation by scavenging for alternative nitrogen sources through the transcriptional activation of transport systems and catabolic and biosynthetic operons by the global transcriptional regulator NtrC. Nitrogen-starved bacterial cells also synthesize the (pppGpp effector molecules of a second global bacterial stress response - the stringent response. Recently, we showed that the transcription of relA, the gene which encodes the major (pppGpp synthetase in E. coli, is activated by NtrC during nitrogen starvation. Our results revealed that in E. coli and related bacteria, NtrC functions in combinatorial stress and serves to couple two major stress responses, the Ntr response and stringent response.

  18. Chemoprotective effect of a nuclear factor-kappaB inhibitor, pyrrolidine dithiocarbamate, against cisplatin-induced testicular damage in rats.

    Science.gov (United States)

    Ilbey, Yusuf Ozlem; Ozbek, Emin; Simsek, Abdulmuttalip; Cekmen, Mustafa; Otunctemur, Alper; Somay, Adnan

    2009-01-01

    The objective of this study was to evaluate inducible nitric oxide synthase (iNOS) and nuclear factor-kappaB inhibitor (NF-kappaB) expression and the potential chemoprotective effects of an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), against cisplatin-induced testicular damage in rats. Rats were divided into 4 equal groups: group 1, control; group 2, injected with cisplatin (CIS) for 5 days (7 mg/kg/day intraperitoneally [IP]); group 3, injected with PDTC alone; group 4, injected with CIS plus PDTC (100 mg/kg IP). Body and testicular weights, plasma testosterone levels, and histopathologic structure of the testicular tissue were determined. The iNOS and NF-kappaB activity were evaluated immunohistochemically by staining p65 to define NF-kappaB activity. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels and glutathione peroxidase (GSH-Px) activity were assessed in testicular tissue. Body and testicular weights, plasma testosterone levels, activity of GSH-Px, and GSH levels were all significantly decreased, whereas the levels of MDA and NO were significantly increased in rats of the CIS group. PDTC treatment increased plasma testosterone levels. A significant increase in GSH levels and GSH-Px activity and a decrease in MDA and NO levels in testicular tissue were observed in the CIS + PDTC group. Immunohistochemically, there was a marked staining for iNOS and NF-kappaB/p65 expression in rats injected with CIS compared with the control (P < .001). CIS caused irregular seminiferous tubules, reduction of seminiferous epithelial layers, significant arrest of maturation, and perivascular fibrosis. Moreover, PDTC administration to CIS-treated rats significantly prevented these histopathologic chances, as well. CIS induces iNOS expression through activation of NF-kappaB/p65, and CIS-induced testicular toxicity may be prevented by PDTC, which is a selective NF-kappaB inhibitor.

  19. A whole genome RNAi screen identifies replication stress response genes.

    Science.gov (United States)

    Kavanaugh, Gina; Ye, Fei; Mohni, Kareem N; Luzwick, Jessica W; Glick, Gloria; Cortez, David

    2015-11-01

    Proper DNA replication is critical to maintain genome stability. When the DNA replication machinery encounters obstacles to replication, replication forks stall and the replication stress response is activated. This response includes activation of cell cycle checkpoints, stabilization of the replication fork, and DNA damage repair and tolerance mechanisms. Defects in the replication stress response can result in alterations to the DNA sequence causing changes in protein function and expression, ultimately leading to disease states such as cancer. To identify additional genes that control the replication stress response, we performed a three-parameter, high content, whole genome siRNA screen measuring DNA replication before and after a challenge with replication stress as well as a marker of checkpoint kinase signalling. We identified over 200 replication stress response genes and subsequently analyzed how they influence cellular viability in response to replication stress. These data will serve as a useful resource for understanding the replication stress response.

  20. Studies on the protective effect of dietary fish oil on cisplatin induced nephrotoxicity in rats.

    Science.gov (United States)

    Naqshbandi, Ashreeb; Khan, Md Wasim; Rizwan, Sana; Rehman, Sayeed Ur; Khan, Farah

    2012-02-01

    Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, however, dose dependent nephrotoxicity remains the major concern for its long term use. Several agents/strategies were attempted to prevent CP nephrotoxicity but were not found suitable for clinical practice. Dietary fish oil (FO) enriched in ω-3 fatty acids has been shown to prevent/reduce the progression of certain types of cancers, cardiovascular and renal disorders. The present study was undertaken to see whether FO can prevent CP-induced nephrotoxic and other deleterious effects. Rats were prefed experimental diets for 10days and then received a single dose of CP (6mg/kg body weight) intraperitoneally while still on diet. Serum/urine parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM) and oxidative stress in rat kidney were analyzed. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP decreased the activities of metabolic enzymes, antioxidant defense system and BBM enzymes. In contrast, FO alone increased enzyme activities of carbohydrate metabolism and brush border membrane (BBM). FO feeding to CP treated rats markedly enhanced resistance to CP-elicited deleterious effects. Dietary FO supplementation ameliorated CP induced specific metabolic alterations and oxidative damage due to its intrinsic biochemical antioxidant properties.

  1. Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

    Science.gov (United States)

    De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

    2016-01-01

    While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments.

  2. Hydrogen protects auditory hair cells from cisplatin-induced free radicals.

    Science.gov (United States)

    Kikkawa, Yayoi S; Nakagawa, Takayuki; Taniguchi, Mirei; Ito, Juichi

    2014-09-05

    Cisplatin is a widely used chemotherapeutic agent for the treatment of various malignancies. However, its maximum dose is often limited by severe ototoxicity. Cisplatin ototoxicity may require the production of reactive oxygen species (ROS) in the inner ear by activating enzymes specific to the cochlea. Molecular hydrogen was recently established as an antioxidant that selectively reduces ROS, and has been reported to protect the central nervous system, liver, kidney and cochlea from oxidative stress. The purpose of this study was to evaluate the potential of molecular hydrogen to protect cochleae against cisplatin. We cultured mouse cochlear explants in medium containing various concentrations of cisplatin and examined the effects of hydrogen gas dissolved directly into the media. Following 48-h incubation, the presence of intact auditory hair cells was assayed by phalloidin staining. Cisplatin caused hair cell loss in a dose-dependent manner, whereas the addition of hydrogen gas significantly increased the numbers of remaining auditory hair cells. Additionally, hydroxyphenyl fluorescein (HPF) staining of the spiral ganglion showed that formation of hydroxyl radicals was successfully reduced in hydrogen-treated cochleae. These data suggest that molecular hydrogen can protect auditory tissues against cisplatin toxicity, thus providing an additional strategy to protect against drug-induced inner ear damage.

  3. Protective Effect of Standardized Extract of Ginkgo biloba against Cisplatin-Induced Nephrotoxicity

    Directory of Open Access Journals (Sweden)

    Jie Song

    2013-01-01

    Full Text Available Cisplatin (CDDP is a potent antitumor compound widely used with a notably side effect of nephrotoxicity inducing oxidative stress and apoptosis in kidneys. Standardized extract from the leaves of the Ginkgo biloba trees, labeled EGb761 (EGb, has been available on the market for its beneficial effects. The purpose of this study was to investigate the ability of EGb to prevent the nephrotoxic effect of CDDP and the mechanisms involved. Our results showed that EGb treatment restored the levels of creatinine, BUN, MDA, NO, SOD, CAT, GPx, and GSSG/GSH ratio in kidneys after CDDP injection. EGb also exhibited a tendency to decrease the elevated NF-κB translocation and caspase-3 protein levels in CDDP-treated kidneys. We further used a porcine kidney proximal tubular epithelial (LLC-PK1 cell line, finding that EGb accordingly inhibited ROS accumulation and iNOS increase induced by CDDP in vitro. EGb also attenuated IκB degradation and p65 NF-κB phosphorylation triggered by CDDP in LLC-PK1 cells. But EGb failed to influence CDDP-stimulated caspase cascade. These findings suggested that EGb’s renoprotective effect might be mediated by not only its well-known antioxidant activity but also the anti-inflammatory activity.

  4. The Potential Role of Azadirachta indica Treatment on Cisplatin-Induced Hepatotoxicity and Oxidative Stress in Female Rats

    OpenAIRE

    Mohamed A Dkhil; Saleh Al-Quraishy; Aref, Ahmed M.; Othman, Mohamed S.; Kamal M. El-Deib; Ahmed E Abdel Moneim

    2013-01-01

    Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative...

  5. Protective role of Diospyros lotus on cisplatin-induced changes in sperm characteristics, testicular damage and oxidative stress in rats.

    Science.gov (United States)

    Saral, S; Ozcelik, E; Cetin, A; Saral, O; Basak, N; Aydın, M; Ciftci, O

    2016-04-01

    The aim of this study was to investigate the protective effect of Diospyros lotus (DL) on cisplatin (CP)-induced testicular damage in male rats. Twenty-eight male rats were randomly divided into four groups: group 1 - control, given isotonic saline solution; group 2 - CP 7 mg kg(-1) given intraperitoneally as single dose; group 3 - DL 1000 mg kg(-1) per day given orally for 10 days; group 4 - CP and DL given together at the same doses. CP caused a significant increase in thiobarbituric acid-reactive substances (TBARS) level and a significant decrease in superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione (GSH) levels in rats testis tissues compared to the control group. CP caused a significant increase in lipid peroxidation in testis tissues compared to the control group, whereas DL led to a significant increase in SOD and GSH levels. However, there were no statistically significant changes in GPx and CAT levels. In addition, serum testosterone levels, sperm concentration and sperm motility were significantly decreased, but abnormal sperm rate and histological changes were increased with CP. However, these effects of CP on sperm parameters, histological changes and the tissue weights were eliminated by DL treatment. In conclusion, our study showed that the reproductive toxicity caused by CP may be prevented by DL treatment.

  6. Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats.

    Science.gov (United States)

    Mundhe, Nitin Arunrao; Kumar, Parveen; Ahmed, Sahabuddin; Jamdade, Vinayak; Mundhe, Sanjay; Lahkar, Mangala

    2015-09-01

    Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats.

  7. Asparagus racemosus ameliorates cisplatin induced toxicities and augments its antileishmanial activity by immunomodulation in vivo.

    Science.gov (United States)

    Sachdeva, Heena; Sehgal, Rakesh; Kaur, Sukhbir

    2014-02-01

    Current drugs for the treatment of visceral leishmaniasis are inadequate and their efficacies are also compromised due to suppression of immune function associated during the course of infection. To overcome this problem, efforts are needed to develop therapies with effective immunomodulatory agents where decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In this study we have evaluated a new therapeutic approach based on combination of Asparagus racemosus, an immunomodulatory drug, in combination with cisplatin against Leishmania donovani infected BALB/c mice. We demonstrate that A. racemosus (650 mg/kg b.wt./day for 15 days, orally) in combination with cisplatin (5 mg/kg b.wt./day for 5 days, intraperitoneally) enhanced the clearance of parasites as determined by Giemsa-stained liver impression smears. Besides having better killing activity, this combination group achieved increased production of disease resolving Th-1 response (IFN-gamma, IL-2), heightened DTH (delayed type hypersensitivity) response and augmented levels of IgG2a. Moreover, A. racemosus in combination with cisplatin not only provided enhanced protective immune response but also resulted in remarkable improved kidney and liver function tests as manifested by normal levels of SGOT, SGPT, alkaline phosphatase, creatinine and urea in blood plasma with normal histological observations as compared to only cisplatin treated L. donovani infected BALB/c mice. Through this study we have ascertained that A. racemosus in combination with cisplatin in L. donovani infected BALB/c mice boosted as well as restored both cellular and humoral immunity. Thus in view of severe immunosuppression in visceral leishmaniasis, a better and effective strategy for optimum efficacy of future antileishmanial drugs would direct not only killing of parasite by the drug, but also simultaneous generation of immunity against the disease.

  8. p-Methoxyl-diphenyl diselenide protects against cisplatin-induced renal toxicity in mice.

    Science.gov (United States)

    Wilhelm, Ethel A; Bortolatto, Cristiani F; Nogueira, Cristina W

    2012-05-01

    The present study was designed to investigate the effects of p-methoxyl-diphenyl diselenide (OMePhSe)(2) on oxidative stress and renal damage parameters of mice exposed to cisplatin. (OMePhSe)(2) (50 and 100 mg/kg/day) was orally administered to mice for six consecutive days. On the third day after the beginning of (OMePhSe)(2) treatment, the renal toxicity was induced by injecting cisplatin (10 mg/kg intraperitoneal) in mice. (OMePhSe)(2) treatment (50 mg/kg) partially reduced plasma urea and creatinine levels increased by cisplatin. Histopathological examination of kidneys showed that (OMePhSe)(2) ameliorated renal injury caused by cisplatin. (OMePhSe)(2) attenuated the decrease in reduced glutathione (GSH) and ascorbic acid (AA) levels, the inhibition of glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and catalase (CAT) activities caused by cisplatin in kidney. (OMePhSe)(2) treatment partially protected against the inhibition of renal δ-aminolevulinic dehydratase (δ-ALA-D) activity caused by cisplatin. No alteration in renal lipid peroxidation levels was found in cisplatin and/or (OMePhSe)(2) groups. (OMePhSe)(2) was effective against the increase in reactive species (RS) levels caused by the cisplatin exposure. Based on the renoprotective and antioxidant actions of (OMePhSe)(2) we suggest that this organoselenium compound could be considered a feasible candidate to protect against toxicity commonly encountered in cisplatin exposure.

  9. Personality traits modulate emotional and physiological responses to stress.

    Science.gov (United States)

    Childs, Emma; White, Tara L; de Wit, Harriet

    2014-09-01

    An individual's susceptibility to psychological and physical disorders associated with chronic stress exposure, for example, cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease. This study examined the relationships between personality and acute responses to stress in 125 healthy adults, using hierarchical linear regression. We assessed personality traits using the Multidimensional Personality Questionnaire (MPQ-BF), and responses to acute stress (cortisol, heart rate, blood pressure, mood) using a standardized laboratory psychosocial stress task, the Trier Social Stress Test. Individuals with high Negative Emotionality exhibited greater emotional distress and lower blood pressure responses to the Trier Social Stress Test. Individuals with high agentic Positive Emotionality exhibited prolonged heart rate responses to stress, whereas those with high communal Positive Emotionality exhibited smaller cortisol and blood pressure responses. Separate personality traits differentially predicted emotional, cardiovascular, and cortisol responses to a psychosocial stressor in healthy volunteers. Future research investigating the association of personality with chronic stress-related disease may provide further clues to the relationship between acute stress reactivity and susceptibility to disease.

  10. Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity.

    Science.gov (United States)

    Bulacio, Romina Paula; Anzai, Naohiko; Ouchi, Motoshi; Torres, Adriana Mónica

    2015-08-17

    Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.

  11. Stress responses in probiotic Lactobacillus casei.

    Science.gov (United States)

    Hosseini Nezhad, Marzieh; Hussain, Malik Altaf; Britz, Margaret Lorraine

    2015-01-01

    Survival in harsh environments is critical to both the industrial performance of lactic acid bacteria (LAB) and their competitiveness in complex microbial ecologies. Among the LAB, members of the Lactobacillus casei group have industrial applications as acid-producing starter cultures for milk fermentations and as specialty cultures for the intensification and acceleration of flavor development in certain bacterial-ripened cheese varieties. They are amongst the most common organisms in the gastrointestinal (GI) tract of humans and other animals, and have the potential to function as probiotics. Whether used in industrial or probiotic applications, environmental stresses will affect the physiological status and properties of cells, including altering their functionality and biochemistry. Understanding the mechanisms of how LAB cope with different environments is of great biotechnological importance, from both a fundamental and applied perspective: hence, interaction between these strains and their environment has gained increased interest in recent years. This paper presents an overview of the important features of stress responses in Lb. casei, and related proteomic or gene expression patterns that may improve their use as starter cultures and probiotics.

  12. N-acetylcysteine improves renal hemodynamics in rats with cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Abdelrahman, Aly M; Al Salam, Suhail; AlMahruqi, Ahmed S; Al husseni, Ishaq S; Mansour, Mohamed A; Ali, Badreldin H

    2010-01-01

    This work investigated the effect of N-acetylcysteine (NAC), on renal hemodynamics in cisplatin (CP)-induced nephrotoxicity in Wistar-Kyoto (WKY) rats. The animals were divided into four groups (n = 5 or 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) N-acetylcysteine (500 mg kg(-1) per day for 9 days), respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (5 mg kg(-1)) and an i.p. injection of CP (5 mg kg(-1)) together with i.p. NAC (500 mg kg(-1) per day for 9 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE) for measurement of renal vasoconstrictor responses. CP caused a significant reduction in renal blood flow but did not affect NE-induced renal vasoconstriction. In addition, CP significantly increased plasma concentrations of urea and creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and kidney relative weight. CP decreased body weight and creatinine clearance. Histopathologically, CP caused remarkable renal damage compared with control. NAC alone did not produce any significant change in any of the variables measured. However, NAC significantly ameliorated CP-induced hemodynamic, biochemical and histopathological changes. The concentration of platinum in the kidneys of CP ? NAC treated rats was less than in CP-treated rats by 37%. The results show that administration of i.p. NAC (500 mg kg(-1) per day for 9 days) reversed the renal hemodynamic changes as well as the biochemical and histopathological indices of CP-induced nephrotoxicity in WKY rats.

  13. The Role of the Transcriptional Response to DNA Replication Stress.

    Science.gov (United States)

    Herlihy, Anna E; de Bruin, Robertus A M

    2017-03-02

    During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress checkpoint response has been well established. However, recent work has revealed an important role for transcription in the cellular response to DNA replication stress. In this review, we will provide an overview of current knowledge of the cellular response to DNA replication stress with a specific focus on the DNA replication stress checkpoint transcriptional response and its role in the prevention of replication stress-induced DNA damage.

  14. Attenuation of cisplatin induced ototoxicity by sound preonditioning through NO pathway

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective:To explore the protective effect of sound preconditioning against ototoxicity induced by cisplatin and its possible mechanism with respect to the nitric oxide (NO) pathway. Methods:Albino guinea pigs were divided into silent control, CDDP,sound preconditioning and sound preconditioning+CDDP groups. The animals of the CDDP group were injected with cisplatin intravenously 8 mg/kg b.w. The animals in the sound preconditioning were exposed to white noise at 85dB SPL, 5h/d, for 10 d (sound preconditioning). The animals in the sound preconditioning+CDDP group were treated with sound preconditioning first and then administrated with cisplatin intravenously 8 mg/kg b.w. Hearing thresholds of auditory brainstem responses (ABRs) of all animals were measured to evaluate hearing function. Hair cell loss was estimated via surface preparation. Cochlear tissue was assayed for measurement of NO level and immunohistochemistry method was used for inducible nitric oxide synthase (iNOS) analysis. Results:There was no significant difference between the silent control and sound preconditioning animals with respect to either functional or histological measures. Among the animals in the CDDP group, there was a significant elevation of threshold at the high test frequencies after administration compared with the silent control group (P<0.05). Morphological examination showed that there was obvious loss of the OHC, especially in the third row of the basal turn. The NO level and immunoreactivity to iNOS in this group were higher and more intensive than those of the silent control group (P<0.05). The ABR thresholds in the sound preconditioning + CDDP group were much lower than those of the CDDP group (P<0.05). Slight sporadic loss of OHC was found in this group. The immunoreactivity to iNOS and the level of NO in cochlea decreased significantly compared with the CDDP group (P<0. 05). Conclusion:It is suggested that sound preconditioning, to some extent, provides protective

  15. The Plant Heat Stress Transcription Factors (HSFs): Structure, Regulation, and Function in Response to Abiotic Stresses.

    Science.gov (United States)

    Guo, Meng; Liu, Jin-Hong; Ma, Xiao; Luo, De-Xu; Gong, Zhen-Hui; Lu, Ming-Hui

    2016-01-01

    Abiotic stresses such as high temperature, salinity, and drought adversely affect the survival, growth, and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological, and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs), including heat stress transcription factors (HSFs). HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps). In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

  16. The plant heat stress transcription factors (HSFs: structure, regulation and function in response to abiotic stresses

    Directory of Open Access Journals (Sweden)

    Meng eGuo

    2016-02-01

    Full Text Available Abiotic stresses such as high temperature, salinity and drought adversely affect the survival, growth and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs, including heat stress transcription factors (HSFs. HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps. In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

  17. Comparative analysis of cisplatin-induced nephrotoxicity in head and neck cancer and carcinoma cervix during concurrent chemoradiotherapy

    Directory of Open Access Journals (Sweden)

    Puneet Kumar Bagri

    2014-01-01

    Full Text Available Background: Cisplatin is widely used as radio sensitizer in head and neck cancer (HNC and carcinoma cervix (CaCx. This study aims to see comparative nephrotoxicity of cisplatin in HNC and in CaCx without obstructive uropathy treated by concurrent chemoradiotherapy (CCRT. Materials and Methods: Fifty patients of HNC and 50 patients of CaCx stage II/III without obstructive uropathy were included in this study. Cisplatin 50 mg intravenous weekly was given before EBRT with adequate hydration and premedication in both groups. Before chemotherapy; blood urea, serum creatinine, and glomerular filtration rate (GFR were measured. GFR was measured using 99m Tc diethylene triamine pentacaetic acid (DTPA renogram study. Results: At the end of 4 th week, blood urea level 41-45 mg% was in 40 and 4% in HNC and CaCx, respectively (P = 0.018. At the end of 3 rd and 4 th week, blood urea level >45 mg% was 10 and 6% in HNC cases, respectively. At the end of 4 th week, serum creatinine level 1.1-1.5 mg% was 50 and 8% in HNC and CaCx, respectively (P = 0.047. Serum creatinine level >1.5 mg% was 6, 8, and 22% in HNC at the end of 2 nd , 3 rd , and 4 th week, respectively. GFR <80 ml/min at the end of 4 th week was 14% in HNC and only 2% in CaCx. GFR <100ml/min was significant at the end of 4 th week (P = 0.04. Univariate analysis showed significant relation between reduced oral fluid intake and reduced GFR (P < 0.001. Conclusion: In HNC, during concurrent chemoradiation, as the 3 rd -4 th week is reached, oral mucosal reactions increase and affect oral intake which further add to the cisplatin-induced nephrotoxicity. In CaCx without obstructive uropathy, renal function impairment is less severe as oral intake of water and liquid is not much impaired.

  18. Personality traits modulate emotional and physiological responses to stress

    OpenAIRE

    2014-01-01

    An individual’s susceptibility to psychological and physical disorders associated with chronic stress exposure e.g., cardiovascular and infectious disease, may also be predicted by their reactivity to acute stress. One factor associated with both stress resilience and health outcomes is personality. An understanding of how personality influences responses to acute stress may shed light upon individual differences in susceptibility to chronic stress-linked disease.

  19. Role of shame and body esteem in cortisol stress responses.

    Science.gov (United States)

    Lupis, Sarah B; Sabik, Natalie J; Wolf, Jutta M

    2016-04-01

    Studies assessing the role of shame in HPA axis reactivity report mixed findings. Discrepancies may be due to methodological difficulties and inter-individual differences in the propensity to experience shame in a stressful situation. Hence, the current study combined self-report of shame and facial coding of shame expressions and assessed the role of body esteem as a moderator of the shame-stress link. For this, 44 healthy students (24F, age 20.5 ± 2.1 years) were exposed to an acute psychosocial stress paradigm (Trier Social Stress Test: TSST). Salivary cortisol levels were measured throughout the protocol. Trait shame was measured before the stress test, and state shame immediately afterwards. Video recordings of the TSST were coded to determine emotion expressions. State shame was neither associated with cortisol stress responses nor with body esteem (self-report: all ps ≥ .24; expression: all ps ≥ .31). In contrast, higher trait shame was associated with both negative body esteem (p = .049) and stronger cortisol stress responses (p = .013). Lastly, having lower body esteem predicted stronger cortisol stress responses (p = .022); however, it did not significantly moderate the association between shame indices and cortisol stress responses (all ps ≥ .94). These findings suggest that body esteem and trait shame independently contribute to strength of cortisol stress responses. Thus, in addition to trait shame, body esteem emerged as an important predictor of cortisol stress responses and as such, a potential contributor to stress-related negative health outcomes.

  20. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

    Science.gov (United States)

    Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  1. Stressors, Resources, and Stress Responses in Pregnant African American Women

    Science.gov (United States)

    Giurgescu, Carmen; Kavanaugh, Karen; Norr, Kathleen F.; Dancy, Barbara L.; Twigg, Naomi; McFarlin, Barbara L.; Engeland, Christopher G.; Hennessy, Mary Dawn; White-Traut, Rosemary C.

    2013-01-01

    This research aimed to develop an initial understanding of the stressors, stress responses, and personal resources that impact African American women during pregnancy, potentially leading to preterm birth. Guided by the ecological model, a prospective, mixed-methods, complementarity design was used with 11 pregnant women and 8 of their significant others. Our integrated analysis of quantitative and qualitative data revealed 2 types of stress responses: high stress responses (7 women) and low stress responses (4 women). Patterns of stress responses were seen in psychological stress and cervical remodeling (attenuation or cervical length). All women in the high stress responses group had high depression and/or low psychological well-being and abnormal cervical remodeling at one or both data collection times. All but 1 woman had at least 3 sources of stress (racial, neighborhood, financial, or network). In contrast, 3 of the 4 women in the low stress responses group had only 2 sources of stress (racial, neighborhood, financial, or network) and 1 had none; these women also reported higher perceived support. The findings demonstrate the importance of periodically assessing stress in African American women during pregnancy, particularly related to their support network as well as the positive supports they receive. PMID:23360946

  2. Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line.

    Science.gov (United States)

    Jeong, Hyun-Ja; Kim, Su-Jin; Moon, Phil-Dong; Kim, Na-Hyun; Kim, Jung-Sun; Park, Rae-Kil; Kim, Min-Sun; Park, Byung-Rim; Jeong, Sejin; Um, Jae-Young; Kim, Hyung-Min; Hong, Seung-Heon

    2007-03-01

    Cisplatin is a highly effective chemotherapeutic agent but with significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to an ototoxic level of cisplatin. The present study investigated the effects of the cannabinoid receptor 2 (CB2) ligand JWH-015 on cisplatin-induced apoptosis. CB2 mRNA was constitutively expressed in the auditory cell line HEI-OC1. By using MTT assay, DNA fragmentation, and FACS analysis, we demonstrated that apoptosis induced by cisplatin was inhibited by treatment with JWH-015 in a dose-dependent manner. Activation of caspase-3, caspase-8, and caspase-9 was detected after treatment with cisplatin, and the cleavage of poly-(ADP)-ribose polymerase (PARP) was observed within cisplatin-treated HEI-OC1 cells. JWH-015 inhibited the activation of caspase-3, caspase-8, and caspase-9; cleavage of PARP; and release of cytochrome c. JWH-015 also inhibited the apoptosis through activation of the extracellular signal-regulated kinase pathway. Finally, JWH-015 inhibited cisplatin-induced reactive oxygen species and tumor necrosis factor-alpha production. Collectively, these findings show that blocking a critical step in apoptosis by using JWH-015 may be a useful strategy to prevent harmful side effects of cisplatin ototoxicity in patients having to undergo chemotherapy.

  3. Salinomycin enhances cisplatin-induced cytotoxicity in human lung cancer cells via down-regulation of AKT-dependent thymidylate synthase expression.

    Science.gov (United States)

    Ko, Jen-Chung; Zheng, Hao-Yu; Chen, Wen-Ching; Peng, Yi-Shuan; Wu, Chia-Hung; Wei, Chia-Li; Chen, Jyh-Cheng; Lin, Yun-Wei

    2016-12-15

    Salinomycin, a polyether antibiotic, acts as a highly selective potassium ionophore and has anticancer activity on various cancer cell lines. Cisplatin has been proved as chemotherapy drug for advanced human non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) is a key enzyme in the pyrimidine salvage pathway, and increased expression of TS is thought to be associated with resistance to cisplatin. In this study, we showed that salinomycin (0.5-2μg/mL) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung adenocarcinoma A549 and squamous cell carcinoma H1703 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of salinomycin. A combination of cisplatin and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-AKT, and TS expression. Overexpression of a constitutive active AKT (AKT-CA) expression vector reversed the salinomycin and cisplatin-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in salinomycin and cisplatin cotreated cells. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the cisplatin-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with cisplatin for lung cancer treatment.

  4. MiR-182-5p protects inner ear hair cells from cisplatin-induced apoptosis by inhibiting FOXO3a

    Science.gov (United States)

    Li, Yimeng; Li, Ao; Wu, Jingfang; He, Yingzi; Yu, Huiqian; Chai, Renjie; Li, Huawei

    2016-01-01

    Cisplatin is widely used for chemotherapy of a variety of malignancies. However, the clinical application of cisplatin is hampered by the resultant irreversible hearing loss due to hair cell apoptosis. To date, no practical regimen to resolve this has been developed. Meanwhile, the role of microRNA in protecting hair cells from cisplatin-induced apoptosis in the inner ear has not been extensively investigated. In this study, we monitored miR-183, -96, and -182 turnover in the cochlea during cisplatin treatment in vitro. We found that overexpression of miR-182, but not miR-183 and -96, improved hair cell survival after 3 μM cisplatin treatment in vitro. We demonstrated that overexpression of miR-182 repressed the intrinsic apoptotic pathway by inhibiting the translation of FOXO3a. Our study offers a new therapeutic target for alleviating cisplatin-induced hair cell apoptosis in a rapid and tissue-specific manner. PMID:27607577

  5. Waterborne aripiprazole blunts the stress response in zebrafish

    Science.gov (United States)

    Barcellos, Heloísa Helena De Alcantara; Kalichak, Fabiana; da Rosa, João Gabriel Santos; Oliveira, Thiago Acosta; Koakoski, Gessi; Idalencio, Renan; de Abreu, Murilo Sander; Giacomini, Ana Cristina Varrone; Fagundes, Michele; Variani, Cristiane; Rossini, Mainara; Piato, Angelo L.; Barcellos, Leonardo José Gil

    2016-11-01

    Here we provide, at least to our knowledge, the first evidence that aripiprazole (APPZ) in the water blunts the stress response of exposed fish in a concentration ten times lower than the concentration detected in the environment. Although the mechanism of APPZ in the neuroendocrine axis is not yet determined, our results highlight that the presence of APPZ residues in the environment may interfere with the stress responses in fish. Since an adequate stress response is crucial to restore fish homeostasis after stressors, fish with impaired stress response may have trouble to cope with natural and/or imposed stressors with consequences to their welfare and survival.

