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Sample records for extrinsic apoptotic pathways

  1. Regulation of Intrinsic and Extrinsic Apoptotic Pathways in Osteosarcoma Cells Following Oleandrin Treatment.

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    Ma, Yunlong; Zhu, Bin; Yong, Lei; Song, Chunyu; Liu, Xiao; Yu, Huilei; Wang, Peng; Liu, Zhongjun; Liu, Xiaoguang

    2016-11-23

    Our previous study has reported the anti-tumor effect of oleandrin on osteosarcoma (OS) cells. In the current study, we mainly explored its potential regulation on intrinsic and extrinsic apoptotic pathway in OS cells. Cells apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected using fluorescence staining and flow cytometry. Caspase-3 activity was detected using a commercial kit. The levels of cytoplasmic cytochrome c, mitochondrial cytochrome c, bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3 were detected by Western blotting. z-VAD-fmk was applied to block both intrinsic and extrinsic apoptosis pathways, and cells apoptosis was also tested. Furthermore, we used z-LEHD-fmk and Fas blocking antibody to inhibit intrinsic and extrinsic pathways, separately, and the selectivity of oleandrin on these pathways was explored. Results showed that oleandrin induced the apoptosis of OS cells, which was accompanied by an increase in ROS and a decrease in MMP. Furthermore, cytochrome c level was reduced in mitochondria but elevated in the cytoplasm. Caspase-3 activity was enhanced by oleandrin in a concentration- and time-dependent manner. Oleandrin also down-regulated the expression of bcl-2, but up-regulated bax, caspase-9, Fas, FasL, caspase-8 and caspase-3. In addition, the suppression of both apoptotic pathways by z-VAD-fmk greatly reverted the oleandrin-induced apoptosis. Moreover, the suppression of one pathway by a corresponding inhibitor did not affect the regulation of oleandrin on another pathway. Taken together, we concluded that oleandrin induced apoptosis of OS cells via activating both intrinsic and extrinsic apoptotic pathways.

  2. Sesamol induced apoptotic effect in lung adenocarcinoma cells through both intrinsic and extrinsic pathways.

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    Siriwarin, Boondaree; Weerapreeyakul, Natthida

    2016-07-25

    Sesamol is a phenolic lignan found in sesame seeds (Sesamum indicum L.) and sesame oil. The anticancer effects and molecular mechanisms underlying its apoptosis-inducing effect were investigated in human lung adenocarcinoma (SK-LU-1) cells. Sesamol inhibited SK-LU-1 cell growth with an IC50 value of 2.7 mM and exhibited less toxicity toward normal Vero cells after 48 h of treatment (Selective index = 3). Apoptotic bodies-the hallmark of apoptosis-were observed in sesamol-treated SK-LU-1 cells, stained with DAPI. Sesamol increased the activity of caspase 8, 9, and 3/7, indicating that apoptotic cell death occurred through both extrinsic and intrinsic pathways. Sesamol caused the loss of mitochondrial transmembrane potential signifying intrinsic apoptosis induction. Decreasing Bid expression revealed crosstalk between the intrinsic and extrinsic apoptotic pathways; demonstrating clearly that sesamol induces apoptosis through both pathways in human lung adenocarcinoma (SK-LU-1) cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress.

    Science.gov (United States)

    Juárez-Rojas, Adriana Lizbeth; García-Lorenzana, Mario; Aragón-Martínez, Andrés; Gómez-Quiroz, Luis Enrique; Retana-Márquez, María del Socorro

    2015-01-01

    Testicular apoptosis is activated by stress, but it is not clear which signaling pathway is activated in response to stress. The aim of this study was to investigate whether intrinsic, extrinsic, or both apoptotic signaling pathways are activated by acute and chronic stress. Adult male rats were subjected to cold water immersion-induced stress for 1, 20, 40, and 50 consecutive days. The seminiferous tubules:apoptotic cell ratio was assayed on acute (1 day) and chronic (20, 40, 50 days) stress. Apoptotic markers, including cleaved-caspase 3 and 8, the pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were also determined after acute and chronic stress induction. Additionally, epididymal sperm quality was evaluated, as well as corticosterone and testosterone levels. An increase in tubule apoptotic cell count percentage after an hour of acute stress and during chronic stress induction was observed. The apoptotic cells rate per tubule increment was only detected one hour after acute stress, but not with chronic stress. Accordingly, there was an increase in Bax, cleaved caspase-8 and caspase-3 pro-apoptotic proteins with a decrease of anti-apoptotic Bcl-2 in both acutely and chronically stressed male testes. In addition, sperm count, viability, as well as total and progressive motility were low in chronically stressed males. Finally, the levels of corticosterone increased whereas testosterone levels decreased in chronically stressed males. Activation of the extrinsic apoptotic pathway was shown by cleaved caspase-8 increase whereas the intrinsic apoptotic pathway activation was determined by the increase of Bax, along with Bcl-2 decrease, making evident a cross-talk between these two pathways with the activation of caspase-3. These results suggest that both acute and chronic stress can potentially activate the intrinsic/extrinsic apoptosis pathways in testes. Chronic stress also reduces the quality of epididymal spermatozoa, possibly due to a decrease in testosterone.

  4. Cardiac extrinsic apoptotic pathway is silent in young but activated in elder mice overexpressing bovine GH: interplay with the intrinsic pathway.

    Science.gov (United States)

    Bogazzi, Fausto; Russo, Dania; Raggi, Francesco; Bohlooly-Y, Mohammad; Tornell, Jan; Sardella, Chiara; Lombardi, Martina; Urbani, Claudio; Manetti, Luca; Brogioni, Sandra; Martino, Enio

    2011-08-01

    Apoptosis may occur through the mitochondrial (intrinsic) pathway and activation of death receptors (extrinsic pathway). Young acromegalic mice have reduced cardiac apoptosis whereas elder animals have increased cardiac apoptosis. Multiple intrinsic apoptotic pathways have been shown to be modulated by GH and other stimuli in the heart of acromegalic mice. However, the role of the extrinsic apoptotic pathways in acromegalic hearts is currently unknown. In young (3-month-old) acromegalic mice, expression of proteins of the extrinsic apoptotic pathway did not differ from that of wild-type animals, suggesting that this mechanism did not participate in the lower cardiac apoptosis levels observed at this age. On the contrary, the extrinsic pathway was active in elder (9-month-old) animals (as shown by increased expression of TRAIL, FADD, TRADD and increased activation of death inducing signaling complex) leading to increased levels of active caspase 8. It is worth noting that changes of some pro-apoptotic proteins were induced by GH, which seemed to have, in this context, pro-apoptotic effects. The extrinsic pathway influenced the intrinsic pathway by modulating t-Bid, the cellular levels of which were reduced in young and increased in elder animals. However, in young animals this effect was due to reduced levels of Bid regulated by the extrinsic pathway, whereas in elder animals the increased levels of t-Bid were due to the increased levels of active caspase 8. In conclusion, the extrinsic pathway participates in the cardiac pro-apoptotic phenotype of elder acromegalic animals either directly, enhancing caspase 8 levels or indirectly, increasing t-Bid levels and conveying death signals to the intrinsic pathway.

  5. Exploration of intrinsic and extrinsic apoptotic pathways in zearalenone-treated rat sertoli cells.

    Science.gov (United States)

    Xu, Ming-Long; Hu, Jin; Guo, Bao-Ping; Niu, Ya-Ru; Xiao, Cheng; Xu, Yin-Xue

    2016-12-01

    Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin produced mainly by Fusarium. ZEA causes reproductive disorders and is both cytotoxic and genotoxic in animals; however, little is known regarding the molecular mechanism(s) leading to ZEA toxicity. Sertoli cells are somatic cells that support the development of spermatogenic cells. The objective of this study was to explore the effects of ZEA on the proliferation, apoptosis, and necrosis of rat Sertoli cells to uncover signaling pathways underlying ZEA cytotoxicity. ZEA reduced the proliferation of rat Sertoli cells in a dose-dependent manner, as indicated by a CCK8 assay, while flow cytometry revealed that ZEA caused both apoptosis and necrosis. Immunoblotting revealed that ZEA treatment increased the ratio of Bax/Bcl-2, as well as the expression of FasL and caspases-3, -8, and -9, in a dose-dependent manner. Collectively, these data suggest that ZEA induced apoptosis and necrosis in rat Sertoli cells via extrinsic and intrinsic apoptotic pathways. This study provides new insights into the molecular mechanisms by which ZEA exhibits cytotoxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1731-1739, 2016. © 2015 Wiley Periodicals, Inc.

  6. Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand.

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    Saralamma, Venu Venkatarame Gowda; Nagappan, Arulkumar; Hong, Gyeong Eun; Lee, Ho Jeong; Yumnam, Silvia; Raha, Suchismita; Heo, Jeong Doo; Lee, Sang Joon; Lee, Won Sup; Kim, Eun Hee; Kim, Gon Sup

    2015-09-18

    Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects of Poncirin in AGS human gastric cancer cells (gastric adenocarcinoma). The results revealed that Poncirin could inhibit the proliferation of AGS cells in a dose-dependent manner. It was observed Poncirin induced accumulation of sub-G1 DNA content, apoptotic cell population, apoptotic bodies, chromatin condensation, and DNA fragmentation in a dose-dependent manner in AGS cells. The expression of Fas Ligand (FasL) protein was up-regulated dose dependently in Poncirin-treated AGS cells Moreover, Poncirin in AGS cells induced activation of Caspase-8 and -3, and subsequent cleavage of poly(ADP-ribose) polymerase (PARP). Inhibitor studies' results confirm that the induction of caspase-dependent apoptotic cell death in Poncirin-treated AGS cells was led by the Fas death receptor. Interestingly, Poncirin did not show any effect on mitochondrial membrane potential (ΔΨm), pro-apoptotic proteins (Bax and Bak) and anti-apoptotic protein (Bcl-xL) in AGS-treated cells followed by no activation in the mitochondrial apoptotic protein caspase-9. This result suggests that the mitochondrial-mediated pathway is not involved in Poncirin-induced cell death in gastric cancer. These findings suggest that Poncirin has a potential anti-cancer effect via extrinsic pathway-mediated apoptosis, possibly making it a strong therapeutic agent for human gastric cancer.

  7. Expression of Fas, FasL, caspase-8 and other factors of the extrinsic apoptotic pathway during the onset of interdigital tissue elimination.

    Science.gov (United States)

    Svandova, E Budisova; Vesela, B; Lesot, H; Poliard, A; Matalova, E

    2017-04-01

    Elimination of the interdigital web is considered to be the classical model for assessing apoptosis. So far, most of the molecules described in the process have been connected to the intrinsic (mitochondrial) pathway. The extrinsic (receptor mediated) apoptotic pathway has been rather neglected, although it is important in development, immunomodulation and cancer therapy. This work aimed to investigate factors of the extrinsic apoptotic machinery during interdigital regression with a focus on three crucial initiators: Fas, Fas ligand and caspase-8. Immunofluorescent analysis of mouse forelimb histological sections revealed abundant expression of these molecules prior to digit separation. Subsequent PCR Array analyses indicated the expression of several markers engaged in the extrinsic pathway. Between embryonic days 11 and 13, statistically significant increases in the expression of Fas and caspase-8 were observed, along with other molecules involved in the extrinsic apoptotic pathway such as Dapk1, Traf3, Tnsf12, Tnfrsf1A and Ripk1. These results demonstrate for the first time the presence of extrinsic apoptotic components in mouse limb development and indicate novel candidates in the molecular network accompanying the regression of interdigital tissue during digitalisation.

  8. Mechanisms of andrographolide-induced platelet apoptosis in human platelets: regulatory roles of the extrinsic apoptotic pathway.

    Science.gov (United States)

    Lien, Li-Ming; Su, Cheng-Chen; Hsu, Wen-Hsien; Lu, Wan-Jung; Chung, Chi-Li; Yen, Ting-Lin; Chiu, Hou-Chang; Sheu, Joen-Rong; Lin, Kuan-Hung

    2013-11-01

    Andrographolide, a novel nuclear factor-κB (NF-κB) inhibitor, is isolated from the leaves of Andrographis paniculata. Platelet activation is relevant to a variety of coronary heart diseases. Our recent studies revealed that andrographolide possesses potent antiplatelet activity by inhibition of the p38 MAPK/(●) HO-NF-κB-ERK2 cascade. Although platelets are anucleated cells, apoptotic machinery apparatus recently has been found to regulate platelet activation and limit platelet lifespan. Therefore, we further investigated the regulatory effects of andrographolide on platelet apoptotic events. In this study, apoptotic signaling events for caspase-3, -8, and Bid were time (10-60 min)- and dose (25-100 μΜ)-dependently activated by andrographolide in human platelets. Andrographolide could also disrupt mitrochondrial membrane potential. In addition, caspase-8 inhibitor (z-IETD-fmk, 50 μΜ) was found to reverse andrographolide-induced caspase-8 activation, whereas the antagonistic anti-Fas receptor (ZB4, 500 ng/mL) and anti-tumor necrosis factor-R1 (H398, 10 µg/mL) monoclonal antibodies did not. In conclusion, this study for the first time demonstrated that andrographolide might limit platelet lifespan by initiating the caspase-8-dependent extrinsic apoptotic pathway, in spite of no direct evidence that death receptors are involved in this process proved. Overall, the various medicinal properties of andrographolide suggest its potential value in treating patients with thromboembolic disorders. Copyright © 2012 John Wiley & Sons, Ltd.

  9. Paraquat induces extrinsic pathway of apoptosis in A549 cells by induction of DR5 and repression of anti-apoptotic proteins, DDX3 and GSK3 expression.

    Science.gov (United States)

    Hathaichoti, Sasiphen; Visitnonthachai, Daranee; Ngamsiri, Pronrumpa; Niyomchan, Apichaya; Tsogtbayar, Oyu; Wisessaowapak, Churaibhon; Watcharasit, Piyajit; Satayavivad, Jutamaad

    2017-08-01

    Paraquat (PQ) is a bipyridyl derivative herbicide known to cause lung toxicity partly through induction of apoptosis. Here we demonstrated that PQ caused apoptosis in A549 cells. PQ increased cleavage of caspase-8 and Bid, indicating caspase-8 activation and truncated Bid, the two key mediators of extrinsic apoptosis. Additionally, PQ treatment caused an increase in DR5 (death receptor-5) and caspase-8 interaction, indicating formation of DISC (death-inducing signaling complex). These results indicate that PQ induces apoptosis through extrinsic pathway in A549 cells. Moreover, PQ drastically increased DR5 expression and membrane localization. Furthermore, PQ caused prominent concentration dependent reductions of DDX3 (the DEAD box protein-3) and GSK3 (glycogen synthase kinase-3) which can associate with DR5 and prevent DISC formation. Additionally, PQ decreased DR5-DDX3 interaction, suggesting a reduction of DDX3/GSK3 anti-apoptotic complex. Inhibition of GSK3, which is known to promote extrinsic apoptosis by its pharmacological inhibitor, BIO accentuated PQ-induced apoptosis. Moreover, GSK3 inhibition caused a further decrease in PQ-reduced DR5-DDX3 interaction. Taken together, these results suggest that PQ may induce extrinsic pathway of apoptosis in A549 cells through upregulation of DR5 and repression of anti-apoptotic proteins, DDX3/GSK3 leading to reduction of anti-apoptotic complex. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Synthesis, characterization and apoptotic activity of quinazolinone Schiff base derivatives toward MCF-7 cells via intrinsic and extrinsic apoptosis pathways

    Science.gov (United States)

    Zahedifard, Maryam; Lafta Faraj, Fadhil; Paydar, Mohammadjavad; Yeng Looi, Chung; Hajrezaei, Maryam; Hasanpourghadi, Mohadeseh; Kamalidehghan, Behnam; Abdul Majid, Nazia; Mohd Ali, Hapipah; Ameen Abdulla, Mahmood

    2015-01-01

    The current study investigated the cytotoxic effect of 3-(5-chloro-2-hydroxybenzylideneamino)-2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H)-one (A) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (B) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. The mechanism involved in apoptosis was assessed to evaluate the possible pathways induced by compound A and B. MTT assay results using A and B showed significant inhibition of MCF-7 cell viability, with IC50 values of 3. 27 ± 0.171 and 4.36 ± 0.219 μg/mL, respectively, after a 72 hour treatment period. Compound A and B did not demonstrate significant cytotoxic effects towards MDA-MB-231, WRL-68 and MCF-10A cells. Acute toxicity tests also revealed an absence of toxic effects on mice. Fluorescent microscopic studies confirmed distinct morphological changes (membrane blebbing and chromosome condensation) corresponding to typical apoptotic features in treated MCF-7 cells. Using Cellomics High Content Screening (HCS), we found that compound A and B could trigger the release of cytochrome c from mitochondria to the cytosol. The release of cytochrome c activated the expression of caspases-9 and then stimulated downstream executioner caspase-3/7. In addition, caspase-8 showed remarkable activity, followed by inhibition of NF-κB activation in A-and B-treated MCF-7 cells. The results indicated that A and B could induce apoptosis via a mechanism that involves either extrinsic or intrinsic pathways. PMID:26108872

  11. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Freeman Robert S

    2011-02-01

    Full Text Available Abstract Background Thrombolytic therapy with tissue plasminogen activator (tPA benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3, Axl, Mer receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult. Results We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutant AktK179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM, we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates

  12. The extrinsic and intrinsic apoptotic pathways are involved in manganese toxicity in rat astrocytoma C6 cells.

    Science.gov (United States)

    Alaimo, Agustina; Gorojod, Roxana M; Kotler, Mónica L

    2011-08-01

    Manganese (Mn) is a trace element known to be essential for maintaining the proper function and regulation of many biochemical and cellular reactions. However, chronic exposure to high levels of Mn in occupational or environmental settings can lead to its accumulation in the brain resulting in a degenerative brain disorder referred to as Manganism. Astrocytes are the main Mn store in the central nervous system and several lines of evidence implicate these cells as major players in the role of Manganism development. In the present study, we employed rat astrocytoma C6 cells as a sensitive experimental model for investigating molecular mechanisms involved in Mn neurotoxicity. Our results show that C6 cells undergo reactive oxygen species-mediated apoptotic cell death involving caspase-8 and mitochondrial-mediated pathways in response to Mn. Exposed cells exhibit typical apoptotic features, such as chromatin condensation, cell shrinkage, membrane blebbing, caspase-3 activation and caspase-specific cleavage of the endogenous substrate poly (ADP-ribose) polymerase. Participation of the caspase-8 dependent pathway was assessed by increased levels of FasL, caspase-8 activation and Bid cleavage. The involvement of the mitochondrial pathway was demonstrated by the disruption of the mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore, cytochrome c release, caspase-9 activation and the increased mitochondrial levels of the pro-apoptotic Bcl-2 family proteins. In addition, our data also shows for the first time that mitochondrial fragmentation plays a relevant role in Mn-induced apoptosis. Taking together, these findings contribute to a deeper elucidation of the molecular signaling mechanisms underlying Mn-induced apoptosis. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Exercise Ameliorates Renal Cell Apoptosis in Chronic Kidney Disease by Intervening in the Intrinsic and the Extrinsic Apoptotic Pathways in a Rat Model

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    Kuan-Chou Chen

    2013-01-01

    Full Text Available We hypothesized that doxorubicin (DR induced chronic kidney disease (CKD could trigger the intrinsic and the extrinsic renal cell apoptotic pathways, while treadmill exercise could help prevent adverse effects. Male Sprague-Dawley rats were subjected to treadmill running exercise at a speed of 30 m/min, 30 or 60 min/day, 3 times per week, for a total period of 11 weeks. The physiological and biochemical parameters were seen substantially improved (DR-CKD control, 30 min, 60 min exercise: the ratio of kidney weight/body weight (0.89, 0.74, and 0.72; the WBC (1.35, 1.08, and 1.42 × 104 cells/μL; RBC (5.30, 6.38, and 6.26 × 106 cells/μL; the platelet count (15.1, 12.8, and 11.3 × 105/μL; serum cholesterol (659, 360, and 75 mg/dL; serum triglyceride (542, 263, and 211 mg/dL; BUN (37, 25, and 22 mg/dL. Bcl-2 and intramitochondrial cytochrome c were upregulated, while the levels of Bax, SOD, MDA, cleaved caspases 9, 3, 8, 12, and calpain were all downregulated in DRCKD groups with exercise. CHOP (GADD153 and GRP78 were totally unaffected. FAS (CD95 was only slightly suppressed in the 60 min exercise DRCKD group. Conclusively, exercise can ameliorate CKD through the regulation of the intrinsic and extrinsic apoptosis pathways. The 60 min exercise yields more beneficial effect than the 30 min counterpart.

  14. The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells.

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    Sun, Shuqin; Yang, Shuo; Dai, Min; Jia, Xiujuan; Wang, Qiyan; Zhang, Zheng; Mao, Yongjun

    2017-06-13

    Apoptosis plays a critical role in the progression of diabetic cardiomyopathy (DC). Astragalus polysaccharides (APS), an extract of astragalus membranaceus (AM), is an effective cardioprotectant. Currently, little is known about the detailed mechanisms underlying cardioprotective effects of APS. The aims of this study were to investigate the potential effects and mechanisms of APS on apoptosis employing a model of high glucose induction of apoptosis in H9C2 cells. A model of high glucose induction of H9C2 cell apoptosis was adopted in this research. The cell viabilities were analyzed by MTT assay, and the apoptotic response was quantified by flow cytometry. The expression levels of the apoptosis related proteins were determined by Real-time PCR and western blotting. Incubation of H9C2 cells with various concentrations of glucose (i.e., 5.5, 12.5, 25, 33 and 44 mmol/L) for 24 h revealed that cell viability was reduced by high glucose dose-dependently. Pretreatment of cells with APS could inhibit high glucose-induced H9C2 cell apoptosis by decreasing the expressions of caspases and the release of cytochrome C from mitochondria to cytoplasm. Further experiments also showed that APS could modulate the ratio of Bcl-2 to Bax in mitochondria. APS decreases high glucose-induced H9C2 cell apoptosis by inhibiting the expression of pro-apoptotic proteins of both the extrinsic and intrinsic pathways and modulating the ratio of Bcl-2 to Bax in mitochondria.

  15. Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways.

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    Li, Ko-Jen; Wu, Cheng-Han; Shen, Chieh-Yu; Kuo, Yu-Min; Yu, Chia-Li; Hsieh, Song-Chou

    2016-01-01

    The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and

  16. Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Ko-Jen Li

    Full Text Available The biological significance of membrane transfer (trogocytosis between polymorphonuclear neutrophils (PMNs and mononuclear cells (MNCs remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE. By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059 and protein kinase C (Rottlerin. Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on

  17. Apoptotic engulfment pathway and schizophrenia.

    LENUS (Irish Health Repository)

    Chen, Xiangning

    2009-01-01

    BACKGROUND: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. METHODOLOGY\\/PRINCIPAL FINDINGS: Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. CONCLUSIONS\\/SIGNIFICANCE: From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

  18. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

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    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  19. CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFκB signaling pathways.

    Science.gov (United States)

    Wang, Chaoqun; Fok, Kin Lam; Cai, Zhiming; Chen, Hao; Chan, Hsiao Chang

    2017-01-10

    CD147 null mutant male mice are infertile with arrested spermatogenesis and increased apoptotic germ cells. Our previous studies have shown that CD147 prevents apoptosis in mouse spermatocytes but not spermatogonia. However, the underlying mechanism remains elusive. In the present study, we aim to determine the CD147-regulated apoptotic pathway in mouse spermatocytes. Our results showed that immunodepletion of CD147 triggered apoptosis through extrinsic apoptotic pathway in mouse testis and spermatocyte cell line (GC-2 cells), accompanied by activation of non-canonical NFκB signaling and suppression of canonical NFκB signaling. Furthermore, CD147 was found to interact with TRAF2, a factor known to regulate NFκB and extrinsic apoptotic signaling, and interfering CD147 led to the decrease of TRAF2. Consistently, depletion of CD147 by CRISPR/Cas9 technique in GC-2 cells down-regulated TRAF2 and resulted in cell death with suppressed canonical NFκB and activated non-canonical NFκB signaling. On the contrary, interfering of CD147 had no effect on NFκB signaling pathways as well as TRAF2 protein level in mouse spermatogonia cell line (GC-1 cells). Taken together, these results suggested that CD147 plays a key role in reducing extrinsic apoptosis in spermatocytes, but not spermatogonia, through modulating NFκB signaling pathway.

  20. Chalepin: A Compound from Ruta angustifolia L. Pers Exhibits Cell Cycle Arrest at S phase, Suppresses Nuclear Factor-Kappa B (NF-κB) Pathway, Signal Transducer and Activation of Transcription 3 (STAT3) Phosphorylation and Extrinsic Apoptotic Pathway in Non-small Cell Lung Cancer Carcinoma (A549).

    Science.gov (United States)

    Richardson, Jaime Stella Moses; Aminudin, Norhaniza; Abd Malek, Sri Nurestri

    2017-10-01

    Plants have been a major source of inspiration in developing novel drug compounds in the treatment of various diseases that afflict human beings worldwide. Ruta angustifolia L. Pers known locally as Garuda has been conventionally used for various medicinal purposes such as in the treatment of cancer. A dihydrofuranocoumarin named chalepin, which was isolated from the chloroform extract of the plant, was tested on its ability to inhibit molecular pathways of human lung carcinoma (A549) cells. Cell cycle analysis and caspase 8 activation were conducted using a flow cytometer, and protein expressions in molecular pathways were determined using Western blot technique. Cell cycle analysis showed that cell cycle was arrested at the S phase. Further studies using Western blotting technique showed that cell cycle-related proteins such as cyclins, cyclin-dependent kinases (CDKs), and inhibitors of CDKs correspond to a cell cycle arrest at the S phase. Chalepin also showed inhibition in the expression of inhibitors of apoptosis proteins. Nuclear factor-kappa B (NF-κB) pathway, signal transducer and activation of transcription 3 (STAT-3), cyclooxygenase-2, and c-myc were also downregulated upon treatment with chalepin. Chalepin was found to induce extrinsic apoptotic pathway. Death receptors 4 and 5 showed a dramatic upregulation at 24 h. Analysis of activation of caspase 8 with the flow cytometer showed an increase in activity in a dose- and time-dependent manner. Activation of caspase 8 induced cleavage of BH3-interacting domain death agonist, which initiated a mitochondrial-dependent or -independent apoptosis. Chalepin causes S phase cell cycle arrest, NF-κB pathway inhibition, and STAT-3 inhibition, induces extrinsic apoptotic pathway, and could be an excellent chemotherapeutic agent. This study reports the capacity of an isolated bioactive compound known as chalepin to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, signal

  1. Apoptotic pathways as regulators of recombination

    International Nuclear Information System (INIS)

    Gauny, S.S.; Kronenberg, A.; Liu, W.-C.

    2003-01-01

    Apoptosis, or programmed cell death (PCD), is a fundamental process that protects organismal integrity. In earlier work, we demonstrated that over-expression of either of two anti-apoptotic members of the BCL-2 family (BCL-2 or BCL-X L could elevate the frequency of radiation-induced mutations at the autosomal TK1 locus in human TK6 lymphoblasts that express wild-type TP53. Ectopic expression of BCL-X L also elevated the frequencies of double-strand break-induced gene conversion. The purpose of this study is to determine if BCL-2 family proteins promote radiation mutagenesis indirectly through their suppression of PCD, or whether the 'pro-mutagenic' function of these proteins can be separated from their anti-apoptotic function. We developed stable transfectants of TK6 cells that express a mutated form of BCL-X L with a single amino acid substitution in the BH1 domain that is known to interfere with the ability to suppress PCD (BCL-X L gly159ala). We also developed stable transfectants of TK6 cells that express a dominant negative caspase-9 that suppresses PCD. The results to date indicate that the mutated form of BCL-X L (gly159ala) does not suppress x-ray-induced PCD in TK6 cells, but it elevates radiation-induced TK1 mutant frequencies to the same extent as high level expression of wild-type BCL-X L . These data suggest that the anti-apoptotic function of BCL-2 family proteins is not required to elevate radiation mutagenesis. Separate experiments using TK6 cells that express a dominant negative caspase-9 indicate that this protein inhibits x-ray-induced PCD but TK1 mutant frequencies are not elevated. Taken together, the results suggest there is a separate function of BCL-2 family proteins that elevates radiation-induced mutagenesis independent of the well-known anti-apoptotic effect of these proteins of importance in human carcinogenesis

  2. The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.

    Science.gov (United States)

    Toth, Csaba; Funke, Sarah; Nitsche, Vanessa; Liverts, Anna; Zlachevska, Viktoriya; Gasis, Marcia; Wiek, Constanze; Hanenberg, Helmut; Mahotka, Csaba; Schirmacher, Peter; Heikaus, Sebastian

    2017-05-02

    Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic

  3. Apoptotic pathways of epothilone BMS 310705.

    Science.gov (United States)

    Uyar, Denise; Takigawa, Nagio; Mekhail, Tarek; Grabowski, Dale; Markman, Maurie; Lee, Francis; Canetta, Renzo; Peck, Ron; Bukowski, Ronald; Ganapathi, Ram

    2003-10-01

    BMS 310705 is a novel water-soluble analog of epothilone B currently in phase I clinical evaluation in the treatment of malignancies such as ovarian, renal, bladder, and lung carcinoma. Using an early passage cell culture model derived from the ascites of a patient clinically refractory to platinum/paclitaxel therapy, we evaluated the pathway of caspase-mediated apoptosis. Cells were treated for 1 h and subsequently evaluated for apoptosis, survival, and caspase activity. Apoptosis was determined by fluorescent microscopy. Caspase-3, -8, and -9 activities were determined by fluorometry using target tetrapeptide substrates. Mitochondrial release of cytochrome c was determined by immunoblot analysis. After treatment with BMS 310705, apoptosis was confirmed in >25% of cells at 24 h. Survival was significantly lower (P < 0.02) in cells treated with 0.05 micro M BMS 310705 vs paclitaxel. Analysis revealed an increase of caspase-9 and -3 activity; no caspase -8 activity was observed. Release of cytochrome c was detected at 12 h following treatment. SN-38 and topotecan failed to induce apoptosis. BMS 310705 induces significant apoptosis, decreases survival, and utilizes the mitochondrial-mediated pathway for apoptosis in this model.

  4. Surfactant protein D delays Fas- and TRAIL-mediated extrinsic pathway of apoptosis in T cells.

    Science.gov (United States)

    Djiadeu, Pascal; Kotra, Lakshmi P; Sweezey, Neil; Palaniyar, Nades

    2017-05-01

    Only a few extracellular soluble proteins are known to modulate apoptosis. We considered that surfactant-associated protein D (SP-D), an innate immune collectin present on many mucosal surfaces, could regulate apoptosis. Although SP-D is known to be important for immune cell homeostasis, whether SP-D affects apoptosis is unknown. In this study we aimed to determine the effects of SP-D on Jurkat T cells and human T cells dying by apoptosis. Here we show that SP-D binds to Jurkat T cells and delays the progression of Fas (CD95)-Fas ligand and TRAIL-TRAIL receptor induced, but not TNF-TNF receptor-mediated apoptosis. SP-D exerts its effects by reducing the activation of initiator caspase-8 and executioner caspase-3. SP-D also delays the surface exposure of phosphatidylserine. The effect of SP-D was ablated by the presence of caspase-8 inhibitor, but not by intrinsic pathway inhibitors. The binding ability of SP-D to dying cells decreases during the early stages of apoptosis, suggesting the release of apoptotic cell surface targets during apoptosis. SP-D also delays FasL-induced death of primary human T cells. SP-D delaying the progression of the extrinsic pathway of apoptosis could have important implications in regulating immune cell homeostasis at mucosal surfaces.

  5. Epothilone B induces extrinsic pathway of apoptosis in human SKOV-3 ovarian cancer cells.

    Science.gov (United States)

    Rogalska, Aneta; Gajek, Arkadiusz; Marczak, Agnieszka

    2014-06-01

    The molecular mechanisms underlying epothilone B (EpoB) induced apoptosis were investigated in SKOV-3 human ovarian cancer cells. The aim of this research was to compare EpoB's, which belongs to the new class of anticancer drugs, with paclitaxel's (PTX) ability to induce apoptosis. The mode of cell death was assessed colorimetrically, fluorimetrically and by immunoblot analyses through measuring DNA fragmentation, the level of intracellular calcium, the level of cytochrome c, TRAIL, the cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-9, -8 and -3. EpoB leads to an increase of the cytosolic level of cytochrome c after 4 h of cell treatment. After 24 and 48 h of cell treatment the level of intracellular calcium also increased by about 21% and 24% respectively. Moreover, EpoB, similarly to PTX, promoted the expression of TRAIL in lymphocytes, although high TRAIL expression on tumor cells was detected only after adding EpoB to SKOV-3 cells. EpoB mediates caspases-8 and -3 activation, which is independent of the reduction in the amount of caspase-9. Epitope-specific monoclonal and polyclonal antibodies revealed characteristic apoptotic changes that included cleavage of the 116 kDa PARP polypeptide to 25 kDa fragments. The results of our study show that EpoB induces mainly the extrinsic pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma.

    Science.gov (United States)

    Syed, Deeba N; Lall, Rahul K; Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

    2014-12-01

    The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

  7. Differential regulation of caspase-9 by ionizing radiation- and UV-induced apoptotic pathways in thymic cells

    Energy Technology Data Exchange (ETDEWEB)

    Okamoto, Mayumi; Koga, Satomi [Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Hiroshima 727-0023 (Japan); Tatsuka, Masaaki, E-mail: tatsuka@pu-hiroshima.ac.jp [Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Hiroshima 727-0023 (Japan)

    2010-06-01

    In mouse thymic lymphoma 3SB cells bearing wild type p53, ionizing radiation (IR) and UV light are potent triggers of caspase-3-dependent apoptosis. Although cytochrome c was released from mitochondria as expected, caspase-9 activation was not observed in UV-exposed cells. Laser scanning confocal microscopy analysis showed that caspase-9 is localized in an unusual punctuated pattern in UV-induced apoptotic cells. In agreement with differences in the status of caspase-9 activation between IR and UV, subcellular protein fractionation experiments showed that pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1), normally a part of the apoptosome assembled in response to the release of cytochrome c from mitochondria, and B-cell lymphoma extra long (Bcl-xL), an inhibitor of the change in mitochondrial membrane permeability, were redistributed by the IR-exposure but not by the UV-exposure. Instead of the sequestration of the capase-9/apoptosome activation in UV-induced apoptotic cells, the extrinsic apoptotic signaling generated by caspase-8 activation and consequent activation of B-cell lymphoma extra long (Bid) to release cytochrome c from mitochondria was observed. Thus, the post-mitochondrial apoptotic pathway downstream of cytochrome c release cannot operate the apoptosome function in UV-induced apoptosis in thymic 3SB cells. The intracellular redistribution and sequestration of apoptosis-related proteins upon mitochondrion-based apoptotic signaling was identified as a novel cellular mechanism to respond to DNA damage in an agent type-specific manner. This finding suggests that the kind of the critical ultimate apoptosis-inducing DNA lesion complex form resulting from the agent-specific DNA damage responses is important to determine which of apoptosis signals would be activated.

  8. Profile of cell proliferation and apoptosis activated by the intrinsic and extrinsic pathways in the prostate of aging rats.

    Science.gov (United States)

    Gonzaga, Amanda C R; Campolina-Silva, Gabriel H; Werneck-Gomes, Hipácia; Moura-Cordeiro, Júnia D; Santos, Letícia C; Mahecha, Germán A B; Morais-Santos, Mônica; Oliveira, Cleida A

    2017-06-01

    Estrogens acting through the receptors ERα and ERβ participate in prostate normal growth and cancer. ERβ is highly expressed in the prostate epithelium, playing pro-apoptotic, anti-proliferative, and pro-differentiation roles. Apoptosis is activated by the intrinsic pathway after castration and by the extrinsic pathway after ERβ agonist treatment. This differential activation of apoptotic pathways is important since a major problem in the treatment of prostate cancer is the recurrence of tumors after androgen withdrawal. However, a comprehensive study about the pattern of apoptosis in the aging prostate is lacking, a knowledge gap that we aimed to address herein. Cellular age-related proliferative and apoptotic profiles of prostate tissue obtained from aging Wistar rats were evaluated. Cell death (caspase-3, -8, -9, TNFα) was assessed by immunohistochemistry, immunofluorescence, and TUNEL. Cell proliferation (MCM7) and cell survival factors (ERK1/2, p-ERK1/2, p-Akt, and NF-κB) were determined by immunohistochemistry. As the rats aged, the number of proliferating cells gradually reduced in the normal epithelium of all prostate lobes, while increasing in focal areas of intraepithelial proliferation. Interestingly, in areas of intraepithelial proliferation, we observed a reduction in the number of cells positive for caspase-3, -8, and -9. Regardless the animal's age, few prostate epithelial cells were positive for caspase-3, caspase-9, and TUNEL. In contrast, a progressive increase was seen in the positivity for caspase-8, especially in the atrophic epithelium of ventral prostate, which coincided with a reduction in TNFα immunoreaction. However, morphology of most caspase-8 positive cells suggests that they were not apoptotic. We also found reduced ERβ expression in the same areas. Possibly, low levels of the pro-apoptotic inductors TNFα and ERβ direct caspase-8 activity to an alternative pro-survival role in the atrophic epithelium. This hypothesis is

  9. Novel levamisole derivative induces extrinsic pathway of apoptosis in cancer cells and inhibits tumor progression in mice.

    Directory of Open Access Journals (Sweden)

    Mahesh Hegde

    Full Text Available BACKGROUND: Levamisole, an imidazo(2,1-bthiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4'-fluorophenyl-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole. MATERIALS AND METHODS: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. RESULTS: We have determined the IC(50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC(50 5 µM. Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. CONCLUSION: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.

  10. Genes of the mitochondrial apoptotic pathway in Mytilus galloprovincialis.

    Directory of Open Access Journals (Sweden)

    Noelia Estévez-Calvar

    Full Text Available Bivalves play vital roles in marine, brackish, freshwater and terrestrial habitats. In recent years, these ecosystems have become affected through anthropogenic activities. The ecological success of marine bivalves is based on the ability to modify their physiological functions in response to environmental changes. One of the most important mechanisms involved in adaptive responses to environmental and biological stresses is apoptosis, which has been scarcely studied in mollusks, although the final consequence of this process, DNA fragmentation, has been frequently used for pollution monitoring. Environmental stressors induce apoptosis in molluscan cells via an intrinsic pathway. Many of the proteins involved in vertebrate apoptosis have been recognized in model invertebrates; however, this process might not be universally conserved. Mytilus galloprovincialis is presented here as a new model to study the linkage between molecular mechanisms that mediate apoptosis and marine bivalve ecological adaptations. Therefore, it is strictly necessary to identify the key elements involved in bivalve apoptosis. In the present study, six mitochondrial apoptotic-related genes were characterized, and their gene expression profiles following UV irradiation were evaluated. This is the first step for the development of potential biomarkers to assess the biological responses of marine organisms to stress. The results confirmed that apoptosis and, more specifically, the expression of the genes involved in this process can be used to assess the biological responses of marine organisms to stress.

  11. BAD-mediated apoptotic pathway is associated with human cancer development.

    Science.gov (United States)

    Stickles, Xiaomang B; Marchion, Douglas C; Bicaku, Elona; Al Sawah, Entidhar; Abbasi, Forough; Xiong, Yin; Bou Zgheib, Nadim; Boac, Bernadette M; Orr, Brian C; Judson, Patricia L; Berry, Amy; Hakam, Ardeshir; Wenham, Robert M; Apte, Sachin M; Berglund, Anders E; Lancaster, Johnathan M

    2015-04-01

    The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, pBAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

  12. Involvement of caspase-dependent and -independent apoptotic pathways in cisplatin-induced apoptosis

    Science.gov (United States)

    Liu, Lei; Zhang, Yingjie; Wang, Xianwang

    2009-02-01

    Cisplatin, an efficient anticancer agent, can trigger multiple apoptotic pathways in cancer cells. However, the signal transduction pathways in response to cisplatin-based chemotherapy are complicated, and the mechanism is not fully understood. In current study, we showed that, during cisplatin-induced apoptosis of human lung adenocarcinoma cells, both the caspase-dependent and -independent pathways were activated. Herein, we reported that after cisplatin treatment, the activities of caspase-9/-3 were sharply increased; pre-treatment with Z-LEHD-fmk (inhibitor of caspase-9), Z-DEVD-fmk (inhibitor of caspase-3), and Z-VAD-fmk (a pan-caspase inhibitor) increased cell viability and decreased apoptosis, suggesting that caspase-mediated apoptotic pathway was activated following cisplatin treatment. Confocal imaging of the cells transfected with AIF-GFP demonstrated that AIF release occurred about 9 h after cisplatin treatment. The event proceeded progressively over time, coinciding with a nuclear translocation and lasting for more than 2 hours. Down-regulation of AIF by siRNA also significantly increased cell viability and decreased apoptosis, these results suggested that AIF-mediated caspase-independent apoptotic pathway was involved in cispatin-induced apoptosis. In conclusion, the current study demonstrated that both caspase-dependent and -independent apoptotic pathways were involved in cisplatin-induced apoptosis in human lung adenocarcinoma cells.

  13. Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis

    International Nuclear Information System (INIS)

    Goc, Anna; Kochuparambil, Samith T; Al-Husein, Belal; Al-Azayzih, Ahmad; Mohammad, Shuaib; Somanath, Payaningal R

    2012-01-01

    Recent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood. Effect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin. Data indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5. Our study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent

  14. Extrinsic and Intrinsic Apoptotic Responses Induced by Shiitake Culinary-Medicinal Mushroom Lentinus edodes (Agaricomycetes) Aqueous Extract against a Larynx Carcinoma Cell Line.

    Science.gov (United States)

    Finimundy, Tiane C; Scola, Gustavo; Scariot, Fernando J; Dillon, Aldo J P; Moura, Sidnei; Echeverrigaray, Sérgio; Henriques, João Pegas; Roesch-Ely, Mariana

    2018-01-01

    Cumulative evidence from research studies has shown that the shiitake culinary-medicinal mushroom, Lentinus edodes, is an excellent source of natural antitumor agents and is capable of inhibiting cancer cell growth. However, the cell signaling pathway that leads tumor cells to apoptosis is not well understood because many chemical compounds may be acting. This study investigated the chemopreventive effects of an L. edodes aqueous extract on human HEp-2 epithelial larynx carcinoma cells and normal human MRC-5 lung fibroblasts by identifying proliferative and apoptotic pathways. The chemical characterization of the dry powder was assessed by high-performance liquid chromatography. Antiproliferative and proapoptotic effects induced by the extract were evaluated by assessing proliferative markers, cell sorting through flow cytometry, and expression levels of apoptotic proteins with Western blotting. The results suggest that inhibition of cell proliferation was more prominent in HEp-2 than in MRC-5 cells. Cell death analysis showed the appearance of cell populations in the sub-G1 phase, with late apoptotic signal increased in a dose-dependent manner. In addition, the aqueous extract induced depolarization of mitochondria, activating the generation of intracellular reactive oxygen species in HEp-2 cells. These observations suggest that L. edodes extract may exert a chemopreventive effect, regulating mitotic induction of apoptogenic signals. These findings highlight the mushroom's pharmacological potential in cancer treatment.

  15. Tributyltin induces apoptotic signaling in hepatocytes through pathways involving the endoplasmic reticulum and mitochondria

    International Nuclear Information System (INIS)

    Grondin, Melanie; Marion, Michel; Denizeau, Francine; Averill-Bates, Diana A.

    2007-01-01

    Tri-n-butyltin is a widespread environmental toxicant, which accumulates in the liver. This study investigates whether tri-n-butyltin induces pro-apoptotic signaling in rat liver hepatocytes through pathways involving the endoplasmic reticulum and mitochondria. Tri-n-butyltin activated the endoplasmic reticulum pathway of apoptosis, which was demonstrated by the activation of the protease calpain, its translocation to the plasma membrane, followed by cleavage of the calpain substrates, cytoskeletal protein vinculin, and caspase-12. Caspase-12 is localized to the cytoplasmic side of the endoplasmic reticulum and is involved in apoptosis mediated by the endoplasmic reticulum. Tri-n-butyltin also caused translocation of the pro-apoptotic proteins Bax and Bad from the cytosol to mitochondria, as well as changes in mitochondrial membrane permeability, events which can activate the mitochondrial death pathway. Tri-n-butyltin induced downstream apoptotic events in rat hepatocytes at the nuclear level, detected by chromatin condensation and by confocal microscopy using acridine orange. We investigated whether the tri-n-butyltin-induced pro-apoptotic events in hepatocytes could be linked to perturbation of intracellular calcium homeostasis, using confocal microscopy. Tri-n-butyltin caused changes in intracellular calcium distribution, which were similar to those induced by thapsigargin. Calcium was released from a subcellular compartment, which is likely to be the endoplasmic reticulum, into the cytosol. Cytosolic acidification, which is known to trigger apoptosis, also occurred and involved the Cl - /HCO 3 - exchanger. Pro-apoptotic events in hepatocytes were inhibited by the calcium chelator, Bapta-AM, and by a calpain inhibitor, which suggests that changes in intracellular calcium homeostasis are involved in tri-n-butyltin-induced apoptotic signaling in rat hepatocytes

  16. Ellagic acid radiosensitizes tumor cells by evoking apoptotic pathway

    International Nuclear Information System (INIS)

    Ahire, Vidhula R.; Mishra, K.P.

    2016-01-01

    Cancer causes millions of deaths each year globally. In most patients, the cause of treatment failure is found associated with the resistance to chemotherapy and radiotherapy. The development of tumor cell resistance evokes multiple intracellular molecular pathways. In addition, the limitation in treatment outcome arises due to unintended cytotoxic effects of the synthetic anticancer drugs to normal cells and tissues. Considerable focus of research is, therefore, devoted to examine plant-based herbal compounds which may prove potential anticancer drug for developing effective cancer therapy. Research results from our laboratory have shown that ellagic acid (EA), a natural flavonoid displays enhanced tumor toxicity in combination with gamma radiation to many types of cancers in vitro as well as in vivo. Studies on the underlying mechanisms of toxicity suggest that EA employs the cellular signaling pathways in producing the observed effects. This paper gives an account of molecular mechanisms of EA-induced apoptosis process in tumor cytotoxicity. It is suggested that EA acts as a novel radiosensitizer for tumors and a radioprotector for normal cells which may offer a novel protocol for cancer treatment. (author)

  17. Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators

    International Nuclear Information System (INIS)

    Claveria, Cristina; Torres, Miguel

    2003-01-01

    Multicellular organisms eliminate unwanted or damaged cells by cell death, a process essential to the maintenance of tissue homeostasis. Cell death is a tightly regulated event, whose alteration by excess or defect is involved in the pathogenesis of many diseases such as cancer, autoimmune syndromes, and neurodegenerative processes. Studies in model organisms, especially in the nematode Caenorhabditis elegans, have been crucial in identifying the key molecules implicated in the regulation and execution of programmed cell death. In contrast, the study of cell death in Drosophila melanogaster, often an excellent model organism, has identified regulators and mechanisms not obviously conserved in other metazoans. Recent molecular and cellular analyses suggest, however, that the mechanisms of action of the main programmed cell death regulators in Drosophila include a canonical mitochondrial pathway

  18. Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions.

    Science.gov (United States)

    Deegan, Shane; Saveljeva, Svetlana; Logue, Susan E; Pakos-Zebrucka, Karolina; Gupta, Sanjeev; Vandenabeele, Peter; Bertrand, Mathieu J M; Samali, Afshin

    2014-01-01

    Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.

  19. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

    Science.gov (United States)

    Pérez-Garijo, Ainhoa; Fuchs, Yaron; Steller, Hermann

    2013-01-01

    Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions. DOI: http://dx.doi.org/10.7554/eLife.01004.001 PMID:24066226

  20. Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

    Directory of Open Access Journals (Sweden)

    Xu HL

    2015-05-01

    Full Text Available Huanli Xu,1 Xin Zhao,2 Xiaohui Liu,1 Pingxiang Xu,1 Keming Zhang,2 Xiukun Lin11Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 2Department of Hepatobiliary Surgery, 302 Hospital of Chinese People’s Liberation Army, Beijing, People’s Republic of ChinaAbstract: Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM has been used in the People’s Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented.Keywords: traditional Chinese medicine, antitumor effects, apoptotic pathway

  1. Induction of discrete apoptotic pathways by bromo-substituted indirubin derivatives in invasive breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Nicolaou, Katerina A. [Department of Biological Sciences, University of Cyprus, Nicosia (Cyprus); Liapis, Vasilis; Evdokiou, Andreas [Department of Surgery, Basil Hetzel Institute, Adelaide University, Adelaide (Australia); Constantinou, Constantina [St. George' s University of London Medical School at the University of Nicosia, Nicosia (Cyprus); Magiatis, Prokopios; Skaltsounis, Alex L. [Faculty of Pharmacy, University of Athens, Athens (Greece); Koumas, Laura; Costeas, Paul A. [Center for Study of Hematological Malignancies, Nicosia (Cyprus); Constantinou, Andreas I., E-mail: andreasc@ucy.ac.cy [Department of Biological Sciences, University of Cyprus, Nicosia (Cyprus)

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer The effects of 6BIO and 7BIO are evaluated against five breast cancer cell lines. Black-Right-Pointing-Pointer 6BIO induces a caspase dependent apoptotic effect via the intrinsic pathway. Black-Right-Pointing-Pointer 7BIO promotes G{sub 2}/M cells cycle arrest. Black-Right-Pointing-Pointer 7BIO triggers a caspase-8 mediated apoptotic pathway. Black-Right-Pointing-Pointer 7BIO triggers and a caspase independent pathway. -- Abstract: Indirubin derivatives gained interest in recent years for their anticancer and antimetastatic properties. The objective of the present study was to evaluate and compare the anticancer properties of the two novel bromo-substituted derivatives 6-bromoindirubin-3 Prime -oxime (6BIO) and 7-bromoindirubin-3 Prime -oxime (7BIO) in five different breast cancer cell lines. Cell viability assays identified that 6BIO and 7BIO are most effective in preventing the proliferation of the MDA-MB-231-TXSA breast cancer cell line from a total of five breast cancer cell lined examined. In addition it was found that the two compounds induce apoptosis via different mechanisms. 6BIO induces caspase-dependent programmed cell death through the intrinsic (mitochondrial) caspase-9 pathway. 7BIO up-regulates p21 and promotes G{sub 2}/M cell cycle arrest which is subsequently followed by the activation of two different apoptotic pathways: (a) a pathway that involves the upregulation of DR4/DR5 and activation of caspase-8 and (b) a caspase independent pathway. In conclusion, this study provides important insights regarding the molecular pathways leading to cell cycle arrest and apoptosis by two indirubin derivatives that can find clinical applications in targeted cancer therapeutics.

  2. Apoptotic effect of novel Schiff based CdCl₂(C₁₄H₂₁N₃O₂) complex is mediated via activation of the mitochondrial pathway in colon cancer cells.

    Science.gov (United States)

    Hajrezaie, Maryam; Paydar, Mohammadjavad; Looi, Chung Yeng; Moghadamtousi, Soheil Zorofchian; Hassandarvish, Pouya; Salga, Muhammad Saleh; Karimian, Hamed; Shams, Keivan; Zahedifard, Maryam; Majid, Nazia Abdul; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen

    2015-03-13

    The development of metal-based agents has had a tremendous role in the present progress in cancer chemotherapy. One well-known example of metal-based agents is Schiff based metal complexes, which hold great promise for cancer therapy. Based on the potential of Schiff based complexes for the induction of apoptosis, this study aimed to examine the cytotoxic and apoptotic activity of a CdCl2(C14H21N3O2) complex on HT-29 cells. The complex exerted a potent suppressive effect on HT-29 cells with an IC50 value of 2.57 ± 0.39 after 72 h of treatment. The collapse of the mitochondrial membrane potential and the elevated release of cytochrome c from the mitochondria to the cytosol indicate the involvement of the intrinsic pathway in the induction of apoptosis. The role of the mitochondria-dependent apoptotic pathway was further proved by the significant activation of the initiator caspase-9 and the executioner caspases-3 and -7. In addition, the activation of caspase-8, which is associated with the suppression of NF-κB translocation to the nucleus, also revealed the involvement of the extrinsic pathway in the induced apoptosis. The results suggest that the CdCl2(C14H21N3O2) complex is able to induce the apoptosis of colon cancer cells and is a potential candidate for future cancer studies.

  3. Nogo-B (Reticulon-4B) functions as a negative regulator of the apoptotic pathway through the interaction with c-FLIP in colorectal cancer cells.

    Science.gov (United States)

    Kawaguchi, Nao; Tashiro, Keitaro; Taniguchi, Kohei; Kawai, Masaru; Tanaka, Keitaro; Okuda, Junji; Hayashi, Michihiro; Uchiyama, Kazuhisa

    2018-08-01

    Nogo-B is a member of the Nogo/Reticulon-4 family and has been reported to be an inducer of apoptosis in certain types of cancer cells. However, the role of Nogo-B in human cancer remains less understood. Here, we demonstrated the functions of Nogo-B in colorectal cancer cells. In clinical colorectal cancer specimens, Nogo-B was obviously overexpressed, as determined by immunohistochemistry; and Western blot analysis showed its expression level to be significantly up-regulated. Furthermore, knockdown of Nogo-B in two colorectal cancer cell lines, SW480 and DLD-1, by transfection with si-RNA (siR) resulted in significantly reduced cell viability and a dramatic increase in apoptosis with insistent overexpression of cleaved caspase-8 and cleaved PARP. The transfection with Nogo-B plasmid cancelled that apoptosis induced by siRNogoB in SW480 cells. Besides, combinatory treatment with siR-Nogo-B/staurosporine (STS) or siR-Nogo-B/Fas ligand (FasL) synergistically reduced cell viability and increased the expression of apoptotic signaling proteins in colorectal cancer cells. These results strongly support our contention that Nogo-B most likely played an oncogenic role in colorectal cancer cells, mainly by negatively regulating the extrinsic apoptotic pathway in them. Finally, we revealed that suppression of Nogo-B caused down-regulation of c-FLIP, known as a major anti-apoptotic protein, and activation of caspase-8 in the death receptor pathway. Interaction between Nogo-B and c-FLIP was shown by immunoprecipitation and immunofluorescence studies. In conclusion, Nogo-B was shown to play an important negative role in apoptotic signaling through its interaction with c-FLIP in colorectal cancer cells, and may thus become a novel therapeutic target for colorectal cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. The extrinsic cell death pathway and the élan mortel.

    Science.gov (United States)

    Wallach, D; Kang, T-B; Kovalenko, A

    2008-10-01

    Early in the exploration of the chemical nature of life, it was widely believed that the molecules of living organisms, by their very nature, differ from those of inorganic material molecules and possess a vital force ('élan vital'). Similarly, early scientific thinking on the subject of cell death and its induction by cytotoxic cells of the immune system was pervaded by a sense that the molecules mediating these functions possess intrinsic deadly activity and are dedicated exclusively to death-related tasks. This impression was also reflected in the initial notions of the mode of action of intracellular proteins that signal for death. It is now gradually becoming clear, however, that proteins participating in death induction also have functions unrelated to death. Nevertheless, as exemplified by studies of the function of caspase-8 (an enzyme that signals both for activation of the extrinsic cell-death pathway and for non-death-related effects), analysis of the mechanistic basis for such heterogeneity might allow identification of distinct structural determinants in the proteins participating in death induction that do bear death specificity.

  5. Apoptotic intrinsic pathway proteins predict survival in canine cutaneous mast cell tumours.

    Science.gov (United States)

    Barra, C N; Macedo, B M; Cadrobbi, K G; Pulz, L H; Huete, G C; Kleeb, S R; Xavier, J G; Catão-Dias, J L; Nishiya, A T; Fukumasu, H; Strefezzi, R F

    2018-03-01

    Mast cell tumours (MCTs) are the most frequent canine round cell neoplasms and show variable biological behaviours with high metastatic and recurrence rates. The disease is treated surgically and wide margins are recommended. Adjuvant chemotherapy and radiotherapy used in this disease cause DNA damage in neoplastic cells, which is aimed to induce apoptotic cell death. Resisting cell death is a hallmark of cancer, which contributes to the development and progression of tumours. The aim of this study was to investigate the expression of the proteins involved in the apoptotic intrinsic pathway and to evaluate their potential use as prognostic markers for canine cutaneous MCTs. Immunohistochemistry for BAX, BCL2, APAF1, Caspase-9, and Caspase-3 was performed in 50 canine cases of MCTs. High BAX expression was associated with higher mortality rate and shorter survival. BCL2 and APAF1 expressions offered additional prognostic information to the histopathological grading systems. The present results indicate that variations in the expression of apoptotic proteins are related to malignancy of cutaneous MCTs in dogs. © 2017 John Wiley & Sons Ltd.

  6. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells

    Science.gov (United States)

    Rivera, Mariela; Ramos, Yanilda; Rodríguez-Valentín, Madeline; López-Acevedo, Sheila; Cubano, Luis A.; Zou, Jin; Zhang, Qiang; Wang, Guangdi

    2017-01-01

    Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses. PMID:28628644

  7. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Mariela Rivera

    Full Text Available Curcumin, an extract from the turmeric rhizome (Curcuma longa, is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12 and Poly (ADP-ribose polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

  8. A study on apoptotic signaling pathway in HL-60 cells induced by radiation

    International Nuclear Information System (INIS)

    Kim, Hye Jung; Moon, Sung Keun; Lee, Jae Hoon; Moon, Sun Rock

    2001-01-01

    The mechanical insights of death at cancer cells by ionizing radiation are not yet clearly defined. Recent evidences have demonstrated that radiation therapy may induce cell death via activation of signaling pathway for apoptosis in target cells. This study is designed whether ionizing radiation may activate the signaling cascades of apoptosis including caspase family cysteine proteases, Bcl2/Bax, cytochrome c and Fas/Fas-L in target cells. HL-60 cells were irradiated in vitro with 6 MV X-ray at dose ranges from 2 Gy to 32 Gy. The cell viability was tested by MTT assay and the extent of apoptosis was determined using agarose gel electrophoresis. The activities of caspase proteases were measured by proteolytic cleavages of substrates. Western blot analysis was used to monitor PARP, caspase-3, Cytochrome-c, BcI-2, Bax, Fas and Fas-L. Ionizing radiation decreases the viability of HL -60 cells in a time and dose dependent manner. Ionizing radiation-induced death in HL- 60 cells is an apoptotic death which is revealed as characteristic ladder-pattern fragmentation at genomic DNA over 16 Gy at 4 hours. Ionizing radiation induces the activation of caspase-2, 3, 6, 8 and 9 of HL --60 cells in a time-dependent manner. The activation of caspase- 3 protease is also evidenced by the digestion of poly (ADP-ribose) polymerase and procaspase 3 with 16Gy ionizing irradiation. Anti-apoptotic Bcl2 expression is decreased but apoptotic Bax expression is increased with mitochondrial cytochrome c release in a time- dependent manner. In addition, expression of Fas and Fas-L is also increased in a time dependent manner. These data suggest that ionizing radiation-induced apoptosis is mediated by the activation of various signaling pathways including caspase family cysteine proteases, BcI 2 /Bax, Fas and Fas-L in a time and dose dependent manner

  9. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

    Science.gov (United States)

    Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines.

    Science.gov (United States)

    Choi, Won-Tak; Kaul, Marcus; Kumar, Santosh; Wang, Jun; Kumar, I M Krishna; Dong, Chang-Zhi; An, Jing; Lipton, Stuart A; Huang, Ziwei

    2007-03-09

    As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120(IIIB), and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

  11. Huperzine A attenuates hepatic ischemia reperfusion injury via anti-oxidative and anti-apoptotic pathways.

    Science.gov (United States)

    Xu, Zhe; Wang, Yang

    2014-08-01

    Hepatic ischemia reperfusion (HI/R) injury may occur during liver transplantation and remains a serious concern in clinical practice. Huperzine A (HupA), an alkaloid isolated from the Chinese traditional medicine Huperzia serrata, has been demonstrated to possess anti‑oxidative and anti‑apoptotic properties. In the present study, a rat model of HI/R was established by clamping the hepatic artery, the hepatoportal vein and the bile duct with a vascular clamp for 30 min followed by reperfusion for 6 h under anesthesia. HupA was injected into the tail vein 5 min prior to the induction of HI/R at doses of 167 and 500 µg/kg. The histopathological assessment of the liver was performed using hematoxylin and eosin staining. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed in the serum samples. The tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA) and glutathione (GSH) were also measured spectrophotometrically. Furthermore, the protein expression of caspase‑3, Bcl‑2 and Bax in hepatic tissues was detected via western blot analysis. Treatment of Wistar rats with HupA at doses of 167 and 500 µg/kg markedly attenuated HI/R injury as observed histologically. In addition, the significant reductions of serum ALT and AST were observed in HupA‑treated ischemic rats. Furthermore, HupA treatment enhanced the activity of hepatic tissue SOD, CAT and GSH, but decreased the MDA tissue content. Western blot analysis revealed elevated levels of Bcl‑2 expression but decreased Bax and caspase‑3 tissue expression at the protein level in the HupA‑treated group. The present data suggest that HupA attenuates the HI/R injury of rats through its anti‑oxidative and anti‑apoptotic signaling pathways.

  12. AKT delays the early-activated apoptotic pathway in UVB-irradiated keratinocytes via BAD translocation.

    Science.gov (United States)

    Claerhout, Sofie; Decraene, David; Van Laethem, An; Van Kelst, Sofie; Agostinis, Patrizia; Garmyn, Marjan

    2007-02-01

    Upon irradiation with a high dose of UVB, keratinocytes undergo apoptosis as a protective mechanism. In previous work, we demonstrated the existence of an early-activated UVB-induced apoptotic pathway in growth factor-depleted human keratinocytes, which can be substantially delayed by the exclusive supplementation of IGF-1. We now show that in human keratinocytes, IGF-1 inhibits the onset of UVB-triggered apoptosis through a transcriptional independent, AKT-mediated mechanism, involving BAD serine 136 phosphorylation. Our results show that the early UVB-induced apoptosis in growth factor-depleted human keratinocytes is exclusively triggered through the mitochondrial pathway. It is accompanied by BAX translocation, cytochrome c release, and procaspase-9 cleavage, but not by procaspase-8 or BID cleavage. In human keratinocytes, IGF-1 supplementation inhibits these events in a transcription-independent manner. Both IGF-1 supplementation and the transduction of a membrane-targeted form of AKT result in a shift of the BH3-only protein BAD from the mitochondria to the cytoplasm, paralleled by an increase of AKT-specific Ser136 phospho-BAD bound to 14-3-3zeta protein. These data indicate that AKT-induced BAD phosphorylation and its subsequent cytoplasmic sequestration by 14-3-3zeta is a major mechanism responsible for the postponement of UVB-induced apoptosis in human keratinocytes.

  13. H2O2 INDUCES APOPTOSIS OF RABBIT CHONDROCYTES VIA BOTH THE EXTRINSIC AND THE CASPASE-INDEPENDENT INTRINSIC PATHWAYS

    Directory of Open Access Journals (Sweden)

    CAIPING ZHUANG

    2013-07-01

    Full Text Available Osteoarthritis (OA, one of the most common joint diseases with unknown etiology, is characterized by the progressive destruction of articular cartilage and the apoptosis of chondrocytes. The purpose of this study is to elucidate the molecular mechanisms of H2O2-mediated rabbit chondrocytes apoptosis. CCK-8 assay showed that H2O2 treatment induced a remarkable reduction of cell viability, which was further verified by the remarkable phosphatidylserine externalization after H2O2 treatment for 1 h, the typical characteristics of apoptosis. H2O2 treatment induced a significant dysfunction of mitochondrial membrane potential (ΔΨm, but did not induce casapse-9 activation, indicating that H2O2 treatment induced caspase-independent intrinsic apoptosis that was further verified by the fact that silencing of AIF but not inhibiting caspase-9 potently prevented H2O2-induced apoptosis. H2O2 treatment induced a significant increase of caspase-8 and -3 activation, and inhibition of caspase-8 or -3 significantly prevented H2O2-induced apoptosis, suggesting that the extrinsic pathway played an important role. Collectively, our findings demonstrate that H2O2 induces apoptosis via both the casapse-8-mediated extrinsic and the caspase-independent intrinsic apoptosis pathways in rabbit chondrocytes.

  14. Allicin protects against cisplatin-induced vestibular dysfunction by inhibiting the apoptotic pathway.

    Science.gov (United States)

    Wu, Xianmin; Cai, Jing; Li, Xiaofei; Li, He; Li, Jianfeng; Bai, Xiaohui; Liu, Wenwen; Han, Yuechen; Xu, Lei; Zhang, Daogong; Wang, Haibo; Fan, Zhaomin

    2017-06-15

    Cisplatin is an anticancer drug that causes the impairment of inner ear function as side effects, including hearing loss and balance dysfunction. The purpose of this study was to investigate the effects of allicin against cisplatin-induced vestibular dysfunction in mice and to make clear the mechanism underlying the protective effects of allicin on oto-vestibulotoxicity. Mice intraperitoneally injected with cisplatin exhibited vestibular dysfunction in swimming test, which agreed with impairment in vestibule. However, these impairments were significantly prevented by pre-treatment with allicin. Allicin markedly reduced cisplatin-activated expression of cleaved-caspase-3 in hair cells and vascular layer cells of utricule, saccule and ampulla, but also decreased AIF nuclear translocation of hair cells in utricule, saccule and ampulla. These results showed that allicin played an effective role in protecting vestibular dysfunction induced by cisplatin via inhibiting caspase-dependent and caspase-independent apoptotic pathways. Therefore, allicin may be useful in preventing oto-vestibulotoxicity mediated by cisplatin. Copyright © 2017. Published by Elsevier B.V.

  15. Camel Milk Triggers Apoptotic Signaling Pathways in Human Hepatoma HepG2 and Breast Cancer MCF7 Cell Lines through Transcriptional Mechanism

    Directory of Open Access Journals (Sweden)

    Hesham M. Korashy

    2012-01-01

    Full Text Available Few published studies have reported the use of crude camel milk in the treatment of stomach infections, tuberculosis and cancer. Yet, little research was conducted on the effect of camel milk on the apoptosis and oxidative stress associated with human cancer. The present study investigated the effect and the underlying mechanisms of camel milk on the proliferation of human cancer cells using an in vitro model of human hepatoma (HepG2 and human breast (MCF7 cancer cells. Our results showed that camel milk, but not bovine milk, significantly inhibited HepG2 and MCF7 cells proliferation through the activation of caspase-3 mRNA and activity levels, and the induction of death receptors in both cell lines. In addition, Camel milk enhanced the expression of oxidative stress markers, heme oxygenase-1 and reactive oxygen species production in both cells. Mechanistically, the increase in caspase-3 mRNA levels by camel milk was completely blocked by the transcriptional inhibitor, actinomycin D; implying that camel milk increased de novo RNA synthesis. Furthermore, Inhibition of the mitogen activated protein kinases differentially modulated the camel milk-induced caspase-3 mRNA levels. Taken together, camel milk inhibited HepG2 and MCF7 cells survival and proliferation through the activation of both the extrinsic and intrinsic apoptotic pathways.

  16. MicroRNA-145 protects cardiomyocytes against hydrogen peroxide (H₂O₂-induced apoptosis through targeting the mitochondria apoptotic pathway.

    Directory of Open Access Journals (Sweden)

    Ruotian Li

    Full Text Available MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, has been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia/reperfusion induced cardiac injury. Here, we report microRNA-145, a tumor suppressor miRNA, can protect cardiomyocytes from hydrogen peroxide H₂O₂-induced apoptosis through targeting the mitochondrial pathway. Quantitative real-time PCR (qPCR demonstrated that the expression of miR-145 in either ischemia/reperfused mice myocardial tissues or H₂O₂-treated neonatal rat ventricle myocytes (NRVMs was markedly down-regulated. Over-expression of miR-145 significantly inhibited the H₂O₂-induced cellular apoptosis, ROS production, mitochondrial structure disruption as well as the activation of key signaling proteins in mitochondrial apoptotic pathway. These protective effects of miR-145 were abrogated by over-expression of Bnip3, an initiation factor of the mitochondrial apoptotic pathway in cardiomyocytes. Finally, we utilized both luciferase reporter assay and western blot analysis to identify Bnip3 as a direct target of miR-145. Our results suggest miR-145 plays an important role in regulating mitochondrial apoptotic pathway in heart challenged with oxidative stress. MiR-145 may represent a potential therapeutic target for treatment of oxidative stress-associated cardiovascular diseases, such as myocardial ischemia/reperfusion injury.

  17. 1-Benzyl-2-Phenylbenzimidazole (BPB, a Benzimidazole Derivative, Induces Cell Apoptosis in Human Chondrosarcoma through Intrinsic and Extrinsic Pathways

    Directory of Open Access Journals (Sweden)

    Ju-Fang Liu

    2012-12-01

    Full Text Available In this study, we investigated the anticancer effects of a new benzimidazole derivative, 1-benzyl-2-phenyl -benzimidazole (BPB, in human chondrosarcoma cells. BPB-mediated apoptosis was assessed by the MTT assay and flow cytometry analysis. The in vivo efficacy was examined in a JJ012 xenograft model. Here we found that BPB induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 but not in primary chondrocytes. BPB induced upregulation of Bax, Bad and Bak, downregulation of Bcl-2, Bid and Bcl-XL and dysfunction of mitochondria in chondrosarcoma. In addition, BPB also promoted cytosolic releases AIF and Endo G. Furthermore, it triggered extrinsic death receptor-dependent pathway, which was characterized by activating Fas, FADD and caspase-8. Most importantly, animal studies revealed a dramatic 40% reduction in tumor volume after 21 days of treatment. Thus, BPB may be a novel anticancer agent for the treatment of chondrosarcoma.

  18. Apoptotic effect of novel Schiff Based CdCl2(C14H21N3O2) complex is mediated via activation of the mitochondrial pathway in colon cancer cells

    Science.gov (United States)

    Hajrezaie, Maryam; Paydar, Mohammadjavad; Looi, Chung Yeng; Moghadamtousi, Soheil Zorofchian; Hassandarvish, Pouya; Salga, Muhammad Saleh; Karimian, Hamed; Shams, Keivan; Zahedifard, Maryam; Majid, Nazia Abdul; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen

    2015-01-01

    The development of metal-based agents has had a tremendous role in the present progress in cancer chemotherapy. One well-known example of metal-based agents is Schiff based metal complexes, which hold great promise for cancer therapy. Based on the potential of Schiff based complexes for the induction of apoptosis, this study aimed to examine the cytotoxic and apoptotic activity of a CdCl2(C14H21N3O2) complex on HT-29 cells. The complex exerted a potent suppressive effect on HT-29 cells with an IC50 value of 2.57 ± 0.39 after 72 h of treatment. The collapse of the mitochondrial membrane potential and the elevated release of cytochrome c from the mitochondria to the cytosol indicate the involvement of the intrinsic pathway in the induction of apoptosis. The role of the mitochondria-dependent apoptotic pathway was further proved by the significant activation of the initiator caspase-9 and the executioner caspases-3 and -7. In addition, the activation of caspase-8, which is associated with the suppression of NF-κB translocation to the nucleus, also revealed the involvement of the extrinsic pathway in the induced apoptosis. The results suggest that the CdCl2(C14H21N3O2) complex is able to induce the apoptosis of colon cancer cells and is a potential candidate for future cancer studies. PMID:25764970

  19. A Novel Mitochondria-Dependent Apoptotic Pathway (MAP) in Prostate Cancer (Pca) Cells

    National Research Council Canada - National Science Library

    Chandra, Dhyan

    2004-01-01

    ...) are also up-regulated (Chandra et al., J. Biol. Chem., 277, 50842-54; 2002). Later, when the apoptotic machinery is activated, I notice that there is prominent localization of active caspase-9 and -3 in the mitochondria...

  20. Apoptotic Cell Death Induced by Resveratrol Is Partially Mediated by the Autophagy Pathway in Human Ovarian Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Fangfang Lang

    Full Text Available Resveratrol (trans-3,4,5'-trihydroxystilbene is an active compound in food, such as red grapes, peanuts, and berries. Resveratrol exhibits an anticancer effect on various human cancer cells. However, the mechanism of resveratrol-induced anti-cancer effect at the molecular level remains to be elucidated. In this study, the mechanism underlying the anti-cancer effect of resveratrol in human ovarian cancer cells (OVCAR-3 and Caov-3 was investigated using various molecular biology techniques, such as flow cytometry, western blotting, and RNA interference, with a major focus on the potential role of autophagy in resveratrol-induced apoptotic cell death. We demonstrated that resveratrol induced reactive oxygen species (ROS generation, which triggers autophagy and subsequent apoptotic cell death. Resveratrol induced ATG5 expression and promoted LC3 cleavage. The apoptotic cell death induced by resveratrol was attenuated by both pharmacological and genetic inhibition of autophagy. The autophagy inhibitor chloroquine, which functions at the late stage of autophagy, significantly reduced resveratrol-induced cell death and caspase 3 activity in human ovarian cancer cells. We also demonstrated that targeting ATG5 by siRNA also suppressed resveratrol-induced apoptotic cell death. Thus, we concluded that a common pathway between autophagy and apoptosis exists in resveratrol-induced cell death in OVCAR-3 human ovarian cancer cells.

  1. Sanguinarine induces apoptosis of human osteosarcoma cells through the extrinsic and intrinsic pathways

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hyunjin; Bergeron, Eric; Senta, Helena; Guillemette, Kim [Cell-Biomaterial Biohybrid Systems, Universite de Sherbrooke, Department of Chemical Engineering and Biotechnological Engineering, Canada J1K 2R1 (Canada); Beauvais, Sabrina [Cell-Biomaterial Biohybrid Systems, Universite de Sherbrooke, Department of Chemical Engineering and Biotechnological Engineering, Canada J1K 2R1 (Canada); Development of Bioprocess, Universite de Sherbrooke, Department of Chemical Engineering and Biotechnological Engineering, Canada J1K 2R1 (Canada); Blouin, Richard [Universite de Sherbrooke, Department of Biology, Canada J1K 2R1 (Canada); Sirois, Joel [Development of Bioprocess, Universite de Sherbrooke, Department of Chemical Engineering and Biotechnological Engineering, Canada J1K 2R1 (Canada); Faucheux, Nathalie, E-mail: Nathalie.Faucheux@Usherbrooke.ca [Cell-Biomaterial Biohybrid Systems, Universite de Sherbrooke, Department of Chemical Engineering and Biotechnological Engineering, Canada J1K 2R1 (Canada)

    2010-08-27

    Research highlights: {yields} We show for the first time the effect of sanguinarine (SA) on MG63 and SaOS-2 cells. {yields} SA altered osteosarcoma cell viability in a concentration and time dependent manner. {yields} SA induced osteosarcoma cell apoptosis and increased caspase-8 and -9 activities. {yields} SA decreased dose dependently the Bcl-2 protein level only in MG63 cells. {yields} SaOS-2 which are osteoblast-derived, seemed more resistant to SA than MG63. -- Abstract: The quaternary benzo[c]phenanthridine alkaloid sanguinarine inhibits the proliferation of cancerous cells from different origins, including lung, breast, pancreatic and colon, but nothing is known of its effects on osteosarcoma, a primary malignant bone tumour. We have found that sanguinarine alters the morphology and reduces the viability of MG-63 and SaOS-2 human osteosarcoma cell lines in concentration- and time-dependent manner. Incubation with 1 {mu}mol/L sanguinarine for 4 and 24 h killed more efficiently MG-63 cells than SaOS-2 cells, while incubation with 5 {mu}mol/L sanguinarine killed almost 100% of both cell populations within 24 h. This treatment also changed the mitochondrial membrane potential in both MG-63 and SaOS-2 cells within 1 h, caused chromatin condensation and the formation of apoptotic bodies. It activated multicaspases, and increased the activities of caspase-8 and caspase-9 in both MG-63 and SaOS-2 cells. These data highlight sanguinarine as a novel potential agent for bone cancer therapy.

  2. Activation of the intrinsic-apoptotic pathway in LNCaP prostate cancer cells by genistein- topotecan combination treatments

    Directory of Open Access Journals (Sweden)

    Vanessa Hörmann

    2013-03-01

    Full Text Available ABSTRACTBackground: Prostate cancer is the second most common cancer in American men. The development of alternative preventative and/or treatment options utilizing a combination of phytochemicals and chemotherapeutic drugs could be an attractive alternative compared to conventional carcinoma treatments. Genistein isoflavone is the primary dietary phytochemical found in soy and has demonstrated anti-tumor activities in LNCaP prostate cancer cells. Topotecan Hydrochloride (Hycamtin is an FDA-approved chemotherapy for secondary treatment of lung, ovarian and cervical cancers. The purpose of this study was to detail the potential activation of the intrinsic apoptotic pathway in LNCaP prostate cancer cells through genistein-topotecan combination treatments.Methods: LNCaP cells were cultured in complete RPMI medium in a monolayer (70-80% confluency at 37ºC and 5% CO2. Treatment consisted of single and combination groups of genistein and topotecan for 24 hours. The treated cells were assayed for i growth inhibition through trypan blue exclusion assay and microphotography , ii classification of cellular death through acridine/ ethidium bromide fluorescent staining, and iii activation of the intrinsic apoptotic pathway through Jc-1: mitochondrial membrane potential assay, cytochrome c release and Bcl-2 protein expression.Results: The overall data indicated that genistein-topotecan combination was significantly more efficacious in reducing the prostate carcinoma’s viability compared to the single treatment options. In all treatment groups, cell death occurred primarily through the activation of the intrinsic apoptotic pathway.Conclusion: The combination of topotecan and genistein has the potential to lead to treatment options with equal therapeutic efficiency as traditional chemo- and radiation therapies, but lower cell cytotoxicity and fewer side effects in patients.

  3. The anti-apoptotic activity associated with phosphatidylinositol transfer protein alpha activates the MAPK and Akt/PKB pathway.

    Science.gov (United States)

    Schenning, Martijn; Goedhart, Joachim; Gadella, Theodorus W J; Avram, Diana; Wirtz, Karel W A; Snoek, Gerry T

    2008-10-01

    The conditioned medium (CM) from mouse NIH3T3 fibroblast cells overexpressing phosphatidylinositol transfer protein alpha (PI-TPalpha; SPIalpha cells) demonstrates an increased anti-apoptotic activity compared with CM from wild type NIH3T3 (wtNIH3T3) cells. As previously shown, the anti-apoptotic activity acts by activating a G protein-coupled receptor, most probably a cannabinoid 1 (CB1)-like receptor as the activity was blocked by both pertussis toxin and rimonabant [M. Schenning, C.M. van Tiel, D. Van Manen, J.C. Stam, B.M. Gadella, K.W. Wirtz and G.T. Snoek, Phosphatidylinositol transfer protein alpha regulates growth and apoptosis of NIH3T3 cells: involvement of a cannabinoid 1-like receptor, J. Lipid Res. 45 (2004) 1555-1564]. The CB1 receptor appears to be expressed in mouse fibroblast cells, at levels in the order SPIalpha>wtNIH3T3>SPIbeta cells (i.e. wild type cells overexpressing PI-TPbeta). Upon incubation of SPIbeta cells with the PI-TPalpha-dependent anti-apoptotic factors, both the ERK/MAP kinase and the Akt/PKB pathway are activated in a CB1 receptor dependent manner as shown by Western blotting. In addition, activation of ERK2 was also shown by EYFP-ERK2 translocation to the nucleus, as visualized by confocal laser scanning microscopy. The subsequent activation of the anti-apoptotic transcription factor NF-kappaB is in line with the increased resistance towards UV-induced apoptosis. On the other hand, receptor activation by CM from SPIalpha cells was not linked to phospholipase C activation as the YFP-labelled C2-domain of protein kinase C was not translocated to the plasma membrane of SPIbeta cells as visualized by confocal laser scanning microscopy.

  4. Reactive oxygen species are key mediators of the nitric oxide apoptotic pathway in anterior pituitary cells.

    Science.gov (United States)

    Machiavelli, Leticia I; Poliandri, Ariel H; Quinteros, Fernanda A; Cabilla, Jimena P; Duvilanski, Beatriz H

    2007-03-01

    We previously showed that long-term exposure of anterior pituitary cells to nitric oxide (NO) induces apoptosis. The intracellular signals underlying this effect remained unclear. In this study, we searched for possible mechanisms involved in the early stages of the NO apoptotic cascade. Caspase 3 was activated by NO with no apparent disruption of mitochondrial membrane potential. NO caused a rapid increase of reactive oxygen species (ROS), and this increase seems to be dependent of mitochondrial electron transport chain. The antioxidant N-acetyl-cysteine avoided ROS increase, prevented the NO-induced caspase 3 activation, and reduced the NO apoptotic effect. Catalase was inactivated by NO, while glutathione peroxidase (GPx) activity and reduced glutathione (GSH) were not modified at first, but increased at later times of NO exposure. The increase of GSH level is important for the scavenging of the NO-induced ROS overproduction. Our results indicate that ROS have an essential role as a trigger of the NO apoptotic cascade in anterior pituitary cells. The permanent inhibition of catalase may strengthen the oxidative damage induced by NO. GPx activity and GSH level augment in response to the oxidative damage, though this increase seems not to be enough to rescue the cells from the NO effect.

  5. Involvement of caspase-12-dependent apoptotic pathway in ionic radiocontrast urografin-induced renal tubular cell injury

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Cheng Tien [Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Weng, Te I. [Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Chen, Li Ping [Department of Dentistry, Chang Gang Memorial Hospital, Chang Gang University, Taoyuan, Taiwan (China); Chiang, Chih Kang [Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (China); Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (China); Liu, Shing Hwa, E-mail: shinghwaliu@ntu.edu.tw [Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Department of Urology, National Taiwan University Hospital, Taipei, Taiwan (China)

    2013-01-01

    Contrast medium (CM) induces a direct toxic effect on renal tubular cells. This toxic effect subjects in the disorder of CM-induced nephropathy. Our previous work has demonstrated that CM shows to activate the endoplasmic reticulum (ER)-related adaptive unfolding protein response (UPR) activators. Glucose-regulated protein 78 (GRP78)/eukaryotic initiation factor 2α (eIF2α)-related pathways play a protective role during the urografin (an ionic CM)-induced renal tubular injury. However, the involvement of ER stress-related apoptotic signals in the urografin-induced renal tubular cell injury remains unclear. Here, we examined by the in vivo and in vitro experiments to explore whether ER stress-regulated pro-apoptotic activators participate in urografin-induced renal injury. Urografin induced renal tubular dilation, tubular cells detachment, and necrosis in the kidneys of rats. The tubular apoptosis, ER stress-related pro-apoptotic transcriptional factors, and kidney injury marker-1 (kim-1) were also conspicuously up-regulated in urografin-treated rats. Furthermore, treatment of normal rat kidney (NRK)-52E tubular cells with urografin augmented the expressions of activating transcription factor-6 (ATF-6), C/EBP homologous protein (CHOP), Bax, caspase-12, JNK, and inositol-requiring enzyme (IRE) 1 signals. Urografin-induced renal tubular cell apoptosis was not reversed by the inhibitors of ATF-6, JNK signals or CHOP siRNA transfection, but it could be partially reversed by the inhibitor of caspase-12. Taken together, the present results and our previous findings suggest that exposure of CM/urografin activates the ER stress-regulated survival- and apoptosis-related signaling pathways in renal tubular cells. Caspase-12-dependent apoptotic pathway may be partially involved in the urografin-induced nephropathy. -- Highlights: ► Ionic contrast medium-urografin induces renal tubular cell apoptosis. ► Urografin induces the ER stress-regulated survival and apoptosis

  6. Co-ordinate but disproportionate activation of apoptotic, regenerative and inflammatory pathways characterizes the liver response to acute amebic infection.

    Science.gov (United States)

    Pelosof, Lorraine C; Davis, Paul H; Zhang, Zhi; Zhang, Xiaochun; Stanley, Samuel L

    2006-03-01

    The liver has the remarkable ability to respond to injury with repair and regeneration. The protozoan parasite Entamoeba histolytica is the major cause of liver abscess worldwide. We report a transcriptional analysis of the response of mouse liver to E. histolytica infection, the first study looking at acute liver infection by a non-viral pathogen. Focusing on early time points, we identified 764 genes with altered transcriptional levels in amebic liver abscess. The response to infection is rapid and complex, with concurrent increased expression of genes linked to host defence through IL-1, TLR2, or interferon-induced pathways, liver regeneration via activation of IL-6 pathways, and genes associated with programmed cell death possibly through TNFalpha or Fas pathways. A comparison of amebic liver infection with the liver response to partial hepatectomy or toxins reveals striking similarities between amebic liver abscess and non-infectious injury in key components of the liver regeneration pathways. However, the response in amebic liver abscess is biased towards apoptosis when compared with acute liver injury from hepatectomy, toxins, or other forms of liver infection. E. histolytica infection of the liver simultaneously activates inflammatory, regenerative and apoptotic pathways, but the sum of these early responses is biased towards programmed cell death.

  7. In vitro assays for predicting tumor cell response to radiation by apoptotic pathways

    International Nuclear Information System (INIS)

    Algan, Oe.; Hanks, G.E.; Biade, S.; Chapman, J.D.

    1995-01-01

    Purpose: We had previously shown that the rate of spontaneous and radiation-induced apoptosis was significantly greater in well-differentiated compared to anaplastic Dunning prostate carcinomas. The goal of this study was to define the most useful assay for quantifying radiation-induced apoptotic cell death and to determine if measured rates of radiation-induced apoptosis in tumor cell populations can predict treatment outcome. Materials and Methods: The time course and extent of radiation-induced apoptosis after single doses of Cesium-137 gamma-rays were measured by five different assays. These included gross DNA degradation, nucleosome ladder formation, labeling of 3'-OH ends in DNA with an immunofluorescence probe, immunofluorescence vital stains (LIVE/DEAD[reg] EUKOLIGHT TM ) and trypan blue. The majority of these studies were performed with DU-145 human prostate cells. Data was analyzed to determine the component of cell inactivation resulting from apoptosis with the modified linear quadratic equation, -1n (SF) = (α a + α p ) D + β p D 2 , were α a represents cell inactivation by radiation-induced apoptosis, α p and β p represent cell death by proliferative mechanisms and D represents radiation dose. Results: These studies indicated that DU-145 cell death after radiation occurs over two distinct time periods. The first phase of death begins shortly after irradiation and plateaus within 16-24 hr. This process of cell death has properties consistent with apoptosis as determined by 3'-OH DNA end-labeling and nucleosome ladder assays. The second phase of cell death (determined by viability staining) begins approximately 48 hr after irradiation and continues until the remainder of inactivated cells express their death. This longer phase of cell inactivation probably represents proliferative cell death and other non-apoptotic mechanisms. The five different assays were performed on DU-145 cells 24 hr after irradiation with 10 Gy. Significant nucleosome ladders

  8. Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways.

    Science.gov (United States)

    Chong, Zhao Zhong; Maiese, Kenneth

    2008-08-01

    Focus upon therapeutic strategies that intersect between pathways that govern cellular metabolism and cellular survival may offer the greatest impact for the treatment of a number of neurodegenerative and metabolic disorders, such as diabetes mellitus. In this regard, we investigated the role of a Drosophila nicotinamidase (DN) in mammalian SH-SY5Y neuronal cells during oxidative stress. We demonstrate that during free radical exposure to nitric oxide generators DN neuronal expression significantly increased cell survival and blocked cellular membrane injury. Furthermore, DN neuronal expression prevented both apoptotic late DNA degradation and early phosphatidylserine exposure that may serve to modulate inflammatory cell activation in vivo. Nicotinamidase activity that limited nicotinamide cellular concentrations appeared to be necessary for DN neuroprotection, since application of progressive nicotinamide concentrations could abrogate the benefits of DN expression during oxidative stress. Pathways that involved sirtuin activation and SIRT1 were suggested to be vital, at least in part, for DN to confer protection through a series of studies. First, application of resveratrol increased cell survival during oxidative stress either alone or in conjunction with the expression of DN to a similar degree, suggesting that DN may rely upon SIRT1 activation to foster neuronal protection. Second, the overexpression of either SIRT1 or DN in neurons prevented apoptotic injury specifically in neurons expressing these proteins during oxidative stress, advancing the premise that DN and SIRT1 may employ similar pathways for neuronal protection. Third, inhibition of sirtuin activity with sirtinol was detrimental to neuronal survival during oxidative stress and prevented neuronal protection during overexpression of DN or SIRT1, further supporting that SIRT1 activity may be necessary for DN neuroprotection during oxidative stress. Implementation of further work to elucidate the

  9. Corn silk maysin induces apoptotic cell death in PC-3 prostate cancer cells via mitochondria-dependent pathway.

    Science.gov (United States)

    Lee, Jisun; Lee, Seul; Kim, Sun-Lim; Choi, Ji Won; Seo, Jeong Yeon; Choi, Doo Jin; Park, Yong Il

    2014-12-05

    Despite recent advances in prostate cancer diagnostics and therapeutics, the overall survival rate still remains low. This study was aimed to assess potential anti-cancer activity of maysin, a major flavonoid of corn silk (CS, Zea mays L.), in androgen-independent human prostate cancer cells (PC-3). Maysin was isolated from CS of Kwangpyeongok, a Korean hybrid corn, via methanol extraction and preparative C18 reverse phase column chromatography. Maysin cytotoxicity was determined by either monitoring cell viability in various cancer cell lines by MTT assay or morphological changes. Apoptotic cell death was assessed by annexin V-FITC/PI double staining, depolarization of mitochondrial membrane potential (MMP), expression levels of Bcl-2 and pro-caspase-3 and by terminal transferase mediated dUTP-fluorescein nick end labeling (TUNEL) staining. Underlying mechanism in maysin-induced apoptosis of PC-3 cells was explored by evaluating its effects on Akt and ERK pathway. Maysin dose-dependently reduced the PC-3 cell viability, with an 87% reduction at 200 μg/ml. Maysin treatment significantly induced apoptotic cell death, DNA fragmentation, depolarization of MMP, and reduction in Bcl-2 and pro-caspase-3 expression levels. Maysin also significantly attenuated phosphorylation of Akt and ERK. A combined treatment with maysin and other known anti-cancer agents, including 5-FU, etoposide, cisplatin, or camptothecin, synergistically enhanced PC-3 cell death. These results suggested for the first time that maysin inhibits the PC-3 cancer cell growth via stimulation of mitochondria-dependent apoptotic cell death and may have a strong therapeutic potential for the treatment of either chemo-resistant or androgen-independent human prostate cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Regulation of apoptotic pathways by Stylophora pistillata (Anthozoa, Pocilloporidae to survive thermal stress and bleaching.

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    Hagit Kvitt

    Full Text Available Elevated seawater temperatures are associated with coral bleaching events and related mortality. Nevertheless, some coral species are able to survive bleaching and recover. The apoptotic responses associated to this ability were studied over 3 years in the coral Stylophora pistillata from the Gulf of Eilat subjected to long term thermal stress. These include caspase activity and the expression profiles of the S. pistillata caspase and Bcl-2 genes (StyCasp and StyBcl-2-like cloned in this study. In corals exposed to thermal stress (32 or 34°C, caspase activity and the expression levels of the StyBcl-2-like gene increased over time (6-48 h and declined to basal levels within 72 h of thermal stress. Distinct transcript levels were obtained for the StyCasp gene, with stimulated expression from 6 to 48 h of 34°C thermal stress, coinciding with the onset of bleaching. Increased cell death was detected in situ only between 6 to 48 h of stress and was limited to the gastroderm. The bleached corals survived up to one month at 32°C, and recovered back symbionts when placed at 24°C. These results point to a two-stage response in corals that withstand thermal stress: (i the onset of apoptosis, accompanied by rapid activation of anti-oxidant/anti-apoptotic mediators that block the progression of apoptosis to other cells and (ii acclimatization of the coral to the chronic thermal stress alongside the completion of symbiosis breakdown. Accordingly, the coral's ability to rapidly curb apoptosis appears to be the most important trait affecting the coral's thermotolerance and survival.

  11. Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis.

    Science.gov (United States)

    Setia, Shruti; Sanyal, Sankar N

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor. The animals were divided into Control, DMBA, DMBA+ indomethacin and DMBA+ etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining. The occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while co-administration of NSAIDs along with DMBA led to the restoration of apoptosis. DMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin.

  12. E-Cigarette Vapor Induces an Apoptotic Response in Human Gingival Epithelial Cells Through the Caspase-3 Pathway.

    Science.gov (United States)

    Rouabhia, Mahmoud; Park, Hyun Jin; Semlali, Abdelhabib; Zakrzewski, Andrew; Chmielewski, Witold; Chakir, Jamila

    2017-06-01

    Electronic cigarettes represent an increasingly significant proportion of today's consumable tobacco products. E-cigarettes contain several chemicals which may promote oral diseases. The aim of this study was to investigate the effect of e-cigarette vapor on human gingival epithelial cells. Results show that e-cigarette vapor altered the morphology of cells from small cuboidal form to large undefined shapes. Both single and multiple exposures to e-cigarette vapor led to a bulky morphology with large faint nuclei and an enlarged cytoplasm. E-cigarette vapor also increased L-lactate dehydrogenase (LDH) activity in the targeted cells. This activity was greater with repeated exposures. Furthermore, e-cigarette vapor increased apoptotic/necrotic epithelial cell percentages compared to that observed in the control. Epithelial cell apoptosis was confirmed by TUNEL assay showing that exposure to e-cigarette vapor increased apoptotic cell numbers, particularly after two and three exposures. This negative effect involved the caspase-3 pathway, the activity of which was greater with repeated exposure and which decreased following the use of caspase-3 inhibitor. The adverse effects of e-cigarette vapor on gingival epithelial cells may lead to dysregulated gingival cell function and result in oral disease. J. Cell. Physiol. 232: 1539-1547, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Cordycepin enhances cisplatin apoptotic effect through caspase/MAPK pathways in human head and neck tumor cells

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    Chen YH

    2013-07-01

    -Jun NH2-terminal kinase, extracellular signal-regulated kinase, and p38 protein phosphorylations. Moreover, cordycepin plus cisplatin cotreatment significantly activated those proteins with much better effects among three cell lines. Conclusion: Cordycepin plus cisplatin have better apoptotic effect by activating caspase activation with possible MAPK pathway involvement in HNSCC cells. Keywords: cordycepin, cisplatin, apoptosis, caspase, MAPK, HNSCC

  14. Neuromodulatory Effect of Thymoquinone in Attenuating Glutamate-Mediated Neurotoxicity Targeting the Amyloidogenic and Apoptotic Pathways

    Directory of Open Access Journals (Sweden)

    Ibram Amin Fouad

    2018-04-01

    Full Text Available Overexposure of the glutamatergic N-methyl-d-aspartate (NMDA receptor to the excitatory neurotransmitter l-glutamic acid leads to neuronal cell death by excitotoxicity as a result of increased intracellular Ca2+, mitochondrial dysfunction, and apoptosis. Moreover, it was previously reported that prolonged activation of the NMDA receptor increased beta-amyloid (Aβ levels in the brain. Thymoquinone (TQ, the active constituent of Nigella sativa seeds, has been shown to have potent antioxidant and antiapoptotic effects. The aim of the present study was to explore the neuromodulatory effects of different doses of TQ (2.5 and 10 mg/kg against apoptotic cell death and Aβ formation resulting from glutamate administration in rats using vitamin E as a positive control. Behavioral changes were assessed using Y-maze and Morris water maze tests for evaluating spatial memory and cognitive functions. Caspase-3, Lactate dehydrogenase, Aβ-42, and cytochrome c gene expression were determined. TQ-treated groups showed significant decreases in the levels of all tested biochemical and behavioral parameters compared with the glutamate-treated group. These findings demonstrated that TQ has a promising neuroprotective activity against glutamate-induced neurotoxicity and this effect is mediated through its anti-amyloidogenic, antioxidant, and antiapoptotic activities.

  15. Ochratoxin A Inhibits Mouse Embryonic Development by Activating a Mitochondrion-Dependent Apoptotic Signaling Pathway

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    Yan-Der Hsuuw

    2013-01-01

    Full Text Available Ochratoxin A (OTA, a mycotoxin found in many foods worldwide, causes nephrotoxicity, hepatotoxicity, and immunotoxicity, both in vitro and in vivo. In the present study, we explored the cytotoxic effects exerted by OTA on the blastocyst stage of mouse embryos, on subsequent embryonic attachment, on outgrowth in vitro, and following in vivo implantation via embryo transfer. Mouse blastocysts were incubated with or without OTA (1, 5, or 10 μM for 24 h. Cell proliferation and growth were investigated using dual differential staining; apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL assay; and embryo implantation and post-implantation development were assessed by examination of in vitro growth and the outcome of in vivo embryo transfer, respectively. Blastocysts treated with 10 μM OTA displayed a significantly increased level of apoptosis and a reduction in total cell number. Interestingly, we observed no marked difference in implantation success rate between OTA-pretreated and control blastocysts either during in vitro embryonic development (following implantation in a fibronectin-coated culture dish or after in vivo embryo transfer. However, in vitro treatment with 10 μM OTA was associated with increased resorption of post-implantation embryos by the mouse uterus, and decreased fetal weight upon embryo transfer. Our results collectively indicate that in vitro exposure to OTA triggers apoptosis and retards early post-implantation development after transfer of embryos to host mice. In addition, OTA induces apoptosis-mediated injury of mouse blastocysts, via reactive oxygen species (ROS generation, and promotes mitochondrion-dependent apoptotic signaling processes that impair subsequent embryonic development.

  16. Opening up of plasmalemma type-1 VDAC to form apoptotic "find me signal" pathways is essential in early apoptosis - evidence from the pathogenesis of cystic fibrosis resulting from failure of apoptotic cell clearance followed by sterile inflammation.