  6. Origins of asymmetric stress-strain response in phase transformations

    Energy Technology Data Exchange (ETDEWEB)

    Sehitoglu, H.; Gall, K. [Univ. of Illinois, Urbana, IL (United States)

    1997-12-31

    It has been determined that the transformation stress-strain behavior of CuZnAl and NiTi shape memory alloys is dependent on the applied stress state. The uniaxial compressive stress necessary to macroscopically trigger the transformation is approximately 34% (CuZnAl) and 26% (NiTi) larger than the required uniaxial tensile stress. For three dimensional stress states, the response of either alloy system is dependent on the directions of the dominant principal stresses along with the hydrostatic stress component of the stress state. The stress state effects are dominated by the favored growth and nucleation of more martensite plates in tension versus compression. The effect of different hydrostatic pressure levels between stress states on martensite plates volume change is considered small.

  7. Adulthood stress responses in rats are variably altered as a factor of adolescent stress exposure.

    Science.gov (United States)

    Moore, Nicole L T; Altman, Daniel E; Gauchan, Sangeeta; Genovese, Raymond F

    2016-05-01

    Stress exposure during development may influence adulthood stress response severity. The present study investigates persisting effects of two adolescent stressors upon adulthood response to predator exposure (PE). Rats were exposed to underwater trauma (UWT) or PE during adolescence, then to PE after reaching adulthood. Rats were then exposed to predator odor (PO) to test responses to predator cues alone. Behavioral and neuroendocrine assessments were conducted to determine acute effects of each stress experience. Adolescent stress altered behavioral response to adulthood PE. Acoustic startle response was blunted. Bidirectional changes in plus maze exploration were revealed as a factor of adolescent stress type. Neuroendocrine response magnitude did not predict severity of adolescent or adult stress response, suggesting that different adolescent stress events may differentially alter developmental outcomes regardless of acute behavioral or neuroendocrine response. We report that exposure to two different stressors in adolescence may differentially affect stress response outcomes in adulthood. Acute response to an adolescent stressor may not be consistent across all stressors or all dependent measures, and may not predict alterations in developmental outcomes pertaining to adulthood stress exposure. Further studies are needed to characterize factors underlying long-term effects of a developmental stressor.

  8. Immune responses to stress in rheumatoid arthritis and psoriasis

    NARCIS (Netherlands)

    Brouwer, S.J. dr; Middendorp, H. van; Stormink, C.; Kraaimaat, F.W.; Joosten, I.; Radstake, T.R.; Jong, E.M. de; Schalkwijk, J.; Donders, A.R.; Eijsbouts, A.M.M.; Kerkhof, P.C.M. van de; Riel, P.L.C.M. van; Evers, A.W.

    2014-01-01

    OBJECTIVE: Stress is one of the factors that may exacerbate the progression of chronic inflammatory diseases such as RA and psoriasis. We exploratively compared the effects of acute stress on levels of circulating cytokines involved in disease progression and/or the stress response in patients with

  9. Regulation of Stress Responses and Translational Control by Coronavirus

    Science.gov (United States)

    Fung, To Sing; Liao, Ying; Liu, Ding Xiang

    2016-01-01

    Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER) results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed. PMID:27384577

  10. Regulation of Stress Responses and Translational Control by Coronavirus

    Directory of Open Access Journals (Sweden)

    To Sing Fung

    2016-07-01

    Full Text Available Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed.

  11. Longevity and the stress response in Drosophila

    DEFF Research Database (Denmark)

    Vermeulen, Corneel J.; Loeschcke, Volker

    2007-01-01

    to affect lifespan. The progress in modern genetic techniques has allowed researchers to test this idea. The general stress response involves the expression of stress proteins, such as chaperones and antioxidative proteins, downregulation of genes involved in energy metabolism and the release of protective......The concept that lifespan is a function of the capacity to withstand extrinsic stress is very old. In concordance with this, long-lived individuals often have increased resistance against a variety of stresses throughout life. Genes underlying the stress response may therefore have the ability...

  12. The stress response system of proteins: Implications for bioreactor scaleup

    Science.gov (United States)

    Goochee, Charles F.

    1988-01-01

    Animal cells face a variety of environmental stresses in large scale bioreactors, including periodic variations in shear stress and dissolved oxygen concentration. Diagnostic techniques were developed for identifying the particular sources of environmental stresses for animal cells in a given bioreactor configuration. The mechanisms by which cells cope with such stresses was examined. The individual concentrations and synthesis rates of hundreds of intracellular proteins are affected by the extracellular environment (medium composition, dissolved oxygen concentration, ph, and level of surface shear stress). Techniques are currently being developed for quantifying the synthesis rates and concentrations of the intracellular proteins which are most sensitive to environmental stress. Previous research has demonstrated that a particular set of stress response proteins are synthesized by mammalian cells in response to temperature fluctuations, dissolved oxygen deprivation, and glucose deprivation. Recently, it was demonstrated that exposure of human kidney cells to high shear stress results in expression of a completely distinct set of intracellular proteins.

  13. Proteomic studies of drought stress response in Fabaceae

    Directory of Open Access Journals (Sweden)

    Tanja ZADRAŽNIK

    2015-11-01

    Full Text Available Drought stress is a serious threat to crop production that influences plant growth and development and subsequently causes reduced quantity and quality of the yield. Plant stress induces changes in cell metabolism, which includes differential expression of proteins. Proteomics offer a powerful approach to analyse proteins involved in drought stress response of plants. Analyses of changes in protein abundance of legumes under drought stress are very important, as legumes play an important role in human and animal diet and are often exposed to drought. The presented results of proteomic studies of selected legumes enable better understanding of molecular mechanisms of drought stress response. The study of drought stress response of plants with proteomic approach may contribute to the development of potential drought-response markers and to the development of drought-tolerant cultivars of different legume crop species.

  14. Stress in university students and cardiovascular response to academic stressors

    OpenAIRE

    Guimarães,Teresa; Silva, Ana Patrícia; Monteiro, Iolanda; Gomes, Rui

    2014-01-01

    Introduction: University students are frequently exposed to events that can cause stress and anxiety, producing elevated cardiovascular responses. Repeated exposure to academic stress has implications to students’ success and well-being and may contribute to the development of long-term health problems. Objective: To identify stress levels and coping strategies in university students and assess the impact of stress experience in heart rate variability (HRV). Methods: 17 university students, 1...

  15. Hormonal modulation of the heat shock response: insights from fish with divergent cortisol stress responses

    DEFF Research Database (Denmark)

    LeBlanc, Sacha; Höglund, Erik; Gilmour, Kathleen M.;

    2012-01-01

    shock response, we capitalized on two lines of rainbow trout specifically bred for their high (HR) and low (LR) cortisol response to stress. We predicted that LR fish, with a low cortisol but high catecholamine response to stress, would induce higher levels of HSPs after acute heat stress than HR trout......Acute temperature stress in animals results in increases in heat shock proteins (HSPs) and stress hormones. There is evidence that stress hormones influence the magnitude of the heat shock response; however, their role is equivocal. To determine whether and how stress hormones may affect the heat....... We found that HR fish have significantly higher increases in both catecholamines and cortisol compared with LR fish, and LR fish had no appreciable stress hormone response to heat shock. This unexpected finding prevented further interpretation of the hormonal modulation of the heat shock response...

  16. The Flavonoid Apigenin Ameliorates Cisplatin-Induced Nephrotoxicity through Reduction of p53 Activation and Promotion of PI3K/Akt Pathway in Human Renal Proximal Tubular Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Sung Min Ju

    2015-01-01

    Full Text Available Apigenin is a member of the flavone subclass of flavonoids present in fruits and vegetables. Apigenin has long been considered to have various biological activities, such as antioxidant, anti-inflammatory, and antitumorigenic properties, in various cell types. Cisplatin was known to exhibit cytotoxic effect to renal cells by inducing apoptosis through activation of p53. The present study investigated the antiapoptotic effects of apigenin on the cisplatin-treated human renal proximal tubular epithelial (HK-2 cells. HK-2 cells were pretreated with apigenin (5, 10, 20 μM for 1 h and then treated with 40 μM cisplatin for various times. Apigenin inhibited the cisplatin-induced apoptosis of HK-2 cells. Interestingly, apigenin itself exerted cytostatic activity because of its ability to induce cell cycle arrest. Apigenin inhibited caspase-3 activity and PARP cleavage in cisplatin-treated cells. Apigenin reduced cisplatin-induced phosphorylation and expression of p53, with no significant influence on production of ROS that is known to induce p53 activation. Furthermore, apigenin promoted cisplatin-induced Akt phosphorylation, suggesting that enhanced Akt activation may be involved in cytoprotection. Taken together, these results suggest that apigenin ameliorates cisplatin-induced apoptosis through reduction of p53 activation and promotion of PI3K/Akt pathway in HK-2 cells.

  17. Mechanical stress induces biotic and abiotic stress responses via a novel cis-element.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2007-10-01

    Full Text Available Plants are continuously exposed to a myriad of abiotic and biotic stresses. However, the molecular mechanisms by which these stress signals are perceived and transduced are poorly understood. To begin to identify primary stress signal transduction components, we have focused on genes that respond rapidly (within 5 min to stress signals. Because it has been hypothesized that detection of physical stress is a mechanism common to mounting a response against a broad range of environmental stresses, we have utilized mechanical wounding as the stress stimulus and performed whole genome microarray analysis of Arabidopsis thaliana leaf tissue. This led to the identification of a number of rapid wound responsive (RWR genes. Comparison of RWR genes with published abiotic and biotic stress microarray datasets demonstrates a large overlap across a wide range of environmental stresses. Interestingly, RWR genes also exhibit a striking level and pattern of circadian regulation, with induced and repressed genes displaying antiphasic rhythms. Using bioinformatic analysis, we identified a novel motif overrepresented in the promoters of RWR genes, herein designated as the Rapid Stress Response Element (RSRE. We demonstrate in transgenic plants that multimerized RSREs are sufficient to confer a rapid response to both biotic and abiotic stresses in vivo, thereby establishing the functional involvement of this motif in primary transcriptional stress responses. Collectively, our data provide evidence for a novel cis-element that is distributed across the promoters of an array of diverse stress-responsive genes, poised to respond immediately and coordinately to stress signals. This structure suggests that plants may have a transcriptional network resembling the general stress signaling pathway in yeast and that the RSRE element may provide the key to this coordinate regulation.

  18. Response Inhibition and Cognitive Appraisal in Clients with Acute Stress Disorder and Posttraumatic Stress Disorder

    Directory of Open Access Journals (Sweden)

    Abass Abolghasemi

    2013-09-01

    Full Text Available Objective: The purpose of the present study was to compare response inhibition and cognitive appraisal in clients with acute stress disorder, clients with posttraumatic stress disorder, and normal individuals .Method:This was a comparative study. The sample consisted of 40 clients with acute stress disorder, 40 patients with posttraumatic stress disorder, and 40 normal individuals from Mazandaran province selected through convenience sampling method. Data were collected using Composite International Diagnostic Interview, Stroop Color-Word Test, Posttraumatic Cognitions Inventory, and the Impact of Event Scale. Results:Results showed that individuals with acute stress disorder are less able to inhibit inappropriate responses and have more impaired cognitive appraisals compared to those with posttraumatic stress disorder. Moreover, results showed that response inhibition and cognitive appraisal explain 75% of the variance in posttraumatic stress disorder symptoms and 38% of the variance in posttraumatic stress disorder symptoms .Conclusion:The findings suggest that response inhibition and cognitive appraisal are two variables that influence the severity of posttraumatic stress disorder and acute stress disorder symptoms. Also, these results have important implications for pathology, prevention, and treatment of posttraumatic stress disorder and acute stress disorder

  19. Phosphate-dependent root system architecture responses to salt stress

    KAUST Repository

    Kawa, Dorota

    2016-05-20

    Nutrient availability and salinity of the soil affect growth and development of plant roots. Here, we describe how phosphate availability affects root system architecture (RSA) of Arabidopsis and how phosphate levels modulate responses of the root to salt stress. Phosphate (Pi) starvation reduced main root length and increased the number of lateral roots of Arabidopsis Col-0 seedlings. In combination with salt, low Pi dampened the inhibiting effect of mild salt stress (75mM) on all measured RSA components. At higher NaCl concentrations, the Pi deprivation response prevailed over the salt stress only for lateral root elongation. The Pi deprivation response of lateral roots appeared to be oppositely affected by abscisic acid (ABA) signaling compared to the salt stress response. Natural variation in the response to the combination treatment of salt and Pi starvation within 330 Arabidopsis accessions could be grouped into four response patterns. When exposed to double stress, in general lateral roots prioritized responses to salt, while the effect on main root traits was additive. Interestingly, these patterns were not identical for all accessions studied and multiple strategies to integrate the signals from Pi deprivation and salinity were identified. By Genome Wide Association Mapping (GWAS) 13 genomic loci were identified as putative factors integrating responses to salt stress and Pi starvation. From our experiments, we conclude that Pi starvation interferes with salt responses mainly at the level of lateral roots and that large natural variation exists in the available genetic repertoire of accessions to handle the combination of stresses.

  20. Effects of orthostasis on endocrine responses to psychosocial stress.

    Science.gov (United States)

    Nater, Urs M; Ditzen, Beate; Strahler, Jana; Ehlert, Ulrike

    2013-12-01

    Standardized psychological procedures have been designed to induce physiological stress responses. However, the impact of standing (orthostasis) on the physiological reaction after psychological stress remains unclear. The purpose of the current analysis was to examine and quantify the relative contribution of orthostasis to the physiological stress response by comparing a "standing with stress" to a "standing without stress" condition. We investigated the effect of standing with and without stress on responses of the sympathetic-adrenomedullary (SAM) system and the hypothalamic-pituitary-adrenal (HPA) axis using a standardized psychosocial stress protocol (Trier Social Stress Test) and a non-stress condition in a repeated measures design. Subjects (N=30) were exposed to both conditions in randomized order and had to maintain a standing, upright position for 10minutes. In the "standing with stress" condition, significant increases in repeatedly assessed plasma norepinephrine (NE) and epinephrine (EP), as well as in saliva cortisol were found, while in the "standing without stress" condition, no significant changes in plasma epinephrine and saliva cortisol were observed. Calculations of the relative contribution of orthostasis to physiological stress responses revealed that 25.61% of the NE increase, 82.94% of the EP increase, and 68.91% of the cortisol increase, could be attributed to psychosocial stress adjusted for the effects of orthostasis and basal endocrine output. Although these results are indicative for a marked endocrine reaction that is caused by psychosocial stress alone, our findings show that the contribution of orthostasis must be taken into account when interpreting endocrine data collected in a psychosocial stress test.

  1. Disrupted glucocorticoid--Immune interactions during stress response in schizophrenia.

    Science.gov (United States)

    Chiappelli, Joshua; Shi, Qiaoyun; Kodi, Priyadurga; Savransky, Anya; Kochunov, Peter; Rowland, Laura M; Nugent, Katie L; Hong, L Elliot

    2016-01-01

    Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid-immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both pschizophrenia patients (r=.379, p=.027). The trends were significantly different (Z=3.7, p=.0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia.

  2. Stretching the Stress Boundary: Linking Air Pollution Health Effects to a Neurohormonal Stress Response

    Science.gov (United States)

    Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer’s and diabetes. A neurohormonal stress response (referred here as a systemic response produced by activ...

  3. Morphologic effects of the stress response in fish.

    Science.gov (United States)

    Harper, Claudia; Wolf, Jeffrey C

    2009-01-01

    Fish and other aquatic animals are subject to a broad variety of stressors because their homeostatic mechanisms are highly dependent on prevailing conditions in their immediate surroundings. Yet few studies have addressed stress as a potential confounding factor for bioassays that use fish as test subjects. Common stressors encountered by captive fish include physical and mental trauma associated with capture, transport, handling, and crowding; malnutrition; variations in water temperature, oxygen, and salinity; and peripheral effects of contaminant exposure or infectious disease. Some stress responses are detectable through gross or microscopic examination of various organs or tissues; as reported in the literature, stress responses are most consistently observed in the gills, liver, skin, and components of the urogenital tract. In addition to presenting examples of various stressors and corresponding morphologic effects, this review highlights certain challenges of evaluating stress in fish: (1) stress is an amorphous term that does not have a consistently applied definition; (2) procedures used to determine or measure stress can be inherently stressful; (3) interactions between stressors and stress responses are highly complex; and (4) morphologically, stress responses are often difficult to distinguish from tissue damage or compensatory adaptations induced specifically by the stressor. Further investigations are necessary to more precisely define the role of stress in the interpretation of fish research results.

  4. Stress Response and Perinatal Reprogramming: Unraveling (Maladaptive Strategies

    Directory of Open Access Journals (Sweden)

    Laura Musazzi

    2016-01-01

    Full Text Available Environmental stressors induce coping strategies in the majority of individuals. The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders. Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (maladaptations. Indeed, adverse experiences in early life are known to induce long-term stress-related neuropsychiatric disorders in vulnerable individuals. Here, we discuss recent findings about stress remodeling of excitatory neurotransmission and brain morphology in animal models of behavioral stress. These changes are likely driven by epigenetic factors that lie at the core of the stress-response reprogramming in individuals with a history of perinatal stress. We propose that reprogramming mechanisms may underlie the reorganization of excitatory neurotransmission in the short- and long-term response to stressful stimuli.

  5. Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney.

    Science.gov (United States)

    Domitrović, Robert; Cvijanović, Olga; Pugel, Ester Pernjak; Zagorac, Gordana Blagojević; Mahmutefendić, Hana; Škoda, Marko

    2013-08-09

    The aim of this study was to investigate the effects of flavone luteolin against cisplatin (CP)-induced kidney injury in mice. Luteolin at doses of 10mg/kg was administered intraperitoneally (ip) once daily for 3 days following single CP (10 or 20mg/kg) ip injection. Mice were sacrificed 24h after the last dose of luteolin. The CP treatment significantly increased serum creatinine and blood urea nitrogen and induced pathohistological changes in the kidneys. Renal oxidative/nitrosative stress was evidenced by decreased glutathione (GSH) levels and increased 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) formation as well as cytochrome P450 2E1 (CYP2E1) expression. The CP administration triggered inflammatory response in mice kidneys through activation of nuclear factor-kappaB (NF-κB) and overexpression of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). Simultaneously, the increase in renal p53 and caspase-3 expression indicated apoptosis of tubular cells. The administration of luteolin significantly reduced histological and biochemical changes induced by CP, decreased platinum (Pt) levels and suppressed oxidative/nitrosative stress, inflammation and apoptosis in the kidneys. These results suggest that luteolin is an effective nephroprotective agent, with potential to reduce Pt accumulation in the kidneys and ameliorate CP-induced nephrotoxicity.

  6. Involvement of Histone Modifications in Plant Abiotic Stress Responses

    Institute of Scientific and Technical Information of China (English)

    Lianyu Yuan; Xuncheng Liu; Ming Luo; Songguang Yang; Keqiang Wu

    2013-01-01

    As sessile organisms, plants encounter various environmental stimuli including abiotic stresses during their lifecycle. To survive under adverse conditions, plants have evolved intricate mechanisms to perceive external signals and respond accordingly. Responses to various stresses largely depend on the plant capacity to modulate the transcriptome rapidly and specifically. A number of studies have shown that the molecular mechanisms driving the responses of plants to environmental stresses often depend on nucleosome histone post-translational modifications including histone acetylation, methylation, ubiquitination, and phosphorylation. The combined effects of these modifications play an essential role in the regulation of stress responsive gene expression. In this review, we highlight our current understanding of the epigenetic mechanisms of histone modifications and their roles in plant abiotic stress response.

  7. Post-stress rumination predicts HPA axis responses to repeated acute stress.

    Science.gov (United States)

    Gianferante, Danielle; Thoma, Myriam V; Hanlin, Luke; Chen, Xuejie; Breines, Juliana G; Zoccola, Peggy M; Rohleder, Nicolas

    2014-11-01

    Failure of the hypothalamus-pituitary-adrenal (HPA) axis to habituate to repeated stress exposure is related with adverse health outcomes, but our knowledge of predictors of non-habituation is limited. Rumination, defined as repetitive and unwanted past-centered negative thinking, is related with exaggerated HPA axis stress responses and poor health outcomes. The aim of this study was to test whether post-stress rumination was related with non-habituation of cortisol to repeated stress exposure. Twenty-seven participants (n=13 females) were exposed to the Trier Social Stress Test (TSST) twice on consecutive afternoons. Post-stress rumination was measured after the first TSST, and HPA axis responses were assessed by measuring salivary cortisol 1 min before, and 1, 10, 20, 60, and 120 min after both TSSTs. Stress exposure induced HPA axis activation on both days, and this activation showed habituation indicated by lower responses to the second TSST (F=3.7, p=0.015). Post-stress rumination after the first TSST was associated with greater cortisol reactivity after the initial stress test (r=0.45, pHPA axis responses. This finding implicates rumination as one possible mechanism mediating maladaptive stress response patterns, and it might also offer a pathway through which rumination might lead to negative health outcomes.

  8. Nitric Oxide Signaling in Plant Responses to Abiotic Stresses

    Institute of Scientific and Technical Information of China (English)

    Weihua Qiao; LiuMin Fan

    2008-01-01

    Nitric oxide (NO) plays important roles in diverse physiological processes In plants. NO can provoke both beneficial and harmful effects, which depend on the concentration and location of NO in plant cells. This review is focused on NO synthesis and the functions of NO in plant responses to abiotic environmental stresses. Abiotic stresses mostly induce NO production in plants. NO alleviates the harmfulness of reactive oxygen species, and reacts with other target molecules, and regulates the expression of stress responsive genes under various stress conditions.

  9. EVALUATION OF CISPLATIN-INDUCED PICA BEHAVIOUR IN RATS BY MEASURING FAECAL CARMINE-DYE EXCRETION: AN IMPROVED EXPERIMENTAL MODEL TO SCREEN SAMPLES WITH ANTI-EMETIC PROPERTIES

    Directory of Open Access Journals (Sweden)

    Rajesh S.

    2012-02-01

    Full Text Available The objective of the present study is to evaluate the Cisplatin-induced pica behaviour in rats by measuring faecal carmine dye excretion and to evaluate the anti-emetic effect of drugs on Cisplatin-induced pica behaviour in rats. Thirty-two rats were divided into 4 groups of 8 animals each. Rats from group I and II received DM water (10ml/kg p.o. Rats from group III and IV received Himalaya Anti-emetic Tablets (HAT 250 mg/kg p.o. and ondansetron 4mg/kg p.o, respectively. After one hour of the assigned treatment, all the animals except in group I were injected with Cisplatin 3mg/kg i.p. Rats in group I were injected with saline (1ml/kg i.p.. All the animals were fed with normal as well as kaolin pellets (impregnated with carmine dye. The faeces of each rat was collected after 72 hrs of drug administration and analysed for the carmine content.Cisplatin injection (3mg/kg caused a significant increase in kaolin consumption, which was indicated by increased carmine dye excretion in faeces compared to control. Pre-treatment with HAT and ondansetron significantly suppressed kaolin consumption induced by Cisplatin. The present findings showed that the exact kaolin consumption can be quantified by measuring the faecal excretion of carmine, which was added in kaolin pellets and this can be a sensitive model to study the anti-emetic potential of drugs, overcoming the inherent disadvantages of measuring direct kaolin intake. Pre-treatment with ondansetron and HAT significantly decreased kaolin consumption in rats-induced by Cisplatin injection, which was further shown by decrease in faecal excretion of carmine, indicating anti-emetic potential of tested drugs.

  10. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China); Xia, Qiang, E-mail: xiaqiang1@yahoo.com.cn [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  11. Dynamical theory of active cellular response to external stress.

    Science.gov (United States)

    De, Rumi; Safran, Samuel A

    2008-09-01

    We present a comprehensive, theoretical treatment of the orientational response to external stress of active, contractile cells embedded in a gel-like elastic medium. The theory includes both the forces that arise from the deformation of the matrix as well as forces due to the internal regulation of the stress fibers and focal adhesions of the cell. We calculate the time-dependent response of both the magnitude and the direction of the elastic dipole that characterizes the active forces exerted by the cell, for various situations. For static or quasistatic external stress, cells orient parallel to the stress while for high frequency dynamic external stress, cells orient nearly perpendicular. Both numerical and analytical calculations of these effects are presented. In addition we predict the relaxation time for the cellular response for both slowly and rapidly varying external stresses; several characteristic scaling regimes for the relaxation time as a function of applied frequency are predicted. We also treat the case of cells for which the regulation of the stress fibers and focal adhesions is controlled by strain (instead of stress) and show that the predicted dependence of the cellular orientation on the Poisson ratio of the matrix can differentiate strain vs stress regulation of cellular response.

  12. Dynamical theory of active cellular response to external stress

    Science.gov (United States)

    de, Rumi; Safran, Samuel A.

    2008-09-01

    We present a comprehensive, theoretical treatment of the orientational response to external stress of active, contractile cells embedded in a gel-like elastic medium. The theory includes both the forces that arise from the deformation of the matrix as well as forces due to the internal regulation of the stress fibers and focal adhesions of the cell. We calculate the time-dependent response of both the magnitude and the direction of the elastic dipole that characterizes the active forces exerted by the cell, for various situations. For static or quasistatic external stress, cells orient parallel to the stress while for high frequency dynamic external stress, cells orient nearly perpendicular. Both numerical and analytical calculations of these effects are presented. In addition we predict the relaxation time for the cellular response for both slowly and rapidly varying external stresses; several characteristic scaling regimes for the relaxation time as a function of applied frequency are predicted. We also treat the case of cells for which the regulation of the stress fibers and focal adhesions is controlled by strain (instead of stress) and show that the predicted dependence of the cellular orientation on the Poisson ratio of the matrix can differentiate strain vs stress regulation of cellular response.

  13. Association between neuroticism and amygdala responsivity emerges under stressful conditions.

    Science.gov (United States)

    Everaerd, Daphne; Klumpers, Floris; van Wingen, Guido; Tendolkar, Indira; Fernández, Guillén

    2015-05-15

    Increased amygdala reactivity in response to salient stimuli is seen in patients with affective disorders, in healthy subjects at risk for these disorders, and in stressed individuals, making it a prime target for mechanistic studies into the pathophysiology of affective disorders. However, whereas individual differences in neuroticism are thought to modulate the effect of stress on mental health, the mechanistic link between stress, neuroticism and amygdala responsivity is unknown. Thus, we studied the relationship between experimentally induced stress, individual differences in neuroticism, and amygdala responsivity. To this end, fearful and happy faces were presented to a large cohort of young, healthy males (n=120) in two separate functional MRI sessions (stress versus control) in a randomized, controlled cross-over design. We revealed that amygdala reactivity was modulated by an interaction between the factors of stress, neuroticism, and the emotional valence of the facial stimuli. Follow-up analysis showed that neuroticism selectively enhanced amygdala responses to fearful faces in the stress condition. Thus, we show that stress unmasks an association between neuroticism and amygdala responsivity to potentially threatening stimuli. This effect constitutes a possible mechanistic link within the complex pathophysiology of affective disorders, and our novel approach appears suitable for further studies targeting the underlying mechanisms.

  14. Influence of surface stresses on indentation response

    Science.gov (United States)

    Buchwald, J.; Mayr, S. G.

    2015-03-01

    Surface stresses lead to an effective change in the elastic constants of thin films and at surfaces. The development of modern scanning probe techniques like contact resonance atomic force microscopy empowers the experimenter to measure at scales where these effects become increasingly relevant. In this paper we employ a computational multiscale approach where we compare density functional theory (DFT) and molecular dynamics simulations as tools to calculate the thin-film/surface elastic behavior for silicon and strontiumtitanate. From the surface elastic constants gained by DFT calculations we develop a continuum finite-element multilayer model to study the impact of surface stresses on indentation experiments. In general the stress field of an indenter and thus the impact of surface stresses on the indentation modulus depends on its contact radius and on its particular shape. We propose an analytical model that describes the behavior of the indentation modulus as a function of the contact radius. We show that this model fits well to simulation results gained for a spherical and a flat punch indenter. Our results demonstrate a surface-stress-induced reduction of the indentation modulus of about 5% for strontiumtitanate and 6% for silicon for a contact radius of {{r}c}=5 \\text{nm}, irrespective of the indenter shape.