    Science.gov (United States)

    Thinnes, Friedrich P

    2014-04-01

    Cell membrane-standing type-1 VDAC is involved in cell volume regulation and thus apoptosis. The channel has been shown to figure as a pathway for osmolytes of varying classes, ATP included. An early event in apoptotic cell death is the release of "find me signals" by cells that enter the apoptotic process. ATP is one of those signals. Apoptotic cells this way attract phagocytes for an immunologically silent cell clearance. Thus, whenever apoptosis fails by a blockade of plasmalemma type-1 VDAC processes of sterile inflammation must be assumed for cell elimination. This is evident from a close look on the pathogenetic process of cystic fibrosis (CF). However, in normal airway epithelia two different anion channels cooperate to guarantee an appropriate volume of airway surface liquid (ASL) necessary for surface clearing: the cystic fibrosis conductance regulator (CFTR) and the outwardly rectifying chloride channel (ORCC) complex also called "alternate chloride channel" and under the control of the CFTR. There are arguments, that type-1 VDAC forms the channel part of the ORCC complex, and it has been shown that CFTR and type-1 VDAC co-localize in the apical membranes of human surface respiratory epithelium. In cystic fibrosis, the central cAMP-dependent regulation of ion and water transport via functional CFTR is lost. Here, CFTR molecules do not reach the apical membranes of airway epithelia anymore or work in an insufficient way, respectively. In addition, type-1 VDAC is no longer available to work as a "find me signal" pathway. In consequence, clearing away of apoptotic cells is blocked. There are experimental data on the channel characteristics of type-1 VDAC under the anion channel blocker DIDS (4,4-diisothiocyanato-stilbenedisulphonic acid) that argue in favor of this hypothesis. Together, type-1 VDAC should be kept as a "find me signal" pathway, which may give way to several classes of such signals. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells

    International Nuclear Information System (INIS)

    Hayashi, Yoko; Kondo, Takashi; Zhao Qingli; Ogawa Ryohei; Cui Zhengguo; Feril, Loreto B.; Teranishi, Hidetoyo; Kasuya, Minoru

    2004-01-01

    It has been reported that the hexavalent chromium compound (Cr(VI)) can induce both p53-dependent and p53-independent apoptosis. While a considerable amount of information is available on the p53-dependent pathway, only little is known about the p53-independent pathway. To elucidate the p53-independent mechanism, the roles of the Ca 2+ -calpain- and mitochondria-caspase-dependent pathways in apoptosis induced by Cr(VI) were investigated. When human lymphoma U937 cells, p53 mutated cells, were treated with 20 μM Cr(VI) for 24 h, nuclear morphological changes and DNA fragmentation were observed. Production of hydroxyl radicals revealed by electron paramagnetic resonance (EPR)-spin trapping, and increase of intracellular calcium ion concentration monitored by digital imaging were also observed in Cr(VI)-treated cells. An intracellular Ca 2+ chelator, BAPTA-AM, and calpain inhibitors suppressed the Cr(VI)-induced DNA fragmentation. The number of cells showing low mitochondrial membrane potential (MMP), high level of superoxide anion radicals (O 2 - ), and high activity of caspase-3, which are indicators of mitochondria-caspase-dependent pathway, increased significantly in Cr(VI)-treated cells. An antioxidant, N-acetyl-L-cysteine (NAC), decreased DNA fragmentation and inhibited the changes in MMP, O 2 - formation, and activation of caspase-3 induced by Cr(VI). No increase of the expressions of Fas and phosphorylated JNK was observed after Cr(VI) treatment. Cell cycle analysis revealed that the fraction of G2/M phase tended to increase after 24 h of treatment, suggesting that Cr(VI)-induced apoptosis is related to the G2 block. These results indicate that Ca 2+ -calpain- and mitochondria-caspase-dependent pathways play significant roles in the Cr(VI)-induced apoptosis via the G2 block, which are independent of JNK and Fas activation. The inhibition of apoptosis and all its signal transductions by NAC suggests that intracellular reactive oxygen species (ROS) are

  18. The TAM-family receptor Mer mediates production of HGF through the RhoA-dependent pathway in response to apoptotic cells.

    Science.gov (United States)

    Park, Hyun-Jung; Baen, Ji-Yeon; Lee, Ye-Ji; Choi, Youn-Hee; Kang, Jihee Lee

    2012-08-01

    The TAM receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. We investigated the roles of the TAM receptors in mediating the induction of hepatocyte growth factor (HGF) during the interaction of macrophages with apoptotic cells. Mer-specific neutralizing antibody, small interfering RNA (siRNA), and a recombinant Mer protein (Mer/Fc) inhibited HGF mRNA and protein expression, as well as activation of RhoA, Akt, and specific mitogen-activated protein (MAP) kinases in response to apoptotic cells. Inhibition of Axl or Tyro3 with specific antibodies, siRNA, or Fc-fusion proteins did not prevent apoptotic cell-induced HGF mRNA and protein expression and did not inhibit activation of the postreceptor signaling molecules RhoA and certain MAP kinases, including extracellular signal-regulated protein kinase and c-Jun NH(2)-terminal kinase. However, Axl- and Tyro3-specific blockers did inhibit the activation of Akt and p38 MAP kinase in response to apoptotic cells. In addition, none of the TAM receptors mediated the effects of apoptotic cells on transforming growth factor-β or epidermal growth factor mRNA expression. However, they were involved in the induction of vascular endothelial growth factor mRNA expression. Our data provide evidence that when macrophages interact with apoptotic cells, only Mer of the TAM-family receptors is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway.

  19. Research advances in sorafenib-induced apoptotic signaling pathways in liver cancer cells

    Directory of Open Access Journals (Sweden)

    ZHANG Chaoya

    2016-04-01

    Full Text Available Currently, sorafenib is the multi-target inhibitor for the treatment of advanced primary liver cancer, and can effectively prolong the progression-free survival and overall survival in patients with advanced primary liver cancer. The application of sorafenib in the targeted therapy for liver cancer has become a hot topic. Major targets or signaling pathways include Raf/Mek/Erk, Jak/Stat, PI3K/Akt/mTOR, VEGFR and PDGFR, STAT, microRNA, Wnt/β-catenin, autolysosome, and tumor-related proteins, and sorafenib can regulate the proliferation, differentiation, metastasis, and apoptosis of liver cancer cells through these targets. This article reviews the current research on the action of sorafenib on these targets or signaling pathways to provide useful references for further clinical research on sorafenib.

  20. The ER stress-mediated mitochondrial apoptotic pathway and MAPKs modulate tachypacing-induced apoptosis in HL-1 atrial myocytes.

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    Jiaojiao Shi

    Full Text Available Cell apoptosis is a contributing factor in the initiation, progression and relapse of atrial fibrillation (AF, a life-threatening illness accompanied with stroke and heart failure. However, the regulatory cascade of apoptosis is intricate and remains unidentified, especially in the setting of AF. The aim of this study was to explore the roles of endoplasmic reticulum (ER stress, mitochondrial apoptotic pathway (MAP, mitogen-activated protein kinases (MAPKs, and their cross-talking in tachypacing-induced apoptosis.HL-1 cells were cultured in the presence of tachypacing for 24 h to simulate atrial tachycardia remodeling. Results showed that tachypacing reduced cell viability measured by the cell counting kit-8, dissipated mitochondrial membrane potential detected by JC-1 staining and resulted in approximately 50% apoptosis examined by Hoechst staining and annexin V/propidium iodide staining. In addition, the proteins involved in ER stress, MAP and MAPKs were universally up-regulated or activated via phosphorylation, as confirmed by western blotting; and reversely silencing of ER stress, caspase-3 (the ultimate executor of MAP and MAPKs with specific inhibitors prior to pacing partially alleviated apoptosis. An inhibitor of ER stress was applied to further investigate the responses of mitochondria and MAPKs to ER stress, and results indicated that suppression of ER stress comprehensively but incompletely attenuated the activation of MAP and MAPKs aroused by tachypacing, with the exception of ERK1/2, one branch of MAPKs.Our study suggested tachypacing-induced apoptosis is regulated by ER stress-mediated MAP and MAPKs. Thus, the above three components are all promising anti-apoptotic targets in AF patients and ER stress appears to play a dominant role due to its comprehensive effects.

  1. Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway.

    Science.gov (United States)

    Hodroj, Mohammad Hassan; Jardaly, Achraf; Abi Raad, Sarah; Zouein, Annalise; Rizk, Sandra

    2018-01-01

    Topotecan (TP) is an anticancer drug acting as topoisomerase I inhibitor that is used in the treatment of many types of cancers including leukemia, but it has significant side effects. Andrographolide, a compound extracted from Andrographis paniculata , was recently proven to inhibit the growth of cancer cells and can induce apoptosis. The aim of this study is to investigate the possible synergism between TP and andrographolide in acute myeloid cells in vitro. U937 acute myeloid leukemic cells were cultured using Roswell Park Memorial Institute (RPMI) medium and then treated for 24 h with TP and andrographolide prepared through the dilution of dimethyl sulfoxide (DMSO) stocks with RPMI on the day of treatment. Cell proliferation was assessed using cell proliferation assay upon treatment with both compounds separately and in combination. Cell-cycle study and apoptosis detection were performed by staining the cells with propidium iodide (PI) stain and Annexin V/PI stain, respectively, followed by flow cytometry analysis. Western blotting was used to assess the expression of various proteins involved in apoptotic pathways. Both TP and andrographolide showed an antiproliferative effect in a dose-dependent manner when applied on U937 cells separately; however, pretreating the cells with andrographolide before applying TP exhibited a synergistic effect with lower inhibitory concentrations (half-maximal inhibitory concentration). Treating the cells with TP alone led to specific cell-cycle arrest at S phase that was more prominent upon pretreatment combination with andrographolide. Using Annexin V/PI staining to assess the proapoptotic effect following the pretreatment combination showed an increase in the number of apoptotic cells, which was supported by the Western blot results that manifested an upregulation of several proapoptotic proteins expression. The pretreatment of U937 with andrographolide followed by low doses of TP showed an enhancement in inducing apoptosis

  2. Regional imbalanced activation of the calcineurin/BAD apoptotic pathway and the PI3K/Akt survival pathway after myocardial infarction.

    Science.gov (United States)

    Li, Tieluo; Kilic, Ahmet; Wei, Xufeng; Wu, Changfu; Schwartzbauer, Gary; Yankey, G Kwame; DeFilippi, Christopher; Bond, Meredith; Wu, Zhongjun J; Griffith, Bartley P

    2013-06-05

    The underlying molecular mechanisms of the remodeling after myocardial infarction (MI) remain unclear. The purpose of this study was to investigate the role of a survival pathway (PI3K/Akt) and an apoptosis pathway (calcineurin/BAD) in the remodeling after MI in a large animal model. Ten Dorset hybrid sheep underwent 25% MI in the left ventricle (LV, n=10). Five sheep were used as sham control. The regional strain was calculated from sonomicrometry. Apoptosis and the activation of the PI3K/Akt and calcineurin/BAD pathways were evaluated in the non-ischemic adjacent zone and the remote zone relative to infarct by immunoblotting, immunoprecipitation, and immunofluorescence staining. Dilation and dysfunction of LV were present at 12 weeks after MI. The regional strain in the adjacent zone was significantly higher than in the remote zone at 12 weeks (36.6 ± 4.0% vs 9.5 ± 3.6%, pBAD pathways were activated in the adjacent zone. Dephosphorylation and translocation of BAD were evident in the adjacent zone. Regional correlation between the strain and the expression of calcineurin/BAD indicated that the activation was strain-related (R(2)=0.46, 0.48, 0.39 for calcineurin, BAD, mitochondrial BAD, respectively, pBAD apoptotic pathways were concomitantly activated in the non-ischemic adjacent zone after MI. The calcineurin/BAD pathway is strain related and its imbalanced activation may be one of the causes of progressive remodeling after MI. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  3. Trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine induces lipid peroxidation-associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first-trimester placental cell line.

    Science.gov (United States)

    Elkin, Elana R; Harris, Sean M; Loch-Caruso, Rita

    2018-01-01

    Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l-cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast cell line, HTR-8/SVneo. We exposed the cells in vitro to 10-100μM DCVC for various time points up to 24h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p<0.05). DCVC also significantly stimulated caspase 3, 7, 8 and 9 activities after 12h (p<0.05), suggesting that DCVC stimulates the activation of both the intrinsic and extrinsic apoptotic signaling pathways simultaneously. Pre-treatment with the tBID inhibitor Bl-6C9 partially reduced DCVC-stimulated caspase 3 and 7 activity, signifying crosstalk between the two pathways. Additionally, DCVC treatment increased lipid peroxidation in a concentration-dependent manner. Co-treatment with the antioxidant peroxyl radical scavenger (±)-α-tocopherol attenuated caspase 3 and 7 activity, suggesting that lipid peroxidation mediates DCVC-induced apoptosis in extravillous trophoblasts. Our findings suggest that DCVC-induced apoptosis and lipid peroxidation in extravillous trophoblasts could contribute to poor placentation if similar effects occur in vivo in response to TCE exposure, indicating that further studies into this mechanism are warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Inflammatory and apoptotic signalling pathways and concussion severity: a genetic association study.

    Science.gov (United States)

    Mc Fie, Sarah; Abrahams, Shameemah; Patricios, Jon; Suter, Jason; Posthumus, Michael; September, Alison V

    2018-03-06

    The objective was to investigate the relationship between IL-1B rs16944, IL-6 rs1800795, and CASP8 rs3834129 genetic polymorphisms and concussion severity. Rugby players from high school, senior amateur, and professional teams completed a concussion severity questionnaire and donated a DNA sample. Participants (n = 163) were split into symptom severity groups around the median number and duration of symptoms. The frequency of participants with high symptom counts (more than five symptoms) increased across the IL-1B (C/C: 35%; C/T: 51%; T/T: 56%; P = 0.047) and the IL-6 (C/C: 31%; C/G: 44%; G/G: 58%; P = 0.027) genotypes. The C-C inferred interleukin allele construct frequency, created from combining the IL-1B and IL-6 genotype data, was lower in participants reporting a high symptom count (18%), compared to those with a low symptom count (fewer than six symptoms, 36%, P = 0.002). Similarly, the C-C inferred interleukin allele construct frequency was lower in those reporting prolonged symptom duration (more than one week, 16%), as opposed to short symptom duration (less than one week, 34%, P = 0.015). This study provides evidence of novel inflammatory pathway genetic associations with concussion severity, which supports the hypothesis implicating neuroinflammation in the development of concussion symptoms.

  5. Activation of apoptotic pathway in normal, cancer ovarian cells by epothilone B.

    Science.gov (United States)

    Rogalska, Aneta; Szula, Ewa; Gajek, Arkadiusz; Marczak, Agnieszka; Jóźwiak, Zofia

    2013-09-01

    The epothilones, a new class of microtubule-targeting agents, seem to be a very promising alternative to the current strategy of cancer treatment. We have analyzed the aspects of epothilone B (Epo B) on cellular metabolism of tumor (OV-90) and normal (MM 14) ovarian cells. The observed effects were compared with those of paclitaxel (PTX), which is now a standard for the treatment of ovarian cancer. The results provide direct evidence that Epo B is considerably more cytotoxic to human OV-90 ovarian cancer cells than PTX. We have found, that antitumor efficacy of this new drug is related to its apoptosis-inducing ability, which was confirmed during measurements typical markers of the process. Epo B induced changes in morphology of cells, mitochondrial membrane potential and cytochrome c release. Also a slight increase of the intracellular calcium level was observed. Moreover, we have found that ROS production, stimulated by Epo B, is directly involved in the induction of apoptosis via mitochondrial pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Evaluation of the neuronal apoptotic pathways involved in cytoskeletal disruption-induced apoptosis.

    Science.gov (United States)

    Jordà, Elvira G; Verdaguer, Ester; Jimenez, Andrés; Arriba, S Garcia de; Allgaier, Clemens; Pallàs, Mercè; Camins, Antoni

    2005-08-01

    The cytoskeleton is critical to neuronal functioning and survival. Cytoskeletal alterations are involved in several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. We studied the possible pathways involved in colchicine-induced apoptosis in cerebellar granule neurons (CGNs). Although colchicine evoked an increase in caspase-3, caspase-6 and caspase-9 activation, selective caspase inhibitors did not attenuate apoptosis. Inhibitors of other cysteine proteases such as PD150606 (a calpain-specific inhibitor), Z-Phe-Ala fluoromethyl ketone (a cathepsins-inhibitors) and N(alpha)-p-tosyl-l-lysine chloromethyl ketone (serine-proteases inhibitor) also had no effect on cell death/apoptosis induced by colchicine. However, BAPTA-AM 10 microM (intracellular calcium chelator) prevented apoptosis mediated by cytoskeletal alteration. These data indicate that calcium modulates colchicine-induced apoptosis in CGNs. PARP-1 inhibitors did not prevent apoptosis mediated by colchicine. Finally, colchicine-induced apoptosis in CGNs was attenuated by kenpaullone, a cdk5 inhibitor. Kenpaullone and indirubin also prevented cdk5/p25 activation mediated by colchicine. These findings indicate that cytoskeletal alteration can compromise cdk5 activation, regulating p25 formation and suggest that cdk5 inhibitors attenuate apoptosis mediated by cytoskeletal alteration. The present data indicate the potential therapeutic value of drugs that prevent the formation of p25 for the treatment of neurodegenerative disorders.

  7. HSP27 Inhibits Homocysteine-Induced Endothelial Apoptosis by Modulation of ROS Production and Mitochondrial Caspase-Dependent Apoptotic Pathway

    Directory of Open Access Journals (Sweden)

    Xin Tian

    2016-01-01

    Full Text Available Objectives. Elevated plasma homocysteine (Hcy could lead to endothelial dysfunction and is viewed as an independent risk factor for atherosclerosis. Heat shock protein 27 (HSP27, a small heat shock protein, is reported to exert protective effect against atherosclerosis. This study aims to investigate the protective effect of HSP27 against Hcy-induced endothelial cell apoptosis in human umbilical vein endothelial cells (HUVECs and to determine the underlying mechanisms. Methods. Apoptosis, reactive oxygen species (ROS, and mitochondrial membrane potential (MMP of normal or HSP27-overexpressing HUVECs in the presence of Hcy were analyzed by flow cytometry. The mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR and western blot. Results. We found that Hcy could induce cell apoptosis with corresponding decrease of nitric oxide (NO level, increase of endothelin-1 (ET-1, intracellular adhesion molecule-1 (ICAM-1, vascular cellular adhesion molecule-1 (VCAM-1, and monocyte chemoattractant protein-1 (MCP-1 levels, elevation of ROS, and dissipation of MMP. In addition, HSP27 could protect the cell against Hcy-induced apoptosis and inhibit the effect of Hcy on HUVECs. Furthermore, HSP27 could increase the ratio of Bcl-2/Bax and inhibit caspase-3 activity. Conclusions. Therefore, we concluded that HSP27 played a protective role against Hcy-induced endothelial apoptosis through modulation of ROS production and the mitochondrial caspase-dependent apoptotic pathway.

  8. Non-thermal plasma induces mitochondria-mediated apoptotic signaling pathway via ROS generation in HeLa cells.

    Science.gov (United States)

    Li, Wei; Yu, K N; Ma, Jie; Shen, Jie; Cheng, Cheng; Zhou, Fangjian; Cai, Zhiming; Han, Wei

    2017-11-01

    Non-thermal plasma (NTP) has been proposed as a novel therapeutic method for anticancer treatment. Although increasing evidence suggests that NTP selectively induces apoptosis in some types of tumor cells, the molecular mechanisms underlying this phenomenon remain unclear. In this study, we further investigated possible molecular mechanisms for NTP-induced apoptosis of HeLa cells. The results showed that NTP exposure significantly inhibited the growth and viability of HeLa cells. Morphological observation and flow cytometry analysis demonstrated that NTP exposure induced HeLa cell apoptosis. NTP exposure also activated caspase-9 and caspase-3, which subsequently cleaved poly (ADP- ribose) polymerase. Furthermore, NTP exposure suppressed Bcl-2 expression, enhanced Bax expression and translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, followed by the release of cytochrome c. Further studies showed that NTP treatment led to ROS generation, whereas blockade of ROS generation by N-acetyl-l-cysteine (NAC, ROS scavengers) significantly prevented NTP-induced mitochondrial alteration and subsequent apoptosis of HeLa cells via suppressing Bax translocation, cytochrome c and caspase-3 activation. Taken together, our results indicated that NTP exposure induced mitochondria-mediated intrinsic apoptosis of HeLa cells was activated by ROS generation. These findings provide insights to the therapeutic potential and clinical research of NTP as a novel tool in cervical cancer treatment. Copyright © 2017. Published by Elsevier Inc.

  9. The anti-apoptotic activity associated with phosphatidylinositol transfer protein α activates the MAPK and Akt/PKB pathway

    NARCIS (Netherlands)

    Schenning, M.; Goedhart, J.; Gadella (jr.), T.W.J.; Avram, D.; Wirtz, K.W.A.; Snoek, G.T.

    2008-01-01

    The conditioned medium (CM) from mouse NIH3T3 fibroblast cells overexpressing phosphatidylinositol transfer protein α (PI-TPα; SPIα cells) demonstrates an increased anti-apoptotic activity compared with CM from wild type NIH3T3 (wtNIH3T3) cells. As previously shown, the anti-apoptotic activity acts

  10. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Science.gov (United States)

    Saha, Manujendra N; Jiang, Hua; Yang, Yijun; Zhu, Xiaoyun; Wang, Xiaoming; Schimmer, Aaron D; Qiu, Lugui; Chang, Hong

    2012-01-01

    The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK

  11. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Manujendra N Saha

    Full Text Available The low frequency of p53 alterations e.g., mutations/deletions (∼10% in multiple myeloma (MM makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP analysis showed that activated c-Jun binds to the activator protein-1 (AP-1 binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with

  12. FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway

    International Nuclear Information System (INIS)

    Ma, Gui-Fen; Chen, Shi-Yao; Sun, Zhi-Rong; Miao, Qing; Liu, Yi-Mei; Zeng, Xiao-Qing; Luo, Tian-Cheng; Ma, Li-Li; Lian, Jing-Jing; Song, Dong-Li

    2013-01-01

    Highlights: ► The article revealed FoxP3 gene function in gastric cancer firstly. ► Present the novel roles of FoxP3 in inhibiting proliferation and promoting apoptosis in gastric cancer cells. ► Overexpression of FoxP3 increased proapoptotic molecules and repressed antiapoptotic molecules. ► Silencing of FoxP3 reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. ► FoxP3 is sufficient for activating the apoptotic signaling pathway. -- Abstract: Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis in GC cells by regulating apoptotic signaling, which could be a promising therapeutic approach for gastric cancer.

  13. FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Gui-Fen [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Shi-Yao, E-mail: shiyao_chen@163.com [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai (China); Sun, Zhi-Rong [Department of Anesthesiology, Cancer Center, Fudan University, Shanghai (China); Miao, Qing; Liu, Yi-Mei; Zeng, Xiao-Qing; Luo, Tian-Cheng [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Ma, Li-Li; Lian, Jing-Jing [Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai (China); Song, Dong-Li [Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer The article revealed FoxP3 gene function in gastric cancer firstly. Black-Right-Pointing-Pointer Present the novel roles of FoxP3 in inhibiting proliferation and promoting apoptosis in gastric cancer cells. Black-Right-Pointing-Pointer Overexpression of FoxP3 increased proapoptotic molecules and repressed antiapoptotic molecules. Black-Right-Pointing-Pointer Silencing of FoxP3 reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Black-Right-Pointing-Pointer FoxP3 is sufficient for activating the apoptotic signaling pathway. -- Abstract: Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis

  14. Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway

    Directory of Open Access Journals (Sweden)

    Hodroj MH

    2018-05-01

    Full Text Available Mohammad Hassan Hodroj, Achraf Jardaly, Sarah Abi Raad, Annalise Zouein, Sandra Rizk Department of Natural Sciences, Lebanese American University, Beirut, Lebanon Background: Topotecan (TP is an anticancer drug acting as topoisomerase I inhibitor that is used in the treatment of many types of cancers including leukemia, but it has significant side effects. Andrographolide, a compound extracted from Andrographis paniculata, was recently proven to inhibit the growth of cancer cells and can induce apoptosis. The aim of this study is to investigate the possible synergism between TP and andrographolide in acute myeloid cells in vitro. Materials and methods: U937 acute myeloid leukemic cells were cultured using Roswell Park Memorial Institute (RPMI medium and then treated for 24 h with TP and andrographolide prepared through the dilution of dimethyl sulfoxide (DMSO stocks with RPMI on the day of treatment. Cell proliferation was assessed using cell proliferation assay upon treatment with both compounds separately and in combination. Cell-cycle study and apoptosis detection were performed by staining the cells with propidium iodide (PI stain and Annexin V/PI stain, respectively, followed by flow cytometry analysis. Western blotting was used to assess the expression of various proteins involved in apoptotic pathways. Results: Both TP and andrographolide showed an antiproliferative effect in a dose-dependent manner when applied on U937 cells separately; however, pretreating the cells with andrographolide before applying TP exhibited a synergistic effect with lower inhibitory concentrations (half-maximal inhibitory concentration. Treating the cells with TP alone led to specific cell-cycle arrest at S phase that was more prominent upon pretreatment combination with andrographolide. Using Annexin V/PI staining to assess the proapoptotic effect following the pretreatment combination showed an increase in the number of apoptotic cells, which was supported by

  15. Anti-apoptotic effect of heat shock protein 90 on hypoxia-mediated cardiomyocyte damage is mediated via the phosphatidylinositol 3-kinase/AKT pathway.

    Science.gov (United States)

    Wang, Wei; Peng, Yizhi; Wang, Yuanyuan; Zhao, Xiaohui; Yuan, Zhiqiang

    2009-09-01

    1. Hypoxia-induced cardiomyocyte apoptosis contributes significantly to cardiac dysfunction following trauma, shock and burn injury. There is evidence that heat shock protein (HSP) 90 is anti-apoptotic in cardiomyocytes subjected to a variety of apoptotic stimuli. Because HSP90 acts as an upstream regulator of the serine/threonine protein kinase Akt survival pathway during cellular stress, we hypothesized that HSP90 exerts a cardioprotective effect via the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. 2. Neonatal rat cardiomyocytes were subjected to normoxia or hypoxia in the absence or presence of the HSP90 inhibitor geldanamycin (1 μg/mL). Cardiomyocyte apoptosis was assessed by release of lactate dehydrogenase (LDH), terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining and caspase 3 activity. Expression of HSP90, Akt, Bad and cytochrome c release was determined by western blot analysis. 3. Following exposure of cells to hypoxia, HSP90 was markedly elevated in a time-dependent manner, reaching a peak at 6 h (eightfold increase). Geldanamycin significantly increased hypoxia-induced release of LDH by 114%, the percentage of apoptotic cardiomyocytes by 102% and caspase 3 activity by 78%. Pretreatment of cells with geldanamycin also suppressed phosphorylation of both Akt and its downstream target Bad, but promoted the mitochondrial release of cytochrome c. 4. In conclusion, HSP90 activity is enhanced in cardiomyocytes following hypoxic insult. The anti-apoptotic effect of HSP90 on cardiomyocytes subjected to hypoxia is mediated, at least in part, by the PI3-K/Akt pathway. Key words: apoptosis, cardiomyocyte, heart failure, heat shock protein 90, hypoxia, phosphatidylinositol 3-kinase/Akt signalling pathway, serine/threonine protein kinase Akt.

  16. Extrinsic morphology of graphene

    International Nuclear Information System (INIS)

    Li, Teng

    2011-01-01

    Graphene is intrinsically non-flat and corrugates randomly. Since the corrugating physics of atomically thin graphene is strongly tied to its electronics properties, randomly corrugating morphology of graphene poses a significant challenge to its application in nanoelectronic devices for which precise (digital) control is the key. Recent studies revealed that the morphology of substrate-supported graphene is regulated by the graphene–substrate interaction, thus is distinct from the random intrinsic morphology of freestanding graphene. The regulated extrinsic morphology of graphene sheds light on new pathways to fine tune the properties of graphene. To guide further research to explore these fertile opportunities, this paper reviews recent progress on modeling and experimental studies of the extrinsic morphology of graphene under a wide range of external regulation, including two-dimensional and one-dimensional substrate surface features and one-dimensional and zero-dimensional nanoscale scaffolds (e.g. nanowires and nanoparticles)

  17. Isoegomaketone induces apoptosis in SK-MEL-2 human melanoma cells through mitochondrial apoptotic pathway via activating the PI3K/Akt pathway.

    Science.gov (United States)

    Kwon, Soon-Jae; Lee, Ju-Hye; Moon, Kwang-Deog; Jeong, Il-Yun; Yee, Sung-Tae; Lee, Mi-Kyung; Seo, Kwon-Il

    2014-11-01

    Isoegomaketone (IK) is a major biologically active component of Perilla frutescens. In this study, we investigated the contribution of reactive oxygen species (ROS) to IK-induced apoptosis in human melanoma SK-MEL-2 cells. We found that IK inhibited the proliferation of SK-MEL-2 human melanoma cells in a dose-dependent manner. IK also induced sub-G1 DNA accumulation, formation of apoptotic bodies, nuclear condensation, and a DNA ladder in SK-MEL-2 cells. IK also induced activation of caspase-3 and -9, whereas caspase‑8 was unaffected. Further, N-acetyl-L-cysteine (NAC, ROS scavenger) treatment to SK-MEL-2 cells significantly reduced IK-induced cell death. Pretreatment of NAC to SK-MEL-2 cells followed by 100 µM IK reduced the protein levels of Bax and cytochrome c as well as PARP cleavage, whereas the protein level of Bcl-2 increased. Moreover, IK inhibited the phosphorylation of AKT/mTOR protein and cell proliferation induced by LY294002, a PI3K inhibitor. In conclusion, IK-induced ROS generation regulates cell growth inhibition and it induces apoptosis through caspase‑dependent and -independent pathways via modulation of PI3K/AKT signaling in SK-MEL-2 cells.

  18. Phenethyl Isothiocyanate Induces Apoptotic Cell Death Through the Mitochondria-dependent Pathway in Gefitinib-resistant NCI-H460 Human Lung Cancer Cells In Vitro.

    Science.gov (United States)

    Hsia, Te-Chun; Huang, Yi-Ping; Jiang, Yi-Wen; Chen, Hsin-Yu; Cheng, Zheng-Yu; Hsiao, Yung-Ting; Chen, Cheng-Yen; Peng, Shu-Fen; Chueh, Fu-Shin; Chou, Yu-Cheng; Chung, Jing-Gung

    2018-04-01

    Some lung cancer patients treated with gefitinib develop resistance to this drug resulting in unsatisfactory treatment outcomes. Phenethyl isothiocyanate (PEITC), present in our common cruciferous vegetables, exhibits anticancer activities in many human cancer cell lines. Currently, there is no available information on the possible modification of gefitinib resistance of lung cancer in vitro by PEITC. Thus, the effects of PEITC on gefitinib resistant lung cancer NCI-H460 cells were investigated in vitro. The total cell viability, apoptotic cell death, production of reactive oxygen species (ROS) and Ca 2+ , levels of mitochondria membrane potential (ΔΨ m ) and caspase-3, -8 and -9 activities were measured by flow cytometry assay. PEITC induced chromatin condensation was examined by DAPI staining. PEITC-induced cell morphological changes, decreased total viable cell number and induced apoptotic cell death in NCI-H460 and NCI-H460/G cells. PEITC decreased ROS production in NCI-H460 cells, but increased production in NCI-H460/G cells. PEITC increased Ca 2+ production, decreased the levels of ΔΨ m and increased caspase-3, -8 and -9 activities in both NCI-H460 and NCI-H460/G cells. Western blotting was used to examine the effect of apoptotic cell death associated protein expression in NCI-H460 NCI-H460/G cells after exposure to PEITC. Results showed that PEITC increased expression of cleaved caspase-3, PARP, GADD153, Endo G and pro-apoptotic protein Bax in NCI-H460/G cells. Based on these results, we suggest that PEITC induces apoptotic cell death via the caspase- and mitochondria-dependent pathway in NCI-H460/G cells. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway

    International Nuclear Information System (INIS)

    Ramanathan, Mathura P.; Chambers, Jerome A.; Pankhong, Panyupa; Chattergoon, Michael; Attatippaholkun, Watcharee; Dang, Kesen; Shah, Neelima; Weiner, David B.

    2006-01-01

    The West Nile Virus (WNV) non-structural proteins 2B and 3 (NS2B-NS3) constitute the proteolytic complex that mediates the cleavage and processing of the viral polyprotein. NS3 recruits NS2B and NS5 proteins to direct protease and replication activities. In an effort to investigate the biology of the viral protease, we cloned cDNA encoding the NS2B-NS3 proteolytic complex from brain tissue of a WNV-infected dead crow, collected from the Lower Merion area (Merion strain). Expression of the NS2B-NS3 gene cassette induced apoptosis within 48 h of transfection. Electron microscopic analysis of NS2B-NS3-transfected cells revealed ultra-structural changes that are typical of apoptotic cells including membrane blebbing, nuclear disintegration and cytoplasmic vacuolations. The role of NS3 or NS2B in contributing to host cell apoptosis was examined. NS3 alone triggers the apoptotic pathways involving caspases-8 and -3. Experimental results from the use of caspase-specific inhibitors and caspase-8 siRNA demonstrated that the activation of caspase-8 was essential to initiate apoptotic signaling in NS3-expressing cells. Downstream of caspase-3 activation, we observed nuclear membrane ruptures and cleavage of the DNA-repair enzyme, PARP in NS3-expressing cells. Nuclear herniations due to NS3 expression were absent in the cells treated with a caspase-3 inhibitor. Expression of protease and helicase domains themselves was sufficient to trigger apoptosis generating insight into the apoptotic pathways triggered by NS3 from WNV

  20. Multi-level disruption of the extrinsic apoptotic pathway mediates resistance of leukemia cells to TNF-related apoptosis-inducing ligand (TRAIL)

    Czech Academy of Sciences Publication Activity Database

    Leahomschi, S.; Molinsky, J.; Klánová, M.; Anděra, Ladislav; Peterka, Martin; Gasova, Z.; Klener, P.; Trněný, M.; Nečas, E.; Simonova, T.; Živný, J.; Klener, P.Jr.

    2013-01-01

    Roč. 60, č. 2 (2013), s. 223-231 ISSN 0028-2685 Institutional support: RVO:68378050 Keywords : leukemia * drug-resistance * TRAIL * apoptosis * BCL2 family Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.642, year: 2013

  1. Expression of Fas, FasL, caspase-8 and other factors of the extrinsic apoptotic pathway during the onset of interdigital tissue elimination

    Czech Academy of Sciences Publication Activity Database

    Budišová Švandová, Eva; Veselá, Barbora; Lesot, Hervé; Poliard, A.; Matalová, Eva

    2017-01-01

    Roč. 147, č. 4 (2017), s. 497-510 ISSN 0948-6143 Institutional support: RVO:67985904 Keywords : interdigital * forelimb development * apoptosis Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Developmental biology Impact factor: 2.553, year: 2016

  2. Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways.

    Science.gov (United States)

    Haverkamp, Jessica M; Smith, Amber M; Weinlich, Ricardo; Dillon, Christopher P; Qualls, Joseph E; Neale, Geoffrey; Koss, Brian; Kim, Young; Bronte, Vincenzo; Herold, Marco J; Green, Douglas R; Opferman, Joseph T; Murray, Peter J

    2014-12-18

    Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Cytotoxic effect of γ-sitosterol from Kejibeling (Strobilanthes crispus and its mechanism of action towards c-myc gene expression and apoptotic pathway

    Directory of Open Access Journals (Sweden)

    Susi Endrini

    2015-01-01

    Full Text Available Background: This study aimed to analyze the cytotoxicity effect of γ-sitosterol isolated from “Kejibeling” (Strobilanthes crispus, a medicinal plant, on several cancer cell lines. The mechanisms of the effects were studied through the expression of cancer-caused gene, c-myc and apoptotic pathways.Methods: This in vitro study was done using human colon cancer cell lines (Caco-2, liver cancer cell lines (HepG2, hormone-dependent breast cancer cell lines (MCF-7 and the normal liver cell lines (Chang Liver. The cytotoxic effect was measured through MTT assay and the potential cytotoxic value was calculated by determining the toxic concentration which may kill up to 50% of the total cell used (IC50. Meanwhile, the cytotoxic mechanism was studied by determining the effect of adding γ-sitosterol to the c-myc gene expression by reverse transciptase-polymerase chain reaction (RT-PCR. The effect of γ-sitosterol through apoptotic pathway was studied by using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assay.Results: γ-sitosterol was cytotoxic against Caco-2, HepG2, and MCF-7 with IC50-values of 8.3, 21.8, and 28.8 μg/mL, respectively. There were no IC50-values obtained from this compound against Chang Liver cell line. This compound induced apotosis on Caco-2 and HepG2 cell lines and suppressed the c-myc genes expression in both cells.Conclusion: γ-sitosterol was cytotoxic against colon and liver cancer cell lines and the effect was mediated by down-regulation of c-myc expression and induction of the apoptotic pathways.

  4. Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

    International Nuclear Information System (INIS)

    Song, Shasha; Wang, Shuang; Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin; Zhu, Daling

    2013-01-01

    Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway

  5. Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Song, Shasha [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Wang, Shuang [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China); Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Zhu, Daling, E-mail: dalingz@yahoo.com [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China)

    2013-08-01

    Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway.

  6. Wnt1 Neuroprotection Translates into Improved Neurological Function during Oxidant Stress and Cerebral Ischemia Through AKT1 and Mitochondrial Apoptotic Pathways

    Directory of Open Access Journals (Sweden)

    Zhao Zhong Chong

    2010-01-01

    Full Text Available Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression of Wnt1 or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress.

  7. Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS-mediated mitochondrial and p53-related apoptotic pathways

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Chun-Yu [Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Shen, Chao-Yu [School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan (China); Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan (China); School of Medicine, Chung Shan Medical University, Taichung, Taiwan (China); Kang, Chao-Kai [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, (China); Sher, Yuh-Pyng [Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (China); Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan (China); Sheu, Wayne H.-H. [Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan (China); School of Medicine, National Yang Ming University, Taipei, Taiwan (China); School of Medicine, National Defense Medical Center, Taipei, Taiwan (China); Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw [Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan (China); Lee, Tsung-Han, E-mail: thlee@email.nchu.edu.tw [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, (China); Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan (China); Department of Biological Science and Technology, China Medical University, Taichung, Taiwan (China)

    2014-09-15

    Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100 μM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis-related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways. - Highlights: • Oxidized LDL induced cytotoxicity and apoptosis in HK-2 cells. • Pretreatment with taurine attenuated oxLDL-induced nephrotoxicity. • Taurine protected against renal damages through inhibition of ROS generation. • Taurine prevented apoptosis through modulation of the p53 phosphorylation.

  8. Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS-mediated mitochondrial and p53-related apoptotic pathways

    International Nuclear Information System (INIS)

    Chang, Chun-Yu; Shen, Chao-Yu; Kang, Chao-Kai; Sher, Yuh-Pyng; Sheu, Wayne H.-H.; Chang, Chia-Che; Lee, Tsung-Han

    2014-01-01

    Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100 μM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis-related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways. - Highlights: • Oxidized LDL induced cytotoxicity and apoptosis in HK-2 cells. • Pretreatment with taurine attenuated oxLDL-induced nephrotoxicity. • Taurine protected against renal damages through inhibition of ROS generation. • Taurine prevented apoptosis through modulation of the p53 phosphorylation

  9. Manganese activates the mitochondrial apoptotic pathway in rat astrocytes by modulating the expression of proteins of the Bcl-2 family.

    Science.gov (United States)

    Gonzalez, Laura E; Juknat, A Ana; Venosa, Andrea J; Verrengia, Noemi; Kotler, Mónica L

    2008-12-01

    Manganese induces the central nervous system injury leading to manganism, by mechanisms not completely understood. Chronic exposure to manganese generates oxidative stress and induces the mitochondrial permeability transition. In the present study, we characterized apoptotic cell death mechanisms associated with manganese toxicity in rat cortical astrocytes and demonstrated that (i) Mn treatment targets the mitochondria and induces mitochondrial membrane depolarization followed by cytochrome c release to the cytoplasm, (ii) Mn induces both effector caspases 3/7 and 6 as well as PARP-1 cleavage and (iii) Mn shifts the balance of cell death/survival of Bcl-2 family proteins to favor the apoptotic demise of astrocytes. Our model system using cortical rat astrocytes treated with Mn would emerge as a good tool for investigations aimed to elucidate the role of apoptosis in manganism.

  10. Pennogenyl Saponins from Paris quadrifolia L. Induce Extrinsic and Intrinsic Pathway of Apoptosis in Human Cervical Cancer HeLa Cells

    Science.gov (United States)

    Stefanowicz-Hajduk, Justyna; Bartoszewski, Rafal; Bartoszewska, Sylwia; Kochan, Kinga; Adamska, Anna; Kosiński, Igor; Ochocka, J. Renata

    2015-01-01

    Pennogenyl saponins are the active compounds of large number of plant species and consequently many polyherbal formulations. Hence, great interest has been shown in their characterization and in the investigation of their pharmacological and biological properties, especially anticancer. This present study reports on the evaluation of cytotoxic effects and explanation of the molecular mechanisms of action of the two pennogenyl saponins (PS 1 and PS 2) isolated from Paris quadrifolia L. rhizomes on human cervical adenocarcinoma cell line HeLa. To determine the viability of the cells treated with the compounds we used real-time cell proliferation analysis and found that the pennogenyl saponins PS 1 and PS 2 strongly inhibited the tumor cells growth with IC50 values of 1.11 ± 0.04 μg/ml and 0.87 ± 0.05 μg/ml, respectively. The flow cytometry analysis indicated that the two compounds induced apoptosis in a dose-dependent manner and decreased mitochondrial membrane potential in HeLa cells in the early stage of apoptosis. Quantitative PCR and Western Blot analysis showed that the two saponins significantly increased mRNA expression of FADD and BID as well as induced caspase-8 via increased of procaspase-8 processing in the treated cells. The results of this study suggest that both the extrinsic death receptor and intrinsic mitochondrial pathways are involved in the programmed cell death. PMID:26295969

  11. Taurine prevents arsenic-induced cardiac oxidative stress and apoptotic damage: Role of NF-κB, p38 and JNK MAPK pathway

    International Nuclear Information System (INIS)

    Ghosh, Jyotirmoy; Das, Joydeep; Manna, Prasenjit; Sil, Parames C.

    2009-01-01

    Cardiac dysfunction is a major cause of morbidity and mortality worldwide due to its complex pathogenesis. However, little is known about the mechanism of arsenic-induced cardiac abnormalities and the use of antioxidants as the possible protective agents in this pathophysiology. Conditionally essential amino acid, taurine, accounts for 25% to 50% of the amino acid pool in myocardium and possesses antioxidant properties. The present study has, therefore, been carried out to investigate the underlying mechanism of the beneficial role of taurine in arsenic-induced cardiac oxidative damage and cell death. Arsenic reduced cardiomyocyte viability, increased reactive oxygen species (ROS) production and intracellular calcium overload, and induced apoptotic cell death by mitochondrial dependent caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. These changes due to arsenic exposure were found to be associated with increased IKK and NF-κB (p65) phosphorylation. Pre-exposure of myocytes to an IKK inhibitor (PS-1145) prevented As-induced caspase-3 and PARP cleavage. Arsenic also markedly increased the activity of p38 and JNK MAPKs, but not ERK to that extent. Pre-treatment with SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated NF-κB and IKK phosphorylation indicating that p38 and JNK MAPKs are mainly involved in arsenic-induced NF-κB activation. Taurine treatment suppressed these apoptotic actions, suggesting that its protective role in arsenic-induced cardiomyocyte apoptosis is mediated by attenuation of p38 and JNK MAPK signaling pathways. Similarly, arsenic intoxication altered a number of biomarkers related to cardiac oxidative stress and other apoptotic indices in vivo and taurine supplementation could reduce it. Results suggest that taurine prevented arsenic-induced myocardial pathophysiology, attenuated NF-κB activation via IKK, p38 and JNK MAPK signaling pathways and could possibly provide a protection against As

  12. Effects of Downregulation of MicroRNA-181a on H2O2-Induced H9c2 Cell Apoptosis via the Mitochondrial Apoptotic Pathway

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2014-01-01

    Full Text Available Glutathione peroxidase-1 (GPx1 is a pivotal intracellular antioxidant enzyme that enzymatically reduces hydrogen peroxide to water to limit its harmful effects. This study aims to identify a microRNA (miRNA that targets GPx1 to maintain redox homeostasis. Dual luciferase assays combined with mutational analysis and immunoblotting were used to validate the bioinformatically predicted miRNAs. We sought to select miRNAs that were responsive to oxidative stress induced by hydrogen peroxide (H2O2 in the H9c2 rat cardiomyocyte cell line. Quantitative real-time PCR (qPCR demonstrated that the expression of miR-181a in H2O2-treated H9c2 cells was markedly upregulated. The downregulation of miR-181a significantly inhibited H2O2-induced cellular apoptosis, ROS production, the increase in malondialdehyde (MDA levels, the disruption of mitochondrial structure, and the activation of key signaling proteins in the mitochondrial apoptotic pathway. Our results suggest that miR-181a plays an important role in regulating the mitochondrial apoptotic pathway in cardiomyocytes challenged with oxidative stress. MiR-181a may represent a potential therapeutic target for the treatment of oxidative stress-associated cardiovascular diseases.

  13. Involvement of Bcl-xL degradation and mitochondrial-mediated apoptotic pathway in pyrrolizidine alkaloids-induced apoptosis in hepatocytes

    International Nuclear Information System (INIS)

    Ji Lili; Chen Ying; Liu Tianyu; Wang Zhengtao

    2008-01-01

    Pyrrolizidine alkaloids (PAs) are natural hepatotoxins with worldwide distribution in more than 6000 high plants including medicinal herbs or teas. The aim of this study is to investigate the signal pathway involved in PAs-induced hepatotoxicity. Our results showed that clivorine, isolated from Ligularia hodgsonii Hook, decreased cell viability and induced apoptosis in L-02 cells and mouse hepatocytes. Western-blot results showed that clivorine induced caspase-3/-9 activation, mitochondrial release of cytochrome c and decreased anti-apoptotic Bcl-xL in a time (8-48 h)- and concentration (1-100 μM)-dependent manner. Furthermore, inhibitors of pan-caspase, caspase-3 and caspase-9 significantly inhibited clivorine-induced apoptosis and rescued clivorine-decreased cell viability. Polyubiquitination of Bcl-xL was detected after incubation with 100 μM clivorine for 40 h in the presence of proteasome specific inhibitor MG132, indicating possible degradation of Bcl-xL protein. Furthermore, pretreatment with MG132 or calpain inhibitor I for 2 h significantly enhanced clivorine-decreased Bcl-xL level and cell viability. All the other tested PAs such as senecionine, isoline and monocrotaline decreased mouse hepatocytes viability in a concentration-dependent manner. Clivorine (10 μM) induced caspase-3 activation and decreased Bcl-xL was also confirmed in mouse hepatocytes. Meanwhile, another PA senecionine isolated from Senecio vulgaris L also induced apoptosis, caspase-3 activation and decreased Bcl-xL in mouse hepatocytes. In conclusion, our results suggest that PAs may share the same hepatotoxic signal pathway, which involves degradation of Bcl-xL protein and thus leading to the activation of mitochondrial-mediated apoptotic pathway

  14. Carnosic Acid, a Natural Diterpene, Attenuates Arsenic-Induced Hepatotoxicity via Reducing Oxidative Stress, MAPK Activation, and Apoptotic Cell Death Pathway

    Directory of Open Access Journals (Sweden)

    Sonjit Das

    2018-01-01

    Full Text Available The present studies have been executed to explore the protective mechanism of carnosic acid (CA against NaAsO2-induced hepatic injury. CA exhibited a concentration dependent (1–4 μM increase in cell viability against NaAsO2 (12 μM in murine hepatocytes. NaAsO2 treatment significantly enhanced the ROS-mediated oxidative stress in the hepatic cells both in in vitro and in vivo systems. Significant activation of MAPK, NF-κB, p53, and intrinsic and extrinsic apoptotic signaling was observed in NaAsO2-exposed hepatic cells. CA could significantly counteract with redox stress and ROS-mediated signaling and thereby attenuated NaAsO2-mediated hepatotoxicity. NaAsO2 (10 mg/kg treatment caused significant increment in the As bioaccumulation, cytosolic ATP level, DNA fragmentation, and oxidation in the liver of experimental mice (n=6. The serum biochemical and haematological parameters were significantly altered in the NaAsO2-exposed mice (n=6. Simultaneous treatment with CA (10 and 20 mg/kg could significantly reinstate the NaAsO2-mediated toxicological effects in the liver. Molecular docking and dynamics predicted the possible interaction patterns and the stability of interactions between CA and signal proteins. ADME prediction anticipated the drug-likeness characteristics of CA. Hence, there would be an option to employ CA as a new therapeutic agent against As-mediated toxic manifestations in future.

  15. Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways

    Directory of Open Access Journals (Sweden)

    Schniewind Bodo

    2006-11-01

    Full Text Available Abstract Background Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB and the nucleoside analogue gemcitabine (GEM was evaluated and the mechanisms underlying increased cell death were analyzed. Methods Dose escalation studies evaluating the cytotoxicity of PB (0.01–100 mM, GEM (0.01–100 μg/ml and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62. Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. Results Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50–80% (p = 0.012 more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2–2.7 fold compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093 and topoisomerase IIα (KNS62: p = 0.008; Ben: p = 0.064 proliferation indices were clearly reduced in tumors treated by combination

  16. De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells.

    Science.gov (United States)

    Liu, Huiying; Xing, Rong; Cheng, Xuefang; Li, Qingran; Liu, Fang; Ye, Hui; Zhao, Min; Wang, Hong; Wang, Guangji; Hao, Haiping

    2016-09-20

    Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD+ pool. Particularly, the LAT1-NAD+-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD+ synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress.

  17. The Nuclear Orphan Receptor NR4A1 is Involved in the Apoptotic Pathway Induced by LPS and Simvastatin in RAW 264.7 Macrophages.

    Science.gov (United States)

    Kim, Yong Chan; Song, Seok Bean; Lee, Sang Kyu; Park, Sang Min; Kim, Young Sang

    2014-04-01

    Macrophage death plays a role in several physiological and inflammatory pathologies such as sepsis and arthritis. In our previous work, we showed that simvastatin triggers cell death in LPS-activated RAW 264.7 mouse macrophage cells through both caspase-dependent and independent apoptotic pathways. Here, we show that the nuclear orphan receptor NR4A1 is involved in a caspase-independent apoptotic process induced by LPS and simvastatin. Simvastatin-induced NR4A1 expression in RAW 264.7 macrophages and ectopic expression of a dominant-negative mutant form of NR4A1 effectively suppressed both DNA fragmentation and the disruption of mitochondrial membrane potential (MMP) during LPS- and simvastatin-induced apoptosis. Furthermore, apoptosis was accompanied by Bcl-2-associated X protein (Bax) translocation to the mitochondria. Our findings suggest that NR4A1 expression and mitochondrial translocation of Bax are related to simvastatin-induced apoptosis in LPS-activated RAW 264.7 macrophages.

  18. Discovery of Novel Bromophenol Hybrids as Potential Anticancer Agents through the Ros-Mediated Apoptotic Pathway: Design, Synthesis and Biological Evaluation

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    Li-Jun Wang

    2017-11-01

    Full Text Available A series of bromophenol hybrids with N-containing heterocyclic moieties were designed, and their anticancer activities against a panel of five human cancer cell lines (A549, Bel7402, HepG2, HCT116 and Caco2 using MTT assay in vitro were explored. Among them, thirteen compounds (17a, 17b, 18a, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, and 23b exhibited significant inhibitory activity against the tested cancer cell lines. The structure-activity relationships (SARs of bromophenol derivatives were discussed. The promising candidate compound 17a could induce cell cycle arrest at G0/G1 phase and induce apoptosis in A549 cells, as well as caused DNA fragmentations, morphological changes and ROS generation by the mechanism studies. Furthermore, compound 17a suppression of Bcl-2 levels (decrease in the expression of the anti-apoptotic proteins Bcl-2 and down-regulation in the expression levels of Bcl-2 in A549 cells were observed, along with activation caspase-3 and PARP, which indicated that compound 17a induced A549 cells apoptosis in vitro through the ROS-mediated apoptotic pathway. These results might be useful for bromophenol derivatives to be explored and developed as novel anticancer drugs.

  19. Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: Effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway

    International Nuclear Information System (INIS)

    Ahmed, Maha A.E.

    2015-01-01

    The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free β-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoate (10 mg/kg/week, I.M.), taurine (100 mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3β-HSD, and 17β-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF-α, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats. - Highlights: • Nandrolone decanoate (ND) disrupts sperm profile and steroidogenesis in rats. • ND upregulates gene expression of inflammatory and apoptotic markers. • Taurine normalizes sperm profile and serum testosterone level

  20. Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: Effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Maha A.E., E-mail: mahapharm@yahoo.com

    2015-02-01

    The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free β-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoate (10 mg/kg/week, I.M.), taurine (100 mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3β-HSD, and 17β-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF-α, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats. - Highlights: • Nandrolone decanoate (ND) disrupts sperm profile and steroidogenesis in rats. • ND upregulates gene expression of inflammatory and apoptotic markers. • Taurine normalizes sperm profile and serum testosterone level

  1. Ginsenoside Rb1 Protects Neonatal Rat Cardiomyocytes from Hypoxia/Ischemia Induced Apoptosis and Inhibits Activation of the Mitochondrial Apoptotic Pathway

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    Xu Yan

    2014-01-01

    Full Text Available Aim. To investigate the effect of Ginsenoside Rb1 (GS-Rb1 on hypoxia/ischemia (H/I injury in cardiomyocytes in vitro and the mitochondrial apoptotic pathway mediated mechanism. Methods. Neonatal rat cardiomyocytes (NRCMs for the H/I groups were kept in DMEM without glucose and serum, and were placed into a hypoxic jar for 24 h. GS-Rb1 at concentrations from 2.5 to 40 µM was given during hypoxic period for 24 h. NRCMs injury was determined by MTT and lactate dehydrogenase (LDH leakage assay. Cell apoptosis, ROS accumulation, and mitochondrial membrane potential (MMP were assessed by flow cytometry. Cytosolic translocation of mitochondrial cytochrome c and Bcl-2 family proteins were determined by Western blot. Caspase-3 and caspase-9 activities were determined by the assay kit. Results. GS-Rb1 significantly reduced cell death and LDH leakage induced by H/I. It also reduced H/I induced NRCMs apoptosis induced by H/I, in accordance with a minimal reactive oxygen species (ROS burst. Moreover, GS-Rb1 markedly decreased the translocation of cytochrome c from the mitochondria to the cytosol, increased the Bcl-2/ Bax ratio, and preserved mitochondrial transmembrane potential (ΔΨm. Its administration also inhibited activities of caspase-9 and caspase-3. Conclusion. Administration of GS-Rb1 during H/I in vitro is involved in cardioprotection by inhibiting apoptosis, which may be due to inhibition of the mitochondrial apoptotic pathway.

  2. [Pt(O,O'-acac)(gamma-acac)(DMS)], a new Pt compound exerting fast cytotoxicity in MCF-7 breast cancer cells via the mitochondrial apoptotic pathway.

    Science.gov (United States)

    Muscella, A; Calabriso, N; Fanizzi, F P; De Pascali, S A; Urso, L; Ciccarese, A; Migoni, D; Marsigliante, S

    2008-01-01

    We showed previously that a new Pt complex containing an O,O'-chelated acetylacetonate ligand (acac) and a dimethylsulphide in the Pt coordination sphere, [Pt(O,O'-acac)(gamma-acac)(DMS)], induces apoptosis in HeLa cells. The objective of this study was to investigate the hypothesis that [Pt(O,O'-acac)(gamma-acac)(DMS)] is also cytotoxic in a MCF-7 breast cancer cell line relatively insensitive to cisplatin, and to gain a more detailed analysis of the cell death pathways. Cells were treated with Pt compounds and cytotoxicity tests were performed, together with Western blotting of various proteins involved in apoptosis. The mitochondrial membrane potential was assessed by fluorescence microscopy and spectrofluorometry and the Pt bound to cell fractions was measured by atomic absorption spectrometry. In contrast to cisplatin, the cytotoxicity of [Pt(O,O'-acac)(gamma-acac)(DMS)] correlated with cellular accumulation but not with DNA binding. Also, the Pt content in DNA bases was considerably higher for cisplatin than for [Pt(O,O'-acac)(gamma-acac)(DMS)], thus excluding DNA as a target of [Pt(O,O'-acac)(gamma-acac)(DMS)]. [Pt(O,O'-acac)(gamma-acac)(DMS)] exerted high and fast apoptotic processes in MCF-7 cells since it provoked: (a) mitochondria depolarization; (b) cytochrome c accumulation in the cytosol; (c) translocation of Bax and truncated-Bid from cytosol to mitochondria and decreased expression of Bcl-2; (d) cleavage of caspases -7 and -9, and PARP degradation; (e) chromatin condensation and DNA fragmentation. [Pt(O,O'-acac)(gamma-acac)(DMS)] is highly cytotoxic for MCF-7 cells, cells relatively resistant to many chemotherapeutic agents, as it activates the mitochondrial apoptotic pathway. Hence, [Pt(O,O'-acac)(gamma-acac)(DMS)] has the potential to provide us with new opportunities for therapeutic intervention.

  3. Mitochondrial apoptotic pathway activation in the atria of heart failure patients due to mitral and tricuspid regurgitation.

    Science.gov (United States)

    Chang, Jen-Ping; Chen, Mien-Cheng; Liu, Wen-Hao; Lin, Yu-Sheng; Huang, Yao-Kuang; Pan, Kuo-Li; Ho, Wan-Chun; Fang, Chih-Yuan; Chen, Chien-Jen; Chen, Huang-Chung

    2015-08-01

    Apoptosis occurs in atrial cardiomyocytes in mitral and tricuspid valve disease. The purpose of this study was to examine the respective roles of the mitochondrial and tumor necrosis factor-α receptor associated death domain (TRADD)-mediated death receptor pathways for apoptosis in the atrial cardiomyocytes of heart failure patients due to severe mitral and moderate-to-severe tricuspid regurgitation. This study comprised eighteen patients (7 patients with persistent atrial fibrillation and 11 in sinus rhythm). Atrial appendage tissues were obtained during surgery. Three purchased normal human left atrial tissues served as normal controls. Moderately-to-severely myolytic cardiomyocytes comprised 59.7±22.1% of the cardiomyocytes in the right atria and 52.4±12.9% of the cardiomyocytes in the left atria of mitral and tricuspid regurgitation patients with atrial fibrillation group and comprised 58.4±24.8% of the cardiomyocytes in the right atria of mitral and tricuspid regurgitation patients with sinus rhythm. In contrast, no myolysis was observed in the normal human adult left atrial tissue samples. Immunohistochemical analysis showed expression of cleaved caspase-9, an effector of the mitochondrial pathways, in the majority of right atrial cardiomyocytes (87.3±10.0%) of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial cardiomyocytes (90.6±31.4%) and left atrial cardiomyocytes (70.7±22.0%) of mitral and tricuspid regurgitation patients with atrial fibrillation. In contrast, only 5.7% of cardiomyocytes of the normal left atrial tissues showed strongly positive expression of cleaved caspase-9. Of note, none of the atrial cardiomyocytes in right atrial tissue in sinus rhythm and in the fibrillating right and left atria of mitral and tricuspid regurgitation patients, and in the normal human adult left atrial tissue samples showed cleaved caspase-8 expression, which is a downstream effector of TRADD of the death receptor pathway

  4. Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX-Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model.

    Science.gov (United States)

    Zareba, Ilona; Surazynski, Arkadiusz; Chrusciel, Marcin; Miltyk, Wojciech; Doroszko, Milena; Rahman, Nafis; Palka, Jerzy

    2017-01-01

    The effect of impaired intracellular proline availability for proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis was studied. We generated a constitutively knocked-down PRODH/POX MCF-7 breast cancer cell line (MCF-7shPRODH/POX) as a model to analyze the functional consequences of impaired intracellular proline levels. We have used inhibitor of proline utilization in collagen biosynthesis, 2-metoxyestradiol (MOE), inhibitor of prolidase that generate proline, rapamycin (Rap) and glycyl-proline (GlyPro), substrate for prolidase. Collagen and DNA biosynthesis were evaluated by radiometric assays. Cell viability was determined using Nucleo-Counter NC-3000. The activity of prolidase was determined by colorimetric assay. Expression of proteins was assessed by Western blot and immunofluorescence bioimaging. Concentration of proline was analyzed by liquid chromatography with mass spectrometry. PRODH/POX knockdown decreased DNA and collagen biosynthesis, whereas increased prolidase activity and intracellular proline level in MCF-7shPRODH/POX cells. All studied compounds decreased cell viability in MCF-7 and MCF-7shPRODH/POX cells. DNA biosynthesis was similarly inhibited by Rap and MOE in both cell lines, but GlyPro inhibited the process only in MCF-7shPRODH/POX and MOE+GlyPro only in MCF-7 cells. All the compounds inhibited collagen biosynthesis, increased prolidase activity and cytoplasmic proline level in MCF-7shPRODH/POX cells and contributed to the induction of pro-survival mode only in MCF-7shPRODH/POX cells. In contrast, all studied compounds upregulated expression of pro-apoptotic protein only in MCF-7 cells. PRODH/POX was confirmed as a driver of apoptosis and proved the eligibility of MCF-7shPRODH/POX cell line as a highly effective model to elucidate the different mechanisms underlying proline utilization or generation in PRODH/POX-dependent pro-apoptotic pathways. © 2017 The Author(s). Published by S. Karger AG, Basel.

  5. Phenolic extract from oleaster (Olea europaea var. Sylvestris) leaves reduces colon cancer growth and induces caspase-dependent apoptosis in colon cancer cells via the mitochondrial apoptotic pathway.

    Science.gov (United States)

    Zeriouh, Wafa; Nani, Abdelhafid; Belarbi, Meriem; Dumont, Adélie; de Rosny, Charlotte; Aboura, Ikram; Ghanemi, Fatima Zahra; Murtaza, Babar; Patoli, Danish; Thomas, Charles; Apetoh, Lionel; Rébé, Cédric; Delmas, Dominique; Khan, Naim Akhtar; Ghiringhelli, François; Rialland, Mickael; Hichami, Aziz

    2017-01-01

    Dietary polyphenols, derived from natural products, have received a great interest for their chemopreventive properties against cancer. In this study, we investigated the effects of phenolic extract of the oleaster leaves (PEOL) on tumor growth in mouse model and on cell death in colon cancer cell lines. We assessed the effect of oleaster leaf infusion on HCT116 (human colon cancer cell line) xenograft growth in athymic nude mice. We observed that oleaster leaf polyphenol-rich infusion limited HCT116 tumor growth in vivo. Investigations of PEOL on two human CRC cell lines showed that PEOL induced apoptosis in HCT116 and HCT8 cells. We demonstrated an activation of caspase-3, -7 and -9 by PEOL and that pre-treatment with the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), prevented PEOL-induced cell death. We observed an involvement of the mitochondrial pathway in PEOL-induced apoptosis evidenced by reactive oxygen species (ROS) production, a decrease of mitochondrial membrane potential, and cytochrome c release. Increase in intracellular Ca2+ concentration induced by PEOL represents the early event involved in mitochondrial dysfunction, ROS-induced endoplasmic reticulum (ER) stress and apoptosis induced by PEOL, as ruthenium red, an inhibitor of mitochondrial calcium uptake inhibited apoptotic effect of PEOL, BAPTA/AM inhibited PEOL-induced ROS generation and finally, N-acetyl-L-cysteine reversed ER stress and apoptotic effect of PEOL. These results demonstrate that polyphenols from oleaster leaves might have a strong potential as chemopreventive agent in colorectal cancer.

  6. Systems modeling of anti-apoptotic pathways in prostate cancer: psychological stress triggers a synergism pattern switch in drug combination therapy.

    Directory of Open Access Journals (Sweden)

    Xiaoqiang Sun

    Full Text Available Prostate cancer patients often have increased levels of psychological stress or anxiety, but the molecular mechanisms underlying the interaction between psychological stress and prostate cancer as well as therapy resistance have been rarely studied and remain poorly understood. Recent reports show that stress inhibits apoptosis in prostate cancer cells via epinephrine/beta2 adrenergic receptor/PKA/BAD pathway. In this study, we used experimental data on the signaling pathways that control BAD phosphorylation to build a dynamic network model of apoptosis regulation in prostate cancer cells. We then compared the predictive power of two different models with or without the role of Mcl-1, which justified the role of Mcl-1 stabilization in anti-apoptotic effects of emotional stress. Based on the selected model, we examined and quantitatively evaluated the induction of apoptosis by drug combination therapies. We predicted that the combination of PI3K inhibitor LY294002 and inhibition of BAD phosphorylation at S112 would produce the best synergistic effect among 8 interventions examined. Experimental validation confirmed the effectiveness of our predictive model. Moreover, we found that epinephrine signaling changes the synergism pattern and decreases efficacy of combination therapy. The molecular mechanisms responsible for therapeutic resistance and the switch in synergism were explored by analyzing a network model of signaling pathways affected by psychological stress. These results provide insights into the mechanisms of psychological stress signaling in therapy-resistant cancer, and indicate the potential benefit of reducing psychological stress in designing more effective therapies for prostate cancer patients.

  7. A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

    International Nuclear Information System (INIS)

    Serrano, Fabiana A; Machado, Joel Jr; Santos, Edson L; Pesquero, João B; Martins, Rafael M; Travassos, Luiz R; Caires, Antonio CF; Rodrigues, Elaine G; Matsuo, Alisson L; Monteforte, Priscila T; Bechara, Alexandre; Smaili, Soraya S; Santana, Débora P; Rodrigues, Tiago; Pereira, Felipe V; Silva, Luis S

    2011-01-01

    Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd 2 [S (-) C 2 , N-dmpa] 2 (μ-dppe)Cl 2 } named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies. B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a. Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells. The cyclopalladated C7a complex is

  8. Attenuation of Aβ25–35-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    International Nuclear Information System (INIS)

    Meng, Xiangbao; Wang, Min; Sun, Guibo; Ye, Jingxue; Zhou, Yanhui; Dong, Xi; Wang, Tingting; Lu, Shan; Sun, Xiaobo

    2014-01-01

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ 25–35 -induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ 25–35 (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ 25–35 treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ 25–35 treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ 25–35 -induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ 25–35 -induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens or gypenosides

  9. Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells.

    Science.gov (United States)

    Tsai, Jai-Jen; Pan, Po-Jung; Hsu, Fei-Ting

    2017-02-01

    The aim of the present study was to investigate the role of NF-κB inactivation in regorafenib-induced apoptosis in human hepatocellular carcinoma SK-HEP-1 cells. SK-HEP-1 cells were treated with different concentrations of the NF-κB inhibitor 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) or regorafenib for different periods. The effects of QNZ and regorafenib on cell viability, expression of NF-κB-modulated anti-apoptotic proteins and apoptotic pathways were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, DNA gel electrophoresis, flow cytometry and NF-κB reporter gene assay. Inhibitors of various kinases including AKT, c-Jun N-terminal kinase (JNK), P38 and extracellular signal-regulated kinase (ERK) were used to evaluate the mechanism of regorafenib-induced NF-κB inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of anti-apoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-κB activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-κB activation in SK-HEP-1 cells.

  10. Ultraviolet-Ray-Induced Sea Cucumber (Stichopus japonicus) Melting Is Mediated by the Caspase-Dependent Mitochondrial Apoptotic Pathway.

    Science.gov (United States)

    Su, Li; Yang, Jing-Feng; Fu, Xi; Dong, Liang; Zhou, Da-Yong; Sun, Li-Ming; Gong, Zhenwei

    2018-01-10

    Sea cucumber body-wall melting occurs under certain circumstances. We have shown that apoptosis but not autolysis plays a critical role in the initial stage. However, it is still unclear how apoptosis is triggered in this process. In this study, we examined the levels of reactive oxygen species (ROS), the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax) proteins, the depolarization of mitochondrial transmembrane potentials, and cytochrome c (Cyt c) release during sea cucumber melting induced by ultraviolet (UV) exposure. We also investigated the contribution of caspase in this process by injecting a pan-caspase inhibitor. Our data showed that UV exposure stimulates ROS production, dysfunction of mitochondria, and the release of Cyt c in sea cucumber coelomic fluid cells and body walls. We found a decrease of Bcl-2 and increase of Bax in the mitochondria after UV exposure. We also demonstrated that these changes are associated with elevated caspase-9 and -3 activity. Finally, our data showed that the inhibition of caspases-9 and -3 using an inhibitor suppresses UV-induced sea cucumber melting. These results suggest that apoptosis during sea cucumber melting is mediated by mitochondrial dysfunction and follows the activation of the caspase-signaling pathway. This study presents a novel insight into the mechanism of sea cucumber melting.

  11. L-3-n-Butylphthalide Protects HSPB8 K141N Mutation-Induced Oxidative Stress by Modulating the Mitochondrial Apoptotic and Nrf2 Pathways

    Directory of Open Access Journals (Sweden)

    Xiao-Dong Yang

    2017-07-01

    Full Text Available Charcot–Marie–Tooth disease (CMT, also known as hereditary motor and sensory neuropathy, is the most common inherited peripheral nerve disorder. Missense mutations, such as K141N, in the small heat shock protein HSPB8 are known to cause distal hereditary motor neuropathy 2A (dHMN2A or Charcot-Marie-Tooth neuropathy type 2L (CMT2L. However, of critical clinical significance, very few specific therapies for this disease exist. In the present study, we investigated the impact of mutant K141N HSPB8 on mitochondrial distribution and function in a cellular model of CMT2L. Our results indicate that K141N HSPB8 induced mitochondrial aggregation and caused increased oxidative stress injury. As an extraction from Chinese celery Apium graveolens Linn seeds, L-3-n-Butylphthalide (NBP, has been reported to exert many neuroprotective effects, we interrogated whether NBP could elicit a protective effect on the cell injury typically caused by HSPB8 K141N mutations. We found NBP could reverse the pathological processes induced by HSPB8 K141N mutation via an antioxidant effect, modulation of the Bax/Bcl-2 mitochondrial apoptotic and Nrf2 pathways. We propose a novel function of HSPB8, highlighting the consequence of the K141N pathogenic mutation. Furthermore, we suggest NBP may have promising therapeutic potential in the treatment of CMT2L.

  12. Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Yu-Ping Hsiao

    2015-01-01

    Full Text Available Malic acid (MA has been commonly used in cosmetic products, but the safety reports in skin are sparse. To investigate the biological effects of MA in human skin keratinocytes, we investigated the potential cytotoxicity and apoptotic effects of MA in human keratinocyte cell lines (HaCaT. The data showed that MA induced apoptosis based on the observations of DAPI staining, DNA fragmentation, and sub-G1 phase in HaCaT cells and normal human epidermal keratinocytes (NHEKs. Flow cytometric assays also showed that MA increased the production of mitochondrial superoxide (mito-SOX but decreased the mitochondrial membrane potential. Analysis of bioenergetics function with the XF 24 analyzer Seahorse extracellular flux analyzer demonstrated that oxygen consumption rate (OCR was significantly decreased whereas extracellular acidification rate (ECAR was increased in MA-treated keratinocytes. The occurrence of apoptosis was proved by the increased expressions of FasL, Fas, Bax, Bid, caspases-3, -8, -9, cytochrome c, and the declined expressions of Bcl-2, PARP. MA also induced endoplasmic reticulum stress associated protein expression such as GRP78, GADD153, and ATF6α. We demonstrated that MA had anti-proliferative effect in HaCaT cell through the inhibition of cell cycle progression at G0/G1, and the induction of programmed cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways.

  13. The Apoptotic Effect of Ursolic Acid on SK-Hep-1 Cells is Regulated by the PI3K/Akt, p38 and JNK MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Wan-Ling Chuang

    2016-04-01

    Full Text Available Ursolic acid (UA is a pentacyclic triterpene acid that is present in a wide variety of medicinal herbs and edible plants. This study investigated the effect of UA on apoptosis and proliferation of hepatocellular carcinoma SK-Hep-1 cells. After treatment of SK-Hep-1 cells with different concentrations of UA, we observed that cell viability was reduced in a dose- and time-dependent manner. Furthermore, there was a dose-dependent increase in the percentage of cells in the sub-G1 and G2/M phases, with cells treated with 60 μM showing the highest percentages of cells in those phases. UA-induced chromatin condensation of nuclei was observed by using DAPI staining. The western blot results revealed that exposure to UA was associated with decreased expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, Bcl-2, and TCTP and increased expression of apoptosis-related proteins TNF-α, Fas, FADD, Bax, cleaved caspase-3, caspase-8, caspase-9, and PARP. Immunocytochemistry staining showed that treatment with UA resulted in increased expression of caspase-3. Moreover, exposure to UA resulted in the inhibition of the PI3K/Akt and p38 MAPK signaling pathways. These findings suggest that UA inhibits the proliferation of SK-Hep-1 cells and induces apoptosis.

  14. A novel polysaccharide from Ganoderma atrum exerts antitumor activity by activating mitochondria-mediated apoptotic pathway and boosting the immune system.

    Science.gov (United States)

    Zhang, Shenshen; Nie, Shaoping; Huang, Danfei; Feng, Yanling; Xie, Mingyong

    2014-02-19

    Ganoderma is a precious health-care edible medicinal fungus in China. A novel Ganoderma atrum polysaccharide (PSG-1) is the main bioactive component. We investigated the antitumor effect and molecular mechanisms of PSG-1. It exhibited no significant effect on cell proliferation directly. In contrast, administration of PSG-1 markedly suppressed tumor growth in CT26 tumor-bearing mice. It was observed that PSG-1 caused apoptosis in CT26 cells. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c release and intracellular ROS production, elevation of p53 and Bax expression, downregulation of Bcl-2, and the activation of caspase-9 and -3. Moreover, PSG-1 enhanced immune organ index and promoted lymphocyte proliferation as well as cytokine levels in serum. Taken together, our data indicate that PSG-1 has potential antitumor activity in vivo by inducing apoptosis via mitochondria-mediated apoptotic pathway and enhances host immune system function. Therefore, PSG-1 could be a safe and effective antitumor, bioactive agent or functional food.

  15. Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells.

    Science.gov (United States)

    Zahedifard, Maryam; Faraj, Fadhil Lafta; Paydar, Mohammadjavad; Looi, Chung Yeng; Hasandarvish, Pouya; Hajrezaie, Maryam; Kamalidehghan, Behnam; Majid, Nazia Abdul; Khalifa, Shaden A M; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen; El-Seedi, Hesham R

    2015-01-01

    The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.

  16. Phenotypic and Genetic Evaluation of the Influence of Pseudomonas aeruginosa Culture Fractions on the Human Mesenchymal Stem Cells Viability, Apoptotic Pathways and Cytokine Profile.

    Science.gov (United States)

    Holban, Alina Maria; Bleotu, Coralia; Chifiriuc, Mariana Carmen; Lazar, Veronica

    2017-01-01

    The objective of this study was to investigate the effects of P. aeruginosa PAO1 cellular and soluble culture fractions on human mesenchymal stem cells (MSCs) death signaling pathways and cytokine profile. The bone marrow isolated MSCs, incubated for different periods of time with one of the three P. aeruginosa PAO1 culture fractions, i.e. low density whole cultures, heat inactivated bacterial cultures sediments and sterile supernatants, were submitted to the following assays: i) fluorescence microscopy evaluation of cellular morphology and viability; ii) bax, caspase 9, relA and bcl-2 genes expression analysis by qRT-PCR; and iii) quantification of the level of IL-1β, IL-6, IL-8 and IL-10 cytokines released in the MSCs supernatants determined by ELISA. Results were statistically analyzed using the GraphPad In Stat software. The PAO1 whole cultures exhibited the most relevant influences, impacting on MSCs morphology and viability, interfering with apoptotic pathways and significantly stimulating the production of IL-1β and IL-10, while decreasing the production of IL-6 and IL-8. The culture supernatants increased the production of IL-1β and reduced the secretion of all other tested cytokines, while heat-inactivated bacterial cells significantly stimulated both IL-1β and IL-10 production. These data could suggest that in vivo, the fate of P. aeruginosa infection depends on the proportion between different bacterial culture fractions (i.e. the number of viable bacterial cells, the number of dead cells and the amount of bacterial soluble products accumulated locally) that could be influenced by the initial infective dose, by the host defense mechanisms, and also by the administered antimicrobial treatment that may thus interfere with the evolution and magnitude of the induced lesions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Zinc ferrite nanoparticles activate IL-1b, NFKB1, CCL21 and NOS2 signaling to induce mitochondrial dependent intrinsic apoptotic pathway in WISH cells

    Energy Technology Data Exchange (ETDEWEB)

    Saquib, Quaiser; Al-Khedhairy, Abdulaziz A.; Ahmad, Javed; Siddiqui, Maqsood A.; Dwivedi, Sourabh; Khan, Shams T. [Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451 (Saudi Arabia); Chair for DNA Research, Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451 (Saudi Arabia); Musarrat, Javed, E-mail: musarratj1@yahoo.com [Chair for DNA Research, Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451 (Saudi Arabia); Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh 202002, U.P. (India)

    2013-12-01

    The present study has demonstrated the translocation of zinc ferrite nanoparticles (ZnFe{sub 2}O{sub 4}-NPs) into the cytoplasm of human amnion epithelial (WISH) cells, and the ensuing cytotoxicity and genetic damage. The results suggested that in situ NPs induced oxidative stress, alterations in cellular membrane and DNA strand breaks. The [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) and neutral red uptake (NRU) cytotoxicity assays indicated 64.48 ± 1.6% and 50.73 ± 2.1% reduction in cell viability with 100 μg/ml of ZnFe{sub 2}O{sub 4}-NPs exposure. The treated WISH cells exhibited 1.2-fold higher ROS level with 0.9-fold decline in membrane potential (ΔΨm) and 7.4-fold higher DNA damage after 48 h of ZnFe{sub 2}O{sub 4}-NPs treatment. Real-time PCR (qPCR) analysis of p53, CASP 3 (caspase-3), and bax genes revealed 5.3, 1.6, and 14.9-fold upregulation, and 0.18-fold down regulation of bcl 2 gene vis-à-vis untreated control. RT{sup 2} Profiler™ PCR array data elucidated differential up-regulation of mRNA transcripts of IL-1b, NFKB1, NOS2 and CCL21 genes in the range of 1.5 to 3.7-folds. The flow cytometry based cell cycle analysis suggested the transfer of 15.2 ± 2.1% (p < 0.01) population of ZnFe{sub 2}O{sub 4}-NPs (100 μg/ml) treated cells into apoptotic phase through intrinsic pathway. Over all, the data revealed the potential of ZnFe{sub 2}O{sub 4}-NPs to induce cellular and genetic toxicity in cells of placental origin. Thus, the significant ROS production, reduction in ΔΨm, DNA damage, and activation of genes linked to inflammation, oxidative stress, proliferation, DNA damage and repair could serve as the predictive toxicity and stress markers for ecotoxicological assessment of ZnFe{sub 2}O{sub 4}-NPs induced cellular and genetic damage. - Highlights: • First report on the molecular toxicity of ZnFe{sub 2}O{sub 4}-NPs in cells of placental origin • WISH cells treated with ZnFe{sub 2}O{sub 4}-NPs exhibited cytoplasmic

  18. Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model

    Science.gov (United States)

    BOUSSEROUEL, SOUAD; LE GRANDOIS, JULIE; GOSSÉ, FRANCINE; WERNER, DALAL; BARTH, STEPHAN W.; MARCHIONI, ERIC; MARESCAUX, JACQUES; RAUL, FRANCIS

    2013-01-01

    Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 μg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 μg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death-receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID:23754197

  19. Apoptotic activities of cardenolide glycosides from Asclepias subulata.

    Science.gov (United States)

    Rascón-Valenzuela, L A; Velázquez, C; Garibay-Escobar, A; Vilegas, W; Medina-Juárez, L A; Gámez-Meza, N; Robles-Zepeda, R E

    2016-12-04

    Asclepias subulata Decne. (Apocynaceae) is a shrub occurring in Sonora-Arizona desert. The ethnic groups of Sonora, Mexico, Seris and Pimas, use this plant for the treatment of sore eyes, gastrointestinal disorders and cancer. To determine the cell death pathways that the cardenolide glycosides with antiproliferative activity found in the methanol extract of A. subulata are able to activate. The effect of cardenolide glycosides isolated of A. subulata on induction of apoptosis in cancer cells was evaluated through the measuring of several key events of apoptosis. A549 cells were treated for 12h with doses of 3.0, 0.2, 3.0 and 1.0µM of 12, 16-dihydroxicalotropin, calotropin, corotoxigenin 3-O-glucopyranoside and desglucouzarin, respectively. Apoptotic and necrotic cell levels were measured by double staining with annexin V-FITC/PI. Mitochondrial membrane depolarization was examined through JC-1 staining. Apoptosis cell death and the apoptosis pathways activated by cardenolide glycosides isolated of A. subulata were further characterized by the measurement of caspase-3, caspase-8 and caspase-9 activity. Apoptotic assays showed that the four cardenolide glycosides isolated of A. subulata induced apoptosis in A549 cells, which was evidencing by phosphatidylserine externalization in 18.2%, 17.0%, 23.9% and 22.0% for 12, 16-dihydroxicalotropin, calotropin, corotoxigenin 3-O-glucopyranoside and desglucouzarin, respectively, compared with 4.6% of control cells. Cell death was also associated with a decrease in mitochondrial membrane potential, which was more than 75% in the treated cultures respect to control. The activation of caspase-3 was observed in all cardenolide glycosides-treated cancer cells indicating the caspase-dependent apoptosis of A549 cells. Extrinsic and intrinsic apoptosis pathways were activated by cardenolide glycosides treatment at the doses tested. In this study was found that cardenolide glycosides, 12, 16-dihydroxicalotropin, calotropin

  20. Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways.

    Science.gov (United States)

    Karthikeyan, Subburayan; Hoti, Sugeerappa Laxmanappa; Nazeer, Yasin; Hegde, Harsha Vasudev

    2016-07-05

    Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy

  1. Intrinsic and extrinsic mortality reunited

    DEFF Research Database (Denmark)

    Koopman, Jacob J E; Wensink, Maarten J; Rozing, Maarten P

    2015-01-01

    Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However......, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well...... as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic...

  2. Differential Role of the Fas/Fas Ligand Apoptotic Pathway in Inflammation and Lung Fibrosis Associated with Reovirus 1/L-Induced Bronchiolitis Obliterans Organizing Pneumonia and Acute Respiratory Distress Syndrome1

    Science.gov (United States)

    Lopez, Andrea D.; Avasarala, Sreedevi; Grewal, Suman; Murali, Anuradha K.; London, Lucille

    2010-01-01

    Bronchiolitis obliterans organizing pneumonia (BOOP) and acute respiratory distress syndrome (ARDS) are two clinically and histologically distinct syndromes sharing the presence of an inflammatory and fibrotic component. Apoptosis via the Fas/Fas ligand (FasL) pathway plays an important role in the development of acute lung injury and fibrosis characteristic of these and other pulmonary inflammatory and fibrotic syndromes. We evaluated the role of apoptosis via the Fas/FasL pathway in the development of pulmonary inflammation and fibrosis in reovirus 1/L-induced BOOP and ARDS. CBA/J mice were intranasally inoculated with saline, 1 × 106 (BOOP), or 1 × 107 (ARDS) PFU reovirus 1/L, and evaluated at various days postinoculation for in situ apoptosis by TUNEL analysis and Fas/FasL expression. Our results demonstrate the presence of apoptotic cells and up-regulation of Fas/FasL expression in alveolar epithelium and in infiltrating cells during the inflammatory and fibrotic stages of both reovirus 1/L-induced ARDS and BOOP. Treatment of mice with the caspase 8 inhibitor, zIETD-fmk, inhibited apoptosis, inflammation, and fibrotic lesion development in reovirus 1/L-induced BOOP and ARDS. However, CBA/KlJms-Faslpr-cg/J mice, which carry a point mutation in the Fas cytoplasmic region that abolishes the ability of Fas to transduce an apoptotic signal, do not develop pulmonary inflammation and fibrotic lesions associated with reovirus 1/L-induced BOOP, but still develop inflammation and fibrotic lesions associated with reovirus 1/L-induced ARDS. These results suggest a differential role for the Fas/FasL apoptotic pathway in the development of inflammation and fibrotic lesions associated with BOOP and ARDS. PMID:20007588

  3. Differential role of the Fas/Fas ligand apoptotic pathway in inflammation and lung fibrosis associated with reovirus 1/L-induced bronchiolitis obliterans organizing pneumonia and acute respiratory distress syndrome.

    Science.gov (United States)

    Lopez, Andrea D; Avasarala, Sreedevi; Grewal, Suman; Murali, Anuradha K; London, Lucille

    2009-12-15

    Bronchiolitis obliterans organizing pneumonia (BOOP) and acute respiratory distress syndrome (ARDS) are two clinically and histologically distinct syndromes sharing the presence of an inflammatory and fibrotic component. Apoptosis via the Fas/Fas ligand (FasL) pathway plays an important role in the development of acute lung injury and fibrosis characteristic of these and other pulmonary inflammatory and fibrotic syndromes. We evaluated the role of apoptosis via the Fas/FasL pathway in the development of pulmonary inflammation and fibrosis in reovirus 1/L-induced BOOP and ARDS. CBA/J mice were intranasally inoculated with saline, 1 x 10(6) (BOOP), or 1 x 10(7) (ARDS) PFU reovirus 1/L, and evaluated at various days postinoculation for in situ apoptosis by TUNEL analysis and Fas/FasL expression. Our results demonstrate the presence of apoptotic cells and up-regulation of Fas/FasL expression in alveolar epithelium and in infiltrating cells during the inflammatory and fibrotic stages of both reovirus 1/L-induced ARDS and BOOP. Treatment of mice with the caspase 8 inhibitor, zIETD-fmk, inhibited apoptosis, inflammation, and fibrotic lesion development in reovirus 1/L-induced BOOP and ARDS. However, CBA/KlJms-Fas(lpr-cg)/J mice, which carry a point mutation in the Fas cytoplasmic region that abolishes the ability of Fas to transduce an apoptotic signal, do not develop pulmonary inflammation and fibrotic lesions associated with reovirus 1/L-induced BOOP, but still develop inflammation and fibrotic lesions associated with reovirus 1/L-induced ARDS. These results suggest a differential role for the Fas/FasL apoptotic pathway in the development of inflammation and fibrotic lesions associated with BOOP and ARDS.

  4. Blockage of both the extrinsic and intrinsic pathways of diazinon-induced apoptosis in PaTu cells by magnesium oxide and selenium nanoparticles

    Directory of Open Access Journals (Sweden)

    Shiri M

    2016-11-01

    Full Text Available Mahdi Shiri,1,2,* Mona Navaei-Nigjeh,1,3,* Maryam Baeeri,1 Mahban Rahimifard,1 Hossein Mahboudi,4 Ahmad Reza Shahverdi,5 Abbas Kebriaeezadeh,1 Mohammad Abdollahi1,6,7 1Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 2School of Medicine, Artesh University of Medical Sciences, 3Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Biotechnology, Faculty of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 5Department of Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, 6Toxicology Interest Group, USERN, 7Endocrinology & Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran *These authors contributed equally to this work Abstract: Diazinon (DZ is an organophosphorus insecticide that acts as an acetylcholinesterase inhibitor. It is important to note that it can induce oxidative stress, lipid peroxidation, diabetic disorders, and cytotoxicity. Magnesium oxide (MgO and selenium nanoparticles (Se NPs showed promising protection against oxidative stress, lipid peroxidation, cytotoxicity, and diabetic disorders. Therefore, this study was conducted to explore the possible protective mechanisms of MgO and Se NPs against DZ-induced cytotoxicity in PaTu cell line. Cytotoxicity of DZ, in the presence or absence of effective doses of MgO and Se NPs, was determined in human pancreatic cancer cell line (PaTu cells after 24 hours of exposure by using mitochondrial activity and mitochondrial membrane potential assays. Then, the insulin, proinsulin, and C-peptide release; caspase-3 and -9 activities; and total thiol molecule levels were assessed. Determination of cell viability, including apoptotic and necrotic cells, was assessed via acridine orange/ethidium bromide double

  5. ANTITUMOR AND APOPTOTIC EFFECTS OF CUCURBITACIN A IN A-549 LUNG CARCINOMA CELLS IS MEDIATED VIA G2/M CELL CYCLE ARREST AND M-TOR/PI3K/AKT SIGNALLING PATHWAY.

    Science.gov (United States)

    Wang, Wen-Dong; Liu, Yan; Su, Yuan; Xiong, Xian-Zhi; Shang, Dan; Xu, Juan-Juan; Liu, Hong-Ju

    2017-01-01

    The main aim of this study was to demonstrate the antitumor potential of cucurbitacin A on A-549 NSCLC (non-small cell lung cancer cells). The effects of Cucurbitacin A on apoptotic induction, cell physic, cell cycle failure and m-TOR/PI3K/Akt signalling pathway were also investigated in the present study. MTT assay and clonogenic assay were carried out to study effects of this compound on cell cytotoxicity and colony forming tendency in A-549 cells. Moreover, phase and fluorescence microscopic techniques were used to examine the effects on cell morphology and induction of apoptosis. The effects on cell cycle phase distribution were investigated by flow cytometry and effects on m-TOR/PI3K/Akt signalling proteins were assessed by western blot analysis. Results showed that cucurbitacin A induced dose-dependent cytotoxic effects along with suppressing the colony forming tendency in these cells. Cucurbitacin A also induced morphological changes in these cells featuring chromatin condensation, cell shrinkage and apoptotic body formation. G2/M phase cell cycle collapse was also induced by Cucurbitacin A along with inhibition of expression levels of m-TOR/PI3K/Akt proteins. In conclusion, cucurbitacin A inhibits cancer growth in A-549 NSCLC cells by inducing apoptosis, targeting m-TOR/PI3K/Akt signalling pathway and G2/M cell cycle.

  6. Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells

    Directory of Open Access Journals (Sweden)

    Del Pozzo Giovanna

    2009-06-01

    Full Text Available Abstract Background: BPA (bisphenol A or 2,2-bis(4-hydroxy-phenolpropane is present in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA. Thus, it is necessary to investigate the cytotoxicity and apoptosis-inducing activity of this compound. Methods: Cell cycle, apoptosis and differentiation analyses; western blots. Results: BPA is able to induce cell cycle arrest and apoptosis in three different acute myeloid leukemias. Although some granulocytic differentiation concomitantly occurred in NB4 cells upon BPA treatment, the major action was the induction of apoptosis. BPA mediated apoptosis was caspase dependent and occurred by activation of extrinsic and intrinsic cell death pathways modulating both FAS and TRAIL and by inducing BAD phosphorylation in NB4 cells. Finally, also non genomic actions such as the early decrease of both ERK and AKT phosphorylation were induced by BPA thus indicating that a complex intersection of regulations occur for the apoptotic action of BPA. Conclusion: BPA is able to induce apoptosis in leukemia cells via caspase activation and involvement of both intrinsic and extrinsic pathways of apoptosis.

  7. Cisplatin and a potent platinum(IV) complex-mediated enhancement of TRAIL-induced cancer cells killing is associated with modulation of upstream events in the extrinsic apoptotic pathway

    Czech Academy of Sciences Publication Activity Database

    Vondálová Blanářová, Olga; Jelínková, Iva; Szoor, A.; Skender, Belma; Souček, Karel; Horváth, Viktor; Vaculová, Alena; Anděra, Ladislav; Sova, P.; Szollosi, J.; Hofmanová, Jiřina; Vereb, G.; Kozubík, Alois

    2011-01-01

    Roč. 32, č. 1 (2011), s. 42-51 ISSN 0143-3334 R&D Projects: GA ČR(CZ) GA301/07/1557; GA MZd NS9600 Grant - others:GA ČR(CZ) GD303/09/H048 Program:GD Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702; CEZ:AV0Z50520514 Keywords : TRAIL * platinum complexes * apoptosis Subject RIV: BO - Biophysics Impact factor: 5.702, year: 2011

  8. EGCG protects against homocysteine-induced human umbilical vein endothelial cells apoptosis by modulating mitochondrial-dependent apoptotic signaling and PI3K/Akt/eNOS signaling pathways.

    Science.gov (United States)

    Liu, Shumin; Sun, Zhengwu; Chu, Peng; Li, Hailong; Ahsan, Anil; Zhou, Ziru; Zhang, Zonghui; Sun, Bin; Wu, Jingjun; Xi, Yalin; Han, Guozhu; Lin, Yuan; Peng, Jinyong; Tang, Zeyao

    2017-05-01

    Homocysteine (Hcy) induced vascular endothelial injury leads to the progression of endothelial dysfunction in atherosclerosis. Epigallocatechin gallate (EGCG), a natural dietary antioxidant, has been applied to protect against atherosclerosis. However, the underlying protective mechanism of EGCG has not been clarified. The present study investigated the mechanism of EGCG protected against Hcy-induced human umbilical vein endothelial cells (HUVECs) apoptosis. Methyl thiazolyl tetrazolium assay (MTT), transmission electron microscope, fluorescent staining, flow cytometry, western blot were used in this study. The study has demonstrated that EGCG suppressed Hcy-induced endothelial cell morphological changes and reactive oxygen species (ROS) generation. Moreover, EGCG dose-dependently prevented Hcy-induced HUVECs cytotoxicity and apoptotic biochemical changes such as reducing mitochondrial membrane potential (MMP), decreasing Bcl-2/Bax protein ratio and activating caspase-9 and 3. In addition, EGCG enhanced the protein ratio of p-Akt/Akt, endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) formation in injured cells. In conclusion, the present study shows that EGCG prevents Hcy-induced HUVECs apoptosis via modulating mitochondrial apoptotic and PI3K/Akt/eNOS signaling pathways. Furthermore, the results indicate that EGCG is likely to represent a potential therapeutic strategy for atherosclerosis associated with Hyperhomocysteinemia (HHcy).

  9. Intrinsic and extrinsic mortality reunited.

    Science.gov (United States)

    Koopman, Jacob J E; Wensink, Maarten J; Rozing, Maarten P; van Bodegom, David; Westendorp, Rudi G J

    2015-07-01

    Intrinsic and extrinsic mortality are often separated in order to understand and measure aging. Intrinsic mortality is assumed to be a result of aging and to increase over age, whereas extrinsic mortality is assumed to be a result of environmental hazards and be constant over age. However, allegedly intrinsic and extrinsic mortality have an exponentially increasing age pattern in common. Theories of aging assert that a combination of intrinsic and extrinsic stressors underlies the increasing risk of death. Epidemiological and biological data support that the control of intrinsic as well as extrinsic stressors can alleviate the aging process. We argue that aging and death can be better explained by the interaction of intrinsic and extrinsic stressors than by classifying mortality itself as being either intrinsic or extrinsic. Recognition of the tight interaction between intrinsic and extrinsic stressors in the causation of aging leads to the recognition that aging is not inevitable, but malleable through the environment. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Human surfactant protein D alters oxidative stress and HMGA1 expression to induce p53 apoptotic pathway in eosinophil leukemic cell line.

    Directory of Open Access Journals (Sweden)

    Lakshna Mahajan

    Full Text Available Surfactant protein D (SP-D, an innate immune molecule, has an indispensable role in host defense and regulation of inflammation. Immune related functions regulated by SP-D include agglutination of pathogens, phagocytosis, oxidative burst, antigen presentation, T lymphocyte proliferation, cytokine secretion, induction of apoptosis and clearance of apoptotic cells. The present study unravels a novel ability of SP-D to reduce the viability of leukemic cells (eosinophilic leukemic cell line, AML14.3D10; acute myeloid leukemia cell line, THP-1; acute lymphoid leukemia cell lines, Jurkat, Raji; and human breast epithelial cell line, MCF-7, and explains the underlying mechanisms. SP-D and a recombinant fragment of human SP-D (rhSP-D induced G2/M phase cell cycle arrest, and dose and time-dependent apoptosis in the AML14.3D10 eosinophilic leukemia cell line. Levels of various apoptotic markers viz. activated p53, cleaved caspase-9 and PARP, along with G2/M checkpoints (p21 and Tyr15 phosphorylation of cdc2 showed significant increase in these cells. We further attempted to elucidate the underlying mechanisms of rhSP-D induced apoptosis using proteomic analysis. This approach identified large scale molecular changes initiated by SP-D in a human cell for the first time. Among others, the proteomics analysis highlighted a decreased expression of survival related proteins such as HMGA1, overexpression of proteins to protect the cells from oxidative burst, while a drastic decrease in mitochondrial antioxidant defense system. rhSP-D mediated enhanced oxidative burst in AML14.3D10 cells was confirmed, while antioxidant, N-acetyl-L-cysteine, abrogated the rhSP-D induced apoptosis. The rhSP-D mediated reduced viability was specific to the cancer cell lines and viability of human PBMCs from healthy controls was not affected. The study suggests involvement of SP-D in host's immunosurveillance and therapeutic potential of rhSP-D in the eosinophilic leukemia and

  11. Regularized strings with extrinsic curvature

    International Nuclear Information System (INIS)

    Ambjoern, J.; Durhuus, B.

    1987-07-01

    We analyze models of discretized string theories, where the path integral over world sheet variables is regularized by summing over triangulated surfaces. The inclusion of curvature in the action is a necessity for the scaling of the string tension. We discuss the physical properties of models with extrinsic curvature terms in the action and show that the string tension vanishes at the critical point where the bare extrinsic curvature coupling tends to infinity. Similar results are derived for models with intrinsic curvature. (orig.)

  12. Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2 Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway.

    Directory of Open Access Journals (Sweden)

    Qian Fan

    Full Text Available Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2 activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in myocytes, we investigated the effect of cardiomyocyte-specific GRK2 ablation on the acute response to cardiac ischemia/reperfusion (I/R injury. To do this we utilized two independent lines of GRK2 knockout (KO mice where the GRK2 gene was deleted in only cardiomyocytes either constitutively at birth or in an inducible manner that occurred in adult mice prior to I/R. These GRK2 KO mice and appropriate control mice were subjected to a sham procedure or 30 min of myocardial ischemia via coronary artery ligation followed by 24 hrs reperfusion. Echocardiography and hemodynamic measurements showed significantly improved post-I/R cardiac function in both GRK2 KO lines, which correlated with smaller infarct sizes in GRK2 KO mice compared to controls. Moreover, there was significantly less TUNEL positive myocytes, less caspase-3, and -9 but not caspase-8 activities in GRK2 KO mice compared to control mice after I/R injury. Of note, we found that lowering cardiac GRK2 expression was associated with significantly lower cytosolic cytochrome C levels in both lines of GRK2 KO mice after I/R compared to corresponding control animals. Mechanistically, the anti-apoptotic effects of lowering GRK2 expression were accompanied by increased levels of Bcl-2, Bcl-xl, and increased activation of Akt after I/R injury. These findings were reproduced in vitro in cultured cardiomyocytes and GRK2 mRNA silencing. Therefore, lowering GRK2 expression in cardiomyocytes limits I/R-induced injury and improves post-ischemia recovery by decreasing myocyte apoptosis at least partially via Akt/Bcl-2 mediated mitochondrial protection and implicates mitochondrial-dependent actions, solidifying GRK2 as a pro-death kinase in the heart.

  13. Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways

    International Nuclear Information System (INIS)

    Lehnhardt, Marcus; Mueller, Oliver; Klein-Hitpass, Ludger; Kuhnen, Cornelius; Homann, Heinz Herbert; Daigeler, Adrien; Steinau, Hans Ulrich; Roehrs, Sonja; Schnoor, Laura; Steinstraesser, Lars

    2005-01-01

    Because of the high resistance rate of fibrosarcomas against cytotoxic agents clinical chemotherapy of these tumors is not established. A better understanding of the diverse modes of tumor cell death following cytotoxic therapies will provide a molecular basis for new chemotherapeutic strategies. In this study we elucidated the response of a fibrosarcoma cell line to clinically used cytostatic agents on the level of gene expression. HT1080 fibrosarcoma cells were exposed to the chemotherapeutic agents doxorubicin, actinomycin D or vincristine. Total RNA was isolated and the gene expression patterns were analyzed by microarray analysis. Expression levels for 46 selected candidate genes were validated by quantitative real-time PCR. The analysis of the microarray data resulted in 3.309 (actinomycin D), 1.019 (doxorubicin) and 134 (vincristine) probesets that showed significant expression changes. For the RNA synthesis blocker actinomycin D, 99.4% of all differentially expressed probesets were under-represented. In comparison, probesets down-regulated by doxorubicin comprised only 37.4% of all genes effected by this agent. Closer analysis of the differentially regulated genes revealed that doxorubicin induced cell death of HT1080 fibrosarcoma cells mainly by regulating the abundance of factors mediating the mitochondrial (intrinsic) apoptosis pathway. Furthermore doxorubicin influences other pathways and crosstalk to other pathways (including to the death receptor pathway) at multiple levels. We found increased levels of cytochrome c, APAF-1 and members of the STAT-family (STAT1, STAT3), while Bcl-2 expression was decreased. Caspase-1, -3, -6, -8, and -9 were increased indicating that these proteases are key factors in the execution of doxorubicin mediated apoptosis. This study demonstrates that chemotherapy regulates the expression of apoptosis-related factors in fibrosarcoma cells. The number and the specific pattern of the genes depend on the used cytotoxic drug

  14. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms.