  15. Stress Response and Translation Control in Rotavirus Infection

    Directory of Open Access Journals (Sweden)

    Susana López

    2016-06-01

    Full Text Available The general stress and innate immune responses are closely linked and overlap at many levels. The outcomes of these responses serve to reprogram host expression patterns to prevent viral invasions. In turn, viruses counter attack these cell responses to ensure their replication. The mechanisms by which viruses attempt to control host cell responses are as varied as the number of different virus families. One of the most recurrent strategies used by viruses to control the antiviral response of the cell is to hijack the translation machinery of the host, such that viral proteins are preferentially synthesized, while the expression of the stress and antiviral responses of the cell are blocked at the translation level. Here, we will review how rotaviruses, an important agent of acute severe gastroenteritis in children, overcome the stress responses of the cell to establish a productive infectious cycle.

  16. Stress Response and Translation Control in Rotavirus Infection

    Science.gov (United States)

    López, Susana; Oceguera, Alfonso; Sandoval-Jaime, Carlos

    2016-01-01

    The general stress and innate immune responses are closely linked and overlap at many levels. The outcomes of these responses serve to reprogram host expression patterns to prevent viral invasions. In turn, viruses counter attack these cell responses to ensure their replication. The mechanisms by which viruses attempt to control host cell responses are as varied as the number of different virus families. One of the most recurrent strategies used by viruses to control the antiviral response of the cell is to hijack the translation machinery of the host, such that viral proteins are preferentially synthesized, while the expression of the stress and antiviral responses of the cell are blocked at the translation level. Here, we will review how rotaviruses, an important agent of acute severe gastroenteritis in children, overcome the stress responses of the cell to establish a productive infectious cycle. PMID:27338442

  17. Stress Generation and Adolescent Depression: Contribution of Interpersonal Stress Responses

    Science.gov (United States)

    Flynn, Megan; Rudolph, Karen D.

    2011-01-01

    This research examined the proposal that ineffective responses to common interpersonal problems disrupt youths' relationships, which, in turn, contributes to depression during adolescence. Youth (86 girls, 81 boys; M age = 12.41, SD = 1.19) and their primary female caregivers participated in a three-wave longitudinal study. Youth completed a…

  18. Oxidative stress response after laparoscopic versus conventional sigmoid resection

    DEFF Research Database (Denmark)

    Madsen, Michael Tvilling; Kücükakin, Bülent; Lykkesfeldt, Jens;

    2012-01-01

    Surgery is accompanied by a surgical stress response, which results in increased morbidity and mortality. Oxidative stress is a part of the surgical stress response. Minimally invasive laparoscopic surgery may result in reduced oxidative stress compared with open surgery. Nineteen patients...... scheduled for sigmoid resection were randomly allocated to open or laparoscopic sigmoid resection in a double-blind, prospective clinical trial. Three biochemical markers of oxidative stress (malondialdehyde, ascorbic acid, and dehydroascorbic acid) were measured at 6 different time points (preoperatively......, 1 h, 6 h, 24 h, 48 h, and 72 h postoperatively). There were no statistical significant differences between laparoscopic and open surgery for any of the 3 oxidative stress parameters. Malondialdehyde was reduced 1 hour postoperatively (P...

  19. Acute Stress Response in Critically Ill Children

    NARCIS (Netherlands)

    M. den Brinker (Marieke)

    2006-01-01

    textabstractThe understanding of the endocrine changes in critically ill children is important, as it provides insights in the pathophysiology of the acute stress in children and its differences compared with adults. Furthermore, it delineates prognostic factors for survival and supports the rati

  20. Quantification of Bacillus cereus stress responses

    NARCIS (Netherlands)

    Besten, den H.M.W.

    2010-01-01

    The microbial stability and safety of minimally processed foods is controlled by a deliberate combination of preservation hurdles. However, this preservation strategy is challenged by the ability of spoilage bacteria and food-borne pathogens to adapt to stressing environments providing cell robustne

  1. Cell Wall Metabolism in Response to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Hyacinthe Le Gall

    2015-02-01

    Full Text Available This review focuses on the responses of the plant cell wall to several abiotic stresses including drought, flooding, heat, cold, salt, heavy metals, light, and air pollutants. The effects of stress on cell wall metabolism are discussed at the physiological (morphogenic, transcriptomic, proteomic and biochemical levels. The analysis of a large set of data shows that the plant response is highly complex. The overall effects of most abiotic stress are often dependent on the plant species, the genotype, the age of the plant, the timing of the stress application, and the intensity of this stress. This shows the difficulty of identifying a common pattern of stress response in cell wall architecture that could enable adaptation and/or resistance to abiotic stress. However, in most cases, two main mechanisms can be highlighted: (i an increased level in xyloglucan endotransglucosylase/hydrolase (XTH and expansin proteins, associated with an increase in the degree of rhamnogalacturonan I branching that maintains cell wall plasticity and (ii an increased cell wall thickening by reinforcement of the secondary wall with hemicellulose and lignin deposition. Taken together, these results show the need to undertake large-scale analyses, using multidisciplinary approaches, to unravel the consequences of stress on the cell wall. This will help identify the key components that could be targeted to improve biomass production under stress conditions.

  2. Cortisol stress responses and children's behavioral functioning at school

    NARCIS (Netherlands)

    Simons, S.S.H.; Cillessen, A.H.N.; Weerth, C. de

    2017-01-01

    The present study investigated whether cortisol stress responses of 6-year-olds were associated with their behavioral functioning at school. Additionally, the moderating role of stress in the family environment was examined. To this end, 149 healthy children (Magen=n6.09 years; 70 girls) participate

  3. Differentiating anticipatory from reactive cortisol responses to psychosocial stress

    NARCIS (Netherlands)

    Engert, V.; Efanov, S.I.; Duchesne, A.; Vogel, S.; Corbo, V.; Pruessner, J.C.

    2013-01-01

    Most psychosocial stress studies assess the overall cortisol response without further identifying the temporal dynamics within hormone levels. It has been shown, however, that the amplitude of anticipatory cortisol stress levels has a unique predictive value for psychological health. So far, no "bes

  4. Traumatic Experience in Infancy: How Responses to Stress Affect Development

    Science.gov (United States)

    Witten, Molly Romer

    2010-01-01

    Responses to traumatic stress during the earliest years of life can change quickly and can be difficult to identify because of the young child's rapid rate of development. The symptoms of traumatic stress will depend on the child's developmental level and individual coping styles, as well as the quality and nature of the child's most important…

  5. Quorum Sensing Enhances the Stress Response in Vibrio cholerae▿

    OpenAIRE

    Joelsson, Adam; Kan, Biao; Zhu, Jun

    2007-01-01

    Vibrio cholerae lives in aquatic environments and causes cholera. Here, we show that quorum sensing enhances V. cholerae viability under certain stress conditions by upregulating the expression of RpoS, and this regulation acts through HapR, suggesting that a quorum-sensing-enhanced stress response plays a role in V. cholerae environmental survival.

  6. Personality, Stressful Life Events, and Treatment Response in Major Depression

    Science.gov (United States)

    Bulmash, Eric; Harkness, Kate L.; Stewart, Jeremy G.; Bagby, R. Michael

    2009-01-01

    The current study examined whether the personality traits of self-criticism or dependency moderated the effect of stressful life events on treatment response. Depressed outpatients (N = 113) were randomized to 16 weeks of cognitive-behavioral therapy, interpersonal psychotherapy, or antidepressant medication (ADM). Stressful life events were…

  7. The psychophysiological stress response in psoriasis and rheumatoid arthritis

    NARCIS (Netherlands)

    Brouwer, S.J.M. de; Middendorp, H. van; Stormink, C.; Kraaimaat, F.W.; Sweep, F.C.; Jong, E.M.G.J. de; Schalkwijk, J.; Eijsbouts, A.M.M.; Donders, A.R.T.; Kerkhof, P.C.M. van de; Riel, P.L.C.M. van; Evers, A.W.M.

    2014-01-01

    BACKGROUND: Psychosocial stress can be a risk factor for the maintenance and exacerbation of chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis (RA). OBJECTIVES: To gain insight into the specificity of the psychophysiological stress response during chronic inflammation, we ass

  8. Stability analysis of Reynolds stress response functional candidates

    Energy Technology Data Exchange (ETDEWEB)

    Dafinger, M.; Hallatschek, K. [Max-Planck-Institute for Plasma Physics, EURATOM-IPP Association, Garching (Germany); Itoh, K. [National Institute for Fusion Science, Toki 509-5292 (Japan)

    2013-04-15

    Complete information on the behavior of zonal flows in turbulence systems is coded in the turbulent stress response to the respective flow pattern. We show that turbulence stress response functionals containing only the linear first order wavenumber dependence on the flow pattern result in unstable structures up to the system size. A minimal augmentation to reproduce the flow patterns observed in turbulence simulations is discussed.

  9. Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women.

    Science.gov (United States)

    Lupis, Sarah B; Lerman, Michelle; Wolf, Jutta M

    2014-11-01

    While previous research has suggested that anger and fear responses to stress are linked to distinct sympathetic nervous system (SNS) stress responses, little is known about how these emotions predict hypothalamus-pituitary-adrenal (HPA) axis reactivity. Further, earlier research primarily relied on retrospective self-report of emotion. The current study aimed at addressing both issues in male and female individuals by assessing the role of anger and fear in predicting heart rate and cortisol stress responses using both self-report and facial coding analysis to assess emotion responses. We exposed 32 healthy students (18 female; 19.6±1.7 yr) to an acute psychosocial stress paradigm (TSST) and measured heart rate and salivary cortisol levels throughout the protocol. Anger and fear before and after stress exposure was assessed by self-report, and video recordings of the TSST were assessed by a certified facial coder to determine emotion expression (FACS). Self-reported emotions and emotion expressions did not correlate (all p>.23). Increases in self-reported fear predicted blunted cortisol responses in men (β=0.41, p=.04). Also for men, longer durations of anger expression predicted exaggerated cortisol responses (β=0.67 p=.004), and more anger incidences predicted exaggerated cortisol and heart rate responses (β=0.51, p=.033; β=0.46, p=.066, resp.). Anger and fear did not predict SNS or HPA activity for females (all p>.23). The current differential self-report and facial coding findings support the use of multiple modes of emotion assessment. Particularly, FACS but not self-report revealed a robust anger-stress association that could have important downstream health effects for men. For women, future research may clarify the role of other emotions, such as self-conscious expressions of shame, for physiological stress responses. A better understanding of the emotion-stress link may contribute to behavioral interventions targeting health-promoting ways of

  10. Context and strain-dependent behavioral response to stress

    Directory of Open Access Journals (Sweden)

    Baum Amber E

    2008-06-01

    Full Text Available Abstract Background This study posed the question whether strain differences in stress-reactivity lead to differential behavioral responses in two different tests of anxiety. Strain differences in anxiety-measures are known, but strain differences in the behavioral responses to acute prior stress are not well characterized. Methods We studied male Fisher 344 (F344 and Wistar Kyoto (WKY rats basally and immediately after one hour restraint stress. To distinguish between the effects of novelty and prior stress, we also investigated behavior after repeated exposure to the test chamber. Two behavioral tests were explored; the elevated plus maze (EPM and the open field (OFT, both of which are thought to measure activity, exploration and anxiety-like behaviors. Additionally, rearing, a voluntary behavior, and grooming, a relatively automatic, stress-responsive stereotyped behavior were measured in both tests. Results Prior exposure to the test environment increased anxiety-related measures regardless of prior stress, reflecting context-dependent learning process in both tests and strains. Activity decreased in response to repeated testing in both tests and both strains, but prior stress decreased activity only in the OFT which was reversed by repeated testing. Prior stress decreased anxiety-related measures in the EPM, only in F344s, while in the OFT, stress led to increased freezing mainly in WKYs. Conclusion Data suggest that differences in stressfulness of these tests predict the behavior of the two strains of animals according to their stress-reactivity and coping style, but that repeated testing can overcome some of these differences.

  11. Plant Responses to Salt Stress: Adaptive Mechanisms

    Directory of Open Access Journals (Sweden)

    Jose Ramón Acosta-Motos

    2017-02-01

    Full Text Available This review deals with the adaptive mechanisms that plants can implement to cope with the challenge of salt stress. Plants tolerant to NaCl implement a series of adaptations to acclimate to salinity, including morphological, physiological and biochemical changes. These changes include increases in the root/canopy ratio and in the chlorophyll content in addition to changes in the leaf anatomy that ultimately lead to preventing leaf ion toxicity, thus maintaining the water status in order to limit water loss and protect the photosynthesis process. Furthermore, we deal with the effect of salt stress on photosynthesis and chlorophyll fluorescence and some of the mechanisms thought to protect the photosynthetic machinery, including the xanthophyll cycle, photorespiration pathway, and water-water cycle. Finally, we also provide an updated discussion on salt-induced oxidative stress at the subcellular level and its effect on the antioxidant machinery in both salt-tolerant and salt-sensitive plants. The aim is to extend our understanding of how salinity may affect the physiological characteristics of plants.

  12. Low-stress and high-stress singing have contrasting effects on glucocorticoid response

    Directory of Open Access Journals (Sweden)

    Daisy eFancourt

    2015-09-01

    Full Text Available Performing music in public is widely recognised as a potentially stress-inducing activity. However, despite the interest in music performance as an acute psychosocial stressor, there has been relatively little research on the effects of public performance on the endocrine system. This study examined the impact of singing in a low-stress performance situation and a high-stress live concert on levels of glucocorticoids (cortisol and cortisone in 15 professional singers. The results showed a significant decrease in both cortisol and cortisone across the low-stress condition, suggesting that singing in itself is a stress-reducing (and possibly health-promoting activity, but significant increases across the high-stress condition. This is the first study to demonstrate that singing affects glucocorticoid responses and that these responses are modulated by the conditions of performance.

  13. Research Progress in Tomato Responses to Abiotic Stress

    Institute of Scientific and Technical Information of China (English)

    Jianing XU; Gang LIU; Liyun ZHANG

    2016-01-01

    Tomato is a kind of vegetable with high economic benefits in protected farmland.Accounting for 30% of vegetable planting area in the entire protected farmland,tomato plays an essential role in cultivation of protected vegetable.Different abiotic stresses have different degrees of influence on growth and development,yield,and fruit quality of tomatoes.Therefore,finding out life activity rules of tomatoes under different abiotic stresses will be of great significance to breeding for stress tolerance and increasing tomato yield and income.This paper made an overview of research progress in tomato responses to abiotic stress in growth and development,physiology and biochemistry,and gene regulation.

  14. Recent Molecular Advances on Downstream Plant Responses to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Cláudia Regina Batista de Souza

    2012-07-01

    Full Text Available Abiotic stresses such as extremes of temperature and pH, high salinity and drought, comprise some of the major factors causing extensive losses to crop production worldwide. Understanding how plants respond and adapt at cellular and molecular levels to continuous environmental changes is a pre-requisite for the generation of resistant or tolerant plants to abiotic stresses. In this review we aimed to present the recent advances on mechanisms of downstream plant responses to abiotic stresses and the use of stress-related genes in the development of genetically engineered crops.

  15. When does stress help or harm? The effects of stress controllability and subjective stress response on Stroop performance.

    Directory of Open Access Journals (Sweden)

    Roselinde Kaiser Henderson

    2012-06-01

    Full Text Available The ability to engage in goal-directed behavior despite exposure to stress is critical to resilience. Questions of how stress can impair or improve behavioral functioning are important in diverse settings, from athletic competitions to academic testing to clinical therapy. Previous research suggests that controllability is a key factor in the impact of stress on behavior: learning how to control stressors buffers people from the negative effects of stress on subsequent cognitively demanding tasks. In addition, research suggests that the impact of stress on cognitive functioning depends on an individual’s response to stressors: moderate responses to stress can lead to improved performance while extreme (high or low responses can lead to impaired performance. The present studies tested the hypothesis that 1 learning to behaviorally control stressors leads to improved performance on a test of general executive functioning, the color-word Stroop, and that 2 this improvement emerges specifically for people who report moderate (subjective responses to stress. Experiment 1: Stroop performance, measured before and after a stress manipulation, was compared across groups of undergraduate participants (n=109. People who learned to control a noise stressor and received accurate performance feedback demonstrated reduced Stroop interference compared with people exposed to uncontrollable noise stress and feedback indicating an exaggerated rate of failure. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest reduction in Stroop interference. In contrast, in the group exposed to uncontrollable events, self-reported stress failed to predict performance. Experiment 2: In a second sample (n=90, we specifically investigated the role of controllability by keeping the rate of failure feedback constant across groups. In the group who learned behavioral control, those who reported moderate levels of stress

  16. Heart rate variability response to mental arithmetic stress in patients with schizophrenia Autonomic response to stress in schizophrenia

    NARCIS (Netherlands)

    Castro, Mariana N.; Vigo, Daniel E.; Weidema, Hylke; Fahrer, Rodolfo D.; Chu, Elvina M.; De Achaval, Delfina; Nogues, Martin; Leiguarda, Ramon C.; Cardinali, Daniel P.; Guinjoan, Salvador N.

    2008-01-01

    Background: The vulnerability-stress hypothesis is an established model of schizophrenia symptom formation. We sought to characterise the pattern of the cardiac autonomic response to mental arithmetic stress in patients with stable schizophrenia. Methods: We performed heart rate variability (HRV) an

  17. Regulation of abiotic and biotic stress responses by plant hormones

    DEFF Research Database (Denmark)

    Grosskinsky, Dominik Kilian; van der Graaff, Eric; Roitsch, Thomas Georg

    2016-01-01

    Plant hormones (phytohormones) are signal molecules produced within the plant, and occur in very low concentrations. In the present chapter, the current knowledge on the regulation of biotic and biotic stress responses by plant hormones is summarized with special focus on the novel insights into ...... through ubiquitination. The wide range of biotic and abiotic stresses that affect crop plants limits agricultural production.......Plant hormones (phytohormones) are signal molecules produced within the plant, and occur in very low concentrations. In the present chapter, the current knowledge on the regulation of biotic and biotic stress responses by plant hormones is summarized with special focus on the novel insights...

  18. Modulation of immune responses in stress by Yoga

    Directory of Open Access Journals (Sweden)

    Arora Sarika

    2008-01-01

    Full Text Available Stress is a constant factor in today′s fastpaced life that can jeopardize our health if left unchecked. It is only in the last half century that the role of stress in every ailment from the common cold to AIDS has been emphasized, and the mechanisms involved in this process have been studied. Stress influences the immune response presumably through the activation of the hypothalamic-pituitary adrenal axis, hypothalamic pituitary-gonadal axis, and the sympathetic-adrenal-medullary system. Various neurotransmitters, neuropeptides, hormones, and cytokines mediate these complex bidirectional interactions between the central nervous system (CNS and the immune system. The effects of stress on the immune responses result in alterations in the number of immune cells and cytokine dysregulation. Various stress management strategies such as meditation, yoga, hypnosis, and muscle relaxation have been shown to reduce the psychological and physiological effects of stress in cancers and HIV infection. This review aims to discuss the effect of stress on the immune system and examine how relaxation techniques such as Yoga and meditation could regulate the cytokine levels and hence, the immune responses during stress.

  19. Genes Acting on Transcriptional Control during Abiotic Stress Responses

    Directory of Open Access Journals (Sweden)

    Glacy Jaqueline da Silva

    2014-01-01

    Full Text Available Abiotic stresses are the major cause of yield loss in crops around the world. Greater genetic gains are possible by combining the classical genetic improvement with advanced molecular biology techniques. The understanding of mechanisms triggered by plants to meet conditions of stress is of fundamental importance for the elucidation of these processes. Current genetically modified crops help to mitigate the effects of these stresses, increasing genetic gains in order to supply the agricultural market and the demand for better quality food throughout the world. To obtain safe genetic modified organisms for planting and consumption, a thorough grasp of the routes and genes that act in response to these stresses is necessary. This work was developed in order to collect important information about essential TF gene families for transcriptional control under abiotic stress responses.

  20. Dynamics of telomerase activity in response to acute psychological stress

    Science.gov (United States)

    Epel, Elissa S.; Lin, Jue; Dhabhar, Firdaus S.; Wolkowitz, Owen M.; Puterman, E; Karan, Lori; Blackburn, Elizabeth H.

    2010-01-01

    Telomerase activity plays an essential role in cel0l survival, by lengthening telomeres and promoting cell growth and longevity. It is now possible to quantify the low levels of telomerase activity in human leukocytes. Low basal telomerase activity has been related to chronic stress in people and to chronic glucocorticoid exposure in vitro. Here we test whether leukocyte telomerase activity changes under acute psychological stress. We exposed 44 elderly women, including 22 high stress dementia caregivers and 22 matched low stress controls, to a brief laboratory psychological stressor, while examining changes in telomerase activity of peripheral blood mononuclear cells (PBMC). At baseline, caregivers had lower telomerase activity levels than controls, but during stress telomerase activity increased similarly in both groups. Across the entire sample, subsequent telomerase activity increased by 18% one hour after the end of the stressor (p<0.01). The increase in telomerase activity was independent of changes in numbers or percentages of monocytes, lymphocytes, and specific T cell types, although we cannot fully rule out some potential contribution from immune cell redistribution in the change in telomerase activity. Telomerase activity increases were associated with greater cortisol increases in response to the stressor. Lastly, psychological response to the tasks (greater threat perception) was also related to greater telomerase activity increases in controls. These findings uncover novel relationships of dynamic telomerase activity with exposure to an acute stressor, and with two classic aspects of the stress response -- perceived psychological stress and neuroendocrine (cortisol) responses to the stressor. PMID:20018236

  1. Crop and medicinal plants proteomics in response to salt stress

    Directory of Open Access Journals (Sweden)

    Keyvan eAghaei

    2013-01-01

    Full Text Available Increasing of world population marks a serious need to create new crop cultivars and medicinal plants with high growth and production at any environmental situations. Among the environmental unfavorable conditions, salinity is the most widespread in the world. Crop production and growth severely decreases under salt stress; however, some crop cultivars show significant tolerance against the negative effects of salinity. Among salt stress responses of crops, proteomic responses play a pivotal role in their ability to cope with it and have become the main center of notification. Many physiological responses are detectable in terms of protein increase and decrease even before physiological responses take place. Thus proteomic approach makes a short cut in the way of inferring how crops response to salt stress. Nowadays many salt-responsive proteins such as heat shock proteins, pathogen related proteins, protein kinases, ascorbate peroxidase, osmotin, ornithine decarboxylase and some transcription factors, have been detected in some major crops which are thought to give them the ability of withstanding against salt stress. Proteomic analysis of medicinal plants also revealed that alkaloid biosynthesis related proteins such as tryptophan synthase, codeinone reductase, strictosidine synthase and 12-oxophytodienoate reductase might have major role in production of secondary metabolites. In this review we are comparing some different or similar proteomic responses of several crops and medicinal plants to salt stress and discuss about the future prospects.

  2. Stressed out? Associations between perceived and physiological stress responses in adolescents : The TRAILS study

    NARCIS (Netherlands)

    Oldehinkel, Albertine J.; Ormel, Johan; Bosch, Nienke M.; Bouma, Esther M. C.; Van Roon, Arie M.; Rosmalen, Judith G. M.; Riese, Harriette

    2011-01-01

    Studies regarding the interrelation of perceived and physiological stress indices have shown diverging results. Using a population sample of adolescents (N=715, 50.9% girls, mean age 16.11 years, SD=0.59), we tested three hypotheses: (1) perceived responses during social stress covary with concurren

  3. Hemodynamic responses to mental stress during salt loading

    DEFF Research Database (Denmark)

    Gefke, Maria; Christensen, Niels Juel; Bech, Per

    2017-01-01

    PURPOSE: The purpose was to examine whether prolonged moderate stress associated with a student exam would increase the blood pressure response to a salt load in young healthy normotensive individuals. METHODS: Ten healthy young subjects were examined at two different occasions in random order (i......) during preparation for a medical exam (prolonged stress) and (ii) outside the exam period (low stress). All subjects consumed a controlled diet for 3 days with low- or high-salt content in randomized order. The subjective stress was measured by Spielberger's State-Trait Anxiety Inventory-Scale, SCL......, CO as well as plasma levels of NE, E and PRA remained unchanged by changes in stress level. Day-night reduction in SAP was significantly larger during moderate stress and high-salt intake; however, no significant difference was observed during daytime and night-time. Individual increase in mental...

  4. Transcript changes in Vibrio cholerae in response to salt stress.

    Science.gov (United States)

    Fu, Xiuping; Liang, Weili; Du, Pengcheng; Yan, Meiying; Kan, Biao

    2014-01-01

    Vibrio cholerae, which is a serious human intestinal pathogen, often resides and thrives in estuaries but requires major self-regulation to overcome intestinal hyperosmotic stress or high salt stress in water and food. In the present study, we selected multiple O1 and O139 group V. cholerae strains that were isolated from different regions and during different years to study their salt tolerance. Based on the mechanisms that other bacteria use to respond to high salt stress, we selected salt stress-response related genes to study the mechanisms which V. cholerae responds to high salt stress. V. cholerae strains showed salt-resistance characteristics that varied in salt concentrations from 4% to 6%. However, group O1 and group O139 showed no significant difference in the degree of salt tolerance. The primary responses of bacteria to salt stress, including Na(+) exclusion, K(+) uptake and glutamate biosynthesis, were observed in V. cholerae strains. In addition, some sigma factors were up-regulated in V. cholerae strains, suggesting that V. cholerae may recruit common sigma factors to achieve an active salt stress response. However, some changes in gene transcript levels in response to salt stress in V. cholerae were strain-specific. In particular, hierarchical clustering of differentially expressed genes indicated that transcript levels of these genes were correlated with the degree of salt tolerance. Therefore, elevated transcript levels of some genes, including sigma factors and genes involved in peptidoglycan biosynthesis, may be due to the salt tolerance of strains. In addition, high salt-tolerant strains may recruit common as well as additional sigma factors to activate the salt stress response.

  5. Plant transcriptomics and responses to environmental stress: an overview

    Indian Academy of Sciences (India)

    Sameen Ruqia Imadi; Alvina Gul Kazi; Mohammad Abass Ahanger; Salih Gucel; Parvaiz Ahmad

    2015-09-01

    Different stresses include nutrient deficiency, pathogen attack, exposure to toxic chemicals etc. Transcriptomic studies have been mainly applied to only a few plant species including the model plant, Arabidopsis thaliana. These studies have provided valuable insights into the genetic networks of plant stress responses. Transcriptomics applied to cash crops including barley, rice, sugarcane, wheat and maize have further helped in understanding physiological and molecular responses in terms of genome sequence, gene regulation, gene differentiation, posttranscriptional modifications and gene splicing. On the other hand, comparative transcriptomics has provided more information about plant’s response to diverse stresses. Thus, transcriptomics, together with other biotechnological approaches helps in development of stress tolerance in crops against the climate change.

  6. the response of plants to drought stress

    Directory of Open Access Journals (Sweden)

    Rys Magdalena

    2015-08-01

    a wider spectrum of compounds scattering the radiation in the leaves tested, and their subsequent comparative analysis. The impact of drought on metabolism of soybean was clearly visible on spectra and confirmed using cluster analysis. The technical problem of the influence of leaf water content on measurements, which appeared in studies, will be discussed. To conclude, FT-Raman spectroscopy may be a good complement to other non-invasive methods, e.g., fluorescent methods, in assessing the stress-induced damage of crops.

  7. Contrasting urban and rural heat stress responses to climate change

    Science.gov (United States)

    Fischer, E. M.; Oleson, K. W.; Lawrence, D. M.

    2012-02-01

    Hot temperatures in combination with high humidity cause human discomfort and may increase morbidity and mortality. A global climate model with an embedded urban model is used to explore the urban-rural contrast in the wet-bulb globe temperature, a heat stress index accounting for temperature and humidity. Wet-bulb globe temperatures are calculated at each model time step to resolve the heat stress diurnal cycle. The model simulates substantially higher heat stress in urban areas compared to neighbouring rural areas. Urban humidity deficit only weakly offsets the enhanced heat stress due to the large night-time urban heat island. The urban-rural contrast in heat stress is most pronounced at night and over mid-latitudes and subtropics. During heatwaves, the urban heat stress amplification is particularly pronounced. Heat stress strongly increases with doubled CO2 concentrations over both urban and rural surfaces. The tropics experience the greatest increase in number of high-heat-stress nights, despite a relatively weak ˜2°C warming. Given the lack of a distinct annual cycle and high relative humidity, the modest tropical warming leads to exceedance of the present-day record levels during more than half of the year in tropical regions, where adaptive capacity is often low. While the absolute urban and rural heat stress response to 2 × CO2 is similar, the occurrence of nights with extremely high heat stress increases more in cities than surrounding rural areas.

  8. The auditory startle response in post-traumatic stress disorder

    NARCIS (Netherlands)

    Siegelaar, S. E.; Olff, M.; Bour, L. J.; Veelo, D.; Zwinderman, A. H.; van Bruggen, G.; de Vries, G. J.; Raabe, S.; Cupido, C.; Koelman, J. H. T. M.; Tijssen, M. A. J.