    Science.gov (United States)

    Banu, Sakhila K; Lee, JeHoon; Speights, V O; Starzinski-Powitz, Anna; Arosh, Joe A

    2009-08-01

    Endometriosis is a benign chronic gynecological disease of reproductive-age women characterized by the presence of functional endometrial tissues outside the uterine cavity. It is an estrogen-dependent disease. Current treatment modalities to inhibit biosynthesis and actions of estrogen compromise menstruation, pregnancy, and the reproductive health of women and fail to prevent reoccurrence of disease. There is a critical need to identify new specific signaling modules for non-estrogen-targeted therapies for endometriosis. In our previous study, we reported that selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased prostaglandin E(2) (PGE(2)) production. In this study, we determined mechanisms through which PGE(2) promoted survival of human endometriotic cells. Results of the present study indicate that 1) PGE(2) promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, nuclear factor-kappaB, and beta-catenin signaling pathways; 2) selective inhibition of EP2 and EP4 suppresses these cell survival pathways and augments interactions between proapoptotic proteins (Bax and Bad) and antiapoptotic proteins (Bcl-2/Bcl-XL), facilitates the release of cytochrome c, and thus activates caspase-3/poly (ADP-ribose) polymerase-mediated intrinsic apoptotic pathways; and 3) these PGE(2) signaling components are more abundantly expressed in ectopic endometriosis tissues compared with eutopic endometrial tissues during the menstrual cycle in women. These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential therapy, including nonestrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.

  15. A novel compound DT-010 protects against doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by inhibiting reactive oxygen species-mediated apoptotic and autophagic pathways.

    Science.gov (United States)

    Tang, Fan; Zhou, Xinhua; Wang, Liang; Shan, Luchen; Li, Chuwen; Zhou, Hefeng; Lee, Simon Ming-Yuen; Hoi, Maggie Pui-Man

    2018-02-05

    Doxorubicin (Dox) is an effective anti-cancer agent but limited by its cardiotoxicity, thus the search for pharmacological agents for enhancing anti-cancer activities and protecting against cardiotoxicity has been a subject of great interest. We have previously reported the synergistic anti-cancer effects of a novel compound DT-010. In the present study, we further investigated the cardioprotective effects of DT-010 in zebrafish embryos in vivo and the molecular underlying mechanisms in H9c2 cardiomyocytes in vitro. We showed that DT-010 prevented the Dox-induced morphological distortions in the zebrafish heart and the associated cardiac impairments, and especially improved ventricular functions. By using H9c2 cells model, we showed that DT-010 directly inhibited the generation of reactive oxygen species by Dox and protected cell death and cellular damage. We further observed that DT-010 protected against Dox-induced myocardiopathy via inhibiting downstream molecular pathways in response to oxidative stress, including reactive oxygen species-mediated MAPK signaling pathways ERK and JNK, and apoptotic pathways involving the activation of caspase 3, caspase 7, and PARP signaling. Recent studies also suggest the importance of alterations in cardiac autophagy in Dox cardiotoxicity. We further showed that DT-010 could inhibit the induction of autophagosomes formation by Dox via regulating the upstream Akt/AMPK/mTOR signaling. Since Dox-induced cardiotoxicity is multifactorial, our results suggest that multi-functional agent such as DT-010 might be an effective therapeutic agent for combating cardiotoxicity associated with chemotherapeutic agents such as Dox. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway.

    Science.gov (United States)

    Akiyoshi, Takeshi; Matzno, Sumio; Sakai, Mika; Okamura, Noboru; Matsuyama, Kenji

    2009-12-01

    We tried to clarify the cytotoxic mechanism of VK(3) using the breast cancer cell line MCF-7. Cytotoxicity was measured via intracellular esterase activity. DNA fragmentation was assessed by agarose gel electrophoresis. JC-1 staining was applied to measure mitochondrial dysfunction. Caspase activation and reactive oxidative species (ROS) generation were also measured. VK(3) exhibited cytotoxicity that caused DNA fragmentation in MCF-7 cells with an IC(50) of 14.2 microM. JC-1 staining revealed that VK(3) caused mitochondrial dysfunction including a disappearance of mitochondrial membrane potential. Additional investigation showed that the mitochondrial damage was induced by the generation of ROS and the subsequent activation of caspase-7 and -9. Our findings demonstrate that VK(3)-induced apoptosis is selectively initiated by the mitochondria-related pathway and might be useful in breast cancer chemotherapy.

  17. Differential modulation of apoptotic processes by proanthocyanidins as a dietary strategy for delaying chronic pathologies.

    Science.gov (United States)

    Puiggròs, Francesc; Salvadó, Maria-Josepa; Bladé, Cinta; Arola, Lluís

    2014-01-01

    Apoptosis is a biological process necessary for maintaining cellular homeostasis. Several diseases can result if it is deregulated. For example, inhibition of apoptotic signaling pathways is linked to the survival of pathological cells, which contributes to cancer, whereas excessive apoptosis is linked to neurodegenerative diseases, partially via oxidative stress. The activation or restoration of apoptosis via extrinsic or intrinsic pathways combined with cell signaling pathways triggered by reactive oxygen specises (ROS) formation is considered a key strategy by which bioactive foods can exert their health effects. Proanthocyanidins, a class of flavonoids naturally found in fruits, vegetables, and beverages, have attracted a great deal of attention not only because they are strong antioxidants but also because they appear to exert a different modulation of apoptosis, stimulating apoptosis in damaged cells, thus preventing cancer or reducing apoptosis in healthy cells, and as a result, preserving the integrity of normal cells and protecting against neurodegenerative diseases. Therefore, proanthocyanidins could provide a defense against apoptosis induced by oxidative stress or directly inhibit apoptosis, and they could also provide a promising treatment for a variety of diseases. Emerging data suggest that proanthocyanidins, especially those that humans can be persuaded to consume, may be used to prevent and manage cancer and mental disorders.

  18. Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Xiangbao; Wang, Min [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Guibo, E-mail: sunguibo@126.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Ye, Jingxue [Jilin Agricultural University, Changchun, Jilin 130021 (China); Zhou, Yanhui [Center of Cardiology, People' s Hospital of Jilin Province, Changchun, 130021, Jilin (China); Dong, Xi [Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Wang, Tingting; Lu, Shan [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Xiaobo, E-mail: sun_xiaobo163@163.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China)

    2014-08-15

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens

  19. Somatotropinomas, but not nonfunctioning pituitary adenomas, maintain a functional apoptotic RET/Pit1/ARF/p53 pathway that is blocked by excess GDNF.

    Science.gov (United States)

    Diaz-Rodriguez, Esther; Garcia-Rendueles, Angela R; Ibáñez-Costa, Alejandro; Gutierrez-Pascual, Ester; Garcia-Lavandeira, Montserrat; Leal, Alfonso; Japon, Miguel A; Soto, Alfonso; Venegas, Eva; Tinahones, Francisco J; Garcia-Arnes, Juan A; Benito, Pedro; Angeles Galvez, Maria; Jimenez-Reina, Luis; Bernabeu, Ignacio; Dieguez, Carlos; Luque, Raul M; Castaño, Justo P; Alvarez, Clara V

    2014-11-01

    Acromegaly is caused by somatotroph cell adenomas (somatotropinomas [ACROs]), which secrete GH. Human and rodent somatotroph cells express the RET receptor. In rodents, when normal somatotrophs are deprived of the RET ligand, GDNF (Glial Cell Derived Neurotrophic Factor), RET is processed intracellularly to induce overexpression of Pit1 [Transcription factor (gene : POUF1) essential for transcription of Pituitary hormones GH, PRL and TSHb], which in turn leads to p19Arf/p53-dependent apoptosis. Our purpose was to ascertain whether human ACROs maintain the RET/Pit1/p14ARF/p53/apoptosis pathway, relative to nonfunctioning pituitary adenomas (NFPAs). Apoptosis in the absence and presence of GDNF was studied in primary cultures of 8 ACROs and 3 NFPAs. Parallel protein extracts were analyzed for expression of RET, Pit1, p19Arf, p53, and phospho-Akt. When GDNF deprived, ACRO cells, but not NFPAs, presented marked level of apoptosis that was prevented in the presence of GDNF. Apoptosis was accompanied by RET processing, Pit1 accumulation, and p14ARF and p53 induction. GDNF prevented all these effects via activation of phospho-AKT. Overexpression of human Pit1 (hPit1) directly induced p19Arf/p53 and apoptosis in a pituitary cell line. Using in silico studies, 2 CCAAT/enhancer binding protein alpha (cEBPα) consensus-binding sites were found to be 100% conserved in mouse, rat, and hPit1 promoters. Deletion of 1 cEBPα site prevented the RET-induced increase in hPit1 promoter expression. TaqMan qRT-PCR (real time RT-PCR) for RET, Pit1, Arf, TP53, GDNF, steroidogenic factor 1, and GH was performed in RNA from whole ACRO and NFPA tumors. ACRO but not NFPA adenomas express RET and Pit1. GDNF expression in the tumors was positively correlated with RET and negatively correlated with p53. In conclusion, ACROs maintain an active RET/Pit1/p14Arf/p53/apoptosis pathway that is inhibited by GDNF. Disruption of GDNF's survival function might constitute a new therapeutic route in

  20. Lycopene protects human SH-SY5Y neuroblastoma cells against hydrogen peroxide-induced death via inhibition of oxidative stress and mitochondria-associated apoptotic pathways

    Science.gov (United States)

    FENG, CHUNSHENG; LUO, TIANFEI; ZHANG, SHUYAN; LIU, KAI; ZHANG, YANHONG; LUO, YINAN; GE, PENGFEI

    2016-01-01

    Oxidative stress, which is characterized by excessive production of reactive oxygen species (ROS), is a common pathway that results in neuronal injury or death due to various types of pathological stress. Although lycopene has been identified as a potent antioxidant, its effect on hydrogen peroxide (H2O2)-induced neuronal damage remains unclear. In the present study, pretreatment with lycopene was observed to protect SH-SY5Y neuroblastoma cells against H2O2-induced death via inhibition of apoptosis resulting from activation of caspase-3 and translocation of apoptosis inducing factor (AIF) to the nucleus. Furthermore, the over-produced ROS, as well as the reduced activities of anti-oxidative enzymes, superoxide dismutase and catalase, were demonstrated to be alleviated by lycopene. Additionally, lycopene counteracted H2O2-induced mitochondrial dysfunction, which was evidenced by suppression of mitochondrial permeability transition pore opening, attenuation of the decline of the mitochondrial membrane potential, and inhibition of the increase of Bax and decrease of Bcl-2 levels within the mitochondria. The release of cytochrome c and AIF from the mitochondria was also reduced. These results indicate that lycopene is a potent neuroprotectant against apoptosis, oxidative stress and mitochondrial dysfunction, and could be administered to prevent neuronal injury or death. PMID:27035331

  1. Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.

    Science.gov (United States)

    Lin, Ming-Te; Lin, Chia-Liang; Lin, Tzu-Yu; Cheng, Chun-Wen; Yang, Shun-Fa; Lin, Chu-Liang; Wu, Chih-Chien; Hsieh, Yi-Hsien; Tsai, Jen-Pi

    2016-05-01

    Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

  2. Imaging with extrinsic Raman labels

    NARCIS (Netherlands)

    Sijtsema, N M; Duindam, J J; Puppels, G J; Otto, C; Greve, J

    1996-01-01

    In two separate examples we demonstrate the use of extrinsic Raman scattering probes for imaging of biological samples. First, the distribution of cholesterol in a rat eye Lens is determined with the use of the Raman scattered light from filipin, a molecule which binds specifically to cholesterol.

  3. Extrinsic CPT Violation in Neutrino Oscillations

    International Nuclear Information System (INIS)

    Ohlsson, Tommy

    2004-01-01

    In this talk, we investigate extrinsic CPT violation in neutrino oscillations in matter with three flavors. Note that extrinsic CPT violation is different from intrinsic CPT violation. Extrinsic CPT violation is one way of quantifying matter effects, whereas intrinsic CPT violation would mean that the CPT invariance theorem is not valid. We present analytical formulas for the extrinsic CPT probability differences and discuss their implications for long-baseline experiments and neutrino factory setups

  4. The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons.

    Directory of Open Access Journals (Sweden)

    Xiaodong Huang

    Full Text Available Phenylketonuria (PKU, an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe. A recent study showed that the mitochondria-mediated (intrinsic apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic apoptotic pathway and endoplasmic reticulum (ER stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h, suggesting involvement of the Fas receptor (FasR-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients.

  5. Extrinsic incentives and tax compliance

    OpenAIRE

    Sour, Laura; Gutiérrez Andrade, Miguel Ángel

    2011-01-01

    This paper models the impact of extrinsic incentives in a tax compliance model. It also provides experimental evidence that confirms the existence of a positive relationship between rewards and tax compliance. If individuals are audited, rewards for honest taxpayers are effective in increasing the level of tax compliance. These results are particularly relevant in countries where there is little respect for tax law since rewards can contribute to crowding in the intrinsic motivation to comply.

  6. Wide Bandgap Extrinsic Photoconductive Switches

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, James S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2013-07-03

    Semi-insulating Gallium Nitride, 4H and 6H Silicon Carbide are attractive materials for compact, high voltage, extrinsic, photoconductive switches due to their wide bandgap, high dark resistance, high critical electric field strength and high electron saturation velocity. These wide bandgap semiconductors are made semi-insulating by the addition of vanadium (4H and 6HSiC) and iron (2H-GaN) impurities that form deep acceptors. These deep acceptors trap electrons donated from shallow donor impurities. The electrons can be optically excited from these deep acceptor levels into the conduction band to transition the wide bandgap semiconductor materials from a semi-insulating to a conducting state. Extrinsic photoconductive switches with opposing electrodes have been constructed using vanadium compensated 6H-SiC and iron compensated 2H-GaN. These extrinsic photoconductive switches were tested at high voltage and high power to determine if they could be successfully used as the closing switch in compact medical accelerators.

  7. 3'-Hydroxy-3,4'-dimethoxyflavone blocks tubulin polymerization and is a potent apoptotic inducer in human SK-MEL-1 melanoma cells.

    Science.gov (United States)

    Estévez-Sarmiento, Francisco; Said, Mercedes; Brouard, Ignacio; León, Francisco; García, Celina; Quintana, José; Estévez, Francisco

    2017-11-01

    Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. A series of flavonols and their 3-methyl ether derivatives were synthesized and assessed for cytotoxicity. It was found that 3'-hydroxy-3,4'-dimethoxyflavone (flavonoid 7a) displayed strong cytotoxicity against human SK-MEL-1 melanoma cells and blocked tubulin polymerization, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. Our analyses showed that flavonoid 7a induces G 2 -M cell cycle arrest and apoptosis in melanoma cells which is associated with cytochrome c release and activation of both extrinsic and intrinsic apoptotic pathways of cell death. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Activations of Both Extrinsic and Intrinsic Pathways in HCT 116 Human Colorectal Cancer Cells Contribute to Apoptosis through p53-Mediated ATM/Fas Signaling by Emilia sonchifolia Extract, a Folklore Medicinal Plant

    Directory of Open Access Journals (Sweden)

    Yu-Hsuan Lan

    2012-01-01

    Full Text Available Emilia sonchifolia (L. DC (Compositae, an herbaceous plant found in Taiwan and India, is used as folk medicine. The clinical applications include inflammation, rheumatism, cough, cuts fever, dysentery, analgesic, and antibacteria. The activities of Emilia sonchifolia extract (ESE on colorectal cancer cell death have not been fully investigated. The purpose of this study explored the induction of apoptosis and its molecular mechanisms in ESE-treated HCT 116 human colorectal cancer cells in vitro. The methanolic ESE was characterized, and γ-humulene was formed as the major constituent (63.86%. ESE induced cell growth inhibition in a concentration- and time-dependent response by MTT assay. Apoptotic cells (DNA fragmentation, an apoptotic catachrestic were found after ESE treatment by TUNEL assay and DNA gel electrophoresis. Alternatively, ESE stimulated the activities of caspase-3, -8, and -9 and their specific caspase inhibitors protected against ESE-induced cytotoxicity. ESE promoted the mitochondria-dependent and death-receptor-associated protein levels. Also, ESE increased ROS production and upregulated the levels of ATM, p53, and Fas in HCT 116 cells. Strikingly, p53 siRNA reversed ESE-reduced viability involved in p53-mediated ATM/Fas signaling in HCT 116 cells. In summary, our result is the first report suggesting that ESE may be potentially efficacious in the treatment of colorectal cancer.

  9. The anti-apoptotic and cardioprotective effects of salvianolic acid a on rat cardiomyocytes following ischemia/reperfusion by DUSP-mediated regulation of the ERK1/2/JNK pathway.

    Directory of Open Access Journals (Sweden)

    Tongda Xu

    Full Text Available The purpose of this study was to observe the effects of salvianolic acid A (SAA pretreatment on the myocardium during ischemia/reperfusion (I/R and to illuminate the interrelationships among dual specificity protein phosphatase (DUSP 2/4/16, ERK1/2 and JNK pathways during myocardial I/R, with the ultimate goal of elucidating how SAA exerts cardioprotection against I/R injury (IRI. Wistar rats were divided into the following six groups: control group (CON, I/R group, SAA+I/R group, ERK1/2 inhibitor PD098059+I/R group (PD+I/R, PD+SAA+I/R group, and JNK inhibitor SP600125+I/R group (SP+I/R. The cardioprotective effects of SAA on the myocardium during I/R were investigated with a Langendorff device. Heart rate (HR, left ventricular systolic pressure (LVSP, left ventricular end-diastolic pressure (LVEDP, maximum rate of ventricular pressure rise and fall (±dp/dtmax, myocardial infarction areas (MIA, lactate dehydrogenase (LDH, and cardiomyocytes apoptosis were monitored. To determine the crosstalk betwee JNK and ERK1/2 via DUSP2/4/16 with SAA pretreatment, siRNA-DUSP2/4/16 were performed. The expression levels of Bcl-2, Bax, caspase 3, p-JNK, p-ERK1/2 and DUSP2/4/16 in cardiomyocytes were assayed by Western blot. Our results showed that LDH, MIA and cell apoptosis were decreased, and various parameters of heart function were improved by SAA pretreatment and SP application. In the I/R group, the expression levels of p-ERK1/2 and DUSP4/16 were not significantly different compared with the CON group, however, the protein expression levels of p-ERK1/2, Bcl-2 and DUSP4/16 were higher, while p-JNK, Bax, caspase 3 and DUSP2 levels were reduced among the SAA+I/R, PD+SAA+I/R and SP+I/R groups. The above indices were not significantly different between the SAA+I/R and SP+I/R groups. Compared with the SAA+I/R group, p-ERK1/2 was increased and p-JNK was decreased in the SAA+si-DUSP2+I/R, however, p-ERK was downregulated and p-JNK was upregulated in SAA+si-DUSP4

  10. Inhibitory effects of rosmarinic acid on pterygium epithelial cells through redox imbalance and induction of extrinsic and intrinsic apoptosis.

    Science.gov (United States)

    Chen, Ya-Yu; Tsai, Chia-Fang; Tsai, Ming-Chu; Hsu, Yu-Wen; Lu, Fung-Jou

    2017-07-01

    Pterygium is a common tumor-like ocular disease, which may be related to exposure to chronic ultraviolet (UV) radiation. Although the standard treatment for pterygium is surgical intervention, the recurrence rate of pterygium is high when no effective inhibitory drug is used after surgery. Rosmarinic acid (RA) is a polyphenol antioxidant with many biological activities, including anti-UV and anti-tumor properties. This study aimed to examine the inhibitory effects of RA on pterygium epithelial cells (PECs). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to examine the cell cytotoxicity of PECs after RA treatment. A fluorescent probe, DCFH-DA (2',7'-dichlorofluorescin diacetate), was stained with PECs to measure intracellular reactive oxygen species (ROS) levels. Antioxidant activity assays were used to measure the levels of superoxide dismutase (SOD) and catalase (CAT) in PECs. Western blot analysis was used to determine the protein expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), quinone acceptor oxidoreductase 1 (NQO1), and apoptosis-associated proteins. RA significantly reduced the cell viability of the PECs. Treatment with RA remarkably increased the Nrf2 protein expression levels in the nucleus, HO-1 and NQO1 protein expression levels, and the activities of SOD and CAT. As a result, intracellular ROS levels in PECs were decreased. Additionally, the induction of extrinsic apoptosis on PECs by RA was associated with increasing expressions levels of Fas, Fas-associated protein with death domain (FADD), tumor necrosis factor-alpha (TNF-α), and caspase 8 protein. Moreover, the induction of intrinsic apoptotic cell death in PECs was confirmed through upregulation of cytochrome c, Bax, caspase 9, and caspase 3 and downregulation of Bcl-2 and pro-caspase 3. Our study demonstrated that RA could inhibit the viability of PECs through regulation of extrinsic and intrinsic apoptosis pathways. Therefore, RA may have

  11. Carbon ion beam triggers both caspase-dependent and caspase-independent pathway of apoptosis in HeLa and status of PARP-1 controls intensity of apoptosis.

    Science.gov (United States)

    Ghorai, Atanu; Sarma, Asitikantha; Bhattacharyya, Nitai P; Ghosh, Utpal

    2015-04-01

    High linear energy transfer (LET) carbon ion beam (CIB) is becoming very promising tool for various cancer treatments and is more efficient than conventional low LET gamma or X-rays to kill malignant or radio-resistant cells, although detailed mechanism of cell death is still unknown. Poly (ADP-ribose) polymerase-1 (PARP-1) is a key player in DNA repair and its inhibitors are well-known as radio-sensitizer for low LET radiation. The objective of our study was to find mechanism(s) of induction of apoptosis by CIB and role of PARP-1 in CIB-induced apoptosis. We observed overall higher apoptosis in PARP-1 knocked down HeLa cells (HsiI) compared with negative control H-vector cells after irradiation with CIB (0-4 Gy). CIB activated both intrinsic and extrinsic pathways of apoptosis via caspase-9 and caspase-8 activation respectively, followed by caspase-3 activation, apoptotic body, nucleosomal ladder formation and sub-G1 accumulation. Apoptosis inducing factor translocation into nucleus in H-vector but not in HsiI cells after CIB irradiation contributed caspase-independent apoptosis. Higher p53 expression was observed in HsiI cells compared with H-vector after exposure with CIB. Notably, we observed about 37 % fall of mitochondrial membrane potential, activation of caspase-9 and caspase-3 and mild activation of caspase-8 without any detectable apoptotic body formation in un-irradiated HsiI cells. We conclude that reduction of PARP-1 expression activates apoptotic signals via intrinsic and extrinsic pathways in un-irradiated cells. CIB irradiation further intensified both intrinsic and extrinsic pathways of apoptosis synergistically along with up-regulation of p53 in HsiI cells resulting overall higher apoptosis in HsiI than H-vector.

  12. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237 on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway

    Directory of Open Access Journals (Sweden)

    Niu NK

    2015-03-01

    mesenchymal transition (EMT and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K/protein kinase B (Akt/mammalian target of rapamycin (mTOR and p38 mitogen-activated protein kinase (p38 MAPK signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2 in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy. Keywords: ALS, autophagy, apoptosis, osteosarcoma, PI3K/Akt/mTOR pathway, EMT

  13. Role of the mitochondria in immune-mediated apoptotic death of the human pancreatic β cell line βLox5.

    Directory of Open Access Journals (Sweden)

    Yaíma L Lightfoot

    Full Text Available Mitochondria are indispensable in the life and death of many types of eukaryotic cells. In pancreatic beta cells, mitochondria play an essential role in the secretion of insulin, a hormone that regulates blood glucose levels. Unregulated blood glucose is a hallmark symptom of diabetes. The onset of Type 1 diabetes is preceded by autoimmune-mediated destruction of beta cells. However, the exact role of mitochondria has not been assessed in beta cell death. In this study, we examine the role of mitochondria in both Fas- and proinflammatory cytokine-mediated destruction of the human beta cell line, βLox5. IFNγ primed βLox5 cells for apoptosis by elevating cell surface Fas. Consequently, βLox5 cells were killed by caspase-dependent apoptosis by agonistic activation of Fas, but only after priming with IFNγ. This beta cell line undergoes both apoptotic and necrotic cell death after incubation with the combination of the proinflammatory cytokines IFNγ and TNFα. Additionally, both caspase-dependent and -independent mechanisms that require proper mitochondrial function are involved. Mitochondrial contributions to βLox5 cell death were analyzed using mitochondrial DNA (mtDNA depleted βLox5 cells, or βLox5 ρ(0 cells. βLox5 ρ(0 cells are not sensitive to IFNγ and TNFα killing, indicating a direct role for the mitochondria in cytokine-induced cell death of the parental cell line. However, βLox5 ρ(0 cells are susceptible to Fas killing, implicating caspase-dependent extrinsic apoptotic death is the mechanism by which these human beta cells die after Fas ligation. These data support the hypothesis that immune mediators kill βLox5 cells by both mitochondrial-dependent intrinsic and caspase-dependent extrinsic pathways.

  14. Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering.

    Science.gov (United States)

    Chaabane, Wiem; Cieślar-Pobuda, Artur; El-Gazzah, Mohamed; Jain, Mayur V; Rzeszowska-Wolny, Joanna; Rafat, Mehrdad; Stetefeld, Joerg; Ghavami, Saeid; Los, Marek J

    2014-09-01

    The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

  15. Cynodon dactylon (L) Pers (Poaceae) root extract induces apoptotic ...

    African Journals Online (AJOL)

    has also been used for the treatment of weak vision, urinary tract infection, .... with an alternating 12 h dark/light cycle in ... detected by Western blot analysis as described previously .... the cyclin signaling pathways, induced apoptotic cell death ...

  16. Puma and Trail/Dr5 Pathways Control Radiation-Induced Apoptosis in Distinct Populations of Testicular Progenitors

    International Nuclear Information System (INIS)

    Coureuil, M.; Tavernier, M.; Barroca, V.; Fouchet, P.; Allemand, I.; Ugolin, N.; Chevillard, S.

    2010-01-01

    Spermatogonia- stem cells and progenitors of adult spermatogenesis- are killed through a p53-regulated apoptotic process after γ-irradiation but the death effectors are still poorly characterized. Our data demonstrate that both intrinsic and extrinsic apoptotic pathways are involved, and especially that spermatogonia can be split into two main populations, according to apoptotic effectors. Following irradiation both Dr5 and Puma genes are up-regulated in the α 6 -integrin-positive Side Population (SP) fraction, which is highly enriched in spermatogonia. Flow cytometric analysis confirms an increased number of Dr5-expressing SP cells, and Puma-β isoform accumulates in α 6 -integrin positive cellular extracts, enriched in spermatogonia. Trail -/- or Puma -/- spermatogonia display a reduced sensitivity to radiation-induced apoptosis. The TUNEL kinetics strongly suggest that the extrinsic and intrinsic pathways, via Trail/Dr5 and Puma respectively, could be engaged in distinct subpopulations of spermatogonia. Indeed flow cytometric studies show that Dr5 receptor is constitutively present on more than half of the undifferentiated progenitors (Kit - α 6 + SP) and half of the differentiated ones (Kit + α 6 + SP). In addition after irradiation, Puma is not detected in the Dr5-positive cellular fraction isolated by immuno-magnetic purification, while Puma is present in the Dr5-negative cell extracts. In conclusion, adult testicular progenitors are divided into distinct sub-populations by apoptotic effectors, independently of progenitor types (immature Kit-negative versus mature Kit-positive), underscoring differential radiosensitivities characterizing the stem cell/progenitors compartment. (authors)

  17. Lack of a Functional VHL Gene Product Sensitizes Renal Cell Carcinoma Cells to the Apoptotic Effects of the Protein Synthesis Inhibitor Verrucarin A

    Directory of Open Access Journals (Sweden)

    Girma M. Woldemichael

    2012-08-01

    Full Text Available Verrucarin A (VA is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau (VHL gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC.

  18. Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A.

    Science.gov (United States)

    Woldemichael, Girma M; Turbyville, Thomas J; Vasselli, James R; Linehan, W Marston; McMahon, James B

    2012-08-01

    Verrucarin A (VA) is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC) cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau (VHL) gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC.

  19. Lack of a Functional VHL Gene Product Sensitizes Renal Cell Carcinoma Cells to the Apoptotic Effects of the Protein Synthesis Inhibitor Verrucarin A12

    Science.gov (United States)

    Woldemichael, Girma M; Turbyville, Thomas J; Vasselli, James R; Linehan, W Marston; McMahon, James B

    2012-01-01

    Verrucarin A (VA) is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC) cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau (VHL) gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC. PMID:22952429

  20. The apoptotic effects of Brucea javanica fruit extract against HT29 cells associated with p53 upregulation and inhibition of NF-κB translocation

    Directory of Open Access Journals (Sweden)

    Bagheri E

    2018-03-01

    , and tumor necrosis factor receptors, which confirmed the contribution of extrinsic pathway. Meanwhile, increased ROS production in treated cells subsequently activated caspase-9 production, which triggered the intrinsic pathways. In addition, overexpression of cytochrome-c, Bax, and Bad proteins along with suppression of Bcl-2 illustrated that mitochondrial-dependent pathway also contributed to BJEE-induced cell death. Consistent with the findings from this study, BJEE-induced cancer cell death proceeds via extrinsic and intrinsic mitochondrial-dependent and -independent events.Conclusion: From the evidence obtained from this study, it is concluded that the BJEE is a promising natural extract to combat colorectal cancer cells (HT29 cells via induction of apoptosis through activation of extrinsic and intrinsic pathways. Keywords: Brucea javanica, apoptosis, cancer, HT29, mitochondrial pathway, apoptosis protein array

  1. Defining intrinsic vs. extrinsic atopic dermatitis.

    Science.gov (United States)

    Karimkhani, Chante; Silverberg, Jonathan I; Dellavalle, Robert P

    2015-06-16

    Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin condition characterized by eczematous lesions, i.e. ill-demarcated erythematous patches and plaques. AD is commonly associated with elevated immunoglobulin E (IgE) and atopic disorders, such as asthma, hay fever, and food allergies. Rackemann and Mallory were some of the first to distinguish between asthma based on the presence ("extrinsic") or absence ("intrinsic") of allergy. This distinction has subsequently been applied to AD based on the presence ("extrinsic") or absence ("intrinsic") of increased IgE and atopic disease. Although the distinction between intrinsic and extrinsic AD is widely used, it remains controversial.

  2. Analysis of porcine granulosa cell death signaling pathways induced by vinclozolin.

    Science.gov (United States)

    Knet, Malgorzata; Wartalski, Kamil; Hoja-Lukowicz, Dorota; Tabarowski, Zbigniew; Slomczynska, Maria; Duda, Malgorzata

    2015-10-01

    Recent studies suggest that disturbing androgen-signaling pathways in porcine ovarian follicles may cause granulosa cell (GC) death. For this reason, we investigated which apoptotic pathway is initiated after GC exposure to an environmental antiandrogen, vinclozolin (Vnz), in vitro. Immunocytochemistry, Western blots, and fluorometric assays were used to quantify caspase-3 and -9 expression and activity. To elucidate the specific mechanism of Vnz action and toxicity, GCs were assessed for viability, cytotoxicity, and apoptotic activity using the ApoTox-Glo Triplex Assay. To further determine the mechanism of GC death induced by Vnz, we used the Apoptosis Antibody Array Kit. In response to Vnz stimulus, we found an increased level of caspase-3 protein expression (P ≤ 0.001) and an increase in caspase-3 proteolytic activity (P ≤ 0.001), confirming that Vnz is a potent proapoptotic factor. The strong immunoreaction of caspase-9 after Vnz treatment (P ≤ 0.001) suggests that intrinsic mitochondrial apoptosis pathway was activated during GC death. On the other hand, caspase-8, being a part of the extrinsic receptor pathway, was also activated (P ≤ 0.001). Therefore, it is possible that Vnz induces porcine granulosal apoptosis also through a parallel pathway. Activation of these two pathways was confirmed by the Apoptosis Antibody Array Kit. In conclusion, it is possible that the intrinsic signaling pathway may not act as an initial trigger for GC apoptosis but might contribute to the amplification and propagation of apoptotic cell death in the granulosa layer after treatment with this antiandrogen. Moreover, Vnz disturbs the physiological process of programmed cell death. Consequently, this could explain why atretic follicles are rapidly removed and suggests that normal function of the ovarian follicle may be destroyed. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Impact of the p53 status of tumor cells on extrinsic and intrinsic apoptosis signaling.

    Science.gov (United States)

    Wachter, Franziska; Grunert, Michaela; Blaj, Cristina; Weinstock, David M; Jeremias, Irmela; Ehrhardt, Harald

    2013-04-17

    The p53 protein is the best studied target in human cancer. For decades, p53 has been believed to act mainly as a tumor suppressor and by transcriptional regulation. Only recently, the complex and diverse function of p53 has attracted more attention. Using several molecular approaches, we studied the impact of different p53 variants on extrinsic and intrinsic apoptosis signaling. We reproduced the previously published results within intrinsic apoptosis induction: while wild-type p53 promoted cell death, different p53 mutations reduced apoptosis sensitivity. The prediction of the impact of the p53 status on the extrinsic cell death induction was much more complex. The presence of p53 in tumor cell lines and primary xenograft tumor cells resulted in either augmented, unchanged or reduced cell death. The substitution of wild-type p53 by mutant p53 did not affect the extrinsic apoptosis inducing capacity. In summary, we have identified a non-expected impact of p53 on extrinsic cell death induction. We suggest that the impact of the p53 status of tumor cells on extrinsic apoptosis signaling should be studied in detail especially in the context of therapeutic approaches that aim to restore p53 function to facilitate cell death via the extrinsic apoptosis pathway.

  4. Fitness, Extrinsic Complexity and Informing Science

    Directory of Open Access Journals (Sweden)

    Grandon Gill

    2017-03-01

    We raise concerns about society’s continuing investment in academic research that discounts the extrinsic complexity of the domains under study. Future Research We highlight a need for research to operationalize the concepts of fitness and complexity in practice.

  5. Intrinsic and extrinsic motivation for smoking cessation.

    Science.gov (United States)

    Curry, S; Wagner, E H; Grothaus, L C

    1990-06-01

    An intrinsic-extrinsic model of motivation for smoking cessation was evaluated with 2 samples (ns = 1.217 and 151) of smokers who requested self-help materials for smoking cessation. Exploratory and confirmatory principal components analysis on a 36-item Reasons for Quitting (RFQ) scale supported the intrinsic-extrinsic motivation distinction. A 4-factor model, with 2 intrinsic dimensions (concerns about health and desire for self-control) and 2 extrinsic dimensions (immediate reinforcement and social influence), was defined by 20 of the 36 RFQ items. The 20-item measure demonstrated moderate to high levels of internal consistency and convergent and discriminant validity. Logistic regression analyses indicated that smokers with higher levels of intrinsic relative to extrinsic motivation were more likely to achieve abstinence from smoking.

  6. The spinning particle with extrinsic curvature

    International Nuclear Information System (INIS)

    Dhar, A.

    1988-01-01

    We construct and analyse an action for the spinning particle which contains an extrinsic curvature term. A possible generalization of this construction to the case of the spinning string is also discussed. (orig.)

  7. Immunosuppressive effects of apoptotic cells

    Science.gov (United States)

    Voll, Reinhard E.; Herrmann, Martin; Roth, Edith A.; Stach, Christian; Kalden, Joachim R.; Girkontaite, Irute

    1997-11-01

    Apoptotic cell death is important in the development and homeostasis of multicellular organisms and is a highly controlled means of eliminating dangerous, damaged or unnecessary cells without causing an inflammatory response or tissue damage,. We now show that the presence of apoptotic cells during monocyte activation increases their secretion of the anti-inflammatory and immunoregulatory cytokine interleukin 10 (IL-10) and decreases secretion of the proinflammatory cytokines tumour necrosis factor-α (TNF-α), IL-1 and IL-12. This may inhibit inflammation and contribute to impaired cell-mediated immunity in conditions associated with increased apoptosis, such as viral infections, pregnancy, cancer and exposure to radiation.

  8. Prometaphase arrest-dependent phosphorylation of Bcl-2 family proteins and activation of mitochondrial apoptotic pathway are associated with 17α-estradiol-induced apoptosis in human Jurkat T cells.

    Science.gov (United States)

    Han, Cho Rong; Jun, Do Youn; Kim, Yoon Hee; Lee, Ji Young; Kim, Young Ho

    2013-10-01

    In Jurkat T cell clone (JT/Neo), G2/M arrest, apoptotic sub-G1 peak, mitochondrial membrane potential (Δψm) loss, and TUNEL-positive DNA fragmentation were induced following exposure to 17α-estradiol (17α-E2), whereas none of these events (except for G2/M arrest) were induced in Jurkat cells overexpressing Bcl-2 (JT/Bcl-2). Under these conditions, phosphorylation at Thr161 and dephosphorylation at Tyr15 of Cdk1, upregulation of cyclin B1 level, histone H1 phosphorylation, Cdc25C phosphorylation at Thr-48, Bcl-2 phosphorylation at Thr-56 and Ser-70, Mcl-1 phosphorylation, and Bim phosphorylation were detected in the presence of Bcl-2 overexpression. However, the 17α-E2-induced upregulation of Bak levels, activation of Bak, activation of caspase-3, and PARP degradation were abrogated by Bcl-2 overexpression. In the presence of the G1/S blocking agent hydroxyurea, 17α-E2 failed to induce G2/M arrest and all apoptotic events including Cdk1 activation and phosphorylation of Bcl-2, Mcl-1 and Bim. The 17α-E2-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by a Cdk1 inhibitor but not by aurora A and aurora B kinase inhibitors. Immunofluorescence microscopic analysis showed that an aberrant bipolar microtubule array, incomplete chromosome congression at the metaphase plate, and prometaphase arrest, which was reversible, were the underlying factors for 17α-E2-induced mitotic arrest. The in vitro microtubule polymerization assay showed that 17α-E2 could directly inhibit microtubule formation. These results show that the apoptogenic activity of 17α-E2 was due to the impaired mitotic spindle assembly causing prometaphase arrest and prolonged Cdk1 activation, the phosphorylation of Bcl-2, Mcl-1 and Bim, and the activation of Bak and mitochondria-dependent caspase cascade. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Surface code—biophysical signals for apoptotic cell clearance

    International Nuclear Information System (INIS)

    Biermann, Mona; Maueröder, Christian; Brauner, Jan M; Chaurio, Ricardo; Herrmann, Martin; Muñoz, Luis E; Janko, Christina

    2013-01-01

    Apoptotic cell death and the clearance of dying cells play an important and physiological role in embryonic development and normal tissue turnover. In contrast to necrosis, apoptosis proceeds in an anti-inflammatory manner. It is orchestrated by the timed release and/or exposure of so-called ‘find-me’, ‘eat me’ and ‘tolerate me’ signals. Mononuclear phagocytes are attracted by various ‘find-me’ signals, including proteins, nucleotides, and phospholipids released by the dying cell, whereas the involvement of granulocytes is prevented via ‘stay away’ signals. The exposure of anionic phospholipids like phosphatidylserine (PS) by apoptotic cells on the outer leaflet of the plasma membrane is one of the main ‘eat me’ signals. PS is recognized by a number of innate receptors as well as by soluble bridging molecules on the surface of phagocytes. Importantly, phagocytes are able to discriminate between viable and apoptotic cells both exposing PS. Due to cytoskeleton remodeling PS has a higher lateral mobility on the surfaces of apoptotic cells thereby promoting receptor clustering on the phagocyte. PS not only plays an important role in the engulfment process, but also acts as ‘tolerate me’ signal inducing the release of anti-inflammatory cytokines by phagocytes. An efficient and fast clearance of apoptotic cells is required to prevent secondary necrosis and leakage of intracellular danger signals into the surrounding tissue. Failure or prolongation of the clearance process leads to the release of intracellular antigens into the periphery provoking inflammation and development of systemic inflammatory autoimmune disease like systemic lupus erythematosus. Here we review the current findings concerning apoptosis-inducing pathways, important players of apoptotic cell recognition and clearance as well as the role of membrane remodeling in the engulfment of apoptotic cells by phagocytes. (paper)

  10. Intrinsic and Extrinsic Neuromodulation of Olfactory Processing.

    Science.gov (United States)

    Lizbinski, Kristyn M; Dacks, Andrew M

    2017-01-01

    Neuromodulation is a ubiquitous feature of neural systems, allowing flexible, context specific control over network dynamics. Neuromodulation was first described in invertebrate motor systems and early work established a basic dichotomy for neuromodulation as having either an intrinsic origin (i.e., neurons that participate in network coding) or an extrinsic origin (i.e., neurons from independent networks). In this conceptual dichotomy, intrinsic sources of neuromodulation provide a "memory" by adjusting network dynamics based upon previous and ongoing activation of the network itself, while extrinsic neuromodulators provide the context of ongoing activity of other neural networks. Although this dichotomy has been thoroughly considered in motor systems, it has received far less attention in sensory systems. In this review, we discuss intrinsic and extrinsic modulation in the context of olfactory processing in invertebrate and vertebrate model systems. We begin by discussing presynaptic modulation of olfactory sensory neurons by local interneurons (LNs) as a mechanism for gain control based on ongoing network activation. We then discuss the cell-class specific effects of serotonergic centrifugal neurons on olfactory processing. Finally, we briefly discuss the integration of intrinsic and extrinsic neuromodulation (metamodulation) as an effective mechanism for exerting global control over olfactory network dynamics. The heterogeneous nature of neuromodulation is a recurring theme throughout this review as the effects of both intrinsic and extrinsic modulation are generally non-uniform.

  11. ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis.

    Science.gov (United States)

    Trümbach, Dietrich; Pfeiffer, Susanne; Poppe, Manuel; Scherb, Hagen; Doll, Sebastian; Wurst, Wolfgang; Schick, Joel A

    2017-11-25

    As CRISPR/Cas9 mediated screens with pooled guide libraries in somatic cells become increasingly established, an unmet need for rapid and accurate companion informatics tools has emerged. We have developed a lightweight and efficient software to easily manipulate large raw next generation sequencing datasets derived from such screens into informative relational context with graphical support. The advantages of the software entitled ENCoRE (Easy NGS-to-Gene CRISPR REsults) include a simple graphical workflow, platform independence, local and fast multithreaded processing, data pre-processing and gene mapping with custom library import. We demonstrate the capabilities of ENCoRE to interrogate results from a pooled CRISPR cellular viability screen following Tumor Necrosis Factor-alpha challenge. The results not only identified stereotypical players in extrinsic apoptotic signaling but two as yet uncharacterized members of the extrinsic apoptotic cascade, Smg7 and Ces2a. We further validated and characterized cell lines containing mutations in these genes against a panel of cell death stimuli and involvement in p53 signaling. In summary, this software enables bench scientists with sensitive data or without access to informatic cores to rapidly interpret results from large scale experiments resulting from pooled CRISPR/Cas9 library screens.

  12. Apoptotic markers in protozoan parasites

    Directory of Open Access Journals (Sweden)

    Fasel Nicolas

    2010-11-01

    Full Text Available Abstract The execution of the apoptotic death program in metazoans is characterized by a sequence of morphological and biochemical changes that include cell shrinkage, presentation of phosphatidylserine at the cell surface, mitochondrial alterations, chromatin condensation, nuclear fragmentation, membrane blebbing and the formation of apoptotic bodies. Methodologies for measuring apoptosis are based on these markers. Except for membrane blebbing and formation of apoptotic bodies, all other events have been observed in most protozoan parasites undergoing cell death. However, while techniques exist to detect these markers, they are often optimised for metazoan cells and therefore may not pick up subtle differences between the events occurring in unicellular organisms and multi-cellular organisms. In this review we discuss the markers most frequently used to analyze cell death in protozoan parasites, paying special attention to changes in cell morphology, mitochondrial activity, chromatin structure and plasma membrane structure/permeability. Regarding classical regulators/executors of apoptosis, we have reviewed the present knowledge of caspase-like and nuclease activities.

  13. Ouabain enhances ADPKD cell apoptosis via the intrinsic pathway

    Directory of Open Access Journals (Sweden)

    Gustavo eBlanco

    2016-03-01

    Full Text Available Progression of autosomal dominant polycystic kidney disease (ADPKD is highly influenced by factors circulating in blood. We have shown that the hormone ouabain enhances several characteristics of the ADPKD cystic phenotype, including the rate of cell proliferation, fluid secretion and the capacity of the cells to form cysts. In this work, we found that physiological levels of ouabain (3nM also promote programmed cell death of renal epithelial cells obtained from kidney cysts of patients with ADPKD (ADPKD cells. This was determined by Alexa Fluor 488 labeled-Annexin-V staining and TUNEL assay, both biochemical markers of apoptosis. Ouabain-induced apoptosis also takes place when ADPKD cell growth is blocked; suggesting that the effect is not secondary to the stimulatory actions of ouabain on cell proliferation. Ouabain alters the expression of BCL family of proteins, reducing BCL-2 and increasing BAX expression levels, anti- and pro-apoptotic mediators respectively. In addition, ouabain caused the release of cytochrome c from mitochondria. Moreover, ouabain activates caspase-3, a key executioner caspase in the cell apoptotic pathway, but did not affect caspase-8. This suggests that ouabain triggers ADPKD cell apoptosis by stimulating the intrinsic, but not the extrinsic pathway of programmed cell death. The apoptotic effects of ouabain are specific for ADPKD cells and do not occur in normal human kidney cells (NHK cells. Taken together with our previous observations, these results show that ouabain causes an imbalance in cell growth/death, to favor growth of the cystic cells. This event, characteristic of ADPKD, further suggests the importance of ouabain as a circulating factor that promotes ADPKD progression.

  14. Non-apoptotic programmed cell death with paraptotic-like features in bleomycin-treated plant cells is suppressed by inhibition of ATM/ATR pathways or NtE2F overexpression

    Czech Academy of Sciences Publication Activity Database

    Smetana, O.; Široký, Jiří; Houlné, G.; Opatrný, Z.; Chabouté, M.-E.

    2012-01-01

    Roč. 63, č. 7 (2012), s. 2631-2644 ISSN 0022-0957 Institutional research plan: CEZ:AV0Z50040702 Keywords : ATM /ATR pathways * cell cycle * double-strand break response Subject RIV: BO - Biophysics Impact factor: 5.242, year: 2012

  15. Curcumin induces apoptosis and cell cycle arrest via the activation of reactive oxygen species-independent mitochondrial apoptotic pathway in Smad4 and p53 mutated colon adenocarcinoma HT29 cells.

    Science.gov (United States)

    Agarwal, Ayushi; Kasinathan, Akiladdevi; Ganesan, Ramamoorthi; Balasubramanian, Akhila; Bhaskaran, Jahnavi; Suresh, Samyuktha; Srinivasan, Revanth; Aravind, K B; Sivalingam, Nageswaran

    2018-03-01

    Curcumin is a natural dietary polyphenol compound that has various pharmacological activities such as antiproliferative and cancer-preventive activities on tumor cells. Indeed, the role reactive oxygen species (ROS) generated by curcumin on cell death and cell proliferation inhibition in colon cancer is poorly understood. In the present study, we hypothesized that curcumin-induced ROS may promote apoptosis and cell cycle arrest in colon cancer. To test this hypothesis, the apoptosis-inducing potential and cell cycle inhibition effect of ROS induced by curcumin was investigated in Smd4 and p53 mutated HT-29 colon adenocarcinoma cells. We found that curcumin treatment significantly increased the level of ROS in HT-29 cells in a dose- and time-dependent manner. Furthermore, curcumin treatment markedly decreased the cell viability and proliferation potential of HT-29 cells in a dose- and time-dependent manner. Conversely, generation of ROS and inhibitory effect of curcumin on HT-29 cells were abrogated by N-acetylcysteine treatment. In addition, curcumin treatment did not show any cytotoxic effects on HT-29 cells. Furthermore, curcumin-induced ROS generation caused the DNA fragmentation, chromatin condensation, and cell nuclear shrinkage and significantly increased apoptotic cells in a dose- and time-dependent manner in HT-29 cells. However, pretreatment of N-acetylcysteine inhibited the apoptosis-triggering effect of curcumin-induced ROS in HT-29 cells. In addition, curcumin-induced ROS effectively mediated cell cycle inhibition in HT-29 cells. In conclusion, our data provide the first evidence that curcumin induces ROS independent apoptosis and cell cycle arrest in colon cancer cells that carry mutation on Smad4 and p53. Copyright © 2018. Published by Elsevier Inc.

  16. Intrinsic and Extrinsic Motivation among Collegiate Instrumentalists

    Science.gov (United States)

    Diaz, Frank M.