    2006-01-01

    Post-traumatic stress disorder (PTSD) patients are considered to have excessive EMG responses in the orbicularis oculi (OO) muscle and excessive autonomic responses to startling stimuli. The aim of the present study was to gain more insight into the pattern of the generalized auditory startle reflex

  9. Mechanistic insights into aging, cell cycle progression, and stress response

    Directory of Open Access Journals (Sweden)

    Troy Anthony Alan Harkness

    2012-06-01

    Full Text Available The longevity of an organism depends on the health of its cells. Throughout life cells are exposed to numerous intrinsic and extrinsic stresses, such as free radicals, generated through mitochondrial electron transport, and ultraviolet irradiation. The cell has evolved numerous mechanisms to scavenge free radicals and repair damage induced by these insults. One mechanism employed by the yeast Saccharomyces cerevisiae to combat stress utilizes the Anaphase Promoting Complex (APC, an essential multi-subunit ubiquitin-protein ligase structurally and functionally conserved from yeast to humans that controls progression through mitosis and G1. We have observed that yeast cells expressing compromised APC subunits are sensitive to multiple stresses and have shorter replicative and chronological lifespans. In a pathway that runs parallel to that regulated by the APC, members of the Forkhead box (Fox transcription factor family also regulate stress responses. The yeast Fox orthologues Fkh1 and Fkh2 appear to drive the transcription of stress response factors and slow early G1 progression, while the APC seems to regulate chromatin structure, chromosome segregation, and resetting of the transcriptome in early G1. In contrast, under non-stress conditions, the Fkhs play a complex role in cell cycle progression, partially through activation of the APC. Direct and indirect interactions between the APC and the yeast Fkhs appear to be pivotal for lifespan determination. Here we explore the potential for these interactions to be evolutionarily conserved as a mechanism to balance cell cycle regulation with stress responses.

  10. Ontogeny of the stress response in chinook salmon, Oncorhynchus tshawytscha

    Science.gov (United States)

    Feist, G.; Schreck, C.B.

    2001-01-01

    Whole body concentrations of cortisol were determined via radioimmunoassay in chinook salmon, Onchorynchus tshawytscha, during early development in both stressed and non-stressed fish to determine when the corticosteroidogenic stress response first appeared. Progeny from both pooled and individual females were examined to determine if differences existed in offspring from different females. Levels of cortisol were low in eyed eggs, increased at hatch, decreased 2 weeks later and then remained constant thereafter. Differences in cortisol between stressed and control fish were found 1 week after hatch and persisted for the remainder of the study. The magnitude of the stress response, or relative amount of cortisol produced, generally increased from the time when it was first detected, but a decrease in the ability to elicit cortisol was seen 4 weeks after hatching. Cortisol content of separate progeny from two individual females showed a similar pattern to that seen in pooled eggs. Our results indicate that chinook salmon are capable of producing cortisol following a stressful event approximately 1 week after the time of hatching. The decrease in endogenous cortisol content seen 2 weeks after hatching, and the decrease in the magnitude of the stress response seen 4 weeks after hatching may be comparable to developmental events documented in mammals where corticosteroid synthesis is inhibited to neutralize possible detrimental effects of these hormones during critical periods of development.

  11. Gene Response to Salt Stress in Populus euphratica

    Institute of Scientific and Technical Information of China (English)

    Shen Xin; Thomas Teichmenn; Wang Yiqin; Bai Genben; Yu Guangjun; Wang Shasheng

    2003-01-01

    Through construction of a subtracted cDNA library and library screening, a number of salt-induced cDNA fragmentshave been cloned from Populus euphratica. Based on the results of DNA sequencing and Northern analysis, the gene response ofPopulus euphratica to salt stress is discussed. It is indicated that in response to salt treatment the transcription level for some genes ofPopulus euphratica increases by about 1.5 times and significant difference between the responses to osmotic stress and to ion stresshas been observed in gene activity.

  12. The STATs in cell stress-type responses

    Directory of Open Access Journals (Sweden)

    Best James

    2004-08-01

    Full Text Available Abstract In the early 1990's, a new cell signaling pathway was described. This new paradigm, now known as the JAK/STAT pathway, has been extensively investigated in immune-type cells in response to interferons and interleukins. However, recent evidence suggests that the JAK/STAT pathway also mediates diverse cellular responses to various forms of biological stress including hypoxia/reperfusion, endotoxin, ultraviolet light, and hyperosmolarity. The current literature describing the JAK/STAT pathway's role in cellular stress responses has been reviewed herein, but it is clear that our knowledge in this area is far from complete.

  13. The effect of music on the human stress response.

    Directory of Open Access Journals (Sweden)

    Myriam V Thoma

    Full Text Available BACKGROUND: Music listening has been suggested to beneficially impact health via stress-reducing effects. However, the existing literature presents itself with a limited number of investigations and with discrepancies in reported findings that may result from methodological shortcomings (e.g. small sample size, no valid stressor. It was the aim of the current study to address this gap in knowledge and overcome previous shortcomings by thoroughly examining music effects across endocrine, autonomic, cognitive, and emotional domains of the human stress response. METHODS: Sixty healthy female volunteers (mean age = 25 years were exposed to a standardized psychosocial stress test after having been randomly assigned to one of three different conditions prior to the stress test: 1 relaxing music ('Miserere', Allegri (RM, 2 sound of rippling water (SW, and 3 rest without acoustic stimulation (R. Salivary cortisol and salivary alpha-amylase (sAA, heart rate (HR, respiratory sinus arrhythmia (RSA, subjective stress perception and anxiety were repeatedly assessed in all subjects. We hypothesized that listening to RM prior to the stress test, compared to SW or R would result in a decreased stress response across all measured parameters. RESULTS: The three conditions significantly differed regarding cortisol response (p = 0.025 to the stressor, with highest concentrations in the RM and lowest in the SW condition. After the stressor, sAA (p=0.026 baseline values were reached considerably faster in the RM group than in the R group. HR and psychological measures did not significantly differ between groups. CONCLUSION: Our findings indicate that music listening impacted the psychobiological stress system. Listening to music prior to a standardized stressor predominantly affected the autonomic nervous system (in terms of a faster recovery, and to a lesser degree the endocrine and psychological stress response. These findings may help better understanding the

  14. Towards establishment of a rice stress response interactome.

    Directory of Open Access Journals (Sweden)

    Young-Su Seo

    2011-04-01

    Full Text Available Rice (Oryza sativa is a staple food for more than half the world and a model for studies of monocotyledonous species, which include cereal crops and candidate bioenergy grasses. A major limitation of crop production is imposed by a suite of abiotic and biotic stresses resulting in 30%-60% yield losses globally each year. To elucidate stress response signaling networks, we constructed an interactome of 100 proteins by yeast two-hybrid (Y2H assays around key regulators of the rice biotic and abiotic stress responses. We validated the interactome using protein-protein interaction (PPI assays, co-expression of transcripts, and phenotypic analyses. Using this interactome-guided prediction and phenotype validation, we identified ten novel regulators of stress tolerance, including two from protein classes not previously known to function in stress responses. Several lines of evidence support cross-talk between biotic and abiotic stress responses. The combination of focused interactome and systems analyses described here represents significant progress toward elucidating the molecular basis of traits of agronomic importance.

  15. Oxidative stress impairs the heat stress response and delays unfolded protein recovery.

    Directory of Open Access Journals (Sweden)

    Masaaki Adachi

    Full Text Available BACKGROUND: Environmental changes, air pollution and ozone depletion are increasing oxidative stress, and global warming threatens health by heat stress. We now face a high risk of simultaneous exposure to heat and oxidative stress. However, there have been few studies investigating their combined adverse effects on cell viability. PRINCIPAL FINDINGS: Pretreatment of hydrogen peroxide (H(2O(2 specifically and highly sensitized cells to heat stress, and enhanced loss of mitochondrial membrane potential. H(2O(2 exposure impaired the HSP40/HSP70 induction as heat shock response (HSR and the unfolded protein recovery, and enhanced eIF2alpha phosphorylation and/or XBP1 splicing, land marks of ER stress. These H(2O(2-mediated effects mimicked enhanced heat sensitivity in HSF1 knockdown or knockout cells. Importantly, thermal preconditioning blocked H(2O(2-mediated inhibitory effects on refolding activity and rescued HSF1 +/+ MEFs, but neither blocked the effects nor rescued HSF1 -/- MEFs. These data strongly suggest that inhibition of HSR and refolding activity is crucial for H(2O(2-mediated enhanced heat sensitivity. CONCLUSIONS: H(2O(2 blocks HSR and refolding activity under heat stress, thereby leading to insufficient quality control and enhancing ER stress. These uncontrolled stress responses may enhance cell death. Our data thus highlight oxidative stress as a crucial factor affecting heat tolerance.

  16. Interdependence of tetrapyrrole metabolism, the generation of oxidative stress and the mitigative oxidative stress response

    Directory of Open Access Journals (Sweden)

    Andrea W.U. Busch

    2015-04-01

    Full Text Available Tetrapyrroles are involved in light harvesting and light perception, electron-transfer reactions, and as co-factors for key enzymes and sensory proteins. Under conditions in which cells exhibit stress-induced imbalances of photosynthetic reactions, or light absorption exceeds the ability of the cell to use photoexcitation energy in synthesis reactions, redox imbalance can occur in photosynthetic cells. Such conditions can lead to the generation of reactive oxygen species (ROS associated with alterations in tetrapyrrole homeostasis. ROS accumulation can result in cellular damage and detrimental effects on organismal fitness, or ROS molecules can serve as signals to induce a protective or damage-mitigating oxidative stress signaling response in cells. Induced oxidative stress responses include tetrapyrrole-dependent and -independent mechanisms for mitigating ROS generation and/or accumulation. Thus, tetrapyrroles can be contributors to oxidative stress, but are also essential in the oxidative stress response to protect cells by contributing to detoxification of ROS. In this review, we highlight the interconnection and interdependence of tetrapyrrole metabolism with the occurrence of oxidative stress and protective oxidative stress signaling responses in photosynthetic organisms.

  17. Exercise-Induced Oxidative Stress Responses in the Pediatric Population

    Directory of Open Access Journals (Sweden)

    Alexandra Avloniti

    2017-01-01

    Full Text Available Adults demonstrate an upregulation of their pro- and anti-oxidant mechanisms in response to acute exercise while systematic exercise training enhances their antioxidant capacity, thereby leading to a reduced generation of free radicals both at rest and in response to exercise stress. However, less information exists regarding oxidative stress responses and the underlying mechanisms in the pediatric population. Evidence suggests that exercise-induced redox perturbations may be valuable in order to monitor exercise-induced inflammatory responses and as such training overload in children and adolescents as well as monitor optimal growth and development. The purpose of this review was to provide an update on oxidative stress responses to acute and chronic exercise in youth. It has been documented that acute exercise induces age-specific transient alterations in both oxidant and antioxidant markers in children and adolescents. However, these responses seem to be affected by factors such as training phase, training load, fitness level, mode of exercise etc. In relation to chronic adaptation, the role of training on oxidative stress adaptation has not been adequately investigated. The two studies performed so far indicate that children and adolescents exhibit positive adaptations of their antioxidant system, as adults do. More studies are needed in order to shed light on oxidative stress and antioxidant responses, following acute exercise and training adaptations in youth. Available evidence suggests that small amounts of oxidative stress may be necessary for growth whereas the transition to adolescence from childhood may promote maturation of pro- and anti-oxidant mechanisms. Available evidence also suggests that obesity may negatively affect basal and exercise-related antioxidant responses in the peripubertal period during pre- and early-puberty.

  18. Assessment of sup 99m Tc-DMSA renoscintigraphy and uptake compared with creatinine clearance in rats with drug-induced nephrotoxicity, 2; Cisplatin-induced nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Masafumi (Ehime Univ., Shigenobu (Japan). School of Medicine)

    1991-04-01

    For evaluation of technetium-99m dimercaptosuccinic acid ({sup 99m}Tc-DMSA) renal uptake as an absolute renal function, {sup 99m}Tc-DMSA uptake was compared with endogenous creatinine clearance (Ccr) in cisplatin-induced nephrotoxicity. At first, male Wistar rats were given intraperitoneally 1.8 mg/kg/day of cisplatin for periods of 3, 5, 7 and 9 days. On the next day, {sup 99m}Tc-DMSA uptake and Ccr were measured. Ccr of 5-day treated group was significantly lower than that of control (0.13+-0.10 vs 0.34+-0.05 ml/min/100 g; p<0.01) but {sup 99m}Tc-DMSA uptake did not change. {sup 99m}Tc-DMSA uptake of 7-day treated group was significantly lower than that of control (28.57+-7.23 vs 39.84+-2.23%; p<0.01). As the second experiment, cisplatin (3.6 mg/kg/day) was given intraperitoneally on the 1st, 2nd, 15th and 16th day. On the 5th, 8th, 11th, 15th, 20th, 23rd, 26th and 30th day, the same measurements were done as the first one. Ccr was lower in cisplatin treated rats on the 5th day than that in control (0.10+-0.03 vs 0.34+-0.05 ml/min/100 g; p<0.01), thereafter tended to be recovered to the control level. On the other hand, {sup 99m}Tc-DMSA uptake was lower than that of control on the 8th, 11th and 15th day (32.40+-3.86, 32.56+-1.19, 35.21+-2.97 vs 39.84+-2.23%, respectively; p<0.01). The discrepancy between {sup 99m}Tc-DMSA uptake and Ccr was observed in the cisplatin-induced nephrotoxicity. {sup 99m}Tc-DMSA uptake was suggested to be a reliable indicator of a renal function in a different way from Ccr. (author).

  19. Dynamic modeling of cellular response to DNA damage based on p53 stress response networks

    Institute of Scientific and Technical Information of China (English)

    Jinpeng Qi; Yongsheng Ding; Shihuang Shao

    2009-01-01

    Under acute perturbations from the outside, cells can trigger self-defensive mechanisms to fight against genome stress. To investigate the cellular response to continuous ion radiation (IR), a dynamic model for p53 stress response networks at the cellular level is proposed. The model can successfully be used to simulate the dynamic processes of double-strand breaks (DSBs) generation and their repair, switch-like ataxia telangiectasia mutated (ATM) activation, oscillations occurring in the p53-MDM2 feedback loop, as well as toxins elimination triggered by p53 stress response networks. Especially, the model can predict the plausible outcomes of cellular response under different IR dose regimes.

  20. Proteomics analysis of alfalfa response to heat stress.

    Directory of Open Access Journals (Sweden)

    Weimin Li

    Full Text Available The proteome responses to heat stress have not been well understood. In this study, alfalfa (Medicago sativa L. cv. Huaiyin seedlings were exposed to 25 °C (control and 40 °C (heat stress in growth chambers, and leaves were collected at 24, 48 and 72 h after treatment, respectively. The morphological, physiological and proteomic processes were negatively affected under heat stress. Proteins were extracted and separated by two-dimensional polyacrylamide gel electrophoresis (2-DE, and differentially expressed protein spots were identified by mass spectrometry (MS. Totally, 81 differentially expressed proteins were identified successfully by MALDI-TOF/TOF. These proteins were categorized into nine classes: including metabolism, energy, protein synthesis, protein destination/storage, transporters, intracellular traffic, cell structure, signal transduction and disease/defence. Five proteins were further analyzed for mRNA levels. The results of the proteomics analyses provide a better understanding of the molecular basis of heat-stress responses in alfalfa.

  1. Physiological roles of plastid terminal oxidase in plant stress responses

    Indian Academy of Sciences (India)

    Xin Sun; Tao Wen

    2011-12-01

    The plastid terminal oxidase (PTOX) is a plastoquinol oxidase localized in the plastids of plants. It is able to transfer electrons from plastoquinone (PQ) to molecular oxygen with the formation of water. Recent studies have suggested that PTOX is beneficial for plants under environmental stresses, since it is involved in the synthesis of photoprotective carotenoids and chlororespiration, which could potentially protect the chloroplast electron transport chain (ETC) from over-reduction. The absence of PTOX in plants usually results in photo-bleached variegated leaves and impaired adaptation to environment alteration. Although PTOX level and activity has been found to increase under a wide range of stress conditions, the functions of plant PTOX in stress responses are still disputed now. In this paper, the possible physiological roles of PTOX in plant stress responses are discussed based on the recent progress.

  2. Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax- and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells.

    Science.gov (United States)

    Matsumoto, Masaru; Nakajima, Wataru; Seike, Masahiro; Gemma, Akihiko; Tanaka, Nobuyuki

    2016-04-29

    Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53-dependent and -independent manners, respectively. Moreover, in wild-type p53-expressing cells, cisplatin mainly used the Bak-dependent apoptotic pathway, but this apoptotic pathway shifted to the Bax-dependent pathway by loss-of-function of p53. Furthermore, both Bak- and Bax-induced apoptosis was enhanced by the antiapoptotic Bcl-2 family member, Bcl-XL knockdown, but not by Mcl-1 knockdown. From this result, we tested the effect of ABT-263 (Navitoclax), the specific inhibitor of Bcl-2 and Bcl-XL, but not Mcl-1, and found that ABT-263 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells in the presence or absence of p53. These results indicate a novel regulatory system in cisplatin-induced NSCLC cell apoptosis, and a candidate efficient combination chemotherapy method against lung cancers.

  3. Sip-jeon-dea-bo-tang, a traditional herbal medicine, ameliorates cisplatin-induced anorexia via the activation of JAK1/STAT3-mediated leptin and IL-6 production in the fat tissue of mice.

    Science.gov (United States)

    Woo, Sang-Mi; Choi, Youn Kyung; Kim, Ah-Jeong; Yun, Yee Jin; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong Gyu

    2016-04-01

    Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL‑6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.

  4. 5-Azacytidine prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein, pAKT and DNMT1 expression in chemical induced cancer rats.

    Science.gov (United States)

    Tikoo, Kulbhushan; Ali, Idrish Yunus; Gupta, Jeena; Gupta, Chanchal

    2009-12-15

    5-Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme. Inhibitors of DNMT have been reported to potentiate the therapeutic activity of cisplatin in vitro. Dose dependent bone marrow toxicity, neurotoxicity and nephrotoxicity are the major side effects of cisplatin, limiting its use as an effective chemotherapeutic agent. The present study was aimed to reduce the nephrotoxic potential of cisplatin without compensating its potency. To best of our knowledge, this is the first report which shows that the combination of 5-azacytidine with cisplatin leads to remarkable reduction in nephrotoxicity, by involving inhibition of cisplatin induced metallothionein expression. 5-Azacytidine treatment with cisplatin leads to maximum reduction in tumor size in DMH induced colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats. This combination regimen prevents phosphorylation and acetylation of histone H3 which may be involved in inhibition of aberrant gene expression in colon tumors. Further, 5-azacytidine potentiated cisplatin induced antitumor activity by involving decreased expression of pAKT, DNMT1 and an increased expression of p38 in colon tumors. Thus, combination of 5-azactydine with cisplatin attenuates the cisplatin induced nephrotoxicity and potentiates the anti-cancer activity which can have profound clinical implications.

  5. Orientational Polarizability and Stress Response of Biological Cells

    Science.gov (United States)

    Safran, S. A.; de, R.; Zemel, A.

    We present a theoretical treatment of the orientational response to external stress of active, contractile cells embedded in a gel-like elastic medium. The theory includes random forces as well as forces that arise from the deformation of the matrix and those due to the internal regulation of the stress fibers and focal adhesions of the cell. We calculate both the static and high frequency limits of the orientational response in terms of the cellular polarizability. For systems in which the forces due to regulation and activity dominate the mechanical forces, we show that there is a non-linear dynamical response which, in the high frequency limit, causes the cell to orient nearly perpendicular to the direction of the applied stress.

  6. Hormonal contraception use alters stress responses and emotional memory.

    Science.gov (United States)

    Nielsen, Shawn E; Segal, Sabrina K; Worden, Ian V; Yim, Ilona S; Cahill, Larry

    2013-02-01

    Emotionally arousing material is typically better remembered than neutral material. Since norepinephrine and cortisol interact to modulate emotional memory, sex-related influences on stress responses may be related to sex differences in emotional memory. Two groups of healthy women - one naturally cycling (NC women, n=42) and one using hormonal contraceptives (HC women, n=36) - viewed emotionally arousing and neutral images. Immediately after, they were assigned to Cold Pressor Stress (CPS) or a control procedure. One week later, participants received a surprise free recall test. Saliva samples were collected and later assayed for salivary alpha-amylase (biomarker for norepinephrine) and cortisol. Compared to NC women, HC women exhibited significantly blunted stress hormone responses to the images and CPS. Recall of emotional images differed between HC and NC women depending on noradrenergic and cortisol responses. These findings may have important implications for understanding the neurobiology of emotional memory disorders, especially those that disproportionately affect women.

  7. Transcriptional responses of Arabidopsis thaliana plants to As (V stress

    Directory of Open Access Journals (Sweden)

    Yuan Joshua S

    2008-08-01

    Full Text Available Abstract Background Arsenic is toxic to plants and a common environmental pollutant. There is a strong chemical similarity between arsenate [As (V] and phosphate (Pi. Whole genome oligonucleotide microarrays were employed to investigate the transcriptional responses of Arabidopsis thaliana plants to As (V stress. Results Antioxidant-related genes (i.e. coding for superoxide dismutases and peroxidases play prominent roles in response to arsenate. The microarray experiment revealed induction of chloroplast Cu/Zn superoxide dismutase (SOD (at2g28190, Cu/Zn SOD (at1g08830, as well as an SOD copper chaperone (at1g12520. On the other hand, Fe SODs were strongly repressed in response to As (V stress. Non-parametric rank product statistics were used to detect differentially expressed genes. Arsenate stress resulted in the repression of numerous genes known to be induced by phosphate starvation. These observations were confirmed with qRT-PCR and SOD activity assays. Conclusion Microarray data suggest that As (V induces genes involved in response to oxidative stress and represses transcription of genes induced by phosphate starvation. This study implicates As (V as a phosphate mimic in the cell by repressing genes normally induced when available phosphate is scarce. Most importantly, these data reveal that arsenate stress affects the expression of several genes with little or unknown biological functions, thereby providing new putative gene targets for future research.

  8. Formaldehyde stress responses in bacterial pathogens

    Directory of Open Access Journals (Sweden)

    Nathan Houqian Chen

    2016-03-01

    Full Text Available Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent upon glutathione. The more prevalent thiol-dependent formaldehyde detoxification system is found in many bacterial pathogens, almost all of which do not metabolize methane or methanol. This review describes the endogenous and exogenous sources of formaldehyde, its toxic effects and mechanisms of detoxification. The methods of formaldehyde sensing are also described with a focus on the formaldehyde responsive transcription factors HxlR, FrmR and NmlR. Finally, the physiological relevance of detoxification systems for formaldehyde in bacterial pathogens is discussed.

  9. Eccentric-exercise induced inflammation attenuates the vascular responses to mental stress

    NARCIS (Netherlands)

    Paine, N.J.; Ring, C.; Aldred, S.; Bosch, J.A.; Wadley, A.J.; Veldhuijzen van Zanten, J.J.C.S.

    2013-01-01

    Mental stress has been identified as a trigger of myocardial infarction (MI), with inflammation and vascular responses to mental stress independently implicated as contributing factors. This study examined whether inflammation moderates the vascular responses to mental stress. Eighteen healthy male

  10. Knockdown of miR-221 promotes the cisplatin-inducing apoptosis by targeting the BIM-Bax/Bak axis in breast cancer.

    Science.gov (United States)

    Ye, Zhiqiang; Hao, Rutian; Cai, Yefeng; Wang, Xiaobo; Huang, Guanli

    2016-04-01

    Accumulating evidence shows that microRNAs (miRNAs) have a critical role in the initiation and progression of types of human cancer, including breast cancer. Recent research indicated that miRNAs are also related with the chemotherapy on cancers. In this study, the expression of miR-221 in breast cancer (BC) patients' serum and cancer tissues was found to be significantly up-regulated. The results of in vitro MTT assay indicated that although the anti-miR-221 oligonucleotide alone did not influence the viability of BC cell lines markedly, it significantly promoted the cytotoxicity of cisplatin (DDP) to BC cells. Mechanistic studies demonstrated that the gene of BIM (Bcl-2 interacting mediator of cell death), a pro-apoptotic Bcl-2 family protein, was up-regulated by the knockdown of miR-221. We found that the synergetic effect of anti-miR-221 on increasing the sensitivity of MDA-MB-231 was BIM dependant. Furthermore, results of immunoprecipitation showed the up-regulated BIM directly combined with the Bax and Bak, leading to mitochondrial dysfunction. Our results suggest the anti-miR-221 could promote the cisplatin-inducing apoptosis by targeting the Bim-Bax/Bak axis in breast cancer.

  11. Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms

    DEFF Research Database (Denmark)

    Sigurðsson, Haraldur H; Olesen, Christina Wilkens; Dybboe, Rie

    2015-01-01

    UNLABELLED: Despite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2...... upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na(+)/H(+) exchanger (SLC9A1/NHE1) strongly sensitizes ΔNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which ΔNErbB2 regulates cisplatin-induced breast...... cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible ΔNErbB2 expression strongly reduced cisplatin...

  12. Oxidative stress response pathways: Fission yeast as archetype.

    Science.gov (United States)

    Papadakis, Manos A; Workman, Christopher T

    2015-01-01

    Schizosaccharomyces pombe is a popular model eukaryotic organism to study diverse aspects of mammalian biology, including responses to cellular stress triggered by redox imbalances within its compartments. The review considers the current knowledge on the signaling pathways that govern the transcriptional response of fission yeast cells to elevated levels of hydrogen peroxide. Particular attention is paid to the mechanisms that yeast cells employ to promote cell survival in conditions of intermediate and acute oxidative stress. The role of the Sty1/Spc1/Phh1 mitogen-activated protein kinase in regulating gene expression at multiple levels is discussed in detail.

  13. Transcriptional Regulation of Arabidopsis in Response to Salt Stress

    Institute of Scientific and Technical Information of China (English)

    Zhulong Chan

    2012-01-01

    Salt stress is a major factor limiting agricultural productivity worldwide.Adaptations to salt stress include avoidance by reduced sodium uptake,sequestration of toxic sodium ions away from the cytoplasm,or production of compatible solutes or osmoprotectants to reduce molecular disruption.Approaches to engineer salt stress resistance have included regulation of ion transport through introduction of Na+/H+ antiporter; synthesis of compatible solutes; or the introduction of transcription factors regulating expression of stress-responsive genes.On the other hand,naturally occurring variation among wild-type populations of plants also can be used to understand plant adaptive responses to their environments.In this study,we compared phenotypic and transcriptomic effects of constitutive expression of genes intended to confer salt stress tolerance by three different mechanisms:a transcription factor,CBF3/DREB1a; a metabolic gene,M6PR,for mannitol biosynthesis; and the Na+/H+ antiporter,SOS1.In the absence of salt,M6PR and SOS1 lines performed comparably with wild type; CBF3 lines exhibited dwarfing as reported previously.All three transgenes conferred fitness advantage when subjected to 100 mmol/L NaCI in the growth chamber.CBF3 and M6PR affected transcription of numerous abiotic stress-related genes as measured by Affymetrix microarray analysis.M6PR additionally modified expression of biotic stress and oxidative stress genes.Transcriptional effects of SOS1 were smaller and primarily limited to redox-related genes.In addition,we compared natural variations in salt tolerance between Ler and Sha ecotypes based on their responses to salt treatments and the results indicated that Ler was salt-sensitive,but Sha,which obtained a truncated RAS1 protein,was salt-tolerant.Transcriptome analysis revealed that many genes involved in secondary metabolism,photosynthesis,and protein synthesis were mainly down-regulated by salinity effects,while transposable element genes,microRNA and

  14. Stretching the stress boundary: Linking air pollution health effects to a neurohormonal stress response.

    Science.gov (United States)

    Kodavanti, Urmila P

    2016-12-01

    Inhaled pollutants produce effects in virtually all organ systems in our body and have been linked to chronic diseases including hypertension, atherosclerosis, Alzheimer's and diabetes. A neurohormonal stress response (referred to here as a systemic response produced by activation of the sympathetic nervous system and hypothalamus-pituitary-adrenal (HPA)-axis) has been implicated in a variety of psychological and physical stresses, which involves immune and metabolic homeostatic mechanisms affecting all organs in the body. In this review, we provide new evidence for the involvement of this well-characterized neurohormonal stress response in mediating systemic and pulmonary effects of a prototypic air pollutant - ozone. A plethora of systemic metabolic and immune effects are induced in animals exposed to inhaled pollutants, which could result from increased circulating stress hormones. The release of adrenal-derived stress hormones in response to ozone exposure not only mediates systemic immune and metabolic responses, but by doing so, also modulates pulmonary injury and inflammation. With recurring pollutant exposures, these effects can contribute to multi-organ chronic conditions associated with air pollution. This review will cover, 1) the potential mechanisms by which air pollutants can initiate the relay of signals from respiratory tract to brain through trigeminal and vagus nerves, and activate stress responsive regions including hypothalamus; and 2) the contribution of sympathetic and HPA-axis activation in mediating systemic homeostatic metabolic and immune effects of ozone in various organs. The potential contribution of chronic environmental stress in cardiovascular, neurological, reproductive and metabolic diseases, and the knowledge gaps are also discussed. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.

  15. Response to stress in Drosophila is mediated by gender, age and stress paradigm.

    Science.gov (United States)

    Neckameyer, Wendi S; Nieto-Romero, Andres R

    2015-01-01

    All living organisms must maintain equilibrium in response to internal and external challenges within their environment. Changes in neural plasticity (alterations in neuronal populations, dendritic remodeling, and synaptic turnover) are critical components of the homeostatic response to stress, which has been strongly implicated in the onset of affective disorders. However, stress is differentially perceived depending on the type of stress and its context, as well as genetic background, age and sex; therefore, an individual's maintenance of neuronal homeostasis must differ depending upon these variables. We established Drosophila as a model to analyze homeostatic responses to stress. Sexually immature and mature females and males from an isogenic wild-type strain raised under controlled environmental conditions were exposed to four reproducible and high-throughput translatable stressors to facilitate the analysis of a large number of animals for direct comparisons. These animals were assessed in an open-field arena, in a light-dark box, and in a forced swim test, as well as for sensitivity to the sedative effects of ethanol. These studies establish that immature and mature females and males represent behaviorally distinct populations under control conditions as well as after exposure to different stressors. Therefore, the neural substrates mediating the stress response must be differentially expressed depending upon the hormonal status of the brain. In addition, an adaptive response to a given stressor in one paradigm was not predictive for outcomes in other paradigms.