    2010-01-01

    The purpose of this study was to gather and compare information on measures of intrinsic and extrinsic motivation among instrumentalists enrolled in collegiate ensembles. A survey instrument was developed to gather information concerning demographic data and responses to questions on motivational preference. Participants were undergraduate and…

  17. Intrinsic and extrinsic effects on image memorability.

    Science.gov (United States)

    Bylinskii, Zoya; Isola, Phillip; Bainbridge, Constance; Torralba, Antonio; Oliva, Aude

    2015-11-01

    Previous studies have identified that images carry the attribute of memorability, a predictive value of whether a novel image will be later remembered or forgotten. Here we investigate the interplay between intrinsic and extrinsic factors that affect image memorability. First, we find that intrinsic differences in memorability exist at a finer-grained scale than previously documented. Second, we test two extrinsic factors: image context and observer behavior. Building on prior findings that images that are distinct with respect to their context are better remembered, we propose an information-theoretic model of image distinctiveness. Our model can automatically predict how changes in context change the memorability of natural images. In addition to context, we study a second extrinsic factor: where an observer looks while memorizing an image. It turns out that eye movements provide additional information that can predict whether or not an image will be remembered, on a trial-by-trial basis. Together, by considering both intrinsic and extrinsic effects on memorability, we arrive at a more complete and fine-grained model of image memorability than previously available. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. The relationship between primary school teachers extrinsic ...

    African Journals Online (AJOL)

    The study investigated the relationship between primary school teacher's extrinsic motivation and pupils' academic performance in Cross river State, Nigeria. Ex Post Facto research design was adopted for the study. The population of the study consisted of 17,221 teachers and 68,201 Primary Six Pupils in the three ...

  19. VOL 6. NO. 1 2015 EXTRINSIC FACTORS THAT AFFECT ...

    African Journals Online (AJOL)

    Frederick Iraki

    Keywords: Job satisfaction, clergy, extrinsic motivation, extrinsic factors ... woman's work conditions and rewards are inferior to those of a man in comparable positions (a ... that they have embraced the need to professionalize their systems.

  20. Intrinsic and extrinsic factors influencing large African herbivore movements

    NARCIS (Netherlands)

    Venter, J.A.; Prins, H.H.T.; Mashanova, A.; Boer, de W.F.; Slotow, R.

    2015-01-01

    Understanding environmental as well as anthropogenic factors that influence large herbivore ecological patterns and processes should underpin their conservation and management. We assessed the influence of intrinsic, extrinsic environmental and extrinsic anthropogenic factors on movement behaviour

  1. Asian International Graduate Students’ Extrinsic Motivation to Pursue Degrees

    OpenAIRE

    Naomi Takashiro

    2017-01-01

    The author examined the types of extrinsic motivation for Asian international graduate students pursuing graduate degrees. The theoretical framework used was extrinsic motivation within Self-Determination Theory. Even though the presence of Asian international graduate students is steadily increasing worldwide, research into their extrinsic motivation is scarce. It is important for educators to explore and understand Asian international graduate students’ extrinsic motivation since such stude...

  2. RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway.

    Science.gov (United States)

    Keuling, Angela M; Felton, Kathleen E A; Parker, Arabesque A M; Akbari, Majid; Andrew, Susan E; Tron, Victor A

    2009-08-17

    Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10) activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity. Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity.

  3. RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway.

    Directory of Open Access Journals (Sweden)

    Angela M Keuling

    Full Text Available BACKGROUND: Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10 activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity.

  4. Detection of apoptotic cells in tumour paraffin sections

    International Nuclear Information System (INIS)

    Pizem, J.; Coer, A.

    2003-01-01

    Apoptosis is a distinct form of cell death characterised by specific morphological features and regulated by complex molecular mechanisms. Its deregulation is fundamental for tumour growth and progression and, moreover, anticancer therapies suppress tumour growth mainly by induction of apoptosis. Since the extent of apoptosis in a tumour may have prognostic as well as therapeutic implications, much effort has been invested in developing specific methods that can be routinely used to detect apoptotic cells in archival formalin- fixed paraffin-embedded tissue. Complex molecular pathways are involved in the regulation of apoptosis. Pro-apoptotic signals trigger activation of caspases that specifically cleave target proteins. Cleavage of proteins (caspase substrates) is responsible for morphological changes of apoptotic cells and DNA fragmentation. In the last decade, detection of apoptotic cells in formalin-fixed tumour tissue sections has been based mainly on morphology and characteristic DNA fragmentation. Recently, specific antibodies to activated caspases and cleaved target proteins (including cytokeratin 18, actin and PARP) have been produced that enable accurate detection of apoptosis in paraffin sections. (author)

  5. Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase-dependent FasL signaling pathway

    Science.gov (United States)

    KIM, JAE-SUNG; PARK, MI-RA; LEE, SOOK-YOUNG; KIM, DO KYOUNG; MOON, SUNG-MIN; KIM, CHUN SUNG; CHO, SEUNG SIK; YOON, GOO; IM, HEE-JEONG; YOU, JAE-SEEK; OH, JI-SU; KIM, SU-GWAN

    2014-01-01

    Licochalcone A (Lico-A) is a natural phenol licorice compound with multiple bioactivities, including anti-inflammatory, anti-microbial, anti-fungal and osteogenesis-inducing properties. In the present study, we investigated the Lico-A-induced apoptotic effects and examined the associated apoptosis pathway in KB human oral cancer cells. Lico-A decreased the number of viable KB oral cancer cells. However, Lico-A did not have an effect on primary normal human oral keratinocytes. In addition, the IC50 value of Lico-A was determined to be ~50 μM following dose-dependent stimulation. KB oral cancer cells stimulated with Lico-A for 24 h showed chromatin condensation by DAPI staining, genomic DNA fragmentation by agarose gel electrophoresis and a gradually increased apoptotic cell population by FACS analysis. These data suggest that Lico-A induces apoptosis in KB oral cancer cells. Additionally, Lico-A-induced apoptosis in KB oral cancer cells was mediated by the expression of factor associated suicide ligand (FasL) and activated caspase-8 and −3 and poly(ADP-ribose) polymerase (PARP). Furthermore, in the KB oral cancer cells co-stimulation with a caspase inhibitor (Z-VAD-fmk) and Lico-A significantly abolished the apoptotic phenomena. Our findings demonstrated that Lico-A-induced apoptosis in KB oral cancer cells involves the extrinsic apoptotic signaling pathway, which involves a caspase-dependent FasL-mediated death receptor pathway. Our data suggest that Lico-A be developed as a chemotherapeutic agent for the management of oral cancer. PMID:24337492

  6. Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase-dependent FasL signaling pathway.

    Science.gov (United States)

    Kim, Jae-Sung; Park, Mi-Ra; Lee, Sook-Young; Kim, Do Kyoung; Moon, Sung-Min; Kim, Chun Sung; Cho, Seung Sik; Yoon, Goo; Im, Hee-Jeong; You, Jae-Seek; Oh, Ji-Su; Kim, Su-Gwan

    2014-02-01

    Licochalcone A (Lico-A) is a natural phenol licorice compound with multiple bioactivities, including anti-inflammatory, anti-microbial, anti-fungal and osteogenesis-inducing properties. In the present study, we investigated the Lico-A-induced apoptotic effects and examined the associated apoptosis pathway in KB human oral cancer cells. Lico-A decreased the number of viable KB oral cancer cells. However, Lico-A did not have an effect on primary normal human oral keratinocytes. In addition, the IC50 value of Lico-A was determined to be ~50 µM following dose-dependent stimulation. KB oral cancer cells stimulated with Lico-A for 24 h showed chromatin condensation by DAPI staining, genomic DNA fragmentation by agarose gel electrophoresis and a gradually increased apoptotic cell population by FACS analysis. These data suggest that Lico-A induces apoptosis in KB oral cancer cells. Additionally, Lico‑A‑induced apoptosis in KB oral cancer cells was mediated by the expression of factor associated suicide ligand (FasL) and activated caspase-8 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, in the KB oral cancer cells co-stimulation with a caspase inhibitor (Z-VAD-fmk) and Lico-A significantly abolished the apoptotic phenomena. Our findings demonstrated that Lico‑A-induced apoptosis in KB oral cancer cells involves the extrinsic apoptotic signaling pathway, which involves a caspase-dependent FasL-mediated death receptor pathway. Our data suggest that Lico-A be developed as a chemotherapeutic agent for the management of oral cancer.

  7. Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis

    DEFF Research Database (Denmark)

    Martel, Britta Cathrina; Litman, Thomas; Hald, Andreas

    2016-01-01

    Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. In this study, we used microarray analysis to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared...... with mild extrinsic and intrinsic AD similar to previous reports for severe AD. Interestingly, expression of genes involved in inflammatory responses in intrinsic AD resembled that of psoriasis more than that of extrinsic AD. Overall, differences in expression of inflammation-associated genes found among...... patients with mild intrinsic and extrinsic AD correlated with previous findings for patients with severe intrinsic and extrinsic AD....

  8. ONC201 selectively induces apoptosis in cutaneous T-cell lymphoma cells via activating pro-apoptotic integrated stress response and inactivating JAK/STAT and NF-κB pathways.

    Science.gov (United States)

    Ni, Xiao; Zhang, Xiang; Hu, Cheng-Hui; Langridge, Timothy; Tarapore, Rohinton S; Allen, Joshua E; Oster, Wolfgang; Duvic, Madeleine

    2017-09-22

    Cutaneous T-cell lymphomas (CTCLs) are extremely symptomatic and still incurable, and more effective and less toxic therapies are urgently needed. ONC201, an imipridone compound, has shown efficacy in pre-clinical studies in multiple advanced cancers. This study was to evaluate the anti-tumor activity of ONC201 on CTCL cells. The effect of ONC201 on the cell growth and apoptosis were evaluated in CTCL cell lines (n=8) and primary CD4 + malignant T cells isolated from CTCL patients (n=5). ONC201 showed a time-dependent cell growth inhibition in all treated cell lines with a concentration range of 1.25-10.0 μM. ONC201 also induced apoptosis in tested cells with a narrow concentration range of 2.5-10.0 μM, evidenced by increased Annexin V + cells, accompanied by accumulated sub-G1 portions. ONC201 only induced apoptosis in CD4 + malignant T cells, not in normal CD4 + T cells. The activating transcription factor 4 (ATF4), a hallmark of integrated stress response, was upregulated in response to ONC201 whereas Akt was downregulated. In addition, molecules in JAK/STAT and NF-κB pathways, as well as IL-32β, were downregulated following ONC201 treatment. Thus, ONC201 exerts a potent and selective anti-tumor effect on CTCL cells. Its efficacy may involve activating integrated stress response through ATF4 and inactivating JAK/STAT and NF-κB pathways.

  9. Extrinsic spin Nernst effect from first principles.

    Science.gov (United States)

    Tauber, Katarina; Gradhand, Martin; Fedorov, Dmitry V; Mertig, Ingrid

    2012-07-13

    We present an ab initio description of the thermal transport phenomenon called the spin Nernst effect. It refers to generation of a spin accumulation or a pure spin current transverse to an applied temperature gradient. This is similar to the intensively studied spin Hall effect described by intrinsic and extrinsic mechanisms due to an applied electric field. Analogously, several contributions are present for the spin Nernst effect. Here we investigate the extrinsic skew scattering mechanism which is dominant in the limit of dilute alloys. Our calculations are based on a fully relativistic Korringa-Kohn-Rostoker method and a solution of the linearized Boltzmann equation. As a first application, we consider a Cu host with Au, Ti, and Bi impurities.

  10. Extrinsic and intrinsic curvatures in thermodynamic geometry

    Energy Technology Data Exchange (ETDEWEB)

    Hosseini Mansoori, Seyed Ali, E-mail: shossein@bu.edu [Department of Physics, Boston University, 590 Commonwealth Ave., Boston, MA 02215 (United States); Department of Physics, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Mirza, Behrouz, E-mail: b.mirza@cc.iut.ac.ir [Department of Physics, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Sharifian, Elham, E-mail: e.sharifian@ph.iut.ac.ir [Department of Physics, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of)

    2016-08-10

    We investigate the intrinsic and extrinsic curvatures of a certain hypersurface in thermodynamic geometry of a physical system and show that they contain useful thermodynamic information. For an anti-Reissner–Nordström-(A)de Sitter black hole (Phantom), the extrinsic curvature of a constant Q hypersurface has the same sign as the heat capacity around the phase transition points. The intrinsic curvature of the hypersurface can also be divergent at the critical points but has no information about the sign of the heat capacity. Our study explains the consistent relationship holding between the thermodynamic geometry of the KN-AdS black holes and those of the RN (J-zero hypersurface) and Kerr black holes (Q-zero hypersurface) ones [1]. This approach can easily be generalized to an arbitrary thermodynamic system.

  11. Extrinsic and intrinsic curvatures in thermodynamic geometry

    International Nuclear Information System (INIS)

    Hosseini Mansoori, Seyed Ali; Mirza, Behrouz; Sharifian, Elham

    2016-01-01

    We investigate the intrinsic and extrinsic curvatures of a certain hypersurface in thermodynamic geometry of a physical system and show that they contain useful thermodynamic information. For an anti-Reissner–Nordström-(A)de Sitter black hole (Phantom), the extrinsic curvature of a constant Q hypersurface has the same sign as the heat capacity around the phase transition points. The intrinsic curvature of the hypersurface can also be divergent at the critical points but has no information about the sign of the heat capacity. Our study explains the consistent relationship holding between the thermodynamic geometry of the KN-AdS black holes and those of the RN (J-zero hypersurface) and Kerr black holes (Q-zero hypersurface) ones [1]. This approach can easily be generalized to an arbitrary thermodynamic system.

  12. Intrinsic and extrinsic geometry of random surfaces

    International Nuclear Information System (INIS)

    Jonsson, T.

    1992-01-01

    We prove that the extrinsic Hausdorff dimension is always greater than or equal to the intrinsic Hausdorff dimension in models of triangulated random surfaces with action which is quadratic in the separation of vertices. We furthermore derive a few naive scaling relations which relate the intrinsic Hausdorff dimension to other critical exponents. These relations suggest that the intrinsic Hausdorff dimension is infinite if the susceptibility does not diverge at the critical point. (orig.)

  13. Extrinsic Fabry-Perot ultrasonic detector

    Science.gov (United States)

    Kidwell, J. J.; Berthold, John W., III

    1996-10-01

    We characterized the performance of a commercial fiber optic extrinsic Fabry-Perot interferometer for use as an ultrasonic sensor, and compared the performance with a standard lead zirconate titanate (PZT) detector. The interferometer was unstabilized. The results showed that the fiber sensor was about 12 times less sensitive than the PZT detector. Ultrasonic frequency response near 100 kHz was demonstrated. We describe the design of the fiber sensor, the details of the tests performed, and potential applications.

  14. Altered intrinsic and extrinsic connectivity in schizophrenia.

    Science.gov (United States)

    Zhou, Yuan; Zeidman, Peter; Wu, Shihao; Razi, Adeel; Chen, Cheng; Yang, Liuqing; Zou, Jilin; Wang, Gaohua; Wang, Huiling; Friston, Karl J

    2018-01-01

    Schizophrenia is a disorder characterized by functional dysconnectivity among distributed brain regions. However, it is unclear how causal influences among large-scale brain networks are disrupted in schizophrenia. In this study, we used dynamic causal modeling (DCM) to assess the hypothesis that there is aberrant directed (effective) connectivity within and between three key large-scale brain networks (the dorsal attention network, the salience network and the default mode network) in schizophrenia during a working memory task. Functional MRI data during an n-back task from 40 patients with schizophrenia and 62 healthy controls were analyzed. Using hierarchical modeling of between-subject effects in DCM with Parametric Empirical Bayes, we found that intrinsic (within-region) and extrinsic (between-region) effective connectivity involving prefrontal regions were abnormal in schizophrenia. Specifically, in patients (i) inhibitory self-connections in prefrontal regions of the dorsal attention network were decreased across task conditions; (ii) extrinsic connectivity between regions of the default mode network was increased; specifically, from posterior cingulate cortex to the medial prefrontal cortex; (iii) between-network extrinsic connections involving the prefrontal cortex were altered; (iv) connections within networks and between networks were correlated with the severity of clinical symptoms and impaired cognition beyond working memory. In short, this study revealed the predominance of reduced synaptic efficacy of prefrontal efferents and afferents in the pathophysiology of schizophrenia.

  15. Intrinsic-extrinsic factors in sport motivation.

    Science.gov (United States)

    Pedersen, Darhl M

    2002-10-01

    Participants were 83 students (36 men and 47 women). 10 intrinsic-extrinsic factors involved in sport motivation were obtained. The factors were generated from items obtained from the participants rather than items from the experimenter. This was done to avoid the possible influence of preconceptions on the part of the experimenter regarding what the final dimensions may be. Obtained motivational factors were Social Reinforcement, Fringe Benefits, Fame and Fortune, External Forces, Proving Oneself, Social Benefits, Mental Enrichment, Expression of Self, Sense of Accomplishment, and Self-enhancement. Each factor was referred to an intrinsic-extrinsic dimension to describe its relative position on that dimension. The order of the factors as listed indicates increasing intrinsic motivation. i.e., the first four factors were rated in the extrinsic range, whereas the remaining six were rated to be in the intrinsic range. Next, the participants rated the extent to which each of the various factors was involved in their decision to participate in sport activities. The pattern of use of the motivational factors was the same for both sexes except that men indicated greater use of the Fringe Benefits factor. Overall, the more intrinsic a sport motivation factor was rated, the more likely it was to be rated as a factor in actual sport participation.

  16. Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways

    Directory of Open Access Journals (Sweden)

    Chen J

    2014-07-01

    Full Text Available Jiezhong Chen,1,2 Renfu Shao,3 Li Li,4 Zhi Ping Xu,4 Wenyi Gu4 1School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, 2Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, 3GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Queensland, 4Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia Abstract: Colon cancer is the third most common cancer and the third largest cause of cancer-related death. Fluorouracil (5-FU is the front-line chemotherapeutic agent for colon cancer. However, its response rate is less than 60%, even in combination with other chemotherapeutic agents. The side effects of 5-FU also limit its application. Nanoparticles have been used to deliver 5-FU, to increase its effectiveness and reduce side effects. Another common approach for colon cancer treatment is targeted therapy against the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway. A recently-invented inhibitor of this pathway, BEZ-235, has been tested in several clinical trials and has shown effectiveness and low side effects. Thus, it is a very promising drug for colon cancer treatment. The combination of these two drugs, especially nanoparticle-packed 5-FU and BEZ-235, has not been studied. In the present study, we demonstrated that nanoparticles of layered double hydroxide (LDH loaded with 5-FU were more effective than a free drug at inhibiting colon cancer cell growth, and that a combination treatment with BEZ-235 further increased the sensitivity of colon cancer cells to the treatment of LDH-packed 5-FU (LDH-5-FU. BEZ-235 alone can decrease colon cancer HCT-116 cell viability to 46% of the control, and the addition of LDH-5-FU produced a greater effect, reducing cell survival to 8% of the control. Our data indicate that the combination therapy of

  17. Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response.

    Science.gov (United States)

    Zervantonakis, Ioannis K; Iavarone, Claudia; Chen, Hsing-Yu; Selfors, Laura M; Palakurthi, Sangeetha; Liu, Joyce F; Drapkin, Ronny; Matulonis, Ursula; Leverson, Joel D; Sampath, Deepak; Mills, Gordon B; Brugge, Joan S

    2017-08-28

    The lack of effective chemotherapies for high-grade serous ovarian cancers (HGS-OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro-apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-X L ) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.

  18. Studying apoptotic cell death by flow cytometry

    International Nuclear Information System (INIS)

    Ormerod, Michael G.

    1998-01-01

    Full text: Programmed cell death (PCD) is of fundamental importance in the normal development of an animal and also in tumour biology and radiation biology. During PCD a sequence of changes occurs in cells giving rise to an apoptotic cascade of events. The main elements of this cascade are rapidly being elucidated. Flow cytometry has been used to follow many of these changes. It also has been used to quantify the number of apoptotic cells in a culture and, more recently, in clinical samples. In this review, the properties of apoptotic cells and the main feature of apoptotic cascade will be described. How flow cytometry can be used to follow changes during the apoptotic cascade will be discussed

  19. Extrinsic and intrinsic blood supply to the optic chiasm.

    Science.gov (United States)

    Salaud, Céline; Ploteau, Stéphane; Blery, Pauline; Pilet, Paul; Armstrong, Olivier; Hamel, Antoine

    2018-04-01

    Although there have been many studies of the arterial cerebral blood supply, only seven have described the optic chiasm (OC) blood supply and their results are contradictory. The aim of this study was to analyze the extrinsic and intrinsic OC blood supply on cadaveric specimens using dissections and microcomputer tomography (Micro-CT). Thirteen human specimens were dissected and the internal or common carotid arteries were injected with red latex, China Ink with gelatin or barium sulfate. Three Micro-CTs were obtained to reveal the intrinsic blood supply to the OC. The superior hypophyseal arteries (SupHypA) (13/13) and posterior communicating artery (PCoA) (12/13) supplied the pial network on the inferior side of the OC. The first segment of the anterior cerebral artery (ACA) (10/10), SupHypA (7/10), the anterior communicating artery (ACoA) (9/10), and PComA (1/10) supplied the pial network of its superior side. The intrinsic OC blood supply was divided into three networks (two lateral and one central). Capillaries entering the OC originated principally from the inferior pial network. The lateral network capillaries had the same orientation as the visual lateral pathways, but the central network was not correlated with the nasal fibers crossing into the OC. There was no anastomosis in the pial or intrinsic networks. Only SupHypA, PCoA, ACoA, and ACA were involved in the OC blood supply. Because there was no extrinsic or intrinsic anastomosis, all arteries should be preserved. Tumor compression of the inferior intrinsic arterial network could contribute to visual defects. Clin. Anat. 31:432-440, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  20. Reverse-phase phosphoproteome analysis of signaling pathways induced by Rift valley fever virus in human small airway epithelial cells.

    Directory of Open Access Journals (Sweden)

    Taissia G Popova

    Full Text Available Rift valley fever virus (RVFV infection is an emerging zoonotic disease endemic in many countries of sub-Saharan Africa and in Egypt. In this study we show that human small airway epithelial cells are highly susceptible to RVFV virulent strain ZH-501 and the attenuated strain MP-12. We used the reverse-phase protein arrays technology to identify phosphoprotein signaling pathways modulated during infection of cultured airway epithelium. ZH-501 infection induced activation of MAP kinases (p38, JNK and ERK and downstream transcriptional factors [STAT1 (Y701, ATF2 (T69/71, MSK1 (S360 and CREB (S133]. NF-κB phosphorylation was also increased. Activation of p53 (S15, S46 correlated with the increased levels of cleaved effector caspase-3, -6 and -7, indicating activation of the extrinsic apoptotic pathway. RVFV infection downregulated phosphorylation of a major anti-apoptotic regulator of survival pathways, AKT (S473, along with phosphorylation of FOX 01/03 (T24/31 which controls cell cycle arrest downstream from AKT. Consistent with this, the level of apoptosis inhibitor XIAP was decreased. However, the intrinsic apoptotic pathway marker, caspase-9, demonstrated only a marginal activation accompanied by an increased level of the inhibitor of apoptosome formation, HSP27. Concentration of the autophagy marker, LC3B, which often accompanies the pro-survival signaling, was decreased. Cumulatively, our analysis of RVFV infection in lung epithelium indicated a viral strategy directed toward the control of cell apoptosis through a number of transcriptional factors. Analyses of MP-12 titers in challenged cells in the presence of MAPK inhibitors indicated that activation of p38 represents a protective cell response while ERK activation controls viral replication.

  1. Intrinsic and extrinsic neuromodulation of motor circuits.

    Science.gov (United States)

    Katz, P S

    1995-12-01

    Neuromodulation of motor circuits by extrinsic inputs provides enormous flexibility in the production of behavior. Recent work has shown that neurons intrinsic to central pattern-generating circuits can evoke neuromodulatory effects in addition to their neurotransmitting actions. Modulatory neurons often elicit a multitude of different effects attributable to actions at different receptors and/or through the release of co-transmitters. Differences in neuromodulation between species can account for differences in behavior. Modulation of neuromodulation may provide an additional level of flexibility to motor circuits.

  2. Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes

    Directory of Open Access Journals (Sweden)

    Wang G

    2015-08-01

    Full Text Available Gang Wang,1,2,* Jun Jie Wang,1,2,* Tony SS To,3 Hua Fu Zhao,3 Jing Wang3 1Department of Pharmaceutics, Shanghai Eighth People’s Hospital, Shanghai, People’s Republic of China; 2College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei Province, People’s Republic of China; 3Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, People’s Republic of China *These authors contributed equally to this work Abstract: Flavonoids, the major polyphenol components in Cotinus coggygria (CC, have been found to show an anticancer effect in our previous study; however, the exact mechanisms of inducing human glioblastoma (GBM cell death remain to be resolved. In this study, a novel polyvinylpyrrolidone K-30/sodium dodecyl sulfate and polyethyleneglycol-coated liposome loaded with CC flavonoids (CCFs was developed to enhance solubility and the antibrain tumor effect, and the molecular mechanism regarding how CCF nanoliposomes (CCF-NLs induce apoptotic cell death in vitro was investigated. DBTRG-05MG GBM cell lines treated with CCF-NLs showed potential antiproliferative effects. Regarding the underlying mechanisms of inducing apoptosis in DBTRG-05MG GBM cells, CCF-NLs were shown to downregulate the expression of antiapoptotic B-cell lymphoma/leukemia 2 (Bcl-2, an apoptosis-related protein family member, but the expression of proapoptotic Bcl-2-associated X protein was enhanced compared with that in controls. CCF-NLs also inhibited the activity of caspase-3 and -9, which is the initiator caspase of the extrinsic and intrinsic apoptotic pathways. Blockade of caspase activation consistently induced apoptosis and inhibited growth in CCF-NL-treated DBTRG-05MG cells. This study further investigated the role of the Akt pathway in the apoptotic cell death by CCF-NLs, showing that CCF-NLs deactivated Akt. Specifically, CCF-NLs downregulated the expression of p-Akt and SIRT1 as well as the level of

  3. Do intrinsic and extrinsic motivation relate differently to employee outcomes?

    OpenAIRE

    Kuvaas, Bard; Buch, Robert; Weibel, Antoinette; Dysvik, Anders; Nerstad, Christina

    2017-01-01

    In most theories that address how individual financial incentives affect work performance, researchers have assumed that two types of motivation—intrinsic and extrinsic—mediate the relationship between incentives and performance. Empirically, however, extrinsic motivation is rarely investigated. To explore the predictive validity of these theories of intrinsic and extrinsic motivation in work settings, we tested how both intrinsic and extrinsic motivation affected supervisor-ra...

  4. Mitotic and apoptotic activity in colorectal neoplasia.

    Science.gov (United States)

    Kohoutova, Darina; Pejchal, Jaroslav; Bures, Jan

    2018-05-18

    Colorectal cancer (CRC) is third most commonly diagnosed cancer worldwide. The aim of the prospective study was to evaluate mitosis and apoptosis of epithelial cells at each stage of colorectal neoplasia. A total of 61 persons were enrolled into the study: 18 patients with non-advanced colorectal adenoma (non-a-A), 13 patients with advanced colorectal adenoma (a-A), 13 patients with CRC and 17 controls: individuals with normal findings on colonoscopy. Biopsy samples were taken from pathology (patients) and healthy mucosa (patients and healthy controls). Samples were formalin-fixed paraffin-embedded and stained with haematoxylin-eosin. Mitotic and apoptotic activity were evaluated in lower and upper part of the crypts and in the superficial compartment. Apoptotic activity was also assessed using detection of activated caspase-3. In controls, mitotic activity was present in lower part of crypts, accompanied with low apoptotic activity. Mitotic and apoptotic activity decreased (to almost zero) in upper part of crypts. In superficial compartment, increase in apoptotic activity was observed. Transformation of healthy mucosa into non-a-A was associated with significant increase of mitotic activity in lower and upper part of the crypts and with significant increase of apoptotic activity in all three compartments; p colorectal neoplasia were observed. Detection of activated caspase-3 confirmed the above findings in apoptotic activity. Significant dysregulation of mitosis and apoptosis during the progression of colorectal neoplasia, corresponding with histology, was confirmed. In patients with sporadic colorectal neoplasia, healthy mucosa does not display different mitotic and apoptotic activity compared to mucosa in healthy controls and therefore adequate endoscopic/surgical removal of colorectal neoplasia is sufficient.

  5. Silencing of Pokemon enhances caspase-dependent apoptosis via fas- and mitochondria-mediated pathways in hepatocellular carcinoma cells.

    Science.gov (United States)

    Zhang, Yu-Qin; Xiao, Chuan-Xing; Lin, Bi-Yun; Shi, Ying; Liu, Yun-Peng; Liu, Jing-Jing; Guleng, Bayasi; Ren, Jian-Lin

    2013-01-01

    The role of Pokemon (POK erythroid myeloid ontogenic actor), a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC) and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. Western blots showed that p53 expression and phosphorylation were significantly increased in Pokemon defective cells, thereby initiating the mitochondria-mediated and death receptor-mediated apoptotic pathways. In the mitochondria-mediated pathway, expression of pro-apoptotic Bcl-2 family members (including Bad, Bid, Bim and Puma) as well as AIF was increased and decreasing the mitochondrial membrane potential resulted in cytochrome C released from mitochondrial in HepG2 si-Pokemon cells. In addition, upon oxaliplatin treatment of Pokemon-silenced cells, the FAS receptor, FADD and their downstream targets caspase-10 and caspase-8 were activated, causing increased release of caspase-8 active fragments p18 and p10. Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.

  6. Silencing of Pokemon enhances caspase-dependent apoptosis via fas- and mitochondria-mediated pathways in hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Yu-Qin Zhang

    Full Text Available The role of Pokemon (POK erythroid myeloid ontogenic actor, a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. Western blots showed that p53 expression and phosphorylation were significantly increased in Pokemon defective cells, thereby initiating the mitochondria-mediated and death receptor-mediated apoptotic pathways. In the mitochondria-mediated pathway, expression of pro-apoptotic Bcl-2 family members (including Bad, Bid, Bim and Puma as well as AIF was increased and decreasing the mitochondrial membrane potential resulted in cytochrome C released from mitochondrial in HepG2 si-Pokemon cells. In addition, upon oxaliplatin treatment of Pokemon-silenced cells, the FAS receptor, FADD and their downstream targets caspase-10 and caspase-8 were activated, causing increased release of caspase-8 active fragments p18 and p10. Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.

  7. Apoptotic Effect of Nigella sativa on Human Lymphoma U937 Cells.

    Science.gov (United States)

    Arslan, Belkis Atasever; Isik, Fatma Busra; Gur, Hazal; Ozen, Fatih; Catal, Tunc

    2017-10-01

    Nigella sativa is from botanical Ranunculaceae family and commonly known as black seed. Apoptotic effect of N. sativa and its apoptotic signaling pathways on U937 lymphoma cells are unknown. In this study, we investigated selective cytotoxic and apoptotic effects of N. sativa extract and its apoptotic mechanisms on U937 cells. In addition, we also studied selective cytotoxic activity of thymoquinone that is the most active essential oil of N. sativa . Our results showed that N. sativa extract has selective cytotoxicity and apoptotic effects on U937 cells but not ECV304 control cells. However, thymoquinone had no significant cytotoxicity against on both cells. N. sativa extract increased significantly caspase-3, BAD, and p53 gene expressions in U937 cells. N. sativa may have anticancer drug potential and trigger p53-induced apoptosis in U937 lymphoma cells. This is the first study showing the apoptotic effect of Nigella sativa extract on U937 cells. Abbreviations used: CI: Cytotoxicity index, DMEM: Dulbecco's Modified Eagle Medium, HL: Hodgkin's lymphoma, MTT: 3-(4,5-dimethy lthiazol-2yl)-2,5-diphenyl tetrazolium bromide, RPMI: Roswell Park Memorial Institute medium.

  8. Intrinsic and Extrinsic Motivation for Stereotypic and Repetitive Behavior

    Science.gov (United States)

    Joosten, Annette V.; Bundy, Anita C.; Einfeld, Stewart L.

    2009-01-01

    This study provides evidence for intrinsic and extrinsic motivators for stereotypical and repetitive behavior in children with autism and intellectual disability and children with intellectual disability alone. We modified the Motivation Assessment Scale (MAS) (1988b); dividing it into intrinsic and extrinsic measures and adding items to assess…

  9. A prototype empirical framework of intrinsic and extrinsic EERQI indicators

    NARCIS (Netherlands)

    Mooij, Ton

    2012-01-01

    The research question is: What do statistical analyses show us about the relationships between intrinsic and extrinsic indicators of quality and what does this mean when constructing a prototype EERQI framework? The pilot study involved the scoring on both intrinsic and extrinsic indica-tors for 177

  10. A reduced covariant string model for the extrinsic string

    International Nuclear Information System (INIS)

    Botelho, L.C.L.

    1989-01-01

    It is studied a reduced covariant string model for the extrinsic string by using Polyakov's path integral formalism. On the basis of this reduced model it is suggested that the extrinsic string has its critical dimension given by 13. Additionally, it is calculated in a simple way Poliakov's renormalization group law for the string rigidity coupling constants. (A.C.A.S.) [pt

  11. Antitumor and apoptotic effects of cucurbitacin a in A-549 lung ...

    African Journals Online (AJOL)

    Background: The main aim of this study was to demonstrate the antitumor potential of cucurbitacin A on A-549 NSCLC (non-small cell lung cancer cells). The effects of Cucurbitacin A on apoptotic induction, cell physic, cell cycle failure and m-TOR/PI3K/Akt signalling pathway were also investigated in the present study.

  12. Extrinsic Isoperimetric Analysis on Submanifolds with Curvatures bounded from below

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, Vicente

    2010-01-01

    and on the radial part of the intrinsic unit normals at the boundaries of the extrinsic spheres, respectively. In the same vein we also establish lower bounds on the mean exit time for Brownian motions in the extrinsic balls, i.e. lower bounds for the time it takes (on average) for Brownian particles to diffuse......We obtain upper bounds for the isoperimetric quotients of extrinsic balls of submanifolds in ambient spaces which have a lower bound on their radial sectional curvatures. The submanifolds are themselves only assumed to have lower bounds on the radial part of the mean curvature vector field...... within the extrinsic ball from a given starting point before they hit the boundary of the extrinsic ball. In those cases, where we may extend our analysis to hold all the way to infinity, we apply a capacity comparison technique to obtain a sufficient condition for the submanifolds to be parabolic, i...

  13. Asian International Graduate Students’ Extrinsic Motivation to Pursue Degrees

    Directory of Open Access Journals (Sweden)

    Naomi Takashiro

    2017-04-01

    Full Text Available The author examined the types of extrinsic motivation for Asian international graduate students pursuing graduate degrees. The theoretical framework used was extrinsic motivation within Self-Determination Theory. Even though the presence of Asian international graduate students is steadily increasing worldwide, research into their extrinsic motivation is scarce. It is important for educators to explore and understand Asian international graduate students’ extrinsic motivation since such students would provide unique, distinctive cultural aspects in the classroom in their host countries. The research design employed was qualitative. Semi-structured interviews were conducted with 10 graduate students from four Asian countries. The identified themes were a faculty influence, b personal recognition, and c utility for careers. Asian international graduate students expressed that their ultimate extrinsic motivation was to get professional jobs in academia. The author discussed the implications of these findings for instructors.

  14. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    Directory of Open Access Journals (Sweden)

    Maria Dolores Boyano

    2011-03-01

    Full Text Available Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies.

  15. Ziyuglycoside I Inhibits the Proliferation of MDA-MB-231 Breast Carcinoma Cells through Inducing p53-Mediated G2/M Cell Cycle Arrest and Intrinsic/Extrinsic Apoptosis.

    Science.gov (United States)

    Zhu, Xue; Wang, Ke; Zhang, Kai; Zhang, Ting; Yin, Yongxiang; Xu, Fei

    2016-11-22

    Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC) has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of ziyuglycoside I, one of the major components extracted from Chinese anti-tumor herbal Radix Sanguisorbae , on the TNBC cell line MDA-MB-231. The underlying molecular mechanism of the cytotoxic effect ziyuglycoside I on MDA-MB-231 cells was investigated with cell viability assay, flow cytometric analysis and Western blot. Compared to normal mammary gland Hs 578Bst cells, treatment of ziyuglycoside I resulted in a significant growth inhibitory effect on MDA-MB-231 cells. Ziyuglycoside I induced the G2/M phase arrest and apoptosis of MDA-MB-231 cells in a dose-dependent manner. These effects were found to be partially mediated through the up-regulation of p53 and p21 WAF1 , elevated Bax/Bcl-2 ratio, and the activation of both intrinsic (mitochondrial-initiated) and extrinsic (Fas/FasL-initiated) apoptotic pathways. Furthermore, the p53 specific siRNA attenuated these effects. Our study suggested that ziyuglycoside I-triggered MDA-MB-231 cell cycle arrest and apoptosis were probably mediated by p53. This suggests that ziyuglycoside I might be a potential drug candidate for treating TNBC.

  16. siRNA - Mediated LRP/LR knock-down reduces cellular viability of malignant melanoma cells through the activation of apoptotic caspases.

    Science.gov (United States)

    Rebelo, Thalia M; Vania, Leila; Ferreira, Eloise; Weiss, Stefan F T

    2018-07-01

    The 37 kDa/67 kDa laminin receptor (LRP/LR) is over-expressed in tumor cells and has been implicated in several tumourigenic processes such as metastasis and telomerase activation, however, more importantly the focus of the present study is on the maintenance of cellular viability and the evasion of apoptosis. The aim of the study was to investigate the role of LRP/LR on the cellular viability of early (A375) and late stage (A375SM) malignant melanoma cells. Flow cytometry and western blot analysis revealed that A375SM cells contain more cell-surface and total LRP/LR levels in comparison to the A375 cells, respectively. In order to determine the effect of LRP/LR on cell viability and apoptosis, LRP was down-regulated via siRNA technology. MTT assays revealed that LRP knock-down led to significant reductions in the viability of A375 and A375SM cells. Confocal microscopy indicated nuclear morphological changes suggestive of apoptotic induction in both cell lines and Annexin-V FITC/PI assays confirmed this observation. Additionally, caspase-3 activity assays revealed that apoptosis was induced in both cell lines after siRNA-mediated down-regulation of LRP. Caspase-8 and -9 activity assays suggested that post LRP knock-down; A375 cells undergo apoptosis solely via the extrinsic pathway, while A375SM cells undergo apoptosis via the intrinsic pathway. siRNAs mediated LRP knock-down might represent a powerful alternative therapeutic strategy for the treatment of malignant melanoma through the induction of apoptosis. Copyright © 2018. Published by Elsevier Inc.

  17. Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells.

    Science.gov (United States)

    Yajima, Ichiro; Uemura, Noriyuki; Nizam, Saika; Khalequzzaman, Md; Thang, Nguyen D; Kumasaka, Mayuko Y; Akhand, Anwarul A; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

    2012-06-01

    Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.

  18. Bifidobacterium breve reduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner.

    Science.gov (United States)

    Hughes, K R; Harnisch, L C; Alcon-Giner, C; Mitra, S; Wright, C J; Ketskemety, J; van Sinderen, D; Watson, A J M; Hall, L J

    2017-01-01

    Certain members of the microbiota genus Bifidobacterium are known to positively influence host well-being. Importantly, reduced bifidobacterial levels are associated with inflammatory bowel disease (IBD) patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic extrusion of small intestinal epithelial cells (IECs) from villi-a process termed 'cell shedding'. Using a mouse model of pathological cell shedding, we show that mice receiving Bifidobacterium breve UCC2003 exhibit significantly reduced rates of small IEC shedding. Bifidobacterial-induced protection appears to be mediated by a specific bifidobacterial surface exopolysaccharide and interactions with host MyD88 resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under highly inflammatory conditions. Our results reveal an important and previously undescribed role for B. breve, in positively modulating epithelial cell shedding outcomes via bacterial- and host-dependent factors, supporting the notion that manipulation of the microbiota affects intestinal disease outcomes. © 2017 The Authors.

  19. Diffusion by extrinsic noise in the kicked Harper map

    International Nuclear Information System (INIS)

    Park, Gunyoung; Chang, C. S.

    2001-01-01

    A significantly improved analytic understanding of the extrinsically driven diffusion process is presented in a nonlinear dynamical system in which the phase space is divided into periodic two-dimensional tiles of regular motion, separated by a connected separatrix network (web) [previously studied by A. J. Lichtenberg and Blake P. Wood, Phys. Rev. Lett. >62, 2213 (1989)]. The system is represented by the usual 'kicked Harper map' with added extrinsic noise terms. Three different diffusion regimes are found depending upon the strength of the extrinsic perturbation l relative to the web and regular motions. When the extrinsic noise is dominant over the intrinsic stochasticity and the regular rotation motions in the tile, diffusion obeys the random phase scaling l 2 . When the extrinsic noise is dominant over the intrinsic stochasticity, but weaker than the regular rotation motion, the diffusion scales as lK 1/2 , where K is the strength of the intrinsic kick. These findings agree well with numerical simulation results. When the extrinsic noise process is weaker than the stochastic web process, we analytically reproduce the well-known numerical result: The web diffusion is reduced by the ratio of phase-space areas of intrinsic to extrinsic stochasticity

  20. Intrinsic and Extrinsic Motivations: Classic Definitions and New Directions.

    Science.gov (United States)

    Ryan; Deci

    2000-01-01

    Intrinsic and extrinsic types of motivation have been widely studied, and the distinction between them has shed important light on both developmental and educational practices. In this review we revisit the classic definitions of intrinsic and extrinsic motivation in light of contemporary research and theory. Intrinsic motivation remains an important construct, reflecting the natural human propensity to learn and assimilate. However, extrinsic motivation is argued to vary considerably in its relative autonomy and thus can either reflect external control or true self-regulation. The relations of both classes of motives to basic human needs for autonomy, competence and relatedness are discussed. Copyright 2000 Academic Press.

  1. Intrinsic and extrinsic measurement for Brownian motion

    International Nuclear Information System (INIS)

    Castro-Villarreal, Pavel

    2014-01-01

    Based upon the Smoluchowski equation on curved manifolds, three physical observables are considered for Brownian displacement, namely geodesic displacement s, Euclidean displacement δR, and projected displacement δR ⊥ . The Weingarten–Gauss equations are used to calculate the mean-square Euclidean displacements in the short-time regime. Our findings show that from an extrinsic point of view the geometry of the space affects the Brownian motion in such a way that the particle’s diffusion is decelerated, contrasting with the intrinsic point of view where dynamics is controlled by the sign of the Gaussian curvature (Castro-Villarreal, 2010 J. Stat. Mech. P08006). Furthermore, it is possible to give exact formulas for 〈δR〉 and 〈δR 2 〉 on spheres and minimal surfaces, which are valid for all values of time. In the latter case, surprisingly, Brownian motion corresponds to the usual diffusion in flat geometries, albeit minimal surfaces have non-zero Gaussian curvature. Finally, the two-dimensional case is emphasized due to its close relation to surface self-diffusion in fluid membranes. (paper)

  2. Free Radicals and Extrinsic Skin Aging

    Directory of Open Access Journals (Sweden)

    Borut Poljšak

    2012-01-01

    Full Text Available Human skin is constantly directly exposed to the air, solar radiation, environmental pollutants, or other mechanical and chemical insults, which are capable of inducing the generation of free radicals as well as reactive oxygen species (ROS of our own metabolism. Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation (UVR. It is estimated that among all these environmental factors, UVR contributes up to 80%. UV-induced generation of ROS in the skin develops oxidative stress, when their formation exceeds the antioxidant defence ability of the target cell. The primary mechanism by which UVR initiates molecular responses in human skin is via photochemical generation of ROS mainly formation of superoxide anion (O2−•, hydrogen peroxide (H2O2, hydroxyl radical (OH•, and singlet oxygen (1O2. The only protection of our skin is in its endogenous protection (melanin and enzymatic antioxidants and antioxidants we consume from the food (vitamin A, C, E, etc.. The most important strategy to reduce the risk of sun UVR damage is to avoid the sun exposure and the use of sunscreens. The next step is the use of exogenous antioxidants orally or by topical application and interventions in preventing oxidative stress and in enhanced DNA repair.

  3. Plasma opening switch with extrinsic magnetic field

    CERN Document Server

    Dolgachev, G; Maslennikov, D

    2001-01-01

    Summary form only given, as follows. We have demonstrated in series of experiments that plasma opening switch (POS) switching voltage (UPOS) is defined by energy density (w) deposited in the POS plasma. If we then consider a plasma erosion mainly responsible for the effect of POS switching (the erosion effect could be described by Hall or Child-Langmuir models) the energy density (w) could be measured as a function of a system "macro-parameter" such as the initial charging voltage of the capacity storage system (the Marx pulsed voltage generator) UMarx. The POS voltage in this case could be given by UPOS"aw=aUMarx4/7, where a is a constant. This report demonstrates that for the high-impedance POS which has limited charge density transferred through the POS plasma a"2.5 (MV3/7) with no external magnetic field applied. The use of the extrinsic magnetic field allows to increase a up to 3.6 (MV3/7) and to achieve higher voltages at the opening phase - UPOS=3.6UMarx4/7. To verify this approach set of experimental ...

  4. Radiation effects in IRAS extrinsic infrared detectors

    Science.gov (United States)

    Varnell, L.; Langford, D. E.

    1982-01-01

    During the calibration and testing of the Infrared Astronomy Satellite (IRAS) focal plane, it was observed that the extrinsic photoconductor detectors were affected by gamma radiation at dose levels of the order of one rad. Since the flight environment will subject the focal plane to dose levels of this order from protons in single pass through the South Atlantic Anomaly, an extensive program of radiation tests was carried out to measure the radiation effects and to devise a method to counteract these effects. The effects observed after irradiation are increased responsivity, noise, and rate of spiking of the detectors after gamma-ray doses of less than 0.1 rad. The detectors can be returned almost to pre-irradiation performance by increasing the detector bias to breakdown and allowing a large current to flow for several minutes. No adverse effects on the detectors have been observed from this bias boost, and this technique will be used for IRAS with frequent calibration to ensure the accuracy of observations made with the instrument.

  5. Extrinsic spin Hall effect in graphene

    Science.gov (United States)

    Rappoport, Tatiana

    The intrinsic spin-orbit coupling in graphene is extremely weak, making it a promising spin conductor for spintronic devices. In addition, many applications also require the generation of spin currents in graphene. Theoretical predictions and recent experimental results suggest one can engineer the spin Hall effect in graphene by greatly enhancing the spin-orbit coupling in the vicinity of an impurity. The extrinsic spin Hall effect then results from the spin-dependent skew scattering of electrons by impurities in the presence of spin-orbit interaction. This effect can be used to efficiently convert charge currents into spin-polarized currents. I will discuss recent experimental results on spin Hall effect in graphene decorated with adatoms and metallic cluster and show that a large spin Hall effect can appear due to skew scattering. While this spin-orbit coupling is small if compared with what it is found in metals, the effect is strongly enhanced in the presence of resonant scattering, giving rise to robust spin Hall angles. I will present our single impurity scattering calculations done with exact partial-wave expansions and complement the analysis with numerical results from a novel real-space implementation of the Kubo formalism for tight-binding Hamiltonians. The author acknowledges the Brazilian agencies CNPq, CAPES, FAPERJ and INCT de Nanoestruturas de Carbono for financial support.

  6. Anti-apoptotic peptides protect against radiation-induced cell death

    International Nuclear Information System (INIS)

    McConnell, Kevin W.; Muenzer, Jared T.; Chang, Kathy C.; Davis, Chris G.; McDunn, Jonathan E.; Coopersmith, Craig M.; Hilliard, Carolyn A.; Hotchkiss, Richard S.; Grigsby, Perry W.; Hunt, Clayton R.

    2007-01-01

    The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15 Gy radiation. In mice exposed to 5 Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues

  7. Extrinsic and intrinsic regulation of axon regeneration at a crossroads.

    Science.gov (United States)

    Kaplan, Andrew; Ong Tone, Stephan; Fournier, Alyson E

    2015-01-01

    Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.

  8. Stochastic synchronization of neuronal populations with intrinsic and extrinsic noise.

    KAUST Repository

    Bressloff, Paul C; Lai, Yi Ming

    2011-01-01

    We extend the theory of noise-induced phase synchronization to the case of a neural master equation describing the stochastic dynamics of an ensemble of uncoupled neuronal population oscillators with intrinsic and extrinsic noise. The master

  9. The effect of extrinsic motivation on cycle time trial performance

    NARCIS (Netherlands)

    Hulleman, M.; de Koning, J.J.; Hettinga, F.J.; Foster, C.

    2007-01-01

    PURPOSE: Athletes occasionally follow pacing patterns that seem unreasonably aggressive compared with those of prerace performances, potentially because of the motivation provided by competition. This study evaluated the effect of extrinsic motivation on cyclists' time trial performance. METHODS:

  10. On the isoperimetric rigidity of extrinsic minimal balls

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, V.

    2003-01-01

    We consider an m-dimensional minimal submanifold P and a metric R-sphere in the Euclidean space R-n. If the sphere has its center p on P, then it will cut out a well defined connected component of P which contains this center point. We call this connected component an extrinsic minimal R-ball of P....... The quotient of the volume of the extrinsic ball and the volume of its boundary is not larger than the corresponding quotient obtained in the space form standard situation, where the minimal submanifold is the totally geodesic linear subspace R-m. Here we show that if the minimal submanifold has dimension...... larger than 3, if P is not too curved along the boundary of an extrinsic minimal R-ball, and if the inequality alluded to above is an equality for the extrinsic minimal ball, then the minimal submanifold is totally geodesic....

  11. The detrimental effects of extrinsic reinforcement on "Intrinsic motivation".

    Science.gov (United States)

    Dickinson, A M

    1989-01-01

    Extrinsic consequences have been criticized on the grounds that they decrease intrinsic motivation or internally initiated behavior. Two popular rationales for this criticism, Lepper's overjustification hypothesis (1981) and Deci's motivational theory (Deci & Ryan, 1985), are reviewed and the criticism is then redefined behaviorally. "Intrinsically controlled" behavior is defined as behavior maintained by response-produced reinforcers, and the question concerning extrinsic consequences is thus restated as follows: When behavior is maintained by response-produced stimuli, does extrinsic reinforcement decrease the reinforcing value of those stimuli? The empirical support for this detrimental effect is summarized briefly, and several possible explanations for the phenomenon are offered. Research results that reflect on the effect's generality and social significance are discussed next, with the conclusion that the effect is transient and not likely to occur at all if extrinsic rewards are reinforcing, noncompetitive, based on reasonable performance standards, and delivered repetitively.

  12. CT-semiotics and clinical aspects of extrinsic allergic alveolitis

    International Nuclear Information System (INIS)

    Skrynnikova, I.P.; Momot, N.V.; Vakulenko, I.P.; Tanasichuk-Gazhieva, N.V

    2003-01-01

    Extrinsic allergic alveolitis can be a difficult diagnostic problem. The comparison of the results of CT research with the clinical immunological and morphological data allowed to define the forms and diagnose the characteristic symptoms of the disease

  13. On intrinsic and extrinsic origin of plasmon peaks

    International Nuclear Information System (INIS)

    Takayama, Shoichi; Kawai, Jun

    2008-01-01

    The origin of the plasmon loss peaks in X-ray photoelectron spectra are discussed based on the (1) intrinsic, (2) extrinsic, (3) quantum interference between (1) and (2), and (4) mixture of (1) and (2). It was believed that the major part of plasmon was due to the extrinsic, the present analysis concludes the major part is intrinsic, depending the excitation energy. This analysis is based on the electron reflection spectra, but valid for X-ray photoelectron spectra. (author)

  14. The effects of extrinsic rewards on children's intrinsic motivation

    OpenAIRE

    大槻, 千秋

    1981-01-01

    An experiment was conducted with preschool children to test whether a person's intrinsic motivation in an activity may be decreased by extrinsic salient rewards in Japan like in America. Children solved some jigsaw puzzles and received assorted candies, then they were observed how long they did other jigsaw puzzles. The results showed that the effects of extrinsic rewards on intrinsic motivation in an activity varied with the subject's social background. In uptown children's intrinsic motivat...

  15. The Effect of Extrinsic Motivational Factors Towards Iba Student Achievement

    OpenAIRE

    Pangemanan, Sifrid S.; Saerang, David Paul Elia; Rondonuwu, Mariska

    2014-01-01

    The reason students can facing the world of competition because they have a motivation. A thing that help students to get their motivation when they are not get a motivation by themself is through extrinsic motivational factors. There are two objectives of this research are to analyze the effect of extrinsic motivational factors towards student achievement and to identify the most influental factors on student achievement. The method is multiple linear regression analysis to examine the effec...

  16. Self-perception of intrinsic and extrinsic motivation.

    Science.gov (United States)

    Calder, B J; Staw, B M

    1975-04-01

    Self-perception theory predicts that intrinsic and extrinsic motivation do not combine additively but rather interact. To test this predicted interaction, intrinsic and extrinsic motivation were both manipulated as independent variables. The results revealed a significant interaction for task satisfaction and a trend for the interaction on a behavioral measure. These results are discussed in terms of a general approach to the self-perception of motivation.

  17. Comparative Antioxidant, Antiproliferative and Apoptotic Effects of ...

    African Journals Online (AJOL)

    Purpose: To determine and compare the antioxidant, antiproliferative and apoptotic effects of leaf infusions of Ilex laurina ... Both plant infusions inhibited viability and cell growth of SW480 and SW620 cells. .... 100 g of dry extract, from a gallic acid calibration curve [9]. ..... antioxidant capacity and in vitro inhibition of colon.

  18. Comparative Antioxidant, Antiproliferative and Apoptotic Effects of ...

    African Journals Online (AJOL)

    Purpose: To determine and compare the antioxidant, antiproliferative and apoptotic effects of leaf infusions of Ilex laurina and Ilex paraguariensis in colon cancer cells. Methods: Antioxidant activity was determined by ORAC (Oxygen Radical Absorbance Capacity) and FRAP (Ferric Reducing Antioxidant Power). Cytotoxic ...

  19. Detection of apoptotic cells using immunohistochemistry

    NARCIS (Netherlands)

    Newbold, Andrea; Martin, Ben P.; Cullinane, Carleen; Bots, Michael

    2014-01-01

    Immunohistochemistry is commonly used to show the presence of apoptotic cells in situ. In this protocol, B-cell lymphoma cells are injected into recipient mice and, on tumor formation, the mice are treated with the apoptosis inducer vorinostat (a histone deacetylase inhibitor). Tumor samples are

  20. Separating intrinsic from extrinsic fluctuations in dynamic biological systems.

    Science.gov (United States)

    Hilfinger, Andreas; Paulsson, Johan

    2011-07-19

    From molecules in cells to organisms in ecosystems, biological populations fluctuate due to the intrinsic randomness of individual events and the extrinsic influence of changing environments. The combined effect is often too complex for effective analysis, and many studies therefore make simplifying assumptions, for example ignoring either intrinsic or extrinsic effects to reduce the number of model assumptions. Here we mathematically demonstrate how two identical and independent reporters embedded in a shared fluctuating environment can be used to identify intrinsic and extrinsic noise terms, but also how these contributions are qualitatively and quantitatively different from what has been previously reported. Furthermore, we show for which classes of biological systems the noise contributions identified by dual-reporter methods correspond to the noise contributions predicted by correct stochastic models of either intrinsic or extrinsic mechanisms. We find that for broad classes of systems, the extrinsic noise from the dual-reporter method can be rigorously analyzed using models that ignore intrinsic stochasticity. In contrast, the intrinsic noise can be rigorously analyzed using models that ignore extrinsic stochasticity only under very special conditions that rarely hold in biology. Testing whether the conditions are met is rarely possible and the dual-reporter method may thus produce flawed conclusions about the properties of the system, particularly about the intrinsic noise. Our results contribute toward establishing a rigorous framework to analyze dynamically fluctuating biological systems.

  1. Development of the intrinsic and extrinsic innervation of the gut.

    Science.gov (United States)

    Uesaka, Toshihiro; Young, Heather M; Pachnis, Vassilis; Enomoto, Hideki

    2016-09-15

    The gastrointestinal (GI) tract is innervated by intrinsic enteric neurons and by extrinsic efferent and afferent nerves. The enteric (intrinsic) nervous system (ENS) in most regions of the gut consists of two main ganglionated layers; myenteric and submucosal ganglia, containing numerous types of enteric neurons and glial cells. Axons arising from the ENS and from extrinsic neurons innervate most layers of the gut wall and regulate many gut functions. The majority of ENS cells are derived from vagal neural crest cells (NCCs), which proliferate, colonize the entire gut, and first populate the myenteric region. After gut colonization by vagal NCCs, the extrinsic nerve fibers reach the GI tract, and Schwann cell precursors (SCPs) enter the gut along the extrinsic nerves. Furthermore, a subpopulation of cells in myenteric ganglia undergoes a radial (inward) migration to form the submucosal plexus, and the intrinsic and extrinsic innervation to the mucosal region develops. Here, we focus on recent progress in understanding the developmental processes that occur after the gut is colonized by vagal ENS precursors, and provide an up-to-date overview of molecular mechanisms regulating the development of the intrinsic and extrinsic innervation of the GI tract. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Extrinsic value orientation and affective forecasting: overestimating the rewards, underestimating the costs.

    Science.gov (United States)

    Sheldon, Kennon M; Gunz, Alexander; Nichols, Charles P; Ferguson, Yuna

    2010-02-01

    We examined affective forecasting errors as a possible explanation of the perennial appeal of extrinsic values and goals. Study 1 found that although people relatively higher in extrinsic (money, fame, image) compared to intrinsic (growth, intimacy, community) value orientation (REVO) are less happy, they nevertheless believe that attaining extrinsic goals offers a strong potential route to happiness. Study 2's longitudinal experimental design randomly assigned participants to pursue either 3 extrinsic or 3 intrinsic goals over 4 weeks, and REVO again predicted stronger forecasts regarding extrinsic goals. However, not even extrinsically oriented participants gained well-being benefits from attaining extrinsic goals, whereas all participants tended to gain in happiness from attaining intrinsic goals. Study 3 showed that the effect of REVO on forecasts is mediated by extrinsic individuals' belief that extrinsic goals will satisfy autonomy and competence needs. It appears that some people overestimate the emotional benefits of achieving extrinsic goals, to their potential detriment.

  3. The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Cheng Guangming

    2009-07-01

    Full Text Available Abstract Background Increased serum level of parathyroid hormone (PTH was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells. Methods Prostate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential. Results In cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,. Conclusion Taken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.

  4. The antiproliferative and apoptotic effects of apigenin on glioblastoma cells.

    Science.gov (United States)

    Stump, Trevor A; Santee, Brittany N; Williams, Lauren P; Kunze, Rachel A; Heinze, Chelsae E; Huseman, Eric D; Gryka, Rebecca J; Simpson, Denise S; Amos, Samson

    2017-07-01

    Glioblastoma (GBM) is highly proliferative, infiltrative, malignant and the most deadly form of brain tumour. The epidermal growth factor receptor (EGFR) is overexpressed, amplified and mutated in GBM and has been shown to play key and important roles in the proliferation, growth and survival of this tumour. The goal of our study was to investigate the antiproliferative, apoptotic and molecular effects of apigenin in GBM. Proliferation and viability tests were carried out using the trypan blue exclusion, MTT and lactate dehydrogenase (LDH) assays. Flow cytometry was used to examine the effects of apigenin on the cell cycle check-points. In addition, we determined the effects of apigenin on EGFR-mediated signalling pathways by Western blot analyses. Our results showed that apigenin reduced cell viability and proliferation in a dose- and time-dependent manner while increasing cytotoxicity in GBM cells. Treatment with apigenin-induced is poly ADP-ribose polymerase (PARP) cleavage and caused cell cycle arrest at the G2M checkpoint. Furthermore, our data revealed that apigenin inhibited EGFR-mediated phosphorylation of mitogen-activated protein kinase (MAPK), AKT and mammalian target of rapamycin (mTOR) signalling pathways and attenuated the expression of Bcl-xL. Our results demonstrated that apigenin has potent inhibitory effects on pathways involved in GBM proliferation and survival and could potentially be used as a therapeutic agent for GBM. © 2017 Royal Pharmaceutical Society.

  5. INTRINSIC AND EXTRINSIC MOTIVATION - AN INVESTIGATION OF PERFORMANCE CORRELATION

    Directory of Open Access Journals (Sweden)

    Abrudan Maria-Madela

    2011-07-01

    Full Text Available A series of research untaken in the last decade have revealed some interesting aspects regarding the effects of different types of motivation on performance. Among the researchers who have shown interest in this field we can number: Richard Ryan, Edward Deci, Sam Glucksberg, Dan Ariely, Robert Eisenhower, Linda Shanock, analysts from London School of Economics, and others. Their findings suggest that extrinsic incentives may have a negative impact on overall performance, but a general agreement in this respect has not been reached. In this paper we intend to shed some light upon the relationship between intrinsic and extrinsic motivation and performance. Experts define intrinsic motivation as being the execution of a task or activity because of the inherent satisfaction arising from it rather than due to some separate outcome. In contrast with intrinsic motivation, we speak of extrinsic motivation whenever an activity is done in order to attain some separable outcome. With the purpose of contributing to the clarification of the links between concepts, we initiated and conducted an explanatory research. The research is based on the analysis of the relations between the results obtained by third year students and their predominant type of motivation. For this, we formulated and tested four work hypotheses using a combination of quantitative methods (investigation and qualitative methods (focus group. After the validation of the questionnaires, the respondents were divided into four categories: intrinsically motivated, extrinsically motivated, both intrinsically and extrinsically motivated and unmotivated. To analyze the collected data, we made use of Excel and SPSS. Some of the primary conclusions of the research are as follows: as the average increases, the percent of individuals having both extrinsic and intrinsic motivation is decreasing; the highest percentage of unmotivated students is concentrated in the highest average category; Female

  6. Quantifying intrinsic and extrinsic variability in stochastic gene expression models.

    Science.gov (United States)

    Singh, Abhyudai; Soltani, Mohammad

    2013-01-01

    Genetically identical cell populations exhibit considerable intercellular variation in the level of a given protein or mRNA. Both intrinsic and extrinsic sources of noise drive this variability in gene expression. More specifically, extrinsic noise is the expression variability that arises from cell-to-cell differences in cell-specific factors such as enzyme levels, cell size and cell cycle stage. In contrast, intrinsic noise is the expression variability that is not accounted for by extrinsic noise, and typically arises from the inherent stochastic nature of biochemical processes. Two-color reporter experiments are employed to decompose expression variability into its intrinsic and extrinsic noise components. Analytical formulas for intrinsic and extrinsic noise are derived for a class of stochastic gene expression models, where variations in cell-specific factors cause fluctuations in model parameters, in particular, transcription and/or translation rate fluctuations. Assuming mRNA production occurs in random bursts, transcription rate is represented by either the burst frequency (how often the bursts occur) or the burst size (number of mRNAs produced in each burst). Our analysis shows that fluctuations in the transcription burst frequency enhance extrinsic noise but do not affect the intrinsic noise. On the contrary, fluctuations in the transcription burst size or mRNA translation rate dramatically increase both intrinsic and extrinsic noise components. Interestingly, simultaneous fluctuations in transcription and translation rates arising from randomness in ATP abundance can decrease intrinsic noise measured in a two-color reporter assay. Finally, we discuss how these formulas can be combined with single-cell gene expression data from two-color reporter experiments for estimating model parameters.

  7. Stabilization Of Apoptotic Cells: Generation Of Zombie Cells

    Directory of Open Access Journals (Sweden)

    José A. Sánchez Alcázar

    2015-08-01

    Stabilization of apoptotic cells can be used for reliable detection and quantification of apoptosis in cultured cells and may allow a safer administration of apoptotic cells in clinical applications. Furthermore, it opens new avenues in the functional reconstruction of apoptotic cells for longer preservation.

  8. Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation

    International Nuclear Information System (INIS)

    Yadav, Vikas; Varshney, Pallavi; Sultana, Sarwat; Yadav, Jyoti; Saini, Neeru

    2015-01-01

    Pancreatic cancer, one of the most dreadful gastrointestinal tract malignancies, with the current chemotherapeutic drugs has posed a major impediment owing to poor prognosis and chemo-resistance thereby suggesting critical need for additional drugs as therapeutics in combating the situation. Fluoroquinolones have shown promising and significant anti-tumor effects on several carcinoma cell lines. Previously, we reported growth inhibitory effects of fourth generation fluoroquinolone Gatifloxacin, while in the current study we have investigated the anti-proliferative and apoptosis-inducing mechanism of older generation fluoroquinolones Moxifloxacin and Ciprofloxacin on the pancreatic cancer cell-lines MIA PaCa-2 and Panc-1. Cytotoxicity was measured by MTT assay. Apoptosis induction was evaluated using annexin assay, cell cycle assay and activation of caspase-3, 8, 9 were measured by western blotting and enzyme activity assay. Herein, we found that both the fluoroquinolones suppressed the proliferation of pancreatic cancer cells by causing S-phase arrest and apoptosis. Blockade in S-phase of cell cycle was associated with decrease in the levels of p27, p21, CDK2, cyclin-A and cyclin-E. Herein we also observed triggering of extrinsic as well as intrinsic mitochondrial apoptotic pathway as suggested by the activation of caspase-8, 9, 3, and Bid respectively. All this was accompanied by downregulation of antiapoptotic protein Bcl-xL and upregulation of proapoptotic protein Bak. Our results strongly suggest the role of extracellular-signal-regulated kinases (ERK1/2), but not p53, p38 and c-JUN N-terminal kinase (JNK) in fluoroquinolone induced growth inhibitory effects in both the cell lines. Additionally, we also found both the fluoroquinolones to augment the apoptotic effects of broad spectrum anticancer drug Cisplatin via ERK. The fact that these fluoroquinolones synergize the effect of cisplatin opens new insight into therapeutic index in treatment of pancreatic

  9. SYTO probes: markers of apoptotic cell demise.

    Science.gov (United States)

    Wlodkowic, Donald; Skommer, Joanna

    2007-10-01

    As mechanistic studies on tumor cell death advance towards their ultimate translational goal, there is a need for specific, rapid, and high-throughput analytical tools to detect diverse cell demise modes. Patented DNA-binding SYTO probes, for example, are gaining increasing interest as easy-to-use markers of caspase-dependent apoptotic cell death. They are proving convenient for tracking apoptosis in diverse hematopoietic cell lines and primary tumor samples, and, due to their spectral characteristics, appear to be useful for the development of multiparameter flow cytometry assays. Herein, several protocols for multiparametric assessment of apoptotic events using SYTO probes are provided. There are protocols describing the use of green fluorescent SYTO 16 and red fluorescent SYTO 17 dyes in combination with plasma membrane permeability markers. Another protocol highlights the multiparametric use of SYTO 16 dye in conjunction with the mitochondrial membrane potential sensitive probe, tetramethylrhodamine methyl ester (TMRM), and the plasma membrane permeability marker, 7-aminoactinomycin D (7-AAD).

  10. [EXTRINSIC AND INTRINSIC FACTORS FOR FALLS THAT CAUSED HIP FRACTURE].

    Science.gov (United States)

    Tsur, Atzmon; Shakeer, Nael; Segal, Zvi; Itah, Dorit; Eluz, Dana

    2017-05-01

    Among the reasons described as possibly causing falls in older and elderly people are extrinsic factors such as bumping into objects, slipping on a wet floor, etc., and intrinsic factors - those that occur suddenly without warning. To investigate the connection between the reasons for falls, extrinsic or intrinsic and different medical and nonmedical factors. The survey included 82 people, 53 women and 29 men, who fell and broke their hip, underwent surgery, and were treated at the Rehabilitation Department. Data showed that 39 people fell due to extrinsic factors and 43 due to intrinsic reasons. We examined the correlation with several factors, both medical and non-medical, that may have influenced the scenario of each group. Falls due to extrinsic reasons took place at all hours of the day and night, mainly in people who were alone and who wore shoes or sandals at the time of the fall and who either suffered from slight or no disturbances in attention and concentration. Falls due to intrinsic reasons occurred mainly during rest or sleep hours, in people who walked barefoot or with socks or slippers and who suffered moderate or severe disturbances in attention and concentration. Although the differences in the extrinsic vs. intrinsic reasons for falls that led to broken hips were fairly clear, it would be difficult to recommend new tools for prevention of this phenomenon. Trying to predict an infrequent future event such as a traumatic fall is inherently difficult.

  11. Extrinsic versus intrinsic hand muscle dominance in finger flexion.

    Science.gov (United States)

    Al-Sukaini, A; Singh, H P; Dias, J J

    2016-05-01

    This study aims to identify the patterns of dominance of extrinsic or intrinsic muscles in finger flexion during initiation of finger curl and mid-finger flexion. We recorded 82 hands of healthy individuals (18-74 years) while flexing their fingers and tracked the finger joint angles of the little finger using video motion tracking. A total of 57 hands (69.5%) were classified as extrinsic dominant, where the finger flexion was initiated and maintained at proximal interphalangeal and distal interphalangeal joints. A total of 25 (30.5%) were classified as intrinsic dominant, where the finger flexion was initiated and maintained at the metacarpophalangeal joint. The distribution of age, sex, dominance, handedness and body mass index was similar in the two groups. This knowledge may allow clinicians to develop more efficient rehabilitation regimes, since intrinsic dominant individuals would not initiate extrinsic muscle contraction till later in finger flexion, and might therefore be allowed limited early active motion. For extrinsic dominant individuals, by contrast, initial contraction of extrinsic muscles would place increased stress on the tendon repair site if early motion were permitted. © The Author(s) 2016.

  12. Iron-59 absorption from soy hulls: intrinsic vs extrinsic labeling

    International Nuclear Information System (INIS)

    Lykken, G.I.; Mahalko, J.R.; Nielsen, E.J.; Dintzis, F.R.

    1986-01-01

    As part of an evaluation of the validity of the extrinsic labeling technique for measuring iron absorption, absorption from soy hulls extrinsically labeled ( 59 Fe added to bread dough) was compared with that from soy hulls intrinsically labeled ( 59 Fe incorporated into the soy plant during growth). Century soybeans were grown in a greenhouse. After pods had formed and were filling, each plant was stem injected twice, at 3 day intervals, with 22 μCi 59 Fe as FeCl 2 in 25 μl of 0.5 M HCl solution. After the plants had senesced, the soybeans were harvested, dried, shelled and the hulls removed. Standard meals containing 3.5 mg Fe/meal and up to 0.06 μCi 59 Fe in a soy hull bun were fed on 2 consecutive days to free-living volunteers in a crossover design. Absorption of 59 Fe was greater from intrinsically labeled soy hulls than from extrinsically labeled soy hulls, 20 +/- 20% vs 15 +/- 11% (n=14, p > 0.05 by paired t-test). Apparent absorption ranged from 1.3% to 77% from intrinsically labeled soy hulls and .5% to 29% from extrinsically labeled soy hulls with the highest absorption occurring in persons with low serum ferritin (S.F. < 8 ng/ml). These findings provide additional evidence that the extrinsic labeling method is a valid measure of iron bioavailability to humans

  13. Emotion impairs extrinsic source memory--An ERP study.

    Science.gov (United States)

    Mao, Xinrui; You, Yuqi; Li, Wen; Guo, Chunyan

    2015-09-01

    Substantial advancements in understanding emotional modulation of item memory notwithstanding, controversies remain as to how emotion influences source memory. Using an emotional extrinsic source memory paradigm combined with remember/know judgments and two key event-related potentials (ERPs)-the FN400 (a frontal potential at 300-500 ms related to familiarity) and the LPC (a later parietal potential at 500-700 ms related to recollection), our research investigated the impact of emotion on extrinsic source memory and the underlying processes. We varied a semantic prompt (either "people" or "scene") preceding a study item to manipulate the extrinsic source. Behavioral data indicated a significant effect of emotion on "remember" responses to extrinsic source details, suggesting impaired recollection-based source memory in emotional (both positive and negative) relative to neutral conditions. In parallel, differential FN400 and LPC amplitudes (correctly remembered - incorrectly remembered sources) revealed emotion-related interference, suggesting impaired familiarity and recollection memory of extrinsic sources associated with positive or negative items. These findings thus lend support to the notion of emotion-induced memory trade off: while enhancing memory of central items and intrinsic/integral source details, emotion nevertheless disrupts memory of peripheral contextual details, potentially impairing both familiarity and recollection. Importantly, that positive and negative items result in comparable memory impairment suggests that arousal (vs. affective valence) plays a critical role in modulating dynamic interactions among automatic and elaborate processes involved in memory. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Protective properties of sesamin against fluoride-induced oxidative stress and apoptosis in kidney of carp (Cyprinus carpio) via JNK signaling pathway.

    Science.gov (United States)

    Cao, Jinling; Chen, Jianjie; Xie, Lingtian; Wang, Jundong; Feng, Cuiping; Song, Jing

    2015-10-01

    Sesamin, a major lignan derived from sesame seeds, has been reported to have many benefits and medicinal properties. However, its protective effects against fluoride-induced injury in kidney of fish have not been clarified. Previously we found that fluoride exposure caused damage and apoptosis in the kidneys of the common carp, Cyprinus carpio. In this study, the effects of sesamin on renal oxidative stress and apoptosis in fluoride-exposed fish were determined. The results showed that sesamin alleviated significantly fluoride-induced renal damage and apoptosis of carp in a dose-dependent manner, indicated by the histopathological examination and ultrastructural observation. Moreover, treatment with sesamin also inhibited significantly fluoride-induced remarkable enhancement of reactive oxygen species (ROS) production and oxidative stress, such as the increase of lipid peroxidation level and the depletion of intracellular reduced glutathione (GSH) level in kidney. To explore the underlying mechanisms of sesamin action, we found that activities of caspase-3 were notably inhibited by treatment with sesamin in the kidney of fluoride-exposed fish. Sesamin decreased the levels of p-JNK protein in kidney, which in turn inactivated pro-apoptotic signaling events by restoring the balance between mitochondrial pro- and anti-apoptotic Bcl-2 and Bax proteins and by decreasing the release of mitochondrial cytochrome c in kidney of fluoride-exposed fish. JNK was also involved in the mitochondrial extrinsic apoptotic pathways of sesamin effects against fluoride-induced renal injury by regulating the levels of p-c-Jun, necrosis factor-alpha (TNF-α) and Bak proteins. These findings indicated that sesamin could protect kidney against fluoride-induced apoptosis by the oxidative stress downstream-mediated change in the inactivation of JNK signaling pathway. Taken together, sesamin plays an important role in maintaining renal health and preventing kidney from toxic damage induced by

  15. Intrinsic and extrinsic spin Hall effects of Dirac electrons

    International Nuclear Information System (INIS)

    Fukazawa, Takaaki; Kohno, Hiroshi; Fujimoto, Junji

    2017-01-01

    We investigate the spin Hall effect (SHE) of electrons described by the Dirac equation, which is used as an effective model near the L-points in bismuth. By considering short-range nonmagnetic impurities, we calculate the extrinsic as well as intrinsic contributions on an equal footing. The vertex corrections are taken into account within the ladder type and the so-called skew-scattering type. The intrinsic SHE which we obtain is consistent with that of Fuseya et al. It is found that the extrinsic contribution dominates the intrinsic one when the system is metallic. The extrinsic SHE due to the skew scattering is proportional to Δ/n i u, where 2Δ is the band gap, n i is the impurity concentration, and u is the strength of the impurity potential. (author)

  16. Extrinsic Motivation Index: A New Tool for Managing Labor Productivity

    Directory of Open Access Journals (Sweden)

    Berumen, S.A.

    2016-07-01

    Full Text Available The objective of this paper is to provide a tool of practical significance for HR managers and firm executives. This tool, which is called Extrinsic Motivation Index (EMI, is meant to measure the extrinsic motivation of employees. By measuring employees' extrinsic motivation, managers are able to track job satisfaction and, subsequently, implement measures aiming both to raise job satisfaction and to improve organizational commitment. In order to test the validity of the model, we apply the EMI to Faculty members at Spanish and German universities. We also carry out simulation experiments in order to to address all possible situations an organization most probably will have to deal with. The results point out significant differences in the level of motivation and commitment of Faculty members. Additionally, the analysis shows several ways in which an organization may manage job satisfaction issues according to on its level of resources.

  17. Intrinsic and extrinsic motivation for stereotypic and repetitive behavior.

    Science.gov (United States)

    Joosten, Annette V; Bundy, Anita C; Einfeld, Stewart L

    2009-03-01

    This study provides evidence for intrinsic and extrinsic motivators for stereotypical and repetitive behavior in children with autism and intellectual disability and children with intellectual disability alone. We modified the Motivation Assessment Scale (MAS) (1988b); dividing it into intrinsic and extrinsic measures and adding items to assess anxiety as an intrinsic motivator. Rasch analysis of data from 279 MASs (74 children) revealed that the items formed two unidimensional scales. Anxiety was a more likely intrinsic motivator than sensory seeking for children with dual diagnoses; the reverse was true for children with intellectual disability only. Escape and gaining a tangible object were the most common extrinsic motivators for those with dual diagnoses and attention and escape for children with intellectual disability.

  18. Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis

    Science.gov (United States)

    Millet, Arnaud; Martin, Katherine R.; Bonnefoy, Francis; Saas, Philippe; Mocek, Julie; Alkan, Manal; Terrier, Benjamin; Kerstein, Anja; Tamassia, Nicola; Satyanarayanan, Senthil Kumaran; Ariel, Amiram; Ribeil, Jean-Antoine; Guillevin, Loïc; Cassatella, Marco A.; Mueller, Antje; Thieblemont, Nathalie; Lamprecht, Peter; Mouthon, Luc; Perruche, Sylvain; Witko-Sarsat, Véronique

    2015-01-01

    Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology. PMID:26436651

  19. Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

    International Nuclear Information System (INIS)

    Hu, Z.; Li, Ch.; Chen, K.; Wang, L.E.; Sturgis, E.M.; Spitz, M.R.; Wei, Q.; Sturgis, E.M.

    2008-01-01

    Apoptotic capacity (AC) in primary lymphocytes may be a marker for cancer susceptibility, and functional single nucleotide polymorphisms (SNPs) in genes involved in apoptotic pathways may modulate cellular AC in response to DNA damage. To further examine the correlation between apoptotic genotypes and phenotype, we geno typed 14 published SNPs in 11 apoptosis-related genes (i.e., p53, Bcl-2, BAX, CASP9, DR4, Fas, FasL, CASP8, CASP10, CASP3, and CASP7) and assessed the AC in response to benzo[a]pyrene-7,8-9,10-diol epoxide (BPDE) in cultured primary lymphocytes from 172 cancer-free subjects. We found that among these 14 SNPs, R72P, intron 3 16-bp del/ins, and intron 6 G>A in , −938C>A in Bcl-2, and I522L in CASP10 were significant predictors of the BPDE-induced lymphocytic AC in single-locus analysis. In the combined analysis of the three variants, we found that the individuals with the diplotypes carrying 0-1 copy of the common R-del-G haplotype had higher AC values compared to other genotypes. Although the study size may not have the statistical power to detect the role of other SNPs in AC, our findings suggest that some SNPs in genes involved in the intrinsic apoptotic pathway may modulate lymphocytic AC in response to BPDE exposure in the general population. Larger studies are needed to validate these findings for further studying individual susceptibility to cancer and other apoptosis-related diseases

  20. Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.

    Science.gov (United States)

    Liu, Tiantian; Chen, Xiaoxu; Li, Tianjiao; Li, Xueliang; Lyu, Yinghua; Fan, Xiaoteng; Zhang, Pengfei; Zeng, Wenxian

    2017-10-01

    Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis.

    Science.gov (United States)

    Martel, Britta C; Litman, Thomas; Hald, Andreas; Norsgaard, Hanne; Lovato, Paola; Dyring-Andersen, Beatrice; Skov, Lone; Thestrup-Pedersen, Kristian; Skov, Søren; Skak, Kresten; Poulsen, Lars K

    2016-06-01

    Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. In this study, we used microarray analysis to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The primary aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. In contrast to severe AD, expression of the majority of genes associated with skin barrier formation was unchanged or upregulated in patients with mild AD compared to normal healthy skin. Among these, no significant differences in the expression of filaggrin (FLG) and loricrin at both mRNA and protein level were found in lesional skin from patients with mild AD, despite the presence of heterozygous FLG mutations in the majority of patients with mild extrinsic AD. Several inflammation-associated genes such as S100A9, MMP12, CXCL10 and CCL18 were highly expressed in lesional skin from patients with mild psoriasis and were also increased in patients with mild extrinsic and intrinsic AD similar to previous reports for severe AD. Interestingly, expression of genes involved in inflammatory responses in intrinsic AD resembled that of psoriasis more than that of extrinsic AD. Overall, differences in expression of inflammation-associated genes found among patients with mild intrinsic and extrinsic AD correlated with previous findings for patients with severe intrinsic and extrinsic AD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Intrinsic and extrinsic innervation of the heart in zebrafish (Danio rerio).

    Science.gov (United States)

    Stoyek, Matthew R; Croll, Roger P; Smith, Frank M

    2015-08-01

    In the vertebrate heart the intracardiac nervous system is the final common pathway for autonomic control of cardiac output, but the neuroanatomy of this system is not well understood. In this study we investigated the innervation of the heart in a model vertebrate, the zebrafish. We used antibodies against acetylated tubulin, human neuronal protein C/D, choline acetyltransferase, tyrosine hydroxylase, neuronal nitric oxide synthase, and vasoactive intestinal polypeptide to visualize neural elements and their neurotransmitter content. Most neurons were located at the venous pole in a plexus around the sinoatrial valve; mean total number of cells was 197 ± 23, and 92% were choline acetyltransferase positive, implying a cholinergic role. The plexus contained cholinergic, adrenergic, and nitrergic axons and vasoactive intestinal polypeptide-positive terminals, some innervating somata. Putative pacemaker cells near the plexus showed immunoreactivity for hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and the transcription factor Islet-1 (Isl1). The neurotracer neurobiotin showed that extrinsic axons from the left and right vagosympathetic trunks innervated the sinoatrial plexus proximal to their entry into the heart; some extrinsic axons from each trunk also projected into the medial dorsal plexus region. Extrinsic axons also innervated the atrial and ventricular walls. An extracardiac nerve trunk innervated the bulbus arteriosus and entered the arterial pole of the heart to innervate the proximal ventricle. We have shown that the intracardiac nervous system in the zebrafish is anatomically and neurochemically complex, providing a substrate for autonomic control of cardiac effectors in all chambers. © 2015 Wiley Periodicals, Inc.

  3. Intrinsic and extrinsic motivation and intention to breast-feed.

    Science.gov (United States)

    Wells, Kristen J; Thompson, Nancy J; Kloeblen-Tarver, Amy S

    2002-01-01

    To examine the feasibility of using the cognitive evaluation theory to examine pregnant women's intention to breast-feed. A questionnaire designed to measure intrinsic and extrinsic motivation was administered to 228 pregnant women. Results provide evidence for reliability and validity of the revised instrument in this population. A factor analysis suggests the instrument measures 2 types of intrinsic motivation, one type of extrinsic motivation, and motivation related to the baby. The instrument distinguished differences in motivation between women who intend to breast-feed and those who intend to formula feed. This study helps elucidate motivational factors involved in infant-feeding decisions.

  4. Extrinsic passivation of silicon surfaces for solar cells

    OpenAIRE

    Bonilla, R.S.; Reichel, C.; Hermle, M.; Martins, G.; Wilshaw, P.R.

    2015-01-01

    In the present work we study the extent to which extrinsic chemical and field effect passivation can improve the overall electrical passivation quality of silicon dioxide on silicon. Here we demonstrate that, when optimally applied, extrinsic passivation can produce surface recombination velocities below 1.2 cm/s in planar 1 Omega cm n-type Si. This is largely due to the additional field effect passivation component which reduces the recombination velocity below 2.13 cm/s. On textured surface...

  5. CONSUMER EVALUATIONS OF BEAUTIFICATION PRODUCTS: EFFECTS OF EXTRINSIC CUES

    Directory of Open Access Journals (Sweden)

    Md. Humayun Kabir Chowdhury

    2006-01-01

    Full Text Available This study investigates the influence of extrinsic cues, i.e. brand image, perceived price, perceived quality, and perceived country of origin on consumers' evaluative judgments for beautification products. Multi-item measures were used for data collection. Resultsrevealed that three extrinsic cues: brand image, perceived quality, and perceived country of origin have positive and significant influence on consumers' brand evaluation of beautification brands. Only perceived price has shown no such influence on consumers' brand evaluation. Finally, unanswered questions and future researchdirections are presented.

  6. Three-dimensional apoptotic nuclear behavior analyzed by means of Field Emission in Lens Scanning Electron Microscope

    Directory of Open Access Journals (Sweden)

    S. Salucci

    2015-09-01

    Full Text Available Apoptosis is an essential biological function required during embryogenesis, tissue homeostasis, organ development and immune system regulation. It is an active cell death pathway involved in a variety of pathological conditions. During this process cytoskeletal proteins appear damaged and undergo an enzymatic disassembling, leading to formation of apoptotic features. This study was designed to examine the three-dimensional chromatin behavior and cytoskeleton involvement, in particular actin re-modeling. HL-60 cells, exposed to hyperthermia, a known apoptotic trigger, were examined by means of a Field Emission in Lens Scanning Electron Microscope (FEISEM. Ultrastructural observations revealed in treated cells the presence of apoptotic patterns after hyperthermia trigger. In particular, three-dimensional apoptotic chromatin rearrangements appeared involving the translocation of filamentous actin from cytoplasm to the nucleus. FEISEM immunogold techniques showed actin labeling and its precise three-dimensional localization in the diffuse chromatin, well separated from the condensed one. The actin presence in dispersed chromatin inside the apoptotic nucleus can be considered an important feature, indispensable to permit the apoptotic machinery evolution.

  7. Different immunophenotypical apoptotic profiles characterise megakaryocytes of essential thrombocythaemia and primary myelofibrosis.

    Science.gov (United States)

    Florena, A M; Tripodo, C; Di Bernardo, A; Iannitto, E; Guarnotta, C; Porcasi, R; Ingrao, S; Abbadessa, V; Franco, V

    2009-04-01

    Essential thrombocythaemia (ET) and primary myelofibrosis (PMF) share some clinical and pathological features, but show different biological behaviour and prognosis. The latest contributions to understanding the nature of these disorders have focused on bone marrow microenvironment remodelling and proliferative stress, recognising megakaryocytes (MKCs) as "key-cells". The aim of this study was to investigate the apoptotic profile of ET and PMF MKCs in order to further characterise the biology of these disorders. Bone marrow biopsy samples from 30 patients with ET, and 30 patients with PMF, were immunophenotypically studied for the expression of pro-apoptotic (Fas, Fas-L, Bax, Bad) and anti-apoptotic (Bcl-2, Bcl-XL, hTERT (human telomerase reverse transcriptase)) molecules and the "executioner" molecule caspase-3. The fraction of MKCs undergoing apoptosis was assessed by deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Only the mitochondrial pathway seemed to be involved in MKC apoptosis. The anti-apoptotic molecule Bcl-XL was predominantly found in ET MKCs (50.5% of ET MKCs versus 35% of PMF MKCs; p = 0.036), while pro-apoptotic molecules Bax and Bad showed a prevalent expression in PMF MKCs (30.5% of ET MKCs versus 55% of PMF MKCs; 41% of ET MKCs versus 52% of PMF MKCs; p = 0.001 and p = 0.068, respectively). A significant fraction of PMF MKCs were committed to apoptosis according to caspase-3 expression and TUNEL, while only few ET cells were committed to apoptosis. hTERT was significantly more expressed in PMF (32% of ET MKCs versus 46% of PMF MKCs; p = 0.022), in agreement with the proliferative nature of this disease. It was found that ET and PMF MKCs, which barely differ in terms of morphology and aggregation, are characterised by markedly different apoptotic profiles. The rather high apoptotic fraction of PMF was able to support the fibrotic nature of this process, while the anti-apoptotic profile of ET cells fits well with their "steady

  8. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dae-Hee, E-mail: leedneo@gmail.com [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Dong-Wook [Department of Microbiology, Immunology, and Cancer Biology, University of VA (United States); Jung, Chang-Hwa [Division of Metabolism and Functionality Research, Korea Food Research Institute (Korea, Republic of); Lee, Yong J. [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Park, Daeho, E-mail: daehopark@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of)

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  9. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    International Nuclear Information System (INIS)

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J.; Park, Daeho

    2014-01-01

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway

  10. CT Accuracy of Extrinsic Tongue Muscle Invasion in Oral Cavity Cancer.

    Science.gov (United States)

    Junn, J C; Baugnon, K L; Lacayo, E A; Hudgins, P A; Patel, M R; Magliocca, K R; Corey, A S; El-Deiry, M; Wadsworth, J T; Beitler, J J; Saba, N F; Liu, Y; Aiken, A H

    2017-02-01

    Extrinsic tongue muscle invasion in oral cavity cancer upstages the primary tumor to a T4a. Despite this American Joint Committee on Cancer staging criterion, no studies have investigated the accuracy or prognostic importance of radiologic extrinsic tongue muscle invasion, the feasibility of standardizing extrinsic tongue muscle invasion reporting, or the degree of agreement across different disciplines: radiology, surgery, and pathology. The purpose of this study was to assess the agreement among radiology, surgery, and pathology for extrinsic tongue muscle invasion and to determine the imaging features most predictive of extrinsic tongue muscle invasion with surgical/pathologic confirmation. Thirty-three patients with untreated primary oral cavity cancer were included. Two head and neck radiologists, 3 otolaryngologists, and 1 pathologist prospectively evaluated extrinsic tongue muscle invasion. Fourteen of 33 patients had radiologic extrinsic tongue muscle invasion; however, only 8 extrinsic tongue muscle invasions were confirmed intraoperatively. Pathologists were unable to determine extrinsic tongue muscle invasion in post-formalin-fixed samples. Radiologic extrinsic tongue muscle invasion had 100% sensitivity, 76% specificity, 57% positive predictive value, and 100% negative predictive value with concurrent surgical-pathologic evaluation of extrinsic tongue muscle invasion as the criterion standard. On further evaluation, the imaging characteristic most consistent with surgical-pathologic evaluation positive for extrinsic tongue muscle invasion was masslike enhancement. Evaluation of extrinsic tongue muscle invasion is a subjective finding for all 3 disciplines. For radiology, masslike enhancement of extrinsic tongue muscle invasion most consistently corresponded to concurrent surgery/pathology evaluation positive for extrinsic tongue muscle invasion. Intraoperative surgical and pathologic evaluation should be encouraged to verify radiologic extrinsic tongue

  11. Acrylamide induces immunotoxicity through reactive oxygen species production and caspase-dependent apoptosis in mice splenocytes via the mitochondria-dependent signaling pathways.

    Science.gov (United States)

    Zamani, Ehsan; Shaki, Fatemeh; AbedianKenari, Saeid; Shokrzadeh, Mohammad

    2017-10-01

    Acrylamide (AA), a well-known food neo-contamination, can be produced during food preparing at high temperature. The immunotoxicity of AA have been revealed in the experimental animals. In this study, we explored the molecular mechanism responsible for the immunotoxicity of AA. The mice splenocytes exposed to AA concentrations (0,5,10 and 25 mM) and apoptosis cell death was measured through Annexin V/Propidium Iodide staining by flow cytometry method. The role of extrinsic and intrinsic pathways were evaluated respectively by activity of caspase-8 and-9. Furthermore, the spleen mitochondria were obtained using differential centrifugation from mice and mitochondrial toxicity endpoints were determined after AA exposure. Exposure of splenocytes to AA increased the splenocytes' apoptotic cell death. Also, increased activation of both caspase-8 and-9 were observed in mice splenocytes after AA exposure. Treatment of isolated mitochondria with AA lead to disturbance in activity of complex I and III of mitochondrial electron transfer chain that result in increased reactive oxygen species (ROS) production, lipid peroxidation and glutathione oxidation. These events were accompanied by mitochondrial membrane swelling, collapse of mitochondrial membrane potential and significant falling of mitochondrial activity. AA-mediated mitochondrial dysfunction along with mitochondrial oxidative damage seems to be critical events leading to activation of caspase cascade and apoptotic cell death in spleen that finally can attenuate immune system's function. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Optimization of intrinsic and extrinsic tendon healing through controllable water-soluble mitomycin-C release from electrospun fibers by mediating adhesion-related gene expression.

    Science.gov (United States)

    Zhao, Xin; Jiang, Shichao; Liu, Shen; Chen, Shuai; Lin, Zhi Yuan William; Pan, Guoqing; He, Fan; Li, Fengfeng; Fan, Cunyi; Cui, Wenguo

    2015-08-01

    To balance intrinsic and extrinsic healing during tendon repair is challenging in tendon surgery. We hypothesized that by mediating apoptotic gene and collagen synthesis of exogenous fibroblasts, the adhesion formation induced by extrinsic healing could be inhibited. With the maintenance of intrinsic healing, the tendon could be healed with proper function with no adhesion. In this study, we loaded hydrophilic mitomycin-C (MMC) into hyaluronan (HA) hydrosols, which were then encapsulated in poly(L-lactic acid) (PLLA) fibers by micro-sol electrospinning. This strategy successfully provided a controlled release of MMC to inhibit adhesion formations with no detrimental effect on intrinsic healing. We found that micro-sol electrospinning was an effective and facile approach to incorporate and control hydrophilic drug release from hydrophobic polyester fibers. MMC exhibited an initially rapid, and gradually steadier release during 40 days, and the release rates could be tuned by its concentration. In vitro studies revealed that low concentrations of MMC could inhibit fibroblast adhesion and proliferation. When lacerate tendons were healed using the MMC-HA loaded PLLA fibers in vivo, they exhibited comparable mechanical strength to the naturally healed tendons but with no significant presence of adhesion formation. We further identified the up-regulation of apoptotic protein Bax expression and down-regulation of proteins Bcl2, collage I, collagen III and α-SMA during the healing process associated with minimum adhesion formations. This approach presented here leverages new advances in drug delivery and nanotechnology and offers a promising strategy to balance intrinsic and extrinsic tendon healing through modulating genes associated with fibroblast apoptosis and collagen synthesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Generalized isoperimetric inequalities for extrinsic balls in minimal submanifolds

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, Vicente

    2002-01-01

    The volume of an extrinsic ball in a minimal submanifold has a well defined lower bound when the ambient manifold has an upper bound on its sectional curvatures, see e.g. [2] and [10]. When this upper bound is non-positive, the second named author has shown an isoperimetric inequality for such do...

  14. Binding of intrinsic and extrinsic features in working memory.

    Science.gov (United States)

    Ecker, Ullrich K H; Maybery, Murray; Zimmer, Hubert D

    2013-02-01

    There is ongoing debate concerning the mechanisms of feature binding in working memory. In particular, there is controversy regarding the extent to which these binding processes are automatic. The present article demonstrates that binding mechanisms differ depending on whether the to-be-integrated features are perceived as forming a coherent object. We presented a series of experiments that investigated the binding of color and shape, whereby color was either an intrinsic feature of the shape or an extrinsic feature of the shape's background. Results show that intrinsic color affected shape recognition, even when it was incidentally studied and irrelevant for the recognition task. In contrast, extrinsic color did not affect shape recognition, even when the association of color and shape was encoded and retrievable on demand. This strongly suggests that binding of intrinsic intra-item information but not extrinsic contextual information is obligatory in visual working memory. We highlight links to perception as well as implicit and explicit long-term memory, which suggest that the intrinsic-extrinsic dimension is a principle relevant to multiple domains of human cognition. 2013 APA, all rights reserved

  15. Dominance dynamics of competition between intrinsic and extrinsic grouping cues.

    Science.gov (United States)

    Luna, Dolores; Villalba-García, Cristina; Montoro, Pedro R; Hinojosa, José A

    2016-10-01

    In the present study we examined the dominance dynamics of perceptual grouping cues. We used a paradigm in which participants selectively attended to perceptual groups based on several grouping cues in different blocks of trials. In each block, single and competing grouping cues were presented under different exposure durations (50, 150 or 350ms). Using this procedure, intrinsic vs. intrinsic cues (i.e. proximity and shape similarity) were compared in Experiment 1; extrinsic vs. extrinsic cues (i.e. common region and connectedness) in Experiment 2; and intrinsic vs. extrinsic cues (i.e. common region and shape similarity) in Experiment 3. The results showed that in Experiment 1, no dominance of any grouping cue was found: shape similarity and proximity grouping cues showed similar reaction times (RTs) and interference effects. In contrast, in Experiments 2 and 3, common region dominated processing: (i) RTs to common region were shorter than those to connectedness (Exp. 2) or shape similarity (Exp. 3); and (ii) when the grouping cues competed, common region interfered with connectedness (Exp. 2) and shape similarity (Exp. 3) more than vice versa. The results showed that the exposure duration of stimuli only affected the connectedness grouping cue. An important result of our experiments indicates that when two grouping cues compete, both the non-attended intrinsic cue in Experiment 1, and the non-dominant extrinsic cue in Experiments 2 and 3, are still perceived and they are not completely lost. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Alberta Consumers' Valuation of Extrinsic and Intrinsic Red Meat Attributes

    DEFF Research Database (Denmark)

    Steiner, Bodo; Gao, Fei; Unterschultz, Jim

    2010-01-01

    This paper analyzes Alberta consumers’ perceptions toward extrinsic and intrinsic attributes of bison and beef steaks. In contrast to published Canadian consumer studies on bison meat that were undertaken prior to May 2003, before the first BSE case of Canadian origin was identified in beef cattle...

  17. Extrinsic photoresponse enhancement under additional intrinsic photoexcitation in organic semiconductors

    Energy Technology Data Exchange (ETDEWEB)

    Kounavis, P., E-mail: pkounavis@upatras.gr [Department of Electrical and Computer Engineering, School of Engineering, University of Patras, 26504 Patras (Greece)

    2016-06-28

    Dual light beam photoresponse experiments are employed to explore the photoresponse under simultaneous extrinsic and intrinsic photoexcitation of organic semiconductors. The photoresponse of a red modulated light extrinsic photoexcitation is found that can be significantly enhanced under an additional blue bias-light intrinsic photoexcitation in two terminal pentacene films on glass substrates. From the frequency resolved photoresponse, it is deduced that the phenomenon of photoresponse enhancement can be attributed to an increase in the extrinsic photogeneration rate of the red modulated light and/or an improvement of the drift velocity of carriers under an additional blue light intrinsic photoexcitation. The possible predominant extrinsic photogeneration mechanism, which can be compatible with the observed dependence of the photoresponse enhancement on the frequency and on the light intensities of the red and blue light excitation, is the singlet exciton dissociation through electron transfer to acceptor-like traps. Moreover, an improvement in the drift velocity of carriers traversing grain boundaries with potential energy barriers, which may be reduced by trapping of minority carriers created from the intrinsic photoexcitation, may partly contribute to the photoresponse enhancement.

  18. Magnetic order in graphite: Experimental evidence, intrinsic and extrinsic difficulties

    International Nuclear Information System (INIS)

    Esquinazi, P.; Barzola-Quiquia, J.; Spemann, D.; Rothermel, M.; Ohldag, H.; Garcia, N.; Setzer, A.; Butz, T.

    2010-01-01

    We discuss recently obtained data using different experimental methods including magnetoresistance measurements that indicate the existence of metal-free high-temperature magnetic order in graphite. Intrinsic as well as extrinsic difficulties to trigger magnetic order by irradiation of graphite are discussed in view of recently published theoretical work.

  19. Extrinsic photoresponse enhancement under additional intrinsic photoexcitation in organic semiconductors

    International Nuclear Information System (INIS)

    Kounavis, P.