  16. Stress effects on mood, HPA axis, and autonomic response: comparison of three psychosocial stress paradigms.

    Science.gov (United States)

    Giles, Grace E; Mahoney, Caroline R; Brunyé, Tad T; Taylor, Holly A; Kanarek, Robin B

    2014-01-01

    Extensive experimental psychology research has attempted to parse the complex relationship between psychosocial stress, mood, cognitive performance, and physiological changes. To do so, it is necessary to have effective, validated methods to experimentally induce psychosocial stress. The Trier Social Stress Test (TSST) is the most commonly used method of experimentally inducing psychosocial stress, but it is resource intensive. Less resource intense psychosocial stress tasks include the Socially Evaluative Cold Pressor Task (SECPT) and a computerized mental arithmetic task (MAT). These tasks effectively produce a physiological and psychological stress response and have the benefits of requiring fewer experimenters and affording data collection from multiple participants simultaneously. The objective of this study was to compare the magnitude and duration of these three experimental psychosocial stress induction paradigms. On each of four separate days, participants completed either a control non-stressful task or one of the three experimental stressors: the TSST, SECPT, or MAT. We measured mood, working memory performance, salivary cortisol and alpha-amylase (AA), and heart rate. The TSST and SECPT exerted the most robust effects on mood and physiological measures. TSST effects were generally evident immediately post-stress as well as 10- and 20-minutes after stress cessation, whereas SECPT effects were generally limited to the duration of the stressor. The stress duration is a key determinant when planning a study that utilizes an experimental stressor, as researchers may be interested in collecting dependent measures prior to stress cessation. In this way, the TSST would allow the investigator a longer window to administer tasks of interest.

  17. Stress effects on mood, HPA axis, and autonomic response: comparison of three psychosocial stress paradigms.

    Directory of Open Access Journals (Sweden)

    Grace E Giles

    Full Text Available Extensive experimental psychology research has attempted to parse the complex relationship between psychosocial stress, mood, cognitive performance, and physiological changes. To do so, it is necessary to have effective, validated methods to experimentally induce psychosocial stress. The Trier Social Stress Test (TSST is the most commonly used method of experimentally inducing psychosocial stress, but it is resource intensive. Less resource intense psychosocial stress tasks include the Socially Evaluative Cold Pressor Task (SECPT and a computerized mental arithmetic task (MAT. These tasks effectively produce a physiological and psychological stress response and have the benefits of requiring fewer experimenters and affording data collection from multiple participants simultaneously. The objective of this study was to compare the magnitude and duration of these three experimental psychosocial stress induction paradigms. On each of four separate days, participants completed either a control non-stressful task or one of the three experimental stressors: the TSST, SECPT, or MAT. We measured mood, working memory performance, salivary cortisol and alpha-amylase (AA, and heart rate. The TSST and SECPT exerted the most robust effects on mood and physiological measures. TSST effects were generally evident immediately post-stress as well as 10- and 20-minutes after stress cessation, whereas SECPT effects were generally limited to the duration of the stressor. The stress duration is a key determinant when planning a study that utilizes an experimental stressor, as researchers may be interested in collecting dependent measures prior to stress cessation. In this way, the TSST would allow the investigator a longer window to administer tasks of interest.

  18. Response of Saccharomyces cerevisiae to cadmium stress

    Energy Technology Data Exchange (ETDEWEB)

    Moreira, Luciana Mara Costa; Ribeiro, Frederico Haddad; Neves, Maria Jose [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil). Lab. de Radiobiologia], e-mail: luamatu@uol.com.br; Porto, Barbara Abranches Araujo; Amaral, Angela M.; Menezes, Maria Angela B.C. [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Lab. de Ativacao Neutronica], e-mail: menezes@cdtn.br; Rosa, Carlos Augusto [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Microbiologia], e-mail: carlrosa@icb.ufmg

    2009-07-01

    The intensification of industrial activity has been greatly contributing with the increase of heavy metals in the environment. Among these heavy metals, cadmium becomes a serious pervasive environmental pollutant. The cadmium is a heavy metal with no biological function, very toxic and carcinogenic at low concentrations. The toxicity of cadmium and several other metals can be mainly attributed to the multiplicity of coordination complexes and clusters that they can form. Some aspects of the cellular response to cadmium were extensively investigated in the yeast Saccharomyces cerevisiae. The primary site of interaction between many toxic metals and microbial cells is the plasma membrane. Plasma-membrane permeabilisation has been reported in a variety of microorganisms following cadmium exposure, and is considered one mechanism of cadmium toxicity in the yeast. In this work, using the yeast strain S. cerevisiae W303-WT, we have investigated the relationships between Cd uptake and release of cellular metal ions (K{sup +} and Na{sup +}) using neutron activation technique. The neutron activation was an easy, rapid and suitable technique for doing these metal determinations on yeast cells; was observed the change in morphology of the strains during the process of Cd accumulation, these alterations were observed by Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) during incorporation of cadmium. (author)

  19. Renal Function and Cardiovascular Response to Mental Stress

    Science.gov (United States)

    Seliger, Stephen L.; Katzel, Leslie I.; Fink, Jeffrey C.; Weir, Matthew R.; Waldstein, Shari R.

    2008-01-01

    Background/Aims Cardiovascular reactivity (CVR), defined as an exaggerated hemodynamic response to mental stress, is a putative vascular risk factor and may reflect sympathetic hyperactivity. Chronic kidney disease (CKD) is also associated with sympathetic hyperactivity and vascular risk, but its relationship with CVR is unknown. Methods CVR was assessed in 107 individuals without overt cardiovascular disease or diabetes. Blood pressure and heart rate responses were elicited by three experimental tasks designed to evoke mental stress. Glomerular filtration rate (eGFR) was estimated using the MDRD formula. General linear models estimated the association between renal function and CVR, adjusting for potential confounders. Results Mean age was 66 years and 11% had eGFR of <60 ml/min/1.73 m2. After multivariate adjustment, a low eGFR was associated with a greater stress response of systolic blood pressure, heart rate, and pulse pressure. Associations were only partially attenuated after adjustment for lipids and glucose tolerance. When considered as a continuous variable, lower eGFR was associated with a greater blood pressure response after adjustment for glycemia. Conclusion Although there were relatively few participants with CKD, these results suggest a relationship between CKD and greater CVR. Further investigation is warranted into factors that mediate this relationship and potential clinical consequences of this exaggerated response to stress in CKD. PMID:18025779

  20. Dysregulation of the stress response in asthmatic children.

    Science.gov (United States)

    Priftis, K N; Papadimitriou, A; Nicolaidou, P; Chrousos, G P

    2009-01-01

    The stress system co-ordinates the adaptive responses of the organism to stressors of any kind. Inappropriate responsiveness may account for increased susceptibility to a variety of disorders, including asthma. Accumulated evidence from animal models suggests that exogenously applied stress enhances airway reactivity and increases allergen-induced airway inflammation. This is in agreement with the clinical observation that stressful life events increase the risk of a new asthma attack. Activation of the hypothalamic-pituitary-adrenal (HPA) axis by specific cytokines increases the release of cortisol, which in turn feeds back and suppresses the immune reaction. Data from animal models suggest that inability to increase glucocorticoid production in response to stress is associated with increased airway inflammation with mechanical dysfunction of the lungs. Recently, a growing body of evidence shows that asthmatic subjects who are not treated with inhaled corticosteroids (ICS) are likely to have an attenuated activity and/or responsiveness of their HPA axis. In line with this concept, most asthmatic children demonstrate improved HPA axis responsiveness on conventional doses of ICS, as their airway inflammation subsides. Few patients may experience further deterioration of adrenal function, a phenomenon which may be genetically determined.

  1. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour.

    Science.gov (United States)

    Snyder, Jason S; Soumier, Amélie; Brewer, Michelle; Pickel, James; Cameron, Heather A

    2011-08-03

    Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

  2. Reactive oxygen species in response of plants to gravity stress

    Science.gov (United States)

    Jadko, Sergiy

    2016-07-01

    Reactive oxygen species (ROS) as second messengers can induce stress response of plants. Thioredoxins (Trx) and peroxiredoxins (Prx) can function as sensors and transmitters of the ROS in stress signaling and antioxidant response. 12-14 days old tissue culture of Arabidopsis thaliana have been investigated. Hypergravity stress was induced by centrifugation at 10 and 20 g during 30 and 90 min and than intensity of spontaneous chemiluminescence (SChL/ROS content), Trx and Prx activities were determined. All experiments were repeated from 3 to 5 times and the obtained data were statistically treated. In the tissue culture under development of the stress there were an increase in intensity of SChL and Trx and Prx activities. Thus, under hypergravity stress in the plant occurred early increase in the ROS level and the ROS induced the increase in the Trx and Prx activities. Prx and Trx can also participate in the formation of stress respons as acceptors and transducers of the redox signals. Increase in the activity of these enzymes primarily aimed at increasing of the total antioxidant activity in the cells to prevent of the plant to development of oxidative degradation by ROS.

  3. The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast.

    Science.gov (United States)

    Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A

    2014-05-01

    This article focuses on discoveries of the mechanisms governing the regulation of glycerolipid metabolism and stress response signaling in response to the phospholipid precursor, inositol. The regulation of glycerolipid lipid metabolism in yeast in response to inositol is highly complex, but increasingly well understood, and the roles of individual lipids in stress response are also increasingly well characterized. Discoveries that have emerged over several decades of genetic, molecular and biochemical analyses of metabolic, regulatory and signaling responses of yeast cells, both mutant and wild type, to the availability of the phospholipid precursor, inositol are discussed.

  4. Understanding Abiotic Stress Tolerance Mechanisms: Recent Studies on Stress Response in Rice

    Institute of Scientific and Technical Information of China (English)

    Ji-Ping Gao; Dai-Yin Chao; Hong-Xuan Lin

    2007-01-01

    Abiotic stress is the main factor negatively affecting crop growth and productivity worldwide. The advances in physiology, genetics, and molecular biology have greatly improved our understanding of plant responses to stresses. Rice plants are sensitive to various abiotic stresses. In this short review, we present recent progresses in adaptation of rice to salinity, water deficit and submergence. Many studies show that salt tolerance is tightly associated with the ability to maintain ion homeostasis under salinity. Na+ transporter SKC1 unloads NaMrom xylem, plasma membrane NaVHTantiporter SOS1 excludes sodium out of cytosol and tonoplast Na+/H+antiporter NHX1 sequesters Na+ into the vacuole. Silicon deposition in exodermis and endodermis of rice root reduces sodium transport through the apoplastic pathway. A number of transcription factors regulate stress-inducible gene expression that leads to initiating stress responses and establishing plant stress tolerance. Overexpression of some transcription factors, including DREB/CBF and MAC, enhances salt, drought, and cold tolerance in rice. A variant of one of ERF family genes, Sub1A-1, confers immersion tolerance to lowland rice. These findings and their exploitation will hold promise for engineering breeding to protect crop plants from certain abiotic stresses.

  5. Proteomic Analysis of Tomato Seedlings Response to Salt Stress

    Institute of Scientific and Technical Information of China (English)

    Xue Zhao; Feng Han; Shihua Shen

    2012-01-01

    The two species (Solanum pimpinellifolium-PI and S.lycopersicum-MM) of tomato showed marked differences in their responses to NaCI stress.PI appeared to be more tolerant to salt than MM.Comparative two-dimensional electrophoresis revealed that 187 and 110 protein spots were differentially expressed in the roots of PI and MM,respectively,in response to salt stress.Out of these spots,a total of 96 and 61 proteins were identified by MALDI-TOF MS analysis.The proteins identified included many previously characterized stress-responsive proteins and others related to processes including scavenging for reactive species; metabolism of energy,signal transduction; protein synthesis,cell growth and differentiation et al.The role of some of the proteins involved in the antioxidant defense mechanism,ion transport and compartmentalization of ions,and cell signaling pathways were discussed.Collectively,this work suggest that PI has more efficient antioxidant and defense machinery than MM,and that this is important for adapting to salt stress and for withstanding the oxidative stress imposed by high salt levels.

  6. Neural regulation of the stress response: glucocorticoid feedback mechanisms

    Directory of Open Access Journals (Sweden)

    J.P. Herman

    2012-04-01

    Full Text Available The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA axis, driven by a neural signal originating in the paraventricular nucleus (PVN. Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

  7. Silver nanoparticles induce endoplasmatic reticulum stress response in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Christen, Verena [University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Capelle, Martinus [Crucell, P.O. Box 2048, NL-2301 Leiden (Netherlands); Fent, Karl, E-mail: karl.fent@fhnw.ch [University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Swiss Federal Institute of Technology Zürich, Department of Environmental Systems Science, CH-8092 Zürich (Switzerland)

    2013-10-15

    Silver nanoparticles (AgNPs) find increasing applications, and therefore humans and the environment are increasingly exposed to them. However, potential toxicological implications are not sufficiently known. Here we investigate effects of AgNPs (average size 120 nm) on zebrafish in vitro and in vivo, and compare them to human hepatoma cells (Huh7). AgNPs are incorporated in zebrafish liver cells (ZFL) and Huh7, and in zebrafish embryos. In ZFL cells AgNPs lead to induction of reactive oxygen species (ROS), endoplasmatic reticulum (ER) stress response, and TNF-α. Transcriptional alterations also occur in pro-apoptotic genes p53 and Bax. The transcriptional profile differed in ZFL and Huh7 cells. In ZFL cells, the ER stress marker BiP is induced, concomitant with the ER stress marker ATF-6 and spliced XBP-1 after 6 h and 24 h exposure to 0.5 g/L and 0.05 g/L AgNPs, respectively. This indicates the induction of different pathways of the ER stress response. Moreover, AgNPs induce TNF-α. In zebrafish embryos exposed to 0.01, 0.1, 1 and 5 mg/L AgNPs hatching was affected and morphological defects occurred at high concentrations. ER stress related gene transcripts BiP and Synv are significantly up-regulated after 24 h at 0.1 and 5 mg/L AgNPs. Furthermore, transcriptional alterations occurred in the pro-apoptotic genes Noxa and p21. The ER stress response was strong in ZFL cells and occurred in zebrafish embryos as well. Our data demonstrate for the first time that AgNPs lead to induction of ER stress in zebrafish. The induction of ER stress can have several consequences including the activation of apoptotic and inflammatory pathways. - Highlights: • Effects of silver nanoparticles (120 nm AgNPs) are investigated in zebrafish. • AgNPs induce all ER stress reponses in vitro in zebrafish liver cells. • AgNPs induce weak ER stress in zebrafish embryos. • AgNPs induce oxidative stress and transcripts of pro-apoptosis genes.

  8. Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhang

    2014-06-01

    Full Text Available Erythropoietin (EPO regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR, suggest the potential for EPO response in metabolism and disease.

  9. Role of stress-activated MAP kinase P38 in cisplatin-and DTT-induced apoptosis of the esophageal carcinoma cell line Eca109

    Institute of Scientific and Technical Information of China (English)

    Qian-Xian Zhang; Ruo Feng; Wei Zhang; Yi Ding; Ji-Yao Yang; Guo-Hong Liu

    2005-01-01

    AIM: To study the role of P38 kinase in esophageal cancer cell apoptosis induced by genotoxin, cisplatin and the unfolded protein response (UPR) inducer, dithiothreitol(DTT).METHODS: Esophageal carcinoma cell line Eca109 was cultured in RPMI 1640 medium to 70% confluency and treated with either cisplatin, DTT, or cisplatin plus DTT in the presence or absence of P38 inhibitor, SB203580. The untreated cells served as the control. The esophageal carcinoma cell apoptosis was detected by agarose gel DNA ladder analysis and quantified by flow cytometry.The P38 phosphorylation was detected by immunohis-tochemistry using antibodies specific to phosphorylated P38 protein.RESULTS: (1) Both cisplatin and DTT induced apoptosis in the esophageal cancer cell line Eca109 as shown by DNA ladder formation; (2) As detected by antibodies specific for the phosphorylated P38 protein (p-P38), both cisplatin and DTT treatments activated the stress-activated enzyme, MAP kinase P38. The number of positive cells was about 50% for the treatment groups, comparing to that of 10% for untreated group. DTT treatment, but not cisplatin treatment, induces nuclear localization of p-P38;(3) As measured by flow cytometry, inhibition of P38 activity by SB203580 blocks DFT- and cisplatin-induced apoptosis.The rates for DTT, cisplatin, and DTT plus cisplatin-induced apoptosis were 16.8%, 17.1%, and 21.4%, respectively.Addition of the SB compound during the incubation reduced the apoptotic rate to about 7.6% for all the treatment groups, suggesting that P38 activation is essential for cisplatin- and DTT-induced apoptosis in Eca109 cells.CONCLUSION: (1) Both DTT and cisplatin were able to induce apoptosis in esophageal cancer cell line Eca109;(2) P38 MAP kinase is essential for DTT- and cisplatin-induced apoptosis in Eca109 cells; (3) P38 activation may be the common signaling component relaying the multiple upstream signaling events to the downstream cell death program.

  10. REM SLEEP REBOUND AS AN ADAPTIVE RESPONSE TO STRESSFUL SITUATIONS

    Directory of Open Access Journals (Sweden)

    Deborah eSuchecki

    2012-04-01

    Full Text Available Stress and sleep are related to each other in a bidirectional way. If on one hand poor or inadequate sleep exacerbates emotional, behavioral and stress-related responses, on the other hand acute stress induces sleep rebound, most likely as a form to cope with the adverse stimuli. Chronic stress, conversely, has been claimed to be one of the triggering factors of emotional-related sleep disorders, such as insomnia, depressive- and anxiety-disorders. These outcomes are dependent on individual psychobiological characteristics, which confer more complexity to the stress-sleep relationship. Its neurobiology has only recently begun to be explored, through animal models, which are also valuable for the development of potential therapeutic agents and preventive actions. This review seeks to present data on the effects of stress on sleep and the different approaches used to study this relationship as well as possible neurobiological underpinnings and mechanisms involved. The results of numerous studies in humans and animals indicate that increased sleep, especially the REM phase, following a stressful situation is an important adaptive behavior for recovery. However, this endogenous advantage appears to be impaired in human beings and rodent strains that exhibit high levels of anxiety and anxiety-like behavior.

  11. Response and energy dissipation of rock under stochastic stress waves

    Institute of Scientific and Technical Information of China (English)

    DENG Jian; BIAN Li

    2007-01-01

    The response and energy dissipation of rock under stochastic stress waves were analyzed based on dynamic fracture criterion of brittle materials integrating with Fourier transform methods of spectral analysis When the stochastic stress waves transnut through rocks,the frequency and energy ratio of harmonic components were calculated by analytical and discrete analysis methods.The stress waves in shale, malmstone and liparite were taken as examples to illustrate the proposed analysis methods.The results show the harder the rock, the less absorption of energy,the more the useless elastic waves transmitting through rock, and the narrower the cutoff frequency to fracture rock.When the whole stress energy doubles either by doubling the duration time or byincreasing the amplitude of stress wave, ratio of the energy of elastic waves transmitting through rock to me whole stress energy (i.e.energy dissipation ratio)is decreased to 10%-15%. When doubling the duration time.the cutoff frequency to fracture rock remains constant.However, with the increase of the amplitude of stress wave. the cutoff frequency increases accordingly.

  12. Morphological and Physiological Responses of Strawberry Plants to Water Stress

    OpenAIRE

    Krzysztof Klamkowski; Waldemar Treder

    2006-01-01

    The most of previous studies have been focused on the effect of water stress on plant yielding. However, the conditions in which plants grow from the moment of planting might affect their morphology and physiological response. The aim of this study was to examine the effect of water deficiency on growth and plant physiological response of strawberry (Fragaria x ananassa Duch. cv. ‘Salut’) under greenhouse conditions. The plants were grown in plastic containers filled with peat substratum. Wat...

  13. Stress and fear responses in the teleost pallium

    DEFF Research Database (Denmark)

    Silva, Patricia Isabel da Mota E.; Martins, C.I.M.; Khan, Uniza Wahid;

    2015-01-01

    combining skin extract with other challenges are needed to reveal neuroendocrine effects associated with this predator cue. Confinement stress resulted in an elevation of cortisol and serotonin (5-hydroxytryptamine, 5-HT) metabolism in both Dl and Dm. A similar tendency was observed in fish exposed...... been found in the teleost telencephalon. The dorsolateral (Dl) and dorsomedial (Dm) regions of the pallium are thought to perform hippocampus and amygdala-like functions respectively. To what degree these regions are involved in the neuroendocrine responses to stress and predator cues however remains...... largely unknown. In the present study the involvement of Dl and Dm in such responses was investigated by exposing Nile tilapia (Oreochromis niloticus) to a standardized confinement stress and to skin extract from conspecifics. Nile tilapia develops a characteristic anticipatory behaviour to hand feeding...

  14. Husbandry of zebrafish, Danio rerio, and the cortisol stress response.

    Science.gov (United States)

    Pavlidis, Michail; Digka, Nikoletta; Theodoridi, Antonia; Campo, Aurora; Barsakis, Konstantinos; Skouradakis, Gregoris; Samaras, Athanasios; Tsalafouta, Alexandra

    2013-12-01

    The effect of common husbandry conditions (crowding, social environment, water quality, handling, and background color) on the cortisol stress response in adult zebrafish, Danio rerio, was investigated to check the usefulness of zebrafish as a model organism in aquaculture research. In addition, a noninvasive methodology for assessing stress was evaluated. Zebrafish showed a fast cortisol response with high values at 30 min that returned to basal levels within 2 h of poststress. There was a significant positive correlation between trunk cortisol concentrations and the free water cortisol rate (r(2)=0.829-0.850, pzebrafish. It is concluded that adult laboratory zebrafish had a preference for a transparent or black background aquarium, at a number of 10 individuals per 2 L of available water volume, to express their normal behavior and avoid increased cortisol stress reaction.

  15. Enterovirus Control of Translation and RNA Granule Stress Responses

    Directory of Open Access Journals (Sweden)

    Richard E. Lloyd

    2016-03-01

    Full Text Available Enteroviruses such as poliovirus (PV and coxsackievirus B3 (CVB3 have evolved several parallel strategies to regulate cellular gene expression and stress responses to ensure efficient expression of the viral genome. Enteroviruses utilize their encoded proteinases to take over the cellular translation apparatus and direct ribosomes to viral mRNAs. In addition, viral proteinases are used to control and repress the two main types of cytoplasmic RNA granules, stress granules (SGs and processing bodies (P-bodies, PBs, which are stress-responsive dynamic structures involved in repression of gene expression. This review discusses these processes and the current understanding of the underlying mechanisms with respect to enterovirus infections. In addition, the review discusses accumulating data suggesting linkage exists between RNA granule formation and innate immune sensing and activation.

  16. Enterovirus Control of Translation and RNA Granule Stress Responses

    Science.gov (United States)

    Lloyd, Richard E.

    2016-01-01

    Enteroviruses such as poliovirus (PV) and coxsackievirus B3 (CVB3) have evolved several parallel strategies to regulate cellular gene expression and stress responses to ensure efficient expression of the viral genome. Enteroviruses utilize their encoded proteinases to take over the cellular translation apparatus and direct ribosomes to viral mRNAs. In addition, viral proteinases are used to control and repress the two main types of cytoplasmic RNA granules, stress granules (SGs) and processing bodies (P-bodies, PBs), which are stress-responsive dynamic structures involved in repression of gene expression. This review discusses these processes and the current understanding of the underlying mechanisms with respect to enterovirus infections. In addition, the review discusses accumulating data suggesting linkage exists between RNA granule formation and innate immune sensing and activation. PMID:27043612

  17. Phosphate-dependent root system architecture responses to salt stress

    NARCIS (Netherlands)

    Kawa, D.; Julkowska, M.M.; Montero Sommerfeld, H.; ter Horst, A.; Haring, M.A.; Testerink, C.

    2016-01-01

    Nutrient availability and salinity of the soil affect growth and development of plant roots. Here, we describe how phosphate availability affects root system architecture (RSA) of Arabidopsis and how phosphate levels modulate responses of the root to salt stress. Phosphate (Pi) starvation reduced ma

  18. Adaptive Patterns of Stress Responsivity: A Preliminary Investigation

    Science.gov (United States)

    Del Giudice, Marco; Hinnant, J. Benjamin; Ellis, Bruce J.; El-Sheikh, Mona

    2012-01-01

    The adaptive calibration model (ACM) is an evolutionary-developmental theory of individual differences in stress responsivity. In this article, we tested some key predictions of the ACM in a middle childhood sample (N = 256). Measures of autonomic nervous system activity across the sympathetic and parasympathetic branches validated the 4-pattern…

  19. Stress response signaling and virulence: insights from entomopathogenic fungi.

    Science.gov (United States)

    Ortiz-Urquiza, Almudena; Keyhani, Nemat O

    2015-08-01

    The Ascomycete fungal insect pathogens, Beauveria and Metarhizium spp. have emerged as model systems with which to probe diverse aspects of fungal growth, stress response, and pathogenesis. Due to the availability of genomic resources and the development of robust methods for genetic manipulation, the last 5 years have witnessed a rapid increase in the molecular characterization of genes and their pathways involved in stress response and signal transduction in these fungi. These studies have been performed mainly via characterization of gene deletion/knockout mutants and have included the targeting of general proteins involved in stress response and/or virulence, e.g. catalases, superoxide dismutases, and osmolyte balance maintenance enzymes, membrane proteins and signaling pathways including GPI anchored proteins and G-protein coupled membrane receptors, MAPK pathways, e.g. (i) the pheromone/nutrient sensing, Fus3/Kss1, (ii) the cell wall integrity, Mpk1, and (iii) the high osmolarity, Hog1, the PKA/adenyl cyclase pathway, and various downstream transcription factors, e.g. Msn2, CreA and Pac1. Here, we will discuss current research that strongly suggests extensive underlying contributions of these biochemical and signaling pathways to both abiotic stress response and virulence.

  20. Oxidative stress response pathways: Fission yeast as archetype

    DEFF Research Database (Denmark)

    Papadakis, Manos A.; Workman, Christopher

    2015-01-01

    Schizosaccharomyces pombe is a popular model eukaryotic organism to study diverse aspects of mammalian biology, including responses to cellular stress triggered by redox imbalances within its compartments. The review considers the current knowledge on the signaling pathways that govern the transc...

  1. Phospholipid signaling responses in salt-stressed rice leaves

    NARCIS (Netherlands)

    Darwish, E.; Testerink, C.; Khalil, M.; El-Shihy, O.; Munnik, T.

    2009-01-01

    Salinity is one of the major environmental factors limiting growth and productivity of rice plants. In this study, the effect of salt stress on phospholipid signaling responses in rice leaves was investigated. Leaf cuts were radiolabeled with 32 P-orthophosphate and the lipids extracted and analyzed

  2. The insect capa neuropeptides impact desiccation and cold stress responses

    Science.gov (United States)

    Background: Insects are so successful because of great resistance to environmental stress, yet little is known about how such responses may be mediated by the neuroendocrine system. Results: We provide evidence that the capability (capa) neuropeptide gene and peptide are critical mediators of desic...

  3. Genetic mapping of abiotic stress responses in sorghum

    Science.gov (United States)

    Due to rich genetic diversity for tolerance to various abiotic stress conditions, sorghum is an ideal system for genetic mapping and elucidation of genome regions that confer such response among cereal crops. Coupled with the development of DNA marker technologies and most recently the sequencing o...

  4. Interaction between Nitrogen and Phosphate Stress Responses in Sinorhizobium meliloti

    Directory of Open Access Journals (Sweden)

    Kelly Lynn Hagberg

    2016-11-01

    Full Text Available Bacteria have developed various stress response pathways to improve their assimilation and allocation of limited nutrients, such as nitrogen and phosphate. While both the Nitrogen Stress Response (NSR and Phosphate Stress Response (PSR have been studied individually, there are few experiments reported that characterize effects of multiple stresses on one or more pathways in Sinorhizobium meliloti, a facultatively symbiotic, nitrogen-fixing bacteria. The PII proteins, GlnB and GlnK, regulate the NSR activity, but analysis of global transcription changes in a PII deficient mutant suggest that the S. meliloti PII proteins may also regulate the PSR. PII double deletion mutants grow very slowly and pseudoreversion of the slow growth phenotype is common. To understand this phenomenon better, transposon mutants were isolated that had a faster growing phenotype. One mutation was in phoB, the response regulator for a two component regulatory system that is important in the PSR. phoB::Tn5 mutants had different phenotypes in the wild type compared to a PII deficient background. This led to the hypothesis that phosphate stress affects the NSR and conversely, that nitrogen stress affects the PSR. Our results show that phosphate availability affects glutamine synthetase activity and expression, which are often used as indicators of NSR activity, but that nitrogen availability did not affect alkaline phosphatase activity and expression, which are indicators of PSR activity. We conclude that the NSR is co-regulated by nitrogen and phosphate, whereas the PSR does not appear to be co-regulated by nitrogen in addition to its known phosphate regulation.

  5. Interaction between Nitrogen and Phosphate Stress Responses in Sinorhizobium meliloti

    Science.gov (United States)

    Hagberg, Kelly L.; Yurgel, Svetlana N.; Mulder, Monika; Kahn, Michael L.

    2016-01-01

    Bacteria have developed various stress response pathways to improve their assimilation and allocation of limited nutrients, such as nitrogen and phosphate. While both the nitrogen stress response (NSR) and phosphate stress response (PSR) have been studied individually, there are few experiments reported that characterize effects of multiple stresses on one or more pathways in Sinorhizobium meliloti, a facultatively symbiotic, nitrogen-fixing bacteria. The PII proteins, GlnB and GlnK, regulate the NSR activity, but analysis of global transcription changes in a PII deficient mutant suggest that the S. meliloti PII proteins may also regulate the PSR. PII double deletion mutants grow very slowly and pseudoreversion of the slow growth phenotype is common. To understand this phenomenon better, transposon mutants were isolated that had a faster growing phenotype. One mutation was in phoB, the response regulator for a two component regulatory system that is important in the PSR. phoB::Tn5 mutants had different phenotypes in the wild type compared to a PII deficient background. This led to the hypothesis that phosphate stress affects the NSR and conversely, that nitrogen stress affects the PSR. Our results show that phosphate availability affects glutamine synthetase activity and expression, which are often used as indicators of NSR activity, but that nitrogen availability did not affect alkaline phosphatase activity and expression, which are indicators of PSR activity. We conclude that the NSR is co-regulated by nitrogen and phosphate, whereas the PSR does not appear to be co-regulated by nitrogen in addition to its known phosphate regulation. PMID:27965651

  6. Transactional Associations between Youths' Responses to Peer Stress and Depression: The Moderating Roles of Sex and Stress Exposure

    Science.gov (United States)

    Agoston, Anna M.; Rudolph, Karen D.

    2011-01-01

    This study examined transactional associations between responses to peer stress and depression in youth. Specifically, it tested the hypotheses that (a) depression would predict fewer effortful responses and more involuntary, dysregulated responses to peer stress over time; and (b) fewer adaptive and more maladaptive responses would predict…

  7. Response of restraint stress-selected lines of Japanese quail to heat stress and Escherichia coli challenge

    Science.gov (United States)

    Japanese quail selected for divergent corticosterone (Cort) response to restraint stress were evaluated for their susceptibility to heat stress and challenge with Escherichia coli. These quail lines are designated as the high stress (HS), low stress (LS), and the random-bred control (CS) lines. Hea...

  8. Alternative Strategy for Alzheimer’s Disease: Stress Response Triggers

    Directory of Open Access Journals (Sweden)

    Joan Smith Sonneborn

    2012-01-01

    Full Text Available Stress resistance capacity is a hallmark of longevity protection and survival throughout the plant and animal kingdoms. Latent pathway activation of protective cascades, triggered by environmental challenges to tolerate heat, oxygen deprivation, reactive oxygen species (ROS, diet restriction, and exercise provides tolerance to these stresses. Age-related changes and disease vulnerability mark an increase in damage, like damage induced by environmental challenges. An alternative approach to immunotherapy intervention in Alzheimer’s Disease is the use of mimetics of stress to upregulate endogenous protective cascades to repair age damage, shift the balance of apoptosis to regeneration to promote delay of onset, and even progression of Alzheimer’s disease memory dysfunction. Mimetics of environmental stress, hormetic agents, and triggers, endogenous or engineered, can “trick” activation of expression patterns of repair and rejuvenation. Examples of known candidate triggers of heat response, endogenous antioxidants, DNA repair, exercise, hibernation, and telomeres are available for AD intervention trials. Telomeres and telomerase emerge as major regulators in crossroads of senescence, cancer, and rejuvenation responsive to mimetics of telomeres. Lessons emerge from transgenic rodent models, the long-lived mole rat, clinical studies, and conserved innate pathways of stress resistance. Cross-reaction of benefits of different triggers promises intervention into seemingly otherwise unrelated diseases.

  9. Transcriptional regulation of the stress response by mTOR.

    Science.gov (United States)

    Aramburu, Jose; Ortells, M Carmen; Tejedor, Sonia; Buxadé, Maria; López-Rodríguez, Cristina

    2014-07-01

    The kinase mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation that integrates inputs from growth factor receptors, nutrient availability, intracellular ATP (adenosine 5'-triphosphate), and a variety of stressors. Since early works in the mid-1990s uncovered the role of mTOR in stimulating protein translation, this kinase has emerged as a rather multifaceted regulator of numerous processes. Whereas mTOR is generally activated by growth- and proliferation-stimulating signals, its activity can be reduced and even suppressed when cells are exposed to a variety of stress conditions. However, cells can also adapt to stress while maintaining their growth capacity and mTOR function. Despite knowledge accumulated on how stress represses mTOR, less is known about mTOR influencing stress responses. In this review, we discuss the capability of mTOR, in particular mTOR complex 1 (mTORC1), to activate stress-responsive transcription factors, and we outline open questions for future investigation.

  10. Gene Networks in Plant Ozone Stress Response and Tolerance

    Institute of Scientific and Technical Information of China (English)

    Agnieszka Ludwikow; Jan Sadowski

    2008-01-01

    For many plant species ozone stress has become much more severe in the last decade. The accumulating evidence for the significant effects of ozone pollutant on crop and forest yield situate ozone as one of the most important environmental stress factors that limits plant productivity woddwide. Today, transcdptomic approaches seem to give the best coverage of genome level responses. Therefore, microarray serves as an invaluable tool for global gene expression analyses, unravelling new information about gene pathways, in-species and crose-species gene expression comparison, and for the characterization of unknown relationships between genes. In this review we summadze the recent progress in the transcdptomics of ozone to demonstrate the benefits that can be harvested from the application of integrative and systematic analytical approaches to study ozone stress response. We focused our consideration on microarray analyses identifying gene networks responsible for response and tolerance to elevated ozone concentration. From these analyses it is now possible to notice how plant ozone defense responses depend on the interplay between many complex signaling pathways and metabolite signals.

  11. Assessing the Neuroendocrine Stress Response in the Functional Neuroimaging Context

    Science.gov (United States)

    King, Anthony P.; Liberzon, Israel

    2009-01-01

    Neural regulation of stress responses, and the feedback of stress hormones to the brain, reflect complex brain-body interactions that may underlie the effects of psychological stress on health. Elucidating the brain circuitry involved in the cortical control of limbic-hypothalamic-pituitary-adrenal axis, and the cortical “targets” of cortisol that in turn modulates brain function, requires careful assessment of glucocorticoid hormones, in the context of the neuroimaging paradigms. Here we discuss approaches for assessment of endocrine function in the context of neuroimaging, including methods of blood and saliva specimen collection, and methods for drug/hormone administration. We also briefly discuss important temporal considerations, including appropriate timing of sample collections for hormones with different time-courses of activation (e.g. ACTH vs. cortisol), the pharmacokinetics of both endogenous hormones and administered agents, and circadian considerations. These are crucial to experimental designs of rhythmic hormonal systems and multiple feedback loops. We briefly address psychological/behavioral ‘activation’ paradigms used for inducing endogenous LHPA axis responses within or in proximity to scanner, as well as strategies for administration of exogenous hormones or secretagogues. Finally, we discuss some of the analyses issues in terms of hormone responses (e.g. response and area under curve, diurnal variability) and strategies for linking measured levels of peripheral humoral factor to brain activity (e.g. hormone responses as between subject regressors of BOLD activations, hormone levels as within subject regressors in analyses of covariance of brain activity over time, etc.). PMID:19481160

  12. Transgenerational stress memory is not a general response in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Ales Pecinka

    Full Text Available Adverse conditions can trigger DNA damage as well as DNA repair responses in plants. A variety of stress factors are known to stimulate homologous recombination, the most accurate repair pathway, by increasing the concentration of necessary enzymatic components and the frequency of events. This effect has been reported to last into subsequent generations not exposed to the stress. To establish a basis for a genetic analysis of this transgenerational stress memory, a broad range of treatments was tested for quantitative effects on homologous recombination in the progeny. Several Arabidopsis lines, transgenic for well-established recombination traps, were exposed to 10 different physical and chemical stress treatments, and scored for the number of somatic homologous recombination (SHR events in the treated generation as well as in the two subsequent generations that were not treated. These numbers were related to the expression level of genes involved in homologous recombination and repair. SHR was enhanced after the majority of treatments, confirming previous data and adding new effective stress types, especially interference with chromatin. Compounds that directly modify DNA stimulated SHR to values exceeding previously described induction rates, concomitant with an induction of genes involved in SHR. In spite of the significant stimulation in the stressed generations, the two subsequent non-treated generations only showed a low and stochastic increase in SHR that did not correlate with the degree of stimulation in the parental plants. Transcripts coding for SHR enzymes generally returned to pre-treatment levels in the progeny. Thus, transgenerational effects on SHR frequency are not a general response to abiotic stress in Arabidopsis and may require special conditions.

  13. Oxidative stress response of Deinococcus geothermalis via a cystine importer.

    Science.gov (United States)

    Kim, Minwook; Jeong, Sunwook; Lim, Sangyong; Sim, Jeonggu; Rhie, Ho-Gun; Lee, Sung-Jae

    2017-02-01

    A cystine-dependent anti-oxidative stress response is characterized in Deinococcus geothermalis for the first time. Nevertheless, the same transcriptional directed Δdgeo_1985F mutant strain was revealed to have an identical phenotype to the wild-type strain, while the reverse transcriptional directed Δdgeo_1985R mutant strain was more resistant to oxidative stress at a certain concentration of H2O2 than the wild-type strain. The wild-type and mutant strains expressed equal levels of superoxide dismutase and catalase under H2O2-induced stress. Although the expression levels of the general DNA-damage response-related genes recA, pprA, ddrA, and ddrB were up-regulated by more than five-fold in the wild-type strain relative to the Δdgeo_1985R mutant strain, the mutant strain had a higher survival rate than the wild-type under H2O2 stress. The Δdgeo_1985R mutant strain highly expressed a cystine-transporter gene (dgeo_1986), at levels 150-fold higher than the wild-type strain, leading to the conclusion that this cystine transporter might be involved in the defensive response to H2O2 stress. In this study, the cystine transporter was identified and characterized through membrane protein expression analysis, a cystine-binding assay, and assays of intracellular H2O2, cysteine, and thiol levels. The genedisrupted mutant strain of the cystine importer revealed high sensitivity to H2O2 and less absorbed cystine, resulting in low concentrations of total thiol. Thus, the absorbed cystine via this cystine-specific importer may be converted into cysteine, which acts as a primitive defense substrate that non-enzymatically scavenges oxidative stress agents in D. geothermalis.

  14. How are neuroticism and depression related to the psychophysiological stress response to acute stress in healthy older people?

    Science.gov (United States)

    Puig-Perez, Sara; Villada, Carolina; Pulopulos, Matias M; Hidalgo, Vanesa; Salvador, Alicia

    2016-03-15

    Neuroticism and depressive symptomatology have been related to a heightened and diminished physiological stress response, which may partly explain their negative relationship with health and wellbeing. Identifying factors that may increase disease vulnerability is especially relevant in older people, whose physiological systems decline. With this in mind, we investigated the influence of neuroticism and depression on the psychophysiological stress response in healthy older people (from 55 to 76years old). A total of 36 volunteers were exposed to a stressful task (Trier Social Stress Test, TSST), while 35 volunteers performed a control non-stressful task. The physiological stress response was assessed through measures of cortisol, alpha-amylase, heart rate (HR). Our results showed that, neuroticism was not related to physiological stress response. However, depression was related to higher cortisol response and lower HR reactivity in the stress condition. In summary, emotional states such as depressive mood seem to amplify the cortisol stress response and reduce the cardiovascular response, whereas more stable dispositions such as neuroticism did not affect stress response in older people. These findings confirm, in healthy older people, the adverse effects of depression, acting on different subsystems of the stress response.

  15. Molecular Responses of Groundnut (Arachis hypogea L. to Zinc Stress

    Directory of Open Access Journals (Sweden)

    A. John De Britto

    2013-08-01

    Full Text Available Heavy metals are important environmental pollutants and their toxicity is a problem of increasing significance for ecological, evolutionary and environmental reasons. The interference of germination related proteins by heavy metals has not been well documented at the proteomic and genomic level. In the current study, molecular responses of germinating groundnut seeds were investigated under Zinc stress. The SDS-PAGE showed the preliminary changes in the polypeptides patterns under Zinc stress. Restriction digestion banding pattern of EcoRI and Hind III enzymes showed distinct banding pattern in the treated plants.

  16. Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses.

    Science.gov (United States)

    Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana; Herman, James P

    2017-03-01

    In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nuclei also play an important role in neuroendocrine responses to psychogenic stressors mediated by the hypothalamic-pituitary-adrenocortical axis. Further, these nuclei integrate neuroendocrine responses with stress-related behaviors, significantly impacting mood and anxiety. The current review focuses on the prominent brainstem monosynaptic inputs to the endocrine paraventricular hypothalamic nucleus (PVN), including the periaqueductal gray, raphe nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract (NTS). The NTS is a particularly intriguing area, as the region contains multiple cell groups that provide neurochemically-distinct inputs to the PVN. Furthermore, the NTS, under regulatory control by glucocorticoid-mediated feedback, integrates affective processes with physiological status to regulate stress responding. Collectively, these brainstem circuits represent an important avenue for delineating interactions between stress and health.

  17. 沙利度胺对顺铂诱发大鼠异食癖的影响%Effect of thalidomide on cisplatin-induced pica in rats

    Institute of Scientific and Technical Information of China (English)

    马剑; 韩正祥; 高向阳

    2012-01-01

    目的 观察沙利度胺对顺铂引起的大鼠异食癖的作用,探讨其抗化疗呕吐的实验基础.方法 健康大鼠24只,随机分为对照组、模型组、低剂量沙利度胺组、高剂量沙利度胺组,观察72 h内大鼠摄取高岭土所占总进食量的比值;另取大鼠48只,分组同前,分别于实验开始后5、33 h,取大鼠延髓及胃窦组织,放免法测定P物质,免疫组化法测定神经激肽1受体(NK-1R).结果 顺铂10 mg/kg可以引起大鼠异食癖,沙利度胺10 mg/kg在顺铂应用24 h后可以减轻这种异食癖(P<0.05),同时伴有延髓及胃窦P物质的减少(P<0.05),而NK-1R未出现明显变化.结论 沙利度胺可以减轻顺铂引起的大鼠异食癖,提示在抗呕吐治疗中沙利度胺可能有一定的应用前景.%Objective To observe the effect of thalidomide on cisplatin - induced pica in rats , and to explore the experimental basis of thalidomide resistant to chemotherapy - induced nausea and vomiting. Methods 24 healthy rats were randomly devided into 4 groups: control group , model group , thalidomide group (low dose) and thalidomide group (high dose). The ratio of intake of kaolin total food intake within 72 h was observed. Another 48 rats were randomly devided into 4 groups which were the same as stated above , medullar tissue and gastric antrum were taken out at 5 , 33 hours after the start of the experiment, the substance P (SP) were measured by radioimmunoassay and the neurokinin 1 receptor (NK -1R) determined by immunohistochemistry method. Results Cisplatin 10 mg/kg induced pica,which could be decreased by thalidomide at 10 mg/kg 24 h after the application of cisplatin (P < 0.05) , while accompanied with reduced SP level (P < 0. 05) , but NK - 1R did not have significant changes. Conclusion Thalidomide can reduce cisplatin - induced pica in rats, which suggests that thalidomide may have some prospect in the treatment of anti -chemotherapy vomiting.

  18. 5-Aminolevulinic acid protects against cisplatin-induced nephrotoxicity without compromising the anticancer efficiency of cisplatin in rats in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Yoshio Terada

    Full Text Available BACKGROUND/AIMS: Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP-based chemotherapy. 5-Aminolevulinic acid (ALA is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI. METHOD: We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E. We divided four groups of rats: control, CDDP only, CDDP + ALA(post;(ALA 10 mg/kg + Fe in drinking water after CDDP, CDDP + ALA(pre & post. RESULT: CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP. CONCLUSION: These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.

  19. Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells.

    Science.gov (United States)

    Rodríguez-García, Maria Elena; Quiroga, Adoración G; Castro, José; Ortiz, Alberto; Aller, Patricio; Mata, Felicísima

    2009-10-01

    We were interested in analyzing the regulation by mitogen-activated protein kinases (MAPKs) of cisplatin-provoked toxicity in epithelial renal tubule cell lines, when assayed under culture conditions (cell confluence plus serum deprivation), which mimic the characteristics of a nonproliferating epithelium. Under these restrictive growth conditions, cisplatin induced apoptosis with lower efficacy than in exponentially growing cells, and decreased p38-MAPK phosphorylation in NRK-52E and other (LLC-PK1, MDCK, HK2) cell lines. Moreover, cisplatin-provoked apoptosis was potentiated by cotreatment with p38-MAPK-specific inhibitors (SB203580, SB220025) or transfection with a kinase-negative mutant of MKK6, whereas c-Jun NH2-terminal kinase or extracellular signal-regulated kinase/MAPK and ERK Kinase inhibitors were ineffective. By contrast, when applied to exponentially growing cells, cisplatin stimulated p38-MAPK phosphorylation and apoptosis, was attenuated by kinase inhibitors. Treatment of confluent/serum-deprived cells with cisplatin caused mitochondrial transmembrane potential disruption and activated the mitochondrial apoptotic pathway, as indicated by the decrease in Bcl-X(L) expression, increase in Bax expression and cytochrome c release, and these effects were potentiated by cotreatment with SB203580. Treatment of confluent/serum-deprived cells with cisplatin plus SB203580 decreased the intracellular reduced glutathione (GSH) content, and increased intracellular cisplatin accumulation as well as cisplatin binding to DNA. Cotreatment with the GSH-depleting agent D,L-buthionine-R,S-sulfoximine also potentiated cisplatin-provoked apoptosis. In summary, p38-MAPK inhibition potentiates cisplatin-provoked apoptosis in growth-arrested epithelial renal tubule cells, a result that may be explained at least in part by GSH depletion and drug transport alteration.

  20. Stress responses from the endoplasmic reticulum in cancer

    Directory of Open Access Journals (Sweden)

    Hironori eKato

    2015-04-01

    Full Text Available The endoplasmic reticulum (ER is a dynamic organelle that is essential for multiple cellular functions. During cellular stress conditions, including nutrient deprivation and dysregulation of protein synthesis, unfolded/misfolded proteins accumulate in the ER lumen, resulting in activation of the unfolded protein response (UPR. The UPR also contributes to the regulation of various intracellular signalling pathways such as calcium signalling and lipid signalling. More recently, the mitochondria-associated ER membrane (MAM, which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signalling, inflammatory signalling, the autophagic response, and the UPR. Interestingly, in cancer, these signalling pathways from the ER are often dysregulated, contributing to cancer cell metabolism. Thus, the signalling pathway from the ER may be a novel therapeutic target for various cancers. In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

  1. Characterization of the physiological stress response in lingcod

    Science.gov (United States)

    Milston, R.H.; Davis, M.W.; Parker, S.J.; Olla, B.L.; Clements, S.; Schreck, C.B.

    2006-01-01

    The goal of this study was to describe the duration and magnitude of the physiological stress response in lingcod Ophiodon elongatus after exposure to brief handling and sublethal air stressors. The response to these stressors was determined during a 24-h recovery period by measuring concentrations of plasma cortisol, lactate, glucose, sodium, and potassium. Lingcod were subjected to brief handling followed by either a 15-min or a 45-min air stressor in the laboratory. After the 15-min stressor, an increase in cortisol or glucose could not be detected until after 5 min of recovery. Peak concentrations were measured after 30 min for cortisol and after 60 min for glucose and lactate. Glucose and lactate had returned to basal levels after 12 h, whereas cortisol did not return to basal levels until after 24 h of recovery. Immediately following a 45-min air stressor, all measured parameters were significantly elevated over levels in prestressor control fish. Cortisol concentrations tended to increase and reached a measured peak after 8 h of recovery, whereas glucose and lactate reached a measured peak after 1 h of recovery. Cortisol and lactate returned to basal levels within 24 h. Glucose, however, remained elevated even after 24 h of recovery. Plasma ions initially increased during the first hour of recovery, and the concentrations then declined to a level below that measured in control fish for the remainder of the 24-h recovery period. In addition, we evaluated the effect of fish size on the stress response. There was no significant difference between the stress response of smaller (41-49-cm [total length] and larger (50-67-cm) lingcod after 45 min air exposure. In general, both the magnitude and duration of the primary and secondary stress responses in lingcod are comparable to those of salmonids. ?? Copyright by the American Fisheries Society 2006.

  2. Deciphering hepatocellular responses to metabolic and oncogenic stress

    Directory of Open Access Journals (Sweden)

    Kathrina L. Marcelo

    2015-08-01

    Full Text Available Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (MΦ, and sinusoidal endothelial cells (SEC play functionally important and interdependent roles in adaptive processes such as obesity and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. We developed a strategy for the simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression. To demonstrate the utility and applicability of this technique, we quantified liver cell-specific responses to high-fat diet (HFD or diethylnitrosamine (DEN, a liver-specific carcinogen, and found that while there was only a marginal increase in hepatocyte number, MΦ and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, MΦ and SEC identified characteristic gene signatures that define each cell type in their distinct physiological or pathological states. Integration of hepatic gene signatures with available human obesity and liver cancer microarray data provides further insight into the cell-specific responses to metabolic or oncogenic stress. Our data reveal unique gene expression patterns that serve as molecular “fingerprints” for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to metabolic and oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the continuum from metabolic disruption to obesity and ultimately hepatic cancer.

  3. The cellular response to curvature-induced stress

    Science.gov (United States)

    Biton, Y. Y.; Safran, S. A.

    2009-12-01

    We present a theoretical model to explain recent observations of the orientational response of cells to unidirectional curvature. Experiments show that some cell types when plated on a rigid cylindrical surface tend to reorient their shape and stress fibers along the axis of the cylinder, while others align their stress fibers perpendicular to that axis. Our model focuses on the competition of the shear stress—that results from cell adhesion and active contractility—and the anisotropic bending stiffness of the stress fibers. We predict the cell orientation angle that results from the balance of these two forces in a mechanical equilibrium. The conditions under which the different experimental observations can be obtained are discussed in terms of the theory.

  4. The plant response:stress in the daily environment

    Institute of Scientific and Technical Information of China (English)

    FERGUSON Ian B.

    2004-01-01

    @@STRESS IS NORMAL Like animals, plants have evolved to survive in almost every climatic and environmental niche available. They have, however, evolved more sophisticated and varied methods to enable them to survive environmental changes in light, temperature, atmosphere composition, water and nutrients and salinity. This, in part, is necessary because of the sessile nature of plants; they do not have the ability to move to more favourable environments. Stress conditions that plants encounter are not always as rare or unusual as we might at first think. The most common environmental variables, necessary for growth, can impose significant stresses on the plant. But should we think of these as unusual and extreme or just part of the normal diurnal responses experienced by the plant?

  5. Quorum sensing regulates the osmotic stress response in Vibrio harveyi.

    Science.gov (United States)

    van Kessel, Julia C; Rutherford, Steven T; Cong, Jian-Ping; Quinodoz, Sofia; Healy, James; Bassler, Bonnie L

    2015-01-01

    Bacteria use a chemical communication process called quorum sensing to monitor cell density and to alter behavior in response to fluctuations in population numbers. Previous studies with Vibrio harveyi have shown that LuxR, the master quorum-sensing regulator, activates and represses >600 genes. These include six genes that encode homologs of the Escherichia coli Bet and ProU systems for synthesis and transport, respectively, of glycine betaine, an osmoprotectant used during osmotic stress. Here we show that LuxR activates expression of the glycine betaine operon betIBA-proXWV, which enhances growth recovery under osmotic stress conditions. BetI, an autorepressor of the V. harveyi betIBA-proXWV operon, activates the expression of genes encoding regulatory small RNAs that control quorum-sensing transitions. Connecting quorum-sensing and glycine betaine pathways presumably enables V. harveyi to tune its execution of collective behaviors to its tolerance to stress.

  6. Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.

    Science.gov (United States)

    Sachs, Benjamin D; Ni, Jason R; Caron, Marc G

    2015-02-24

    Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.

  7. Cis-element of the rice PDIL2-3 promoter is responsible for inducing the endoplasmic reticulum stress response.

    Science.gov (United States)

    Takahashi, Hideyuki; Wang, Shuyi; Hayashi, Shimpei; Wakasa, Yuhya; Takaiwa, Fumio

    2014-05-01

    A protein disulfide isomerase (PDI) family oxidoreductase, PDIL2-3, is involved in endoplasmic reticulum (ER) stress responses in rice. We identified a critical cis-element required for induction of the ER stress response. The activation of PDIL2-3 in response to ER stress strongly depends on the IRE1-OsbZIP50 signaling pathway.

  8. Particle shape effects on the stress response of granular packings.

    Science.gov (United States)

    Athanassiadis, Athanasios G; Miskin, Marc Z; Kaplan, Paul; Rodenberg, Nicholas; Lee, Seung Hwan; Merritt, Jason; Brown, Eric; Amend, John; Lipson, Hod; Jaeger, Heinrich M

    2014-01-01

    We present measurements of the stress response of packings formed from a wide range of particle shapes. Besides spheres these include convex shapes such as the Platonic solids, truncated tetrahedra, and triangular bipyramids, as well as more complex, non-convex geometries such as hexapods with various arm lengths, dolos, and tetrahedral frames. All particles were 3D-printed in hard resin. Well-defined initial packing states were established through preconditioning by cyclic loading under given confinement pressure. Starting from such initial states, stress-strain relationships for axial compression were obtained at four different confining pressures for each particle type. While confining pressure has the largest overall effect on the mechanical response, we find that particle shape controls the details of the stress-strain curves and can be used to tune packing stiffness and yielding. By correlating the experimentally measured values for the effective Young's modulus under compression, yield stress and energy loss during cyclic loading, we identify trends among the various shapes that allow for designing a packing's aggregate behavior.

  9. Osmotic stress response in the wine yeast Dekkera bruxellensis.

    Science.gov (United States)

    Galafassi, Silvia; Toscano, Marco; Vigentini, Ileana; Piškur, Jure; Compagno, Concetta

    2013-12-01

    Dekkera bruxellensis is mainly associated with lambic beer fermentation and wine production and may contribute in a positive or negative manner to the flavor development. This yeast is able to produce phenolic compounds, such as 4-ethylguaiacol and 4-ethylphenol which could spoil the wine, depending on their concentration. In this work we have investigated how this yeast responds when exposed to conditions causing osmotic stress, as high sorbitol or salt concentrations. We observed that osmotic stress determined the production and accumulation of intracellular glycerol, and the expression of NADH-dependent glycerol-3-phosphate dehydrogenase (GPD) activity was elevated. The involvement of the HOG MAPK pathway in response to this stress condition was also investigated. We show that in D. bruxellensis Hog1 protein is activated by phosphorylation under hyperosmotic conditions, highlighting the conserved role of HOG MAP kinase signaling pathway in the osmotic stress response. Gene Accession numbers in GenBank: DbHOG1: JX65361, DbSTL1: JX965362.

  10. Stress induced hypertensive response: should it be evaluated more carefully?

    Directory of Open Access Journals (Sweden)

    Kucukler Nagehan

    2011-08-01

    Full Text Available Abstract Various diagnostic methods have been used to evaluate hypertensive patients under physical and pharmacological stress. Several studies have shown that exercise hypertension has an independent, adverse impact on outcome; however, other prognostic studies have shown that exercise hypertension is a favorable prognostic indicator and associated with good outcome. Exercise hypertension may be encountered as a warning signal of hypertension at rest and future hypertensive left ventricular hypertrophy. The results of diagnostic stress tests support that hypertensive response to exercise is frequently associated with high rate-pressure product in hypertensives. In addition to the observations on high rate-pressure product and enhanced ventricular contractility in patients with hypertension, evaluation of myocardial contractility by Doppler tissue imaging has shown hyperdynamic myocardial function under pharmacological stress. These recent quantitative data in hypertensives suggest that hyperdynamic myocardial function and high rate-pressure product response to stress may be related to exaggerated hypertension, which may have more importance than that it has been already given in clinical practice.

  11. Herboxidiene triggers splicing repression and abiotic stress responses in plants

    KAUST Repository

    Alshareef, Sahar

    2017-03-27

    Background Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and stresses. Small-molecule inhibitors that perturb splicing provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. Results Here, we show that herboxidiene (GEX1A) inhibits both constitutive and alternative splicing. Moreover, GEX1A activates genome-wide transcriptional patterns involved in abiotic stress responses in plants. GEX1A treatment -activated ABA-inducible promoters, and led to stomatal closure. Interestingly, GEX1A and pladienolide B (PB) elicited similar cellular changes, including alterations in the patterns of transcription and splicing, suggesting that these compounds might target the same spliceosome complex in plant cells. Conclusions Our study establishes GEX1A as a potent splicing inhibitor in plants that can be used to probe the assembly, dynamics, and molecular functions of the spliceosome and to study the interplay between splicing stress and abiotic stresses, as well as having potential biotechnological applications.

  12. Morphological and Physiological Responses of Strawberry Plants to Water Stress

    Directory of Open Access Journals (Sweden)

    Krzysztof Klamkowski

    2006-12-01

    Full Text Available The most of previous studies have been focused on the effect of water stress on plant yielding. However, the conditions in which plants grow from the moment of planting might affect their morphology and physiological response. The aim of this study was to examine the effect of water deficiency on growth and plant physiological response of strawberry (Fragaria x ananassa Duch. cv. ‘Salut’ under greenhouse conditions. The plants were grown in plastic containers filled with peat substratum. Water stress was imposed by reducing the irrigation according to substratum moisture readings. Water stressed plants had the lowest values of water potential and showed strong decrease in gas exchange rate. Also, biomass and leaf area were the lowest in this group of plants. No differences in the length of root system were observed between control and water stressed plants. The lack of water in growing medium resulted also in a decrease of density and reduction of dimensions of stomata on plant leaves. These changes contribute to optimizing the use of assimilates and water use efficiency in periods when water availability is decreased.

  13. Morphological and Physiological Responses of Strawberry Plants to Water Stress

    Directory of Open Access Journals (Sweden)

    Krzysztof Klamkowski

    2006-01-01

    Full Text Available The most of previous studies have been focused on the effect of water stress on plant yielding. However, the conditions in which plants grow from the moment of planting might affect their morphology and physiological response. The aim of this study was to examine the effect of water deficiency on growth and plant physiological response of strawberry (Fragaria x ananassa Duch. cv. ‘Salut’ under greenhouse conditions. The plants were grown in plastic containers filled with peat substratum. Water stress was imposed by reducing the irrigation according to substratum moisture readings. Water stressed plants had the lowest values of water potential and showed strong decrease in gas exchange rate. Also, biomass and leaf area were the lowest in this group of plants. No differences in the length of root system were observed between control and water stressed plants. The lack of water in growing medium resulted also in a decrease of density and reduction of dimensions of stomata on plant leaves.These changes contribute to optimizing the use of assimilates and water use efficiency in periods when water availability is decreased.

  14. Peripheral vascular responses to heat stress after hindlimb suspension

    Science.gov (United States)

    Looft-Wilson, Robin C.; Gisolfi, Carl V.

    2002-01-01

    PURPOSE: The purpose of this study was to determine whether hindlimb suspension (which simulates the effects of microgravity) results in impaired hemodynamic responses to heat stress or alterations in mesenteric small artery sympathetic nerve innervation. METHODS: Over 28 d, 16 male Sprague-Dawley rats were hindlimb-suspended, and 13 control rats were housed in the same type of cage. After the treatment, mean arterial pressure (MAP), colonic temperature (Tcol), and superior mesenteric and iliac artery resistances (using Doppler flowmetry) were measured during heat stress [exposure to 42 degrees C until the endpoint of 80 mm Hg blood pressure was reached (75 +/- 9 min); endpoint Tcore = 43.6 +/- 0.2] while rats were anesthetized (sodium pentobarbital, 50 mg x kg(-1) BW). RESULTS: Hindlimb-suspended and control rats exhibited similar increases in Tcol, MAP, and superior mesenteric artery resistance, and similar decreases in iliac resistance during heat stress (endpoint was a fall in MAP below 80 mm Hg). Tyrosine hydroxylase immunostaining indicated similar sympathetic nerve innervation in small mesenteric arteries from both groups. CONCLUSION: Hindlimb suspension does not alter the hemodynamic or thermoregulatory responses to heat stress in the anesthetized rat or mesenteric sympathetic nerve innervation, suggesting that this sympathetic pathway is intact.

  15. Roles of horseradish peroxidase in response to terbium stress.

    Science.gov (United States)

    Zhang, Xuanbo; Wang, Lihong; Zhou, Qing

    2014-10-01

    The pollution of the environment by rare earth elements (REEs) causes deleterious effects on plants. Peroxidase plays important roles in plant response to various environmental stresses. Here, to further understand the overall roles of peroxidase in response to REE stress, the effects of the REE terbium ion (Tb(3+)) on the peroxidase activity and H2O2 and lignin contents in the leaves and roots of horseradish during different growth stages were simultaneously investigated. The results showed that after 24 and 48 h of Tb(3+) treatment, the peroxidase activity in horseradish leaves decreased, while the H2O2 and lignin contents increased. After a long-term (8 and 16 days) treatment with Tb(3+), these effects were also observed in the roots. The analysis of the changes in peroxidase activity and H2O2 and lignin contents revealed that peroxidase plays important roles in not only reactive oxygen species scavenging but also cell wall lignification in horseradish under Tb(3+) stress. These roles were closely related to the dose of Tb(3+), duration of stress, and growth stages of horseradish.

  16. Magnitude-dependent response of osteoblasts regulated by compressive stress

    Science.gov (United States)

    Shen, Xiao-qing; Geng, Yuan-ming; Liu, Ping; Huang, Xiang-yu; Li, Shu-yi; Liu, Chun-dong; Zhou, Zheng; Xu, Ping-ping

    2017-01-01

    The present study aimed to investigate the role of magnitude in adaptive response of osteoblasts exposed to compressive stress. Murine primary osteoblasts and MC3T3-E1 cells were exposed to compressive stress (0, 1, 2, 3, 4, and 5 g/cm2) in 3D culture. Cell viability was evaluated, and expression levels of Runx2, Alp, Ocn, Rankl, and Opg were examined. ALP activity in osteoblasts and TRAP activity in RAW264.7 cells co-cultured with MC3T3-E1 cells were assayed. Results showed that compressive stress within 5.0 g/cm2 did not influence cell viability. Both osteoblastic and osteoblast-regulated osteoclastic differentiation were enhanced at 2 g/cm2. An increase in stress above 2 g/cm2 did not enhance osteoblastic differentiation further but significantly inhibited osteoblast-regualted osteoclastic differentiation. This study suggested that compressive stress regulates osteoblastic and osteoclastic differentiation through osteoblasts in a magnitude-dependent manner. PMID:28317941

  17. Transcriptome Analysis of Enterococcus faecalis in Response to Alkaline Stress

    Directory of Open Access Journals (Sweden)

    Ran eshujun

    2015-08-01

    Full Text Available E. faecalis is the most commonly isolated species from endodontic failure root canals; its persistence in treated root canals has been attributed to its ability to resist high pH stress. The goal of this study was to characterize the E. faecalis transcriptome and to identify candidate genes for response and resistance to alkaline stress using Illumina HiSeq 2000 sequencing.We found that E. faecalis could survive and form biofilms in a pH 10 environment and that alkaline stress had a great impact on the transcription of many genes in the E. faecalis genome. The transcriptome sequencing results revealed that 613 genes were differentially expressed (DEGs for E. faecalis grown in pH 10 medium; 211 genes were found to be differentially up-regulated and 402 genes differentially down-regulated. Many of the down-regulated genes found are involved in cell energy production and metabolism and carbohydrate and amino acid metabolism, and the up-regulated genes are mostly related to nucleotide transport and metabolism. The results presented here reveal that cultivation of E. faecalis in alkaline stress has a profound impact on its transcriptome. The observed regulation of genes and pathways revealed that E. faecalis reduced its carbohydrate and amino acid metabolism and increased nucleotide synthesis to adapt and grow in alkaline stress. A number of the regulated genes may be useful candidates for the development of new therapeutic approaches for the treatment of E. faecalis infections.

  18. Proteomic Study for Responses to Cadmium Stress in Rice Seedlings

    Institute of Scientific and Technical Information of China (English)

    GE Cai-lin; WANG Ze-gang; WAN Ding-zhen; DING Yan; WANG Yu-long; SHANG Qi; LUO Shi-shi

    2009-01-01

    A proteomic approach including two-dimensional electrophoresis and mass spectrometric (MALDI-TOF MS) analyses was used to investigate the responses to cadmium (Cd) stress in seedlings of rice (Oryza sativa L.) varieties Shanyou 63 and Aizaizhan. Cd stress significantly inhibited root and shoot growth, and affected the global proteome in rice roots and leaves, which induced or upregulated the expression of corresponding proteins in rice roots and leaves when rice seedlings were exposed to 0.1 or 1.0 mmol/L Cd. The Cd-induced proteins are involved in chelation and compartmentation of Cd, elimination of active oxygen free radicals, detoxification of toxic substances, degradation of denatured proteins or inactivated enzymes, regulation of physiologic metabolism and induction of pathogenesis-related proteins. Comparing the Cd-induced proteins between the two varieties, the β-glucosidase and pathogenesis-related protein family 10 proteins were more drastically induced by Cd stress in roots and leaves of Aizaizhan, and the UDP-glucose protein transglucosylase and translational elongation factor Tu were induced by 0.1 mmol/L Cd stress in roots of Shanyou 63. This may be one of the important mechanisms for higher tolerance to Cd stress in Shanyou 63 than in Aizaizhan.

  19. Cardiolipin at the heart of stress response across kingdoms.

    Science.gov (United States)

    de Paepe, Rosine; Lemaire, Stéphane D; Danon, Antoine

    2014-05-20

    Cardiolipin is a key phospholipid most specifically found in the membrane of mitochondria in yeasts, plants, and animals. Cardiolipins are essential for the maintenance, the integrity, and the dynamics of mitochondria. In most eukaryotes mitochondria play a central role in the response and adaptation to stress conditions especially through their importance in the control of programmed cell death. To assess the impact of the absence of cardiolipin, knock-down of the expression of cardiolipin synthase, the last enzyme of cardiolipin synthesis pathway in eukaryotes has been performed in yeasts, animals, and plants. These studies showed that cardiolipin is not only important for mitochondrial ultrastructure and for the stability of respiratory complexes, but it is also a key player in the response to stress, the formation of reactive oxygen species, and the execution of programmed cell death.

  20. Behaviour and stress responses in horses with gastric ulceration

    DEFF Research Database (Denmark)

    Malmkvist, Jens; Poulsen, Janne Møller; Luthersson, Nanna

    2012-01-01

    Only little is known about behaviour and stress responses in horses with gastric ulceration, despite the high prevalence of this condition. Our objectives in the present study was to (i) describe the severity of gastric ulceration in horses, housed under relatively standardised conditions, and (ii......) to investigate whether horses with severe glandular gastric ulceration have increased baseline and response concentration of stress hormones and behave differently than control horses. We investigated stomachs of 96 horses at one stud, and compared an ulcer group (n = 30; with severe lesions in the glandular.......2% and non-glandular lesions in 40.6% of the horses. The amount of starch in the feed (P = 0.006) and paternal stallion (P = 0.031) influenced ulceration in the non-glandular region only; it should be noted that our study does not allow for separating hereditary from environmental influences, as offspring...

  1. Stress-responsive hydroxycinnamate glycosyltransferase modulates phenylpropanoid metabolism in Populus

    OpenAIRE

    2014-01-01

    The diversity of phenylpropanoids offers a rich inventory of bioactive chemicals that can be exploited for plant improvement and human health. Recent evidence suggests that glycosylation may play a role in the partitioning of phenylpropanoid precursors for a variety of downstream uses. This work reports the functional characterization of a stress-responsive glycosyltransferase, GT1-316 in Populus. GT1-316 belongs to the UGT84A subfamily of plant glycosyltransferase family 1 and is designated ...

  2. Metformin and low dose radiation modulates cisplatin-induced oxidative injury in rat via PPAR-γ and MAPK pathways.

    Science.gov (United States)

    Mansour, Heba H; El Kiki, Shereen M; Galal, Shereen M

    2017-02-15

    Cisplatin (CIS) is a chemotherapeutic agent used for therapy of many tumors and has been limited by its toxicity. The aim of this study was to investigate the role of Peroxisome proliferator-activated receptor-gamma (PPAR-γ), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B(NFkB) in the pathogenesis of hepatic damage induced by CIS, and investigated the modulatory effect of metformin (MET) and/or low dose gamma radiation (LDR) on CIS-induced hepatotoxicity in rats. CIS(7.5 mg/kg, i.p.) hepatotoxicity was evidenced by alteration of serum hepatic indices (ALT and AST) accompanied with decreased hepatic PPAR-γ, superoxide dismutase (SOD) activities and reduced glutathione (GSH) content, whereas the levels of malondialdehyde (MDA), total nitrate/nitrite (NOx) and NFkB significantly increased as well as MAPK activity compared with the control, MET and LDR groups. Furthermore, CIS induces apoptosis as indicated by an elevation of hepatic caspase-3. Treatment with MET (150 mg/kg, orally for 14 days) and/or LDR (0.5 Gy), prior to CIS alleviates CIS-induced hepatic damage by mitigating oxidative/ nitrosative stress and PPAR-γ activity reduction, hepatic caspase-3 elevation, and inhibition of NFκB, and MAPK activity levels.

  3. MOF maintains transcriptional programs regulating cellular stress response.

    Science.gov (United States)

    Sheikh, B N; Bechtel-Walz, W; Lucci, J; Karpiuk, O; Hild, I; Hartleben, B; Vornweg, J; Helmstädter, M; Sahyoun, A H; Bhardwaj, V; Stehle, T; Diehl, S; Kretz, O; Voss, A K; Thomas, T; Manke, T; Huber, T B; Akhtar, A

    2016-05-01

    MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes.

  4. Stress Response of Offshore Structures by Equivalent Polynomial Expansion Techniques

    DEFF Research Database (Denmark)

    Sigurdsson, Gudfinnur; Nielsen, Søren R.K.

    This paper concerns an investigation of the effects of nonlinearity of drag loading on offshore structures excited by 2D wave fields, where the nonlinear term in the Morison equation is replaced by an equivalent cubic expansion. The equivalent cubic expansion coefficients for the equivalent drag...... model are obtained using the least mean square procedure. Numerical results are given. The displacement response and stress response processes obtained using the above loading model are compared with simulation results and those obtained from equivalent linearization of the drag term....

  5. Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains.

    Science.gov (United States)

    Jennings, Elaine M; Okine, Bright N; Olango, Weredeselam M; Roche, Michelle; Finn, David P

    2016-01-01

    Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences.

  6. miR-181a and miR-630 regulate cisplatin-induced cancer cell death.

    Science.gov (United States)

    Galluzzi, Lorenzo; Morselli, Eugenia; Vitale, Ilio; Kepp, Oliver; Senovilla, Laura; Criollo, Alfredo; Servant, Nicolas; Paccard, Caroline; Hupé, Philippe; Robert, Thomas; Ripoche, Hugues; Lazar, Vladimir; Harel-Bellan, Annick; Dessen, Philippe; Barillot, Emmanuel; Kroemer, Guido

    2010-03-01

    MicroRNAs (miRNA) are noncoding RNAs that regulate multiple cellular processes, including proliferation and apoptosis. We used microarray technology to identify miRNAs that were upregulated by non-small cell lung cancer (NSCLC) A549 cells in response to cisplatin (CDDP). The corresponding synthetic miRNA precursors (pre-miRNAs) per se were not lethal when transfected into A549 cells yet affected cell death induction by CDDP, C2-ceramide, cadmium, etoposide, and mitoxantrone in an inducer-specific fashion. Whereas synthetic miRNA inhibitors (anti-miRNAs) targeting miR-181a and miR-630 failed to modulate the response of A549 to CDDP, pre-miR-181a and pre-miR-630 enhanced and reduced CDDP-triggered cell death, respectively. Pre-miR-181a and pre-miR-630 consistently modulated mitochondrial/postmitochondrial steps of the intrinsic pathway of apoptosis, including Bax oligomerization, mitochondrial transmembrane potential dissipation, and the proteolytic maturation of caspase-9 and caspase-3. In addition, pre-miR-630 blocked early manifestations of the DNA damage response, including the phosphorylation of the ataxia-telangiectasia mutated (ATM) kinase and of two ATM substrates, histone H2AX and p53. Pharmacologic and genetic inhibition of p53 corroborated the hypothesis that pre-miR-630 (but not pre-miR-181a) blocks the upstream signaling pathways that are ignited by DNA damage and converge on p53 activation. Pre-miR-630 arrested A549 cells in the G0-G1 phase of the cell cycle, correlating with increased levels of the cell cycle inhibitor p27(Kip1) as well as with reduced proliferation rates and resulting in greatly diminished sensitivity of A549 cells to the late S-G2-M cell cycle arrest mediated by CDDP. Altogether, these results identify miR-181a and miR-630 as novel modulators of the CDDP response in NSCLC.

  7. High-resolution laser ablation-inductively coupled plasma-mass spectrometry imaging of cisplatin-induced nephrotoxic side effects.

    Science.gov (United States)

    Van Acker, Thibaut; Van Malderen, Stijn J M; Van Heerden, Marjolein; McDuffie, James Eric; Cuyckens, Filip; Vanhaecke, Frank

    2016-11-16

    Two-dimensional elemental mapping (bioimaging) via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was performed on 5 μm thick formalin-fixed, paraffin-embedded kidney tissue sections from Cynomolgus monkeys administered with increasing pharmacological doses of cisplatin. Laterally resolved pixels of 1 μm were achieved, enabling elemental analysis on a (sub-)cellular level. Zones of high Pt response were observed in the renal cortex, where proximal tubules are present, the epithelium of which is responsible for partial reabsorption of cisplatin. Histopathological evaluation, of hematoxylin and eosin-stained serial sections, adjacent to the sections probed via LA-ICP-MS, revealed minimal to mild cisplatin-related lesions (<100 μm) in the renal cortex. Necrotic proximal tubules with sloughed epithelial cells in their lumen could be linked directly to the areas with the highest accumulation of cisplatin, indicating a direct link between cellular concentration and toxicity, thereby providing more insight into the mechanisms through which renal damage occurs.

  8. Effects of sufentanil and morphine on cisplatin-induced acute kidney injury in rats%舒芬太尼和吗啡对顺铂致大鼠急性肾损伤的影响

    Institute of Scientific and Technical Information of China (English)

    梁桦; 赖晓红; 尹媛萍; 廖美娟; 郑雪琴; 杨承祥

    2015-01-01

    intraperitoneally, followed by injection of sufentanil 2 μg/kg over 5 min via the caudal vein for 3 consecutive days.In group M, cisplatin 16 mg/kg was injected intraperitoneally, followed by injection of morphine 2 μg/kg over 5 min via the caudal vein for 3 consecutive days.The equal volume of normal saline was given in group C.After the end of administration on 3rd day, blood samples were collected from the orbital venous plexus for measurement of serum blood urea nitrogen (BUN) and creatinine (Cr) concentrations.The animals were then sacrificed, and the left kidney specimens were obtained for examination of the pathological changes (under the light microscope) and for determination of the tumor necrosis factor-alpha (TNF-α) , interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) concentrations (by enzyme-linked immunosorbent assay) , and expression of X-linked inhibitor of apoptosis protein (XIAP) , suvivin and caspase-3 (by Western blot).Periodic acid-Schiff's staining was used to evaluate the pathological changes of the renal tubule.Results Compared with group C, the serum BUN, Cr concentrations and renal tubule injury score were significantly increased, the contents of TNF-α, IL-1β and IL-6 were increased, the expression of XIAP and suvivin was down-regulated, and the expression of caspase-3 was up-regulated in Cis,S and M groups (P<0.05).Compared with group Cis, the serum BUN and Cr concentrations and renal tubule injury score were significantly decreased, the contents of TNF-α, IL-1β and IL-6 were decreased, the expression of XIAP and suvivin was up-regulated, and the expression of caspase-3 was down-regulated in S and M groups (P<0.05).There were no significant differences in the indexes mentioned above between group S and group M (P>0.05).Conclusion Both sufentanil and morphine can reduce cisplatin-induced acute kidney injury in rats with similar efficacy, and the mechanism may be related to the inhibition of the inflammatory responses and cell apoptosis.

  9. Differential oxidative stress responses in castor semilooper, Achaea janata.

    Science.gov (United States)

    Pavani, Ayinampudi; Chaitanya, R K; Chauhan, Vinod K; Dasgupta, Anwesha; Dutta-Gupta, Aparna

    2015-11-01

    Balance between reactive oxygen species (ROS) and the antioxidant (AO) defense mechanisms is vital for organism survival. Insects serve as an ideal model to elucidate oxidative stress responses as they are prone to different kinds of stress during their life cycle. The present study demonstrates the modulation of AO enzyme gene expression in the insect pest, Achaea janata (castor semilooper), when subjected to different oxidative stress stimuli. Antioxidant enzymes' (catalase (Cat), superoxide dismutase (Sod), glutathione-S-transferase (GST) and glutathione peroxidase (Gpx)) partial coding sequences were cloned and characterized from larval whole body. Tissue expression studies reveal a unique pattern of AO genes in the larval tissues with maximum expression in the gut and fat body. Ontogeny profile depicts differential expression pattern through the larval developmental stages for each AO gene studied. Using quantitative RT-PCR, the expression pattern of these genes was monitored during sugar-induced (d-galactose feeding), infection-induced (Gram positive, Gram negative and non-pathogenic bacteria) and pesticide-induced oxidative stress (Bt Cry toxin). d-Galactose feeding differentially modulates the expression of AO genes in the larval gut and fat body. Immune challenge with Escherichia coli induces robust upregulation of AO genes when compared to Bacillus coagulans and Bacillus cereus in the larval fat body and gut. Cry toxin feeding predominantly induced GST upregulation in the gut. The current study suggests that though there are multiple ways of generation of oxidative stress in the insect, the organism tailors its response by insult- and tissue-specific recruitment of the antioxidant players and their differential regulation for each inducer.

  10. Cell identity regulators link development and stress responses in the Arabidopsis root.

    Science.gov (United States)

    Iyer-Pascuzzi, Anjali S; Jackson, Terry; Cui, Hongchang; Petricka, Jalean J; Busch, Wolfgang; Tsukagoshi, Hironaka; Benfey, Philip N

    2011-10-18

    Stress responses in plants are tightly coordinated with developmental processes, but interaction of these pathways is poorly understood. We used genome-wide assays at high spatiotemporal resolution to understand the processes that link development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. However, common stress responses appear to exist with many showing cell type specificity. Common stress responses may be mediated by cell identity regulators because mutations in these genes resulted in altered responses to stress. Evidence for a direct role for cell identity regulators came from genome-wide binding profiling of the key regulator SCARECROW, which showed binding to regulatory regions of stress-responsive genes. Coexpression in response to stress was used to identify genes involved in specific developmental processes. These results reveal surprising linkages between stress and development at cellular resolution, and show the power of multiple genome-wide data sets to elucidate biological processes.

  11. Reconstructing a Network of Stress-Response Regulators via Dynamic System Modeling of Gene Regulation

    Directory of Open Access Journals (Sweden)

    Wei-Sheng Wu

    2008-01-01

    Full Text Available Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene’s expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specifi c stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably suffi cient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  12. Reconstructing a network of stress-response regulators via dynamic system modeling of gene regulation.

    Science.gov (United States)

    Wu, Wei-Sheng; Li, Wen-Hsiung; Chen, Bor-Sen

    2008-02-10

    Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs) that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene's expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA) to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specific stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably sufficient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  13. Long Term Salinity Stress Reveals Variety Specific Differences in Root Oxidative Stress Response

    Institute of Scientific and Technical Information of China (English)

    Prasad SENADHEERA; Shamala TIRIMANNE; Frans J M MAATHUIS

    2012-01-01

    Salinity stress induces oxidative stress caused by reactive oxygen species (ROS):superoxide radicals,hydrogen peroxide (H2O2) and hydroxyl radicals.Activities of both enzymatic and non-enzymatic components of the antioxidant system and related growth parameters were studied in the roots of the salt tolerant rice variety FL478 and the sensitive variety IR29 in response to long term stress (12 d) induced by 50 mmol/L NaCl.The comparative study showed that FL478maintained higher relative growth rate and lower Na+/K+ in the roots than IR29 due to a higher membrane stability index that effectively exclude Na+.Lower TBARS (thiobarbituric acid reactive substance) content in FL478 roots indicated that its membrane was relatively unaffected by ROS despite high H2O2 content recorded under the salinity stress.Relatively higher superoxide dismutase activity along with a parallel increase in transcript level of superoxide dismutase (Os07946990) in FL478 indicated that this protein might make a vital contribution to salt stress tolerance.Although the content of ascorbic acid remained unchanged in FL478,the activity of ascorbic peroxidases (APOXs) was reduced comparably in the both varieties.Transcriptomic data showed that a larger number of peroxidase genes were upregulated in FL478 compared to IR29 and several of which might provide engineering targets to improve rice salt tolerance.

  14. Naturalistic Stress and Cortisol Response to Awakening: Adaptation to Seafaring

    Science.gov (United States)

    Liberzon, Jonathan; Abelson, James L.; King, Anthony; Liberzon, Israel

    2008-01-01

    Study of the hypothalmic-pituitary adrenal (HPA) axis has been critical to advancing our understanding of human adaptation to stress. The cortisol response to awakening (CRA) is a potentially useful measure for understanding group and individual differences in HPA axis regulation. In this study, the CRA was examined in the context of a naturalistic stressor – a six-week voyage of work and study aboard an oceangoing ship, including both experienced and novice sailors. Thirty-one subjects provided weekday and weekend baseline CRA data onshore prior to boarding, followed by three CRAs at sea and one shore leave CRA. Subjective measures of sleep, stress and control were also collected. Results suggest that novice sailors' cortisol response to awakening was elevated at sea relative to both a shoreside weekend and a shore leave during the voyage, but the most striking elevation was found during a workday onshore. Inexperienced students' profiles changed differently over the course of the voyage from those of professional crew. CRAs were not affected by sleep variables and were not predicted by subjective ratings. These data support the value of the cortisol response to awakening as a neuroendocrine marker of HPA regulatory responses to a naturalistic stressor, influenced by changes in work and living environment, and perhaps prior experience with the stressor. PMID:18657911

  15. Epigenetic memory for stress response and adaptation in plants.

    Science.gov (United States)

    Kinoshita, Tetsu; Seki, Motoaki

    2014-11-01

    In contrast to the majority of animal species, plants are sessile organisms and are, therefore, constantly challenged by environmental perturbations. Over the past few decades, our knowledge of how plants perceive environmental stimuli has increased considerably, e.g. the mechanisms for transducing environmental stress stimuli into cellular signaling cascades and gene transcription networks. In addition, it has recently been shown that plants can remember past environmental events and can use these memories to aid responses when these events recur. In this mini review, we focus on recent progress in determination of the epigenetic mechanisms used by plants under various environmental stresses. Epigenetic mechanisms are now known to play a vital role in the control of gene expression through small RNAs, histone modifications and DNA methylation. These are inherited through mitotic cell divisions and, in some cases, can be transmitted to the next generation. They therefore offer a possible mechanism for stress memories in plants. Recent studies have yielded evidence indicating that epigenetic mechanisms are indeed essential for stress memories and adaptation in plants.

  16. "Stress entropic load" as a transgenerational epigenetic response trigger.

    Science.gov (United States)

    Bienertová-Vašků, Julie; Nečesánek, Ivo; Novák, Jan; Vinklárek, Jan; Zlámal, Filip

    2014-03-01

    Epigenetic changes are generally based on the switching of alternative functional or structural states and result in the adaptation of cellular expression patterns during proliferation, differentiation or plastic changes in the adult organism, whereas some epigenetic information can be passed on other generations while other is not. Hence, the principal question is: why is some information reset or resolved during the meiosis process and other is passed from one generation to another, or, in other words: what "adaptation trigger" level initiates transgenerationally transmitted epigenome change? Hereto, we propose a theory which states that stress, or, more specifically, the energy cost of an individual's adaptation to stress, represents a viable candidate for the transgenerational transmission trigger of a given acquired trait. It has been reported recently that the higher lifetime entropy generation of a unit's body mass, the higher the entropy stress level (which is a measure of energy released by a unit's organ mass) and the irreversibility within the organ, resulting in faster organ degradation and consequent health problems for the entire biological system. We therefore suggest a new term: "stress entropic load" will reflect the actual energetic cost of an individual's adaptation and may be used to estimate the probability of inducing transgenerational response once characterized or measured.

  17. Mitochondrial Composition,Function and Stress Response in Plants

    Institute of Scientific and Technical Information of China (English)

    Richard P.Jacoby; Lei Li; Shaobai Huang; Chun Pong Lee; A.Harvey Millar; Nicolas L.Taylor

    2012-01-01

    The primary function of mitochondria is respiration,where catabolism of substrates is coupled to ATP synthesis via oxidative phosphorylation.In plants,mitochondrial composition is relatively complex and flexible and has specific pathways to support photosynthetic processes in illuminated leaves.This review begins with outlining current models of mitochondrial composition in plant cells,with an emphasis upon the assembly of the complexes of the classical electron transport chain (ETC).Next,we focus upon the comparative analysis of mitochondrial function from different tissue types.A prominent theme in the plant mitochondrial literature involves linking mitochondrial composition to environmental stress responses,and this review then gives a detailed outline of how oxidative stress impacts upon the plant mitochondrial proteome with particular attention to the role of transition metals.This is followed by an analysis of the signaling capacity of mitochondrial reactive oxygen species,which studies the transcriptional changes of stress responsive genes as a framework to define specific signals emanating from the mitochondrion.Finally,specific mitochondrial roles during exposure to harsh environments are outlined,with attention paid to mitochondrial delivery of energy and intermediates,mitochondrial support for photosynthesis,and mitochondrial processes operating within root cells that mediate tolerance to anoxia and unfavorable soil chemistries.

  18. Motivation, stress, anxiety, and cortisol responses in elite paragliders.

    Science.gov (United States)

    Filaire, Edith; Alix, Deborah; Rouveix, Matthieu; Le Scanff, Christine

    2007-06-01

    In this study metamotivational dominance (measured with the Telic Dominance Scale), precompetition anxiety (evaluated with the CSAI-2), perceived stress (measured with the Perceived Stress Scale), and cortisol responses by 10 paragliding competitors prior to and following a paragliding competition were examined. Saliva was collected for each subject for cortisol analysis on eight occasions: during a resting day (baseline values) and prior to and after competition. Analysis indicated subjects were all paratelic-dominant (characterized by a desire for high arousal, a focus on the present). Scores were high on the Perceived Stress Scale and cognitive nxiety (a telic emotion). Cortisol values showed a significant increase early on the day of the competition and remained elevated all the day, with highest concentrations at the start. Participants' cognitive anxiety and cortisol responses were significantly correlated .79 just before the jump and the direction of the cognitive anxiety was rated as facilitative of performance. These results may suggest that the more frequently the subject is playful in life, the more cortisol they produce when aroused in a less frequent telic state.

  19. Yeast responses to stresses associated with industrial brewery handling.

    Science.gov (United States)

    Gibson, Brian R; Lawrence, Stephen J; Leclaire, Jessica P R; Powell, Chris D; Smart, Katherine A

    2007-09-01

    During brewery handling, production strains of yeast must respond to fluctuations in dissolved oxygen concentration, pH, osmolarity, ethanol concentration, nutrient supply and temperature. Fermentation performance of brewing yeast strains is dependent on their ability to adapt to these changes, particularly during batch brewery fermentation which involves the recycling (repitching) of a single yeast culture (slurry) over a number of fermentations (generations). Modern practices, such as the use of high-gravity worts and preparation of dried yeast for use as an inoculum, have increased the magnitude of the stresses to which the cell is subjected. The ability of yeast to respond effectively to these conditions is essential not only for beer production but also for maintaining the fermentation fitness of yeast for use in subsequent fermentations. During brewery handling, cells inhabit a complex environment and our understanding of stress responses under such conditions is limited. The advent of techniques capable of determining genomic and proteomic changes within the cell is likely vastly to improve our knowledge of yeast stress responses during industrial brewery handling.

  20. Supplementary data: Responses to combined abiotic and biotic stress in tomato are governed by stress intensity and mechanism of resistance

    NARCIS (Netherlands)

    Kissoudis, C.; Sri Sunarti, Sri; Wiel, van de C.C.M.; Visser, R.G.F.; Linden, van der C.G.; Bai, Y.

    2016-01-01

    Stress conditions in agricultural ecosystems can occur in variable intensities. Different resistance mechanisms to abiotic stress and pathogens are deployed by plants. Thus, it is important to examine plant responses to stress combinations under different scenarios. Here, we evaluated the effect of

  1. Responses to combined abiotic and biotic stress in tomato are governed by stress intensity and resistance mechanism

    NARCIS (Netherlands)

    Kissoudis, Christos; Sri Sunarti, Sri; De Wiel, Van Clemens; Visser, Richard G.F.; Linden, van der Gerard; Bai, Yuling

    2016-01-01

    Stress conditions in agricultural ecosystems can occur at variable intensities. Different resistance mechanisms against abiotic stress and pathogens are deployed by plants. Thus, it is important to examine plant responses to stress combinations under different scenarios. Here, we evaluated the effec

  2. Mcm2 phosphorylation and the response to replicative stress

    Directory of Open Access Journals (Sweden)

    Stead Brent E

    2012-05-01

    Full Text Available Abstract Background The replicative helicase in eukaryotic cells is comprised of minichromosome maintenance (Mcm proteins 2 through 7 (Mcm2-7 and is a key target for regulation of cell proliferation. In addition, it is regulated in response to replicative stress. One of the protein kinases that targets Mcm2-7 is the Dbf4-dependent kinase Cdc7 (DDK. In a previous study, we showed that alanine mutations of the DDK phosphorylation sites at S164 and S170 in Saccharomyces cerevisiae Mcm2 result in sensitivity to caffeine and methyl methanesulfonate (MMS leading us to suggest that DDK phosphorylation of Mcm2 is required in response to replicative stress. Results We show here that a strain with the mcm2 allele lacking DDK phosphorylation sites (mcm2AA is also sensitive to the ribonucleotide reductase inhibitor, hydroxyurea (HU and to the base analogue 5-fluorouracil (5-FU but not the radiomimetic drug, phleomycin. We screened the budding yeast non-essential deletion collection for synthetic lethal interactions with mcm2AA and isolated deletions that include genes involved in the control of genome integrity and oxidative stress. In addition, the spontaneous mutation rate, as measured by mutations in CAN1, was increased in the mcm2AA strain compared to wild type, whereas with a phosphomimetic allele (mcm2EE the mutation rate was decreased. These results led to the idea that the mcm2AA strain is unable to respond properly to DNA damage. We examined this by screening the deletion collection for suppressors of the caffeine sensitivity of mcm2AA. Deletions that decrease spontaneous DNA damage, increase homologous recombination or slow replication forks were isolated. Many of the suppressors of caffeine sensitivity suppressed other phenotypes of mcm2AA including sensitivity to genotoxic drugs, the increased frequency of cells with RPA foci and the increased mutation rate. Conclusions Together these observations point to a role for DDK-mediated phosphorylation

  3. Plant natriuretic peptides are apoplastic and paracrine stress response molecules

    KAUST Repository

    Wang, Yuhua

    2011-04-07

    Higher plants contain biologically active proteins that are recognized by antibodies against human atrial natriuretic peptide (ANP). We identified and isolated two Arabidopsis thaliana immunoreactive plant natriuretic peptide (PNP)-encoding genes, AtPNP-A and AtPNP-B, which are distantly related members of the expansin superfamily and have a role in the regulation of homeostasis in abiotic and biotic stresses, and have shown that AtPNP-A modulates the effects of ABA on stomata. Arabidopsis PNP (PNP-A) is mainly expressed in leaf mesophyll cells, and in protoplast assays we demonstrate that it is secreted using AtPNP-A:green fluorescent protein (GFP) reporter constructs and flow cytometry. Transient reporter assays provide evidence that AtPNP-A expression is enhanced by heat, osmotica and salt, and that AtPNP-A itself can enhance its own expression, thereby generating a response signature diagnostic for paracrine action and potentially also autocrine effects. Expression of native AtPNP-A is enhanced by osmotica and transiently by salt. Although AtPNP-A expression is induced by salt and osmotica, ABA does not significantly modulate AtPNP-A levels nor does recombinant AtPNP-A affect reporter expression of the ABA-responsive RD29A gene. Together, these results provide experimental evidence that AtPNP-A is stress responsive, secreted into the apoplastic space and can enhance its own expression. Furthermore, our findings support the idea that AtPNP-A, together with ABA, is an important component in complex plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions. © 2011 The Author.

  4. Significance of downregulation of renal organic cation transporter (SLC47A1 in cisplatin-induced proximal tubular injury

    Directory of Open Access Journals (Sweden)

    Mizuno T

    2015-07-01

    Full Text Available Tomohiro Mizuno,1–3 Waichi Sato,2,3 Kazuhiro Ishikawa,4 Yuki Terao,1 Kazuo Takahashi,2 Yukihiro Noda,5 Yukio Yuzawa,2 Tadashi Nagamatsu1 1Department of Analytical Pharmacology, Meijo University Faculty of Pharmacy, Nagoya, 2Department of Nephrology, School of Medicine, Fujita Health University, Toyoake, 3Department of Nephrology, Nagoya University School of Medicine, Nagoya, 4Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, 5Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan Background/aim: To elucidate the mechanism responsible for developing acute kidney injury in patients with diabetes mellitus, we also evaluated the issue of whether advanced glycation endproducts (AGEs influence the expressions of multi antimicrobial extrusion protein (MATE1/SLC47A1 in tubular cells. Materials and methods: To detect changing expression of MATE1/SLC47A1 in dose- and time-dependent manners, human proximal tubular epithelial cells were incubated with AGE-aggregated-human serum albumin. As a function assay for MATE1/SLC47A1, human proximal tubular epithelial cells were incubated with cisplatin or carboplatin. Results: On incubation with AGEs, the expressions of MATE1/SLC47A1 were decreased in tubular cells. In addition, the toxicities of cisplatin were increased in tubular cells that had been pretreated with AGEs. However, the toxicities of carboplatin were smaller than that of cisplatin in proximal tubular epithelial cells. Conclusion: The expression of the MATE1/SLC47A1 is decreased by AGEs, which increases the risk for proximal tubular injury. Keywords: advanced glycation endproducts, cisplatin, SLC47A1, diabetes mellitus, acute kidney injury

  5. The auditory startle response in post-traumatic stress disorder.

    Science.gov (United States)

    Siegelaar, S E; Olff, M; Bour, L J; Veelo, D; Zwinderman, A H; van Bruggen, G; de Vries, G J; Raabe, S; Cupido, C; Koelman, J H T M; Tijssen, M A J

    2006-09-01

    Post-traumatic stress disorder (PTSD) patients are considered to have excessive EMG responses in the orbicularis oculi (OO) muscle and excessive autonomic responses to startling stimuli. The aim of the present study was to gain more insight into the pattern of the generalized auditory startle reflex (ASR). Reflex EMG responses to auditory startling stimuli in seven muscles rather than the EMG response of the OO alone as well as the psychogalvanic reflex (PGR) were studied in PTSD patients and healthy controls. Ten subjects with chronic PTSD (>3 months) and a history of excessive startling and 11 healthy controls were included. Latency, amplitude and duration of the EMG responses and the amplitude of the PGR to 10 auditory stimuli of 110 dB SPL were investigated in seven left-sided muscles. The size of the startle reflex, defined by the number of muscles activated by the acoustic stimulus and by the amplitude of the EMG response of the OO muscle as well, did not differ significantly between patients and controls. Median latencies of activity in the sternocleidomastoid (SC) (patients 80 ms; controls 54 ms) and the deltoid (DE) muscles (patients 113 ms; controls 69 ms) were prolonged significantly in PTSD compared to controls (P < 0.05). In the OO muscle, a late response (median latency in patients 308 ms; in controls 522 ms), probably the orienting reflex, was more frequently present in patients (56%) than in controls (12%). In patients, the mean PGR was enlarged compared to controls (P < 0.05). The size of the ASR response is not enlarged in PTSD patients. EMG latencies in the PTSD patients are prolonged in SC and DE muscles. The presence of a late response in the OO muscle discriminates between groups of PTSD patients with a history of startling and healthy controls. In addition, the autonomic response, i.e. the enlarged amplitude of the PGR can discriminate between these groups.

  6. Genomic counter-stress changes induced by the relaxation response.

    Directory of Open Access Journals (Sweden)

    Jeffery A Dusek

    Full Text Available Mind-body practices that elicit the relaxation response (RR have been used worldwide for millennia to prevent and treat disease. The RR is characterized by decreased oxygen consumption, increased exhaled nitric oxide, and reduced psychological distress. It is believed to be the counterpart of the stress response that exhibits a distinct pattern of physiology and transcriptional profile. We hypothesized that RR elicitation results in characteristic gene expression changes that can be used to measure physiological responses elicited by the RR in an unbiased fashion.We assessed whole blood transcriptional profiles in 19 healthy, long-term practitioners of daily RR practice (group M, 19 healthy controls (group N(1, and 20 N(1 individuals who completed 8 weeks of RR training (group N(2. 2209 genes were differentially expressed in group M relative to group N(1 (p<0.05 and 1561 genes in group N(2 compared to group N(1 (p<0.05. Importantly, 433 (p<10(-10 of 2209 and 1561 differentially expressed genes were shared among long-term (M and short-term practitioners (N(2. Gene ontology and gene set enrichment analyses revealed significant alterations in cellular metabolism, oxidative phosphorylation, generation of reactive oxygen species and response to oxidative stress in long-term and short-term practitioners of daily RR practice that may counteract cellular damage related to chronic psychological stress. A significant number of genes and pathways were confirmed in an independent validation set containing 5 N(1 controls, 5 N(2 short-term and 6 M long-term practitioners.This study provides the first compelling evidence that the RR elicits specific gene expression changes in short-term and long-term practitioners. Our results suggest consistent and constitutive changes in gene expression resulting from RR may relate to long term physiological effects. Our study may stimulate new investigations into applying transcriptional profiling for accurately measuring

  7. Jasmonates and octadecanoids: signals in plant stress responses and development.

    Science.gov (United States)

    Wasternack, Claus; Hause, Bettrina

    2002-01-01

    Plants are sessile organisms. Consequently they have to adapt constantly to fluctuations in the environment. Some of these changes involve essential factors such as nutrients, light, and water. Plants have evolved independent systems to sense nutrients such as phosphate and nitrogen. However, many of the environmental factors may reach levels which represent stress for the plant. The fluctuations can range between moderate and unfavorable, and the factors can be of biotic or abiotic origin. Among the biotic factors influencing plant life are pathogens and herbivores. In case of bacteria and fungi, symbiotic interactions such as nitrogen-fixating nodules and mycorrhiza, respectively, may be established. In case of insects, a tritrophic interaction of herbivores, carnivores, and plants may occur mutualistically or parasitically. Among the numerous abiotic factors are low temperature, frost, heat, high light conditions, ultraviolet light, darkness, oxidation stress, hypoxia, wind, touch, nutrient imbalance, salt stress, osmotic adjustment, water deficit, and desiccation. In the last decade jasmonates were recognized as being signals in plant responses to most of these biotic and abiotic factors. Signaling via jasmonates was found to occur intracellularly, intercellularly, and systemically as well as interorganismically. Jasmonates are a group of ubiquitously occurring plant growth regulators originally found as the major constituents in the etheric oil of jasmine, and were first suggested to play a role in senescence due to a strong senescence-promoting effect. Subsequently, numerous developmental processes were described in which jasmonates exhibited hormone-like properties. Recent knowledge is reviewed here on jasmonates and their precursors, the octadecanoids. After discussing occurrence and biosynthesis, emphasis is placed upon the signal transduction pathways in plant stress responses in which jasmonates act as a signal. Finally, examples are described on the

  8. Neonatal stress tempers vulnerability of acute stress response in adult socially isolated rats

    Directory of Open Access Journals (Sweden)

    Mariangela Serra

    2014-06-01

    Full Text Available Adverse experiences occurred in early life and especially during childhood and adolescence can have negative impact on behavior later in life and the quality of maternal care is considered a critical moment that can considerably influence the development and the stress responsiveness in offspring. This review will assess how the association between neonatal and adolescence stressful experiences such as maternal separation and social isolation, at weaning, may influence the stress responsiveness and brain plasticity in adult rats. Three hours of separation from the pups (3-14 postnatal days significantly increased frequencies of maternal arched-back nursing and licking-grooming by dams across the first 14 days postpartum and induced a long-lasting increase in their blood levels of corticosterone. Maternal separation, which per sedid not modified brain and plasma allopregnanolone and corticosterone levels in adult rats, significantly reduced social isolation-induced decrease of the levels of these hormones. Moreover, the enhancement of corticosterone and allopregnanolone levels induced by foot shock stress in socially isolated animals that were exposed to maternal separation was markedly reduced respect to that observed in socially isolated animals. Our results suggest that in rats a daily brief separation from the mother during the first weeks of life, which per se did not substantially alter adult function and reactivity of hypothalamic-pituitary-adrenal (HPA axis, elicited a significant protection versus the subsequent long-term stressful experience such that induced by social isolation from weaning. Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy · October 22nd-25th, 2014 · The last ten years, the next ten years in NeonatologyGuest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

  9. Stress responses sculpt the insect immune system, optimizing defense in an ever-changing world.

    Science.gov (United States)

    Adamo, Shelley Anne

    2017-01-01

    A whole organism, network approach can help explain the adaptive purpose of stress-induced changes in immune function. In insects, mediators of the stress response (e.g. stress hormones) divert molecular resources away from immune function and towards tissues necessary for fight-or-flight behaviours. For example, molecules such as lipid transport proteins are involved in both the stress and immune responses, leading to a reduction in disease resistance when these proteins are shifted towards being part of the stress response system. Stress responses also alter immune system strategies (i.e. reconfiguration) to compensate for resource losses that occur during fight-or flight events. In addition, stress responses optimize immune function for different physiological conditions. In insects, the stress response induces a pro-inflammatory state that probably enhances early immune responses.

  10. Sense of responsibility in health workers source of job stress

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    Nedić Olesja

    2002-01-01

    Full Text Available Job stress is a great problem in developed countries of the world, but in Yugoslavia, it is increased due to additional reasons associated with economic crisis in the society. Health services and health workers are in particulary difficult conditions. The aim of this paper was to examine sources and causes of job stress in health workers. Material and methods The research was undertaken among health workers treated at Health Centre "Hospital" in Novi Sad. The study group included health workers - doctors nurses and laboratory workers, and the control group included the rest of non-medical staff. Adapted Siegrist questionnaire was used. Three factors were examined: extrinsic efforts (disturbances at work, sense of great job responsibility and the need for overtime work; intrinsic efforts (major criticism, thinking about the job from the early morning, getting nervous because of minor problems, discontentment because of unsolved problems at work, relaxation at home and so on, and low reward (respect from the superiors and colleagues, support and security at workplace. Answers were scored indicating intensity (high, moderate, low, not at alt. Statistic analysis included testing the level of significance in health workers in relation to non-medical staff (t test and Fisher's exact test. Results Applying the scoring system it has been established that health workers are exposed to greater job stress, great sense of very high job responsibility and frequent overtime work (p<0,001 than the control group. In regard to answers from the second group - intrinsic effort and low reward, there was no statistical significance between the study and control group. Generally high level of risk factors was established, especially presence of one or more risk factors. Discussion Job stress increases absenteeism, reduces work productivity, causes higher expenses of medical treatment, rehabilitation and staff retraining. It is of great importance to identify factors

  11. Stress responses and replication of plasmids in bacterial cells

    Directory of Open Access Journals (Sweden)

    Wegrzyn Alicja

    2002-05-01

    Full Text Available Abstract Plasmids, DNA (or rarely RNA molecules which replicate in cells autonomously (independently of chromosomes as non-essential genetic elements, play important roles for microbes grown under specific environmental conditions as well as in scientific laboratories and in biotechnology. For example, bacterial plasmids are excellent models in studies on regulation of DNA replication, and their derivatives are the most commonly used vectors in genetic engineering. Detailed mechanisms of replication initiation, which is the crucial process for efficient maintenance of plasmids in cells, have been elucidated for several plasmids. However, to understand plasmid biology, it is necessary to understand regulation of plasmid DNA replication in response to different environmental conditions in which host cells exist. Knowledge of such regulatory processes is also very important for those who use plasmids as expression vectors to produce large amounts of recombinant proteins. Variable conditions in large-scale fermentations must influence replication of plasmid DNA in cells, thus affecting the efficiency of recombinant gene expression significantly. Contrary to extensively investigated biochemistry of plasmid replication, molecular mechanisms of regulation of plasmid DNA replication in response to various environmental stress conditions are relatively poorly understood. There are, however, recently published studies that add significant data to our knowledge on relations between cellular stress responses and control of plasmid DNA replication. In this review we focus on plasmids derived from bacteriophage λ that are among the best investigated replicons. Nevertheless, recent results of studies on other plasmids are also discussed shortly.

  12. Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats.

    Science.gov (United States)

    Hadad, Natalie A; Wu, Lizhen; Hiller, Helmut; Krause, Eric G; Schwendt, Marek; Knackstedt, Lori A

    2016-07-01

    Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.

  13. Morphogenetic responses ofPopulus alba L. under salt stress

    Institute of Scientific and Technical Information of China (English)

    Mejda Abassi; Khaled Mguis; Zoubeir Béjaoui; Ali Albouchi

    2014-01-01

    The morphogenetic responses to salt stress of TunisianPopu-lus alba clones were studied in order to promote their plantation in dam-aged saline areas. One year-old plants of threeP. alba clones (MA-104, MA-195 and OG) were subjected to progressive salt stress by irrigation during two consecutive years. The plants were grown in a nursery, inside plastic receptacles containing sandy soil and were irrigated with tap water (control) or 3-6 g/l NaCl solution. During this study, leaf epinasty, elongation rate, vigor, internode length, plant architecture, and number of buds were evaluated. Test clone response was highly dependent on the applied treatment and degree of accommodation.The most pronounced alterations were induced under 6g/l of NaCl treatment including leaf epinasty, leaf elongation rate delay, vigor decrease, internode length shortening, and morphogenetic modifications. These responses were less noticeable in the MA-104 clone with respect to the two other clones. The salt effect induced a delay in the leaf elongation rate on the MA-195 and OG clones leading to an early leaf maturity. The vigour and internode length of the MA-104 clone was less affected than the other clones. The OG clone was the most salt-sensitive thus, it developed shorter branches and more buds number than MA-195 and MA-104. The effect of long-term salt stress was to induce early flowering of theP. alba clones which suggests that mechanism of salt accommodation could be devel-oped.

  14. Stress-responsive hydroxycinnamate glycosyltransferase modulates phenylpropanoid metabolism in Populus.

    Science.gov (United States)

    Babst, Benjamin A; Chen, Han-Yi; Wang, Hong-Qiang; Payyavula, Raja S; Thomas, Tina P; Harding, Scott A; Tsai, Chung-Jui

    2014-08-01

    The diversity of phenylpropanoids offers a rich inventory of bioactive chemicals that can be exploited for plant improvement and human health. Recent evidence suggests that glycosylation may play a role in the partitioning of phenylpropanoid precursors for a variety of downstream uses. This work reports the functional characterization of a stress-responsive glycosyltransferase, GT1-316 in Populus. GT1-316 belongs to the UGT84A subfamily of plant glycosyltransferase family 1 and is designated UGT84A17. Recombinant protein analysis showed that UGT84A17 is a hydroxycinnamate glycosyltransferase and able to accept a range of unsubstituted and substituted cinnamic and benzoic acids as substrates in vitro. Overexpression of GT1-316 in transgenic Populus led to plant-wide increases of hydroxycinnamoyl-glucose esters, which were further elevated under N-limiting conditions. Levels of the two most abundant flavonoid glycosides, rutin and kaempferol-3-O-rutinoside, decreased, while levels of other less abundant flavonoid and phenylpropanoid conjugates increased in leaves of the GT1-316-overexpressing plants. Transcript levels of representative phenylpropanoid pathway genes were unchanged in transgenic plants, supporting a glycosylation-mediated redirection of phenylpropanoid carbon flow as opposed to enhanced phenylpropanoid pathway flux. The metabolic response of N-replete transgenic plants overlapped with that of N-stressed wild types, as the majority of phenylpropanoid derivatives significantly affected by GT1-316 overexpression were also significantly changed by N stress in the wild types. These results suggest that UGT84A17 plays an important role in phenylpropanoid metabolism by modulating biosynthesis of hydroxycinnamoyl-glucose esters and their derivatives in response to developmental and environmental cues.

  15. Exploring the Response of Plants Grown under Uranium Stress

    Energy Technology Data Exchange (ETDEWEB)

    Doustaly, Fany; Berthet, Serge; Bourguignon, Jacques [CEA, iRTSV, Laboratoire de Physiologie Cellulaire Vegetale, UMR 5168 CEA-CNRS-INRA-Univ. Grenoble Alpes (France); Combes, Florence; Vandenbrouck, Yves [CEA, iRTSV, Laboratoire de Biologie a Grande Echelle, EDyP, CEA-Grenoble (France); Carriere, Marie [CEA, INAC, LAN, UMR E3 CEA-Universite Joseph Fourier, Grenoble (France); Vavasseur, Alain [CEA, IBEB, LBDP, Saint Paul lez Durance, CEA Cadarache (France)

    2014-07-01

    Uranium is a natural element which is mainly redistributed in the environment due to human activity, including accidents and spillages. Plants may be useful in cleaning up after incidents, although little is yet known about the relationship between uranium speciation and plant response. We analyzed the impact of different uranium (U) treatments on three plant species namely sunflower, oilseed rape and wheat. Using inductively coupled plasma mass spectrometry elemental analysis, together with a panel of imaging techniques including scanning electron microscopy coupled with energy dispersive spectroscopy, transmission electron microscopy and particle-induced X-ray emission spectroscopy, we have recently shown how chemical speciation greatly influences the accumulation and distribution of U in plants. Uranyl (UO{sub 2}{sup 2+} free ion) is the predominant mobile form in soil surface at low pH in absence of ligands. With the aim to characterize the early plant response to U exposure, complete Arabidopsis transcriptome microarray experiments were conducted on plants exposed to 50 μM uranyl nitrate for 2, 6 and 30 h and highlighted a set of 111 genes with modified expression at these three time points. Quantitative real-time RT-PCR experiments confirmed and completed CATMA micro-arrays results allowing the characterization of biological processes perturbed by U. Functional categorization of deregulated genes emphasizes oxidative stress, cell wall biosynthesis and hormone biosynthesis and signaling. We showed that U stress is perceived by plant cells like a phosphate starvation stress since several phosphate deprivation marker genes were deregulated by U and also highlighted perturbation of iron homeostasis by U. Hypotheses are presented to explain how U perturbs the iron uptake and signaling response. These results give preliminary insights into the pathways affected by uranyl uptake, which will be of interest for engineering plants to help clean areas contaminated with

  16. Individual differences in cortisol responses to a laboratory speech task and their relationship to responses to stressful daily events

    NARCIS (Netherlands)

    van Eck, M; Nicolson, N.A; Berkhof, J.; Sulon, J

    1996-01-01

    A Stress Inducing Speech Task was used to investigate the contribution of perceived stress, individual traits, and current mood states to individual differences in salivary cortisol responses. Additionally, we examined the correspondence between laboratory baseline cortisol levels and overall levels

  17. Co-culture of bone marrow-derived mesenchymal stem cells overexpressing lipocalin 2 with HK-2 and HEK293 cells protects the kidney cells against cisplatin-induced injury.

    Science.gov (United States)

    Halabian, Raheleh; Roudkenar, Mehryar Habibi; Jahanian-Najafabadi, Ali; Hosseini, Kamran Mousavi; Tehrani, Hossein Abdul

    2015-02-01

    Conditioned medium of mesenchymal stem cells (MSCs) is now being used for its cytoprotective effects, especially when the cells are equipped with cytoprotective factors to strengthen them against unfavorable microenvironments. Overexpression of Lcn2 in MSCs mimics in vivo kidney injury. Hence, unraveling how Lcn2-engineered MSCs affect kidney cells has been investigated. Cisplatin treated HK-2 or HEK293 kidney cells were co-cultivated with Lcn2 overexpressing MSCs in upper and lower chambers of transwell plates. Proliferation, apoptosis, and expression of growth factors and cytokines were assessed in the kidney cells. Co-cultivation with the MSCs-Lcn2 not only inhibited cisplatin-induced cytotoxicity in the HK-2 and HEK293 cells, but increased proliferation rate, prevented cisplatin-induced apoptosis, and increased expression of growth factors and the amount of antioxidants in the kidney cells. Thus Lcn2-engineered MSCs can ameliorate and repair injured kidney cells in vitro, which strongly suggests there are beneficial effects of the MSCs-Lcn2 in cell therapy of kidney injury.

  18. Understanding Plant Development and Stress Responses through Integrative Approaches

    Institute of Scientific and Technical Information of China (English)

    Katie Dehesh; Chun-Ming Liu

    2010-01-01

    @@ As the name reflects, integrative plant biology is the core topic of JIPB. In the past few years JIPB has been pursuing the development of this area, to assist the scientific community to bring together all possible research tools to understand plant growth, development and stress responses in micro- and macro-scales. As part of these efforts, JIPB and Yantai University organized the 1st International Symposium on Integrative Plant Biology in the seaside town of Yantai during August 10-12,2009 (Figure 1). The symposium was co-sponsored by Botanical Society of China, Chinese Society for Cell Biology, Genetics Society of China, and Chinese Society for Plant Physiology.

  19. Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer's disease.

    Science.gov (United States)

    Calabrese, Vittorio; Sultana, Rukhsana; Scapagnini, Giovanni; Guagliano, Eleonora; Sapienza, Maria; Bella, Rita; Kanski, Jaroslaw; Pennisi, Giovanni; Mancuso, Cesare; Stella, Anna Maria Giuffrida; Butterfield, D A

    2006-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive and memory decline, personality changes, and synapse loss. Increasing evidence indicates that factors such as oxidative and nitrosative stress, glutathione depletion, and impaired protein metabolism can interact in a vicious cycle, which is central to AD pathogenesis. In the present study, we demonstrate that brains of AD patients undergo oxidative changes classically associated with a strong induction of the so-called vitagenes, including the heat shock proteins (HSPs) heme oxygenase-1 (HO-1), HSP60, and HSP72, as well as thioredoxin reductase (TRXr). In inferior parietal brain of AD patients, a significant increase in the expression of HO-1 and TRXr was observed, whereas HO-2 expression was decreased, compared with controls. TRHr was not increased in AD cerebellum. Plasma GSH was decreased in AD patients, compared with the control group, and was associated with a significant increase in oxidative stress markers (i.e., GSSG, hydroxynonenal, protein carbonyl content, and nitrotyrosine). In AD lymphocytes, we observed an increased expression of inducible nitric oxide synthase, HO-1, Hsp72, HSP60, and TRXr. Our data support a role for nitrative stress in the pathogenesis of AD and indicate that the stress-responsive genes, such as HO-1 and TRXr, may represent important targets for novel cytoprotective strategies.

  20. Transcriptome Analysis of High-Temperature Stress in Developing Barley Caryopses :Early Stress Responses and Effects on Storage Compound Biosynthesis

    Institute of Scientific and Technical Information of China (English)

    Elke Mangelsen; Joachim Kilian; Klaus Harter; Christer Jansson; Dierk Wanke; Eva Sundberg

    2011-01-01

    High-temperature stress,like any abiotic stress,impairs the physiology and development of plants,including the stages of seed setting and ripening.We used the Aflymetrix 22K Barley1 GeneChip microarray to investigate the response of developing barley(Hordeum vulgare)seeds,termed caryopses,after 0.5,3,and 6 h of heat stress exposure;958 induced and 1122 repressed genes exhibited spatial and temporal expression p