    2016-01-01

    Dual light beam photoresponse experiments are employed to explore the photoresponse under simultaneous extrinsic and intrinsic photoexcitation of organic semiconductors. The photoresponse of a red modulated light extrinsic photoexcitation is found that can be significantly enhanced under an additional blue bias-light intrinsic photoexcitation in two terminal pentacene films on glass substrates. From the frequency resolved photoresponse, it is deduced that the phenomenon of photoresponse enhancement can be attributed to an increase in the extrinsic photogeneration rate of the red modulated light and/or an improvement of the drift velocity of carriers under an additional blue light intrinsic photoexcitation. The possible predominant extrinsic photogeneration mechanism, which can be compatible with the observed dependence of the photoresponse enhancement on the frequency and on the light intensities of the red and blue light excitation, is the singlet exciton dissociation through electron transfer to acceptor-like traps. Moreover, an improvement in the drift velocity of carriers traversing grain boundaries with potential energy barriers, which may be reduced by trapping of minority carriers created from the intrinsic photoexcitation, may partly contribute to the photoresponse enhancement.

  20. Extrinsic Rewards and Intrinsic Motivation in Education: Reconsidered Once Again.

    Science.gov (United States)

    Deci, Edward L.; Koestner, Richard; Ryan, Richard M.

    2001-01-01

    Reviews the results of a meta analysis (E. Deci, R. Koestner, and R. Ryan, 1999) that shows that tangible extrinsic rewards do have a substantial undermining effect on intrinsic motivation. Discusses results, which support cognitive evaluation theory, in terms of their relevance for educational practice. (SLD)

  1. College Student Intrinsic and/or Extrinsic Motivation and Learning.

    Science.gov (United States)

    Lin, Yi-Guang; McKeachie, Wilbert J.

    This paper investigates the joint effects of intrinsic and extrinsic goals on college students' learning in an introductory psychology course, a biology course, and several social science courses. The study questioned whether higher levels of motivation lead to better student performance. College students were surveyed using the Intrinsic Goal…

  2. Critical dimension of strings with an extrinsic curvature

    International Nuclear Information System (INIS)

    Matsuki, T.; Viswanathan, K.S.

    1988-01-01

    The conformal anomaly is calculated by using the path-integral method to determine the critical dimension for a string theory with an extrinsic curvature by appropriately defining the first-order form of this Lagrangian. The critical dimension, defined by the vanishing of the Liouville kinetic term, is found to be D = 26, the same as for the ordinary bosonic string theory

  3. Impact of Mentoring on Perceived Adequacy of Extrinsic ...

    African Journals Online (AJOL)

    This study examined the impact of informal mentoring on perceived adequacy of extrinsic organizational rewards such as pay, promotion and fringe benefit. Data were obtained from 161 employees through a survey of a public health organisation in south-western Nigeria. Hierarchical regression analysis revealed that ...

  4. Extrinsic motivation and job satisfaction of teachers' in public post ...

    African Journals Online (AJOL)

    This study was aimed at evaluating the relationship between extrinsic motivation and the job satisfaction of teachers' in public post primary schools in Cross River State, Nigeria. A sample of 125 teachers' was randomly drawn for the study. A four point likert-type questionnaire was used to gather data which was analyzed ...

  5. The Effects of Extrinsic Rewards on Admissions Counselors' Performance

    Science.gov (United States)

    Gardner-Engel, Miriam

    2010-01-01

    This study examines the best ways to motivate college admissions counselors. A review of literature revealed multiple perspectives on intrinsic and extrinsic as well as tangible and intangible rewards. Primary research was designed to examine the impact of tangible rewards and verbal reinforcements with a convenience sample of nine college…

  6. The extrinsic influence of carbon fibre reinforced plastic laminates to ...

    Indian Academy of Sciences (India)

    The extrinsic influence of carbon fibre reinforced plastic laminates to strengthen steel structures ... The intrinsic advantages of strengthening the steel-based structures by the use of fibre reinforced plastic (FRP) material have ... Sadhana | News.

  7. Extrinsic Reinforcement in the Classroom: Bribery or Best Practice

    Science.gov (United States)

    Akin-Little, K. Angeleque; Eckert, Tanya L.; Lovett, Benjamin J.; Little, Steven G.

    2004-01-01

    The debate over the effects of the use of extrinsic reinforcement in classrooms, businesses, and societal settings has been occurring for over 30 years. Some theorists have cautioned against the use of reward, whereas others have found little, if any, detrimental effect. This article examines the debate with an emphasis on data-based findings. The…

  8. Modelling of Extrinsic Fiber Optic Sagnac Ultrasound Interferometer ...

    African Journals Online (AJOL)

    Ultrasonic waves are used extensively in nondestructive testing both for characterization of material properties, in this paper, we describe a fiber optic sensor suitable for detection of ultrasonic waves. This sensor is based on an extrinsic fiber optic sagnac interferometer. The proposed sensor model can act as a conventional ...

  9. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability

    NARCIS (Netherlands)

    Frielink, N.; Schuengel, C.; Embregts, P.J.C.M.

    Background According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and

  10. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability

    NARCIS (Netherlands)

    Frielink, N.; Schuengel, C.; Embregts, P.J.C.M.

    2017-01-01

    Background: According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and

  11. Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells.

    Science.gov (United States)

    Lim, Sung-Chul; Jeon, Ho Jong; Kee, Keun Hong; Lee, Mi Ja; Hong, Ran; Han, Song Iy

    2017-05-01

    Andrographolide, a natural compound isolated from Andrographis paniculata , has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL). Exposure of GC cells to andrographolide altered the expression level of several growth-inhibiting and apoptosis-regulating proteins, including death receptors. It was demonstrated that activity of the TRAIL-R2 (DR5) pathway was critical in the development of andrographolide-mediated rhTRAIL sensitization, since its inhibition significantly reduced the extent of apoptosis induced by the combination of rhTRAIL and andrographolide. In addition, andrographolide increased reactive oxygen species (ROS) generation in a dose-dependent manner. N-acetyl cysteine prevented andrographolide-mediated DR5 induction and the apoptotic effect induced by the combination of rhTRAIL and andrographolide. Collectively, the present study demonstrated that andrographolide enhances TRAIL-induced apoptosis through induction of DR5 expression. This effect appears to involve ROS generation in GCs.

  12. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability

    OpenAIRE

    Frielink, N.; Schuengel, C.; Embregts, P.J.C.M.

    2017-01-01

    Background: According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and integrated motivation. Although it has been argued theoretically that the different types of motivation are universally applicable, Reid et al. () proposed a dichotomy of broad subtypes of extrinsic ...

  13. Engagement in Classroom Learning: Creating Temporal Participation Incentives for Extrinsically Motivated Students through Bonus Credits

    Science.gov (United States)

    Rassuli, Ali

    2012-01-01

    Extrinsic inducements to adjust students' learning motivations have evolved within 2 opposing paradigms. Cognitive evaluation theories claim that controlling factors embedded in extrinsic rewards dissipate intrinsic aspirations. Behavioral theorists contend that if engagement is voluntary, extrinsic reinforcements enhance learning without ill…

  14. New insights into the apoptotic process in mollusks: characterization of caspase genes in Mytilus galloprovincialis.

    Directory of Open Access Journals (Sweden)

    Alejandro Romero

    2011-02-01

    Full Text Available Apoptosis is an essential biological process in the development and maintenance of immune system homeostasis. Caspase proteins constitute the core of the apoptotic machinery and can be categorized as either initiators or effectors of apoptosis. Although the genes encoding caspase proteins have been described in vertebrates and in almost all invertebrate phyla, there are few reports describing the initiator and executioner caspases or the modulation of their expression by different stimuli in different apoptotic pathways in bivalves. In the present work, we characterized two initiator and four executioner caspases in the mussel Mytilus galloprovincialis. Both initiators and executioners showed structural features that make them different from other caspase proteins already described. Evaluation of the genes' tissue expression patterns revealed extremely high expression levels within the gland and gills, where the apoptotic process is highly active due to the clearance of damaged cells. Hemocytes also showed high expression values, probably due to of the role of apoptosis in the defense against pathogens. To understand the mechanisms of caspase gene regulation, hemocytes were treated with UV-light, environmental pollutants and pathogen-associated molecular patterns (PAMPs and apoptosis was evaluated by microscopy, flow cytometry and qPCR techniques. Our results suggest that the apoptotic process could be tightly regulated in bivalve mollusks by overexpression/suppression of caspase genes; additionally, there is evidence of caspase-specific responses to pathogens and pollutants. The apoptotic process in mollusks has a similar complexity to that of vertebrates, but presents unique features that may be related to recurrent exposure to environmental changes, pollutants and pathogens imposed by their sedentary nature.

  15. Does extrinsic goal framing enhance extrinsic goal-oriented individuals' learning and performance? An experimental test of the match perspective versus self-determination theory

    OpenAIRE

    Vansteenkiste, Maarten; Timmermans, Tinneke; Lens, Willy; Soenens, Bart; Van den Broeck, Anja

    2008-01-01

    Previous work within self-determination theory has shown that experimentally framing a learning activity in terms of extrinsic rather than intrinsic goals results in poorer conceptual learning and performance, presumably because extrinsic goal framing detracts attention from the learning activity and is less directly satisfying of basic psychological needs. According to the match perspective, experimental extrinsic, compared to intrinsic, goal framing should enhance learning and performance f...

  16. Induction of apoptotic cell death by putrescine

    DEFF Research Database (Denmark)

    Takao, Koichi; Rickhag, Karl Mattias; Hegardt, Cecilia

    2006-01-01

    that overexpression of a metabolically stable ODC in CHO cells induced a massive cell death unless the cells were grown in the presence of the ODC inhibitor alpha-difluoromethylornithine (DFMO). Cells overexpressing wild-type (unstable) ODC, on the other hand, were not dependent on the presence of DFMO...... for their growth. The induction of cell death was correlated with a dramatic increase in cellular putrescine levels. Analysis using flow cytometry revealed perturbed cell cycle kinetics, with a large accumulation of cells with sub-G1 amounts of DNA, which is a typical sign of apoptosis. Another strong indication...... of apoptosis was the finding that one of the key enzymes in the apoptotic process, caspase-3, was induced when DFMO was omitted from the growth medium. Furthermore, inhibition of the caspase activity significantly reduced the recruitment of cells to the sub-G1 fraction. In conclusion, deregulation of polyamine...

  17. The regulation of apoptotic cell death

    Directory of Open Access Journals (Sweden)

    Amarante-Mendes G.P.

    1999-01-01

    Full Text Available Apoptosis is a fundamental biological phenomenon in which the death of a cell is genetically and biochemically regulated. Different molecules are involved in the regulation of the apoptotic process. Death receptors, coupled to distinct members of the caspases as well as other adapter molecules, are involved in the initiation of the stress signals (The Indictment. Members of the Bcl-2 family control at the mitochondrial level the decision between life and death (The Judgement. The effector caspases are responsible for all morphological and biochemical changes related to apoptosis including the "eat-me" signals perceived by phagocytes and neighboring cells (The Execution. Finally, apoptosis would have little biological significance without the recognition and removal of the dying cells (The Burial.

  18. Protective effects of melittin on transforming growth factor-β1 injury to hepatocytes via anti-apoptotic mechanism

    International Nuclear Information System (INIS)

    Lee, Woo-Ram; Park, Ji-Hyun; Kim, Kyung-Hyun; Park, Yoon-Yub; Han, Sang-Mi; Park, Kwan-kyu

    2011-01-01

    Melittin is a cationic, hemolytic peptide that is the main toxic component in the venom of the honey bee (Apis mellifera). Melittin has multiple effects, including anti-bacterial, anti-viral and anti-inflammatory, in various cell types. However, the anti-apoptotic mechanisms of melittin have not been fully elucidated in hepatocytes. Apoptosis contributes to liver inflammation and fibrosis. Knowledge of the apoptotic mechanisms is important to develop new and effective therapies for treatment of cirrhosis, portal hypertension, liver cancer, and other liver diseases. In the present study, we investigated the anti-apoptotic effect of melittin on transforming growth factor (TGF)-β1-induced apoptosis in hepatocytes. TGF-β1-treated hepatocytes were exposed to low doses (0.5 and 1 μg/mL) and high dose (2 μg/mL) of melittin. The low doses significantly protected these cells from DNA damage in TGF-β1-induced apoptosis compared to the high dose. Also, melittin suppressed TGF-β1-induced apoptotic activation of the Bcl-2 family and caspase family of proteins, which resulted in the inhibition of poly-ADP-ribose polymerase (PARP) cleavage. These results demonstrate that TGF-β1 induces hepatocyte apoptosis and that an optimal dose of melittin exerts anti-apoptotic effects against TGF-β1-induced injury to hepatocytes via the mitochondrial pathway. These results suggest that an optimal dose of melittin can serve to protect cells against TGF-β1-mediated injury. - Highlights: → We investigated the anti-apoptotic effect of melittin on TGF-β1-induced hepatocyte. → TGF-β1 induces hepatocyte apoptosis. → TGF-β1-treated hepatocytes were exposed to low doses and high dose of melittin. → Optimal dose of melittin exerts anti-apoptotic effects to hepatocytes.

  19. Non-apoptotic cell death associated with perturbations of macropinocytosis.

    Science.gov (United States)

    Maltese, William A; Overmeyer, Jean H

    2015-01-01

    Although macropinocytosis is widely recognized as a distinct form of fluid-phase endocytosis in antigen-presenting dendritic cells, it also occurs constitutively in many other normal and transformed cell types. Recent studies have established that various genetic or pharmacological manipulations can hyperstimulate macropinocytosis or disrupt normal macropinosome trafficking pathways, leading to accumulation of greatly enlarged cytoplasmic vacuoles. In some cases, this extreme vacuolization is associated with a unique form of non-apoptotic cell death termed "methuosis," from the Greek methuo (to drink to intoxication). It remains unclear whether cell death related to dysfunctional macropinocytosis occurs in normal physiological contexts. However, the finding that some types of cancer cells are particularly vulnerable to this unusual form of cell death has raised the possibility that small molecules capable of altering macropinosome trafficking or function might be useful as therapeutic agents against cancers that are resistant to drugs that work by inducing apoptosis. Herein we review examples of cell death associated with dysfunctional macropinocytosis and summarize what is known about the underlying mechanisms.

  20. Non-apoptotic cell death associated with perturbations of macropinocytosis

    Directory of Open Access Journals (Sweden)

    William A. Maltese

    2015-02-01

    Full Text Available Although macropinocytosis is widely recognized as a distinct form of fluid-phase endocytosis in antigen-presenting dendritic cells, it also occurs constitutively in many other normal and transformed cell types. Recent studies have established that various genetic or pharmacological manipulations can hyperstimulate macropinocytosis or disrupt normal macropinosome trafficking pathways, leading to accumulation of greatly enlarged cytoplasmic vacuoles. In some cases, this extreme vacuolization is associated with a unique form of non-apoptotic cell death termed ‘methuosis’, from the Greek methuo (to drink to intoxication. It remains unclear whether cell death related to dysfunctional macropinocytosis occurs in normal physiological contexts. However, the finding that some types of cancer cells are particularly vulnerable to this unusual form of cell death has raised the possibility that small molecules capable of altering macropinosome trafficking or function might be useful as therapeutic agents against cancers that are resistant to drugs that work by inducing apoptosis. Herein we review examples of cell death associated with dysfunctional macropinocytosis and summarize what is known about the underlying mechanisms.

  1. Extrinsic CPT violation in neutrino oscillations in matter

    International Nuclear Information System (INIS)

    Jacobson, Magnus; Ohlsson, Tommy

    2004-01-01

    We investigate matter-induced (or extrinsic) CPT violation effects in neutrino oscillations in matter. Especially, we present approximate analytical formulas for the CPT-violating probability differences for three flavor neutrino oscillations in matter with an arbitrary matter density profile. Note that we assume that the CPT invariance theorem holds, which means that the CPT violation effects arise entirely because of the presence of matter. As special cases of matter density profiles, we consider constant and step-function matter density profiles, which are relevant for neutrino oscillation physics in accelerator and reactor long baseline experiments as well as neutrino factories. Finally, the implications of extrinsic CPT violation on neutrino oscillations in matter for several past, present, and future long baseline experiments are estimated

  2. Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation.

    Science.gov (United States)

    Lee, Yoonjung; Byun, Hee Sun; Seok, Jeong Ho; Park, Kyeong Ah; Won, Minho; Seo, Wonhyoung; Lee, So-Ra; Kang, Kidong; Sohn, Kyung-Cheol; Lee, Ill Young; Kim, Hyeong-Geug; Son, Chang Gue; Shen, Han-Ming; Hur, Gang Min

    2016-04-27

    Death receptor (DR) ligation elicits two different modes of cell death (necroptosis and apoptosis) depending on the cellular context. By screening a plant extract library from cells undergoing necroptosis or apoptosis, we identified a water extract of Terminalia chebula (WETC) as a novel and potent dual inhibitor of DR-mediated cell death. Investigation of the underlying mechanisms of its anti-necroptotic and anti-apoptotic action revealed that WETC or its constituents (e.g., gallic acid) protected against tumor necrosis factor-induced necroptosis via the suppression of TNF-induced ROS without affecting the upstream signaling events. Surprisingly, WETC also provided protection against DR-mediated apoptosis by inhibition of the caspase cascade. Furthermore, it activated the autophagy pathway via suppression of mTOR. Of the WETC constituents, punicalagin and geraniin appeared to possess the most potent anti-apoptotic and autophagy activation effect. Importantly, blockage of autophagy with pharmacological inhibitors or genetic silencing of Atg5 selectively abolished the anti-apoptotic function of WETC. These results suggest that WETC protects against dual modes of cell death upon DR ligation. Therefore, WETC might serve as a potential treatment for diseases characterized by aberrantly sensitized apoptotic or non-apoptotic signaling cascades.

  3. Comparison of exit time moment spectra for extrinsic metric balls

    DEFF Research Database (Denmark)

    Hurtado, Ana; Markvorsen, Steen; Palmer, Vicente

    2012-01-01

    We prove explicit upper and lower bounds for the $L^1$-moment spectra for the Brownian motion exit time from extrinsic metric balls of submanifolds $P^m$ in ambient Riemannian spaces $N^n$. We assume that $P$ and $N$ both have controlled radial curvatures (mean curvature and sectional curvature...... obtain new intrinsic comparison results for the exit time spectra for metric balls in the ambient manifolds $N^n$ themselves....

  4. Are competition and extrinsic motivation reliable predictors of academic cheating?

    OpenAIRE

    Gábor eOrosz; Gábor eOrosz; Gábor eOrosz; Dávid eFarkas; Dávid eFarkas; Dávid eFarkas; Christine eRoland-Levy

    2013-01-01

    Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356). Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast,...

  5. Are Competition and Extrinsic Motivation Reliable Predictors of Academic Cheating?

    OpenAIRE

    Orosz, G?bor; Farkas, D?vid; Roland-L?vy, Christine

    2013-01-01

    Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356). Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast,...

  6. Near-UV laser treatment of extrinsic dental enamel stains.

    Science.gov (United States)

    Schoenly, J E; Seka, W; Featherstone, J D B; Rechmann, P

    2012-04-01

    The selective ablation of extrinsic dental enamel stains using a 400-nm laser is evaluated at several fluences for completely removing stains with minimal damage to the underlying enamel. A frequency-doubled Ti:sapphire laser (400-nm wavelength, 60-nanosecond pulse duration, 10-Hz repetition rate) was used to treat 10 extracted human teeth with extrinsic enamel staining. Each tooth was irradiated perpendicular to the surface in a back-and-forth motion over a 1-mm length using an ∼300-µm-diam 10th-order super-Gaussian beam with fluences ranging from 0.8 to 6.4 J/cm(2) . Laser triangulation determined stain depth and volume removed by measuring 3D surface images before and after irradiation. Scanning electron microscopy evaluated the surface roughness of enamel following stain removal. Fluorescence spectroscopy measured spectra of unbleached and photobleached stains in the spectral range of 600-800 nm. Extrinsic enamel stains are removed with laser fluences between 0.8 and 6.4 J/cm(2) . Stains removed on sound enamel leave behind a smooth enamel surface. Stain removal in areas with signs of earlier cariogenic acid attacks resulted in isolated and randomly located laser-induced, 50-µm-diam enamel pits. These pits contain 0.5-µm diam, smooth craters indicative of heat transfer from the stain to the enamel and subsequent melting and water droplet ejection. Ablation stalling of enamel stains is typically observed at low fluences (Laser ablation of extrinsic enamel stains at 400 nm is observed to be most efficient above 3 J/cm(2) with minimal damage to the underlying enamel. Unsound underlying enamel is also observed to be selectively removed after irradiation. Copyright © 2012 Wiley Periodicals, Inc.

  7. Recovery of colonic transit following extrinsic nerve damage in rats.

    Science.gov (United States)

    Ridolfi, Timothy J; Tong, Wei Dong; Kosinski, Lauren; Takahashi, Toku; Ludwig, Kirk A

    2011-06-01

    Injury to pelvic sympathetic and parasympathetic nerves from surgical and obstetrical trauma has long been cited as a cause for abnormal colorectal motility in humans. Using a rat model, acute transaction of these extrinsic nerves has been shown to effect colorectal motility. The aim of this study is to determine in a rat model how transection of these extrinsic nerves affects colonic transit over time. Eighty-two Sprague-Dawley rats underwent placement of a tunneled catheter into the proximal colon. Bilateral hypogastric, pelvic nerves (HGN and PN) or both were transected in 66 rats. The remaining 16 rats received a sham operation. Colonic transit was evaluated at postoperative days (PODs) 1, 3, and 7 by injecting and calculating the geometric center (GC) of the distribution of (51)Cr after 3 h of propagation. At POD 1, transection of PNs significantly delayed colonic transit (GC = 4.9, p < 0.05), while transection of HGNs (GC = 8.5, p < 0.05) or transection of both nerves (GC = 7.8, p < 0.05) significantly accelerated colonic transit, when compared with sham operation (GC = 6.0). A significant trend toward recovery was noted in both the HGN and PN transection groups at POD 7. Damage to the extrinsic sympathetic and/or parasympathetic PNs affects colonic transit acutely. These changes in large bowel motor function normalize over time implicating a compensatory mechanism within the bowel itself.

  8. Intrinsic and extrinsic geometries of a tidally deformed black hole

    International Nuclear Information System (INIS)

    Vega, Ian; Poisson, Eric; Massey, Ryan

    2011-01-01

    A description of the event horizon of a perturbed Schwarzschild black hole is provided in terms of the intrinsic and extrinsic geometries of the null hypersurface. This description relies on a Gauss-Codazzi theory of null hypersurfaces embedded in spacetime, which extends the standard theory of spacelike and timelike hypersurfaces involving the first and second fundamental forms. We show that the intrinsic geometry of the event horizon is invariant under a reparameterization of the null generators, and that the extrinsic geometry depends on the parameterization. Stated differently, we show that while the extrinsic geometry depends on the choice of gauge, the intrinsic geometry is gauge invariant. We apply the formalism to solutions to the vacuum field equations that describe a tidally deformed black hole. In a first instance, we consider a slowly varying, quadrupolar tidal field imposed on the black hole, and in a second instance, we examine the tide raised during a close parabolic encounter between the black hole and a small orbiting body.

  9. Aging in the Male Face: Intrinsic and Extrinsic Factors.

    Science.gov (United States)

    Keaney, Terrence C

    2016-07-01

    Gender is one of the most significant factors that influence facial anatomy and behavior, both key factors in the aging process. To review male facial anatomy, physiology, and behavior and how it contributes to sexual dimorphism in facial aging. A MEDLINE search was performed for publications on gender differences in facial anatomy, aging, cutaneous physiology, and behavior. There are differences in both intrinsic and extrinsic aging factors in men. Men have a thicker epidermis and dermis with more active cutaneous appendages including hair growth. Male skin has a reduced antioxidant capacity and increased ultraviolet-induced immunosuppression. The male face is larger and has a unique square shape with less subcutaneous soft tissue, especially at the medial cheek. Men are also more prone to smoking and exhibiting poor sun-protective behavior. The differences in intrinsic and extrinsic aging factors contribute to poor facial aging in men. Men develop more severe rhytides in a unique pattern, show increased periocular aging changes, and are more prone to hair loss. This review provides insight into the factors contributing to accelerated male facial aging. Understanding gender differences in aging will help physicians tailor cosmetic treatments for men and minimize extrinsic aging factors.

  10. Are competition and extrinsic motivation reliable predictors of academic cheating?

    Directory of Open Access Journals (Sweden)

    Gábor eOrosz

    2013-02-01

    Full Text Available Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356. Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast, extrinsic motivation had no significant effect. Indirect positive influence on cheating, based on some characteristics of hypercompetition, was also found, whereas attitudes towards self-developmental competition had a mediated negative influence. Neither constructive nor destructive competitive classroom climate had a significant impact on academic dishonesty. Acceptance of cheating and guilt has significant and direct effect on self-reported cheating. In comparison with them, the effects of motivational and competition-related variables are relatively small, even negligible. These results suggest that extrinsic motivation and competition are not amongst the most reliable predictors of academic cheating behavior.

  11. Are competition and extrinsic motivation reliable predictors of academic cheating?

    Science.gov (United States)

    Orosz, Gábor; Farkas, Dávid; Roland-Lévy, Christine

    2013-01-01

    Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356). Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast, extrinsic motivation had no significant effect. Indirect positive influence on cheating, based on some characteristics of hypercompetition, was also found, whereas attitudes toward self-developmental competition had a mediated negative influence. Neither constructive nor destructive competitive classroom climate had a significant impact on academic dishonesty. Acceptance of cheating and guilt has significant and direct effect on self-reported cheating. In comparison with them, the effects of motivational and competition-related variables are relatively small, even negligible. These results suggest that extrinsic motivation and competition are not amongst the most reliable predictors of academic cheating behavior.

  12. Effects of empathic paraphrasing - Extrinsic emotion regulation in social conflict

    Directory of Open Access Journals (Sweden)

    Maria eSeehausen

    2012-11-01

    Full Text Available In the present study, we investigated the effects of empathic paraphrasing as an extrinsic emotion regulation technique in social conflict. We hypothesized that negative emotions elicited by social conflict can be regulated extrinsically in a conversation by a listener following the narrator’s perspective and verbally expressing cognitive empathy.20 participants were interviewed on an ongoing or recently self-experienced social conflict. The interviewer utilized ten standardized open questions inviting participants to describe their perception of the conflict. After each of the ten descriptions, the interviewer responded by either paraphrasing or taking notes (control condition. Valence ratings pertaining to the current emotional state were assessed during the interview along with psychophysiological and voice recordings.Participants reported feeling less negative after hearing the interviewer paraphrase what they had said. In addition, we found a lower sound intensity of participants' voices when answering to questions following a paraphrase. At the physiological level, skin conductance response, as well as heart rate, was higher during paraphrasing than during taking notes, while blood volume pulse amplitude was lower during paraphrasing, indicating higher autonomic arousal.The results show that demonstrating cognitive empathy through paraphrasing can extrinsically regulate negative emotion on a short-term basis. Paraphrasing led to enhanced autonomic activation in recipients, while at the same time influencing emotional valence in the direction of feeling better. A possible explanation for these results is that being treated in an empathic manner may stimulate a more intense emotion processing helping to transform and resolve the conflict.

  13. Stochastic synchronization of neuronal populations with intrinsic and extrinsic noise.

    KAUST Repository

    Bressloff, Paul C

    2011-05-03

    We extend the theory of noise-induced phase synchronization to the case of a neural master equation describing the stochastic dynamics of an ensemble of uncoupled neuronal population oscillators with intrinsic and extrinsic noise. The master equation formulation of stochastic neurodynamics represents the state of each population by the number of currently active neurons, and the state transitions are chosen so that deterministic Wilson-Cowan rate equations are recovered in the mean-field limit. We apply phase reduction and averaging methods to a corresponding Langevin approximation of the master equation in order to determine how intrinsic noise disrupts synchronization of the population oscillators driven by a common extrinsic noise source. We illustrate our analysis by considering one of the simplest networks known to generate limit cycle oscillations at the population level, namely, a pair of mutually coupled excitatory (E) and inhibitory (I) subpopulations. We show how the combination of intrinsic independent noise and extrinsic common noise can lead to clustering of the population oscillators due to the multiplicative nature of both noise sources under the Langevin approximation. Finally, we show how a similar analysis can be carried out for another simple population model that exhibits limit cycle oscillations in the deterministic limit, namely, a recurrent excitatory network with synaptic depression; inclusion of synaptic depression into the neural master equation now generates a stochastic hybrid system.

  14. Does Extrinsic Goal Framing Enhance Extrinsic Goal-Oriented Individuals' Learning and Performance? An Experimental Test of the Match Perspective versus Self-Determination Theory

    Science.gov (United States)

    Vansteenkiste, Maarten; Timmermans, Tinneke; Lens, Willy; Soenens, Bart; Van den Broeck, Anja

    2008-01-01

    Previous work within self-determination theory has shown that experimentally framing a learning activity in terms of extrinsic rather than intrinsic goals results in poorer conceptual learning and performance, presumably because extrinsic goal framing detracts attention from the learning activity and is less directly satisfying of basic…

  15. Significance of apoptotic cell death after γ-irradiation

    International Nuclear Information System (INIS)

    Wu, H.G.; Kim, I.H.; Ha, S.W.; Park, C.I.

    2003-01-01

    Full text: The objectives of this study are to investigate the significance of apoptotic death compared to total cell death after γ-ray irradiation in human Hand N cancer cell lines and to find out correlation between apoptosis and radiation sensitivity. Materials and Method: Head and neck cancer cell lines (PCI-1, PCI-13, and SNU-1066), leukemia cell line (CCRF-CEM), and fibroblast cell line (LM217) as a normal control were used for this study. Cells were irradiated using Cs-137 animal experiment irradiator. Total cell death was measured by clonogenic assay. Annexin-V staining was used to detect the fraction of apoptotic death. The resulting data was analyzed with two parameters, apoptotic index (AI) and apoptotic fraction(AF). AI is ratio of apoptotic cells to total cells, and AF is ration of apoptotic cell death to mutant frequencytion ex(Number of apoptotic cells) / (Number of total cells counted) AF = {(AI) / (1-survival fraction)} x 100 (%) Results. Surviving fraction at 2 Gy (SF2) were 0.741, 0.544, 0.313, 0.302, and 0.100 for PCI-1, PCI-13, SNU-1066, CCRF-CEM, and LM217 cell lines, respectively. Apoptosis was detected in all cell lines. Apoptotic index reached peak value at 72 hours after irradiation in head and neck cancer cell lines, and that was at 24 hours in CCRF-CEM and LM217. Total cell death increased exponentially with increasing radiation dose from 0 Gy to 8 Gy, but the change was minimal in apoptotic index (Fig. 1.). Apoptotic fractions at 2 Gy were 46%, 48%, 46%, 24%, and 19% and at 6 Gy were 20%, 33%, 35%, 17%, and 20% for PCI-1, PCI-13, SNU-1066, CCRF-CEM, and LM217, respectively. The radioresistant cell lines showed more higher apoptotic fraction at 2 Gy (Table 1.), but there was not such correlation at 6 Gy. Conclusion: All cell lines used in this study showed apoptosis after irradiation, but time course of apoptosis was different from that of leukemia cell line and normal fibroblast cell line. Reproductive cell death was more important

  16. Scrambled Eggs: Apoptotic Cell Clearance by Non-Professional Phagocytes in the Drosophila Ovary

    Directory of Open Access Journals (Sweden)

    Sandy B. Serizier

    2017-11-01

    Full Text Available For half of a century, it has been known that non-professional phagocytes, such as fibroblasts, endothelial, and epithelial cells, are capable of efferocytosis (engulfment of apoptotic cells. Non-professional phagocytes differ from professional phagocytes in the range and efficiency of engulfment. Much of the recognition and underlying signaling machinery between non-professional and professional phagocytes is the same, but it is not known how the engulfment capacity of non-professional phagocytes is controlled. Moreover, the signaling networks involved in cell corpse recognition, engulfment, and phagosome maturation are only partially understood. The Drosophila ovary provides an excellent system to investigate the regulation of phagocytic activity by epithelial cells, a major class of non-professional phagocytes. During Drosophila oogenesis, mid-stage egg chambers undergo apoptosis of the germline in response to nutrient deprivation. Epithelial follicle cells then undergo major cell shape changes and concomitantly engulf the germline material. Our previous work has established that Draper and the integrin α-PS3/β-PS heterodimer are required in follicle cells for germline cell clearance. In addition, we have characterized phagosome maturation pathways, and found that the JNK pathway amplifies the engulfment response. In this review, we discuss recent advances on the interplay between engulfment pathways in the follicular epithelium for cell clearance in the Drosophila ovary. We also provide a comparison to apoptotic cell clearance mechanisms in C. elegans and mammals, illustrating strong conservation of efferocytosis mechanisms by non-professional phagocytes.

  17. Scrambled Eggs: Apoptotic Cell Clearance by Non-Professional Phagocytes in the Drosophila Ovary.

    Science.gov (United States)

    Serizier, Sandy B; McCall, Kimberly

    2017-01-01

    For half of a century, it has been known that non-professional phagocytes, such as fibroblasts, endothelial, and epithelial cells, are capable of efferocytosis (engulfment of apoptotic cells). Non-professional phagocytes differ from professional phagocytes in the range and efficiency of engulfment. Much of the recognition and underlying signaling machinery between non-professional and professional phagocytes is the same, but it is not known how the engulfment capacity of non-professional phagocytes is controlled. Moreover, the signaling networks involved in cell corpse recognition, engulfment, and phagosome maturation are only partially understood. The Drosophila ovary provides an excellent system to investigate the regulation of phagocytic activity by epithelial cells, a major class of non-professional phagocytes. During Drosophila oogenesis, mid-stage egg chambers undergo apoptosis of the germline in response to nutrient deprivation. Epithelial follicle cells then undergo major cell shape changes and concomitantly engulf the germline material. Our previous work has established that Draper and the integrin α-PS3/β-PS heterodimer are required in follicle cells for germline cell clearance. In addition, we have characterized phagosome maturation pathways, and found that the JNK pathway amplifies the engulfment response. In this review, we discuss recent advances on the interplay between engulfment pathways in the follicular epithelium for cell clearance in the Drosophila ovary. We also provide a comparison to apoptotic cell clearance mechanisms in C. elegans and mammals, illustrating strong conservation of efferocytosis mechanisms by non-professional phagocytes.

  18. Breast Carcinoma Progression and Tumour Vascular Markers Related to Apoptotic Mechanisms

    Directory of Open Access Journals (Sweden)

    Miroslava Bilecova-Rabajdova

    2014-01-01

    Full Text Available Background. In the last few years, the cancer research had tried to identify and characterize new biochemical and molecular pathways in which the inhibition induces prosurvival mechanisms. Our work describes the expression of two different members of apoptotic regulatory pathway and their relationship with a progression of breast carcinoma. Materials and Methods. We compared expression of genes related to apoptosis (DR6 and Gpm6B in the blood of patients suffering from stage I of breast cancer in different grades (I–IV, with healthy controls. After isolation of mRNA, transcription of mRNA into the cDNA was performed. The quantification of gene expression changes in DR6 and Gpm6B was detected by RT-PCR method. Analysis at the protein level was performed by the Western blot.Results. In statistical analysis of Dr6 mRNA level changes we detected significant increase starting in Grading 1 (G1 and reached maximal level in G3.This expression on mRNA levels was similar to protein levels, which copy rising tendency with maximal value in G3. The results of Gpm6B were significantly lower.Conclusion. This result showed that antiapoptotic signalling during neovascularization is increased significantly. It would be advisable in the future to study the influence of cytostatic treatment on the expression of genes related to apoptotic pathways and their relationship with progression of breast cancer tumours.

  19. p53 dependent apoptotic cell death induces embryonic malformation in Carassius auratus under chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Paramita Banerjee Sawant

    Full Text Available Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD, leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD, ultimately resulting in significant (p<0.05 embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos.

  20. Tamoxifen induces apoptotic neutrophil efferocytosis in horses.

    Science.gov (United States)

    Olave, C; Morales, N; Uberti, B; Henriquez, C; Sarmiento, J; Ortloff, A; Folch, H; Moran, G

    2018-03-01

    Macrophages and neutrophils are important cellular components in the process of acute inflammation and its subsequent resolution, and evidence increasingly suggests that they play important functions during the resolution of chronic, adaptive inflammatory processes. Exacerbated neutrophil activity can be harmful to surrounding tissues; this is important in a range of diseases, including allergic asthma and chronic obstructive pulmonary disease in humans, and equine asthma (also known as recurrent airway obstruction (RAO). Tamoxifen (TX) is a non-steroidal estrogen receptor modulator with effects on cell growth and survival. Previous studies showed that TX treatment in horses with induced acute pulmonary inflammation promoted early apoptosis of blood and BALF neutrophils, reduction of BALF neutrophils, and improvement in animals' clinical status. The aim of this study was to describe if TX induces in vitro efferocytosis of neutrophils by alveolar macrophages. Efferocytosis assay, myeloperoxidase (MPO) detection and translocation phosphatidylserine (PS) were performed on neutrophils isolated from peripheral blood samples from five healthy horses. In in vitro samples from heathy horses, TX treatment increases the phenomenon of efferocytosis of peripheral neutrophils by alveolar macrophages. Similar increases in supernatant MPO concentration and PS translocation were observed in TX-treated neutrophils, compared to control cells. In conclusion, these results confirm that tamoxifen has a direct effect on equine peripheral blood neutrophils, through stimulation of the engulfment of apoptotic neutrophils by alveolar macrophages.

  1. Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Shibahara, Daisuke; Tanaka, Kentaro; Iwama, Eiji; Kubo, Naoki; Ota, Keiichi; Azuma, Koichi; Harada, Taishi; Fujita, Jiro; Nakanishi, Yoichi; Okamoto, Isamu

    2018-03-27

    The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)-ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  2. Pro- and anti-apoptotic CD95 signaling in T cells

    Directory of Open Access Journals (Sweden)

    Janssen Ottmar

    2011-04-01

    Full Text Available Abstract The TNF receptor superfamily member CD95 (Fas, APO-1, TNFRSF6 is known as the prototypic death receptor in and outside the immune system. In fact, many mechanisms involved in apoptotic signaling cascades were solved by addressing consequences and pathways initiated by CD95 ligation in activated T cells or other "CD95-sensitive" cell populations. As an example, the binding of the inducible CD95 ligand (CD95L to CD95 on activated T lymphocytes results in apoptotic cell death. This activation-induced cell death was implicated in the control of immune cell homeostasis and immune response termination. Over the past years, however, it became evident that CD95 acts as a dual function receptor that also exerts anti-apoptotic effects depending on the cellular context. Early observations of a potential non-apoptotic role of CD95 in the growth control of resting T cells were recently reconsidered and revealed quite unexpected findings regarding the costimulatory capacity of CD95 for primary T cell activation. It turned out that CD95 engagement modulates TCR/CD3-driven signal initiation in a dose-dependent manner. High doses of immobilized CD95 agonists or cellular CD95L almost completely silence T cells by blocking early TCR-induced signaling events. In contrast, under otherwise unchanged conditions, lower amounts of the same agonists dramatically augment TCR/CD3-driven activation and proliferation. In the present overview, we summarize these recent findings with a focus on the costimulatory capacity of CD95 in primary T cells and discuss potential implications for the T cell compartment and the interplay between T cells and CD95L-expressing cells including antigen-presenting cells.

  3. Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB.

    Science.gov (United States)

    Matteucci, Claudia; Minutolo, Antonella; Marino-Merlo, Francesca; Grelli, Sandro; Frezza, Caterina; Mastino, Antonio; Macchi, Beatrice

    2015-04-15

    The present study addresses the issue of enhanced apoptotic response to AZT following co-treatment with an NF-kB inhibitor. To investigate this issue, different cell lines were assayed for susceptibility to AZT-mediated apoptosis without or with the addition of the NF-kB inhibitor Bay-11-7085. For further investigation, U937 cells were selected as good-responder cells to the combination treatment with 32 or 128 μM AZT, and 1 μM Bay-11-7085. Inhibition of NF-kB activation by Bay-11-7085 in cells treated with AZT was assayed through Western blot analysis of p65 expression and by EMSA. Involvement of the mitochondrial pathway of apoptosis in mechanisms underlying the improved effect of AZT following Bay-11-7085 co-treatment, was evaluated by assaying the cytochrome c release and the mitochondrial membrane potential (MMP) status using the JC-1 dye. Moreover, the transcriptional activity of both anti- and pro-apoptotic genes in U937 cells after combination treatment was quantitatively evaluated through real-time PCR. We found that the combined treatment induced high levels of cytochrome c release and of MMP collapse in association with evident changes in the expression of both anti- and pro-apoptotic genes of the Bcl-2 family. Overexpression of Bcl-2 significantly suppressed the sensitization of U937 cells to an enhanced apoptotic response to AZT following co-treatment with the NF-kB inhibitor. The new findings suggest that a combination regimen based on AZT plus an NF-kB inhibitor could represent a new chemotherapeutic tool for retrovirus-related pathologies.

  4. TAM receptors in apoptotic cell clearance, autoimmunity, and cancer.

    Science.gov (United States)

    Nguyen, Khanh-Quynh; Tsou, Wen-I; Kotenko, Sergei; Birge, Raymond B

    2013-08-01

    Receptor tyrosine kinases, Tyro-3, Axl and Mer, collectively designated as TAM, are involved in the clearance of apoptotic cells. TAM ligands, Gas6 and Protein S, bind to the surfaces of apoptotic cells, and at the same time, interact directly with TAM expressed on phagocytes, impacting the engulfment and clearance of apoptotic cells and debris. The well-tuned and balanced actions of TAM may affect a variety of human pathologies including autoimmunity, retinal degeneration, and cancer. This article emphasizes some of the emerging findings and mechanistic insights into TAM functions that are clinically relevant and possibly therapeutically targeted.

  5. The influence of extrinsic motivation on competition-based selection.

    Science.gov (United States)

    Sänger, Jessica; Wascher, Edmund

    2011-10-10

    The biased competition approach to visuo-spatial attention proposes that the selection of competing information is effected by the saliency of the stimulus as well as by an intention-based bias of attention towards behavioural goals. Wascher and Beste (2010) [32] showed that the detection of relevant information depends on its relative saliency compared to irrelevant conflicting stimuli. Furthermore the N1pc, N2pc and N2 of the EEG varied with the strength of the conflict. However, this system could also be modulated by rather global mechanisms like attentional effort. The present study investigates such modulations by testing the influence of extrinsic motivation on the selection of competing stimuli. Participants had to detect a luminance change in various conditions among others against an irrelevant orientation change. Half of the participants were motivated to maximize their performance by the announcement of a monetary reward for correct responses. Participants who were motivated had lower error rates than participants who were not motivated. The event-related lateralizations of the EEG showed no motivation-related effect on the N1pc, which reflects the initial saliency driven orientation of attention towards the more salient stimulus. The subsequent N2pc was enhanced in the motivation condition. Extrinsic motivation was also accompanied by enhanced fronto-central negativities. Thus, the data provide evidence that the improvement of selection performance when participants were extrinsically motivated by announcing a reward was not due to changes in the initial saliency based processing of information but was foremost mediated by improved higher-level mechanisms. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Theory of extrinsic and intrinsic heterojunctions in thermal equilibrium

    Science.gov (United States)

    Von Ross, O.

    1980-01-01

    A careful analysis of an abrupt heterojunction consisting of two distinct semiconductors either intrinsic or extrinsic is presented. The calculations apply to a one-dimensional, nondegenerate structure. Taking into account all appropriate boundary conditions, it is shown that the intrinsic Fermi level shows a discontinuity at the interface between the two materials which leads to a discontinuity of the valence band edge equal to the difference in the band gap energies of the two materials. The conduction band edge stays continuous however. This result is independent of possible charged interface states and in sharp contrast to the Anderson model. The reasons for this discrepancy are discussed.

  7. Rigid particle revisited: Extrinsic curvature yields the Dirac equation

    Energy Technology Data Exchange (ETDEWEB)

    Deriglazov, Alexei, E-mail: alexei.deriglazov@ufjf.edu.br [Depto. de Matemática, ICE, Universidade Federal de Juiz de Fora, MG (Brazil); Laboratory of Mathematical Physics, Tomsk Polytechnic University, 634050 Tomsk, Lenin Ave. 30 (Russian Federation); Nersessian, Armen, E-mail: arnerses@ysu.am [Yerevan State University, 1 Alex Manoogian St., Yerevan 0025 (Armenia); Laboratory of Mathematical Physics, Tomsk Polytechnic University, 634050 Tomsk, Lenin Ave. 30 (Russian Federation)

    2014-03-01

    We reexamine the model of relativistic particle with higher-derivative linear term on the first extrinsic curvature (rigidity). The passage from classical to quantum theory requires a number of rather unexpected steps which we report here. We found that, contrary to common opinion, quantization of the model in terms of so(3.2)-algebra yields massive Dirac equation. -- Highlights: •New way of canonical quantization of relativistic rigid particle is proposed. •Quantization made in terms of so(3.2) angular momentum algebra. •Quantization yields massive Dirac equation.

  8. The effect of extrinsic motivation on cycle time trial performance.

    Science.gov (United States)

    Hulleman, Michiel; De Koning, Jos J; Hettinga, Florentina J; Foster, Carl

    2007-04-01

    Athletes occasionally follow pacing patterns that seem unreasonably aggressive compared with those of prerace performances, potentially because of the motivation provided by competition. This study evaluated the effect of extrinsic motivation on cyclists' time trial performance. Well-trained recreational cyclists (N=7) completed four 1500-m laboratory time trials including a practice trial, two self-paced trials, and a trial where a monetary reward was offered. Time, total power output, power output attributable to aerobic and anaerobic metabolic sources, VO2, and HR were measured. The time required for the second, third, and last (extrinsically motivated) time trials was 133.1 +/- 2.1, 134.1 +/- 3.4, and 133.6 +/- 3.0 s, respectively, and was not different (P>0.05). There were no differences for total (396 +/- 19, 397 +/- 23, and 401 +/- 17 W), aerobic (253 +/- 12, 254 +/- 10, and 246 +/- 13 W), and anaerobic (143 +/- 14, 143 +/- 21, and 155 +/- 11 W) power output. The highest VO2 was not different over consecutive time trials (3.76 +/- 0.19, 3.73 +/- 0.16, and 3.71 +/- 0.22 L x min(-1)). When ranked by performance, without reference to the extrinsic motivation (131.9 +/- 2.4, 133.4 +/- 2.4, and 135.4 +/- 2.5 s), there was a significant difference for the first 100 m and from 100 to 300 m in power output, with a larger total power (560 +/- 102, 491 +/- 82, and 493 +/- 93; and 571 +/- 94, 513 +/- 41, and 484 +/- 88 W) and power attributable to anaerobic sources (446 +/- 100, 384 +/- 80, and 324 +/- 43; and 381 +/- 87, 383 +/- 90, and 289 +/- 91 W) for the fastest trial. Extrinsic motivation did not change the time trial performance, suggesting that 1500-m performance is extremely stable and not readily changeable with simple external motivation. The results suggest that spontaneous improvement in performance for time trials of this duration is attributable to greater early power output, which is primarily attributable to anaerobic metabolic sources.

  9. Older adults' intrinsic and extrinsic motivation toward physical activity.

    Science.gov (United States)

    Dacey, Marie; Baltzell, Amy; Zaichkowsky, Len

    2008-01-01

    To examine how motives discriminate 3 physical activity levels of inactive, active, and sustained maintainers. Six hundred forty-five adults (M age = 63.8) completed stage-of-change and Exercise Motivations Inventory (EMI-2) scales. Exploratory factor analysis established psychometric properties of the EMI-2 suitable for older adults. Six factors emerged in the EMI-2: health and fitness, social/emotional benefits, weight management, stress management, enjoyment, and appearance. Enjoyment contributed most to differentiating activity levels. Moderators of age and gender were delineated. Intrinsic motivation and self-determined extrinsic motivation distinguish older adults' activity levels.

  10. Intrinsic and extrinsic magnetic properties of the naturally layered manganites

    International Nuclear Information System (INIS)

    Berger, A.; Mitchell, J. F.; Miller, D. J.; Jiang, J. S.; Bader, S. D.

    1999-01-01

    Structural and magnetic properties of the two-layered Ruddlesden-Popper phase SrO(La 1-x Sr x MnO 3 ) 2 with x = 0.3--0.5 are highlighted. Intrinsic properties of these naturally layered manganites include a colossal magnetoresistance, a composition-dependent magnetic anisotropy, and almost no remanence. Above the Curie temperature there is a non-vanishing extrinsic magnetization attributed to intergrowths (stacking faults in the layered structure). These lattice imperfections consist of additional or missing manganite layers, as observed in transmission electron microscopy. Their role in influencing the properties of the host material is highlighted

  11. Extrinsic rewards undermine altruistic tendencies in 20-month-olds.

    Science.gov (United States)

    Warneken, Felix; Tomasello, Michael

    2008-11-01

    The current study investigated the influence of rewards on very young children's helping behavior. After 20-month-old infants received a material reward during a treatment phase, they subsequently were less likely to engage in further helping during a test phase as compared with infants who had previously received social praise or no reward at all. This so-called overjustification effect suggests that even the earliest helping behaviors of young children are intrinsically motivated and that socialization practices involving extrinsic rewards can undermine this tendency.

  12. Restorative Management of Intrinsic and Extrinsic Dental Erosion.

    Science.gov (United States)

    Al-Salehi, Samira Kathryn

    2014-12-01

    The restorative management of tooth surface loss is highlighted through the presentation of two advanced cases of dental erosion. On presentation, the causes of the dental erosion in both patients had been previously diagnosed and stopped. The first patient was a 67 year old with intrinsic erosion and an element of attrition where a multidisciplinary approach was used. The other, a 17 year old patient with extrinsic erosion managed via adhesive restorations. Adhesive techniques are a relatively simple, effective and conservative method for the treatment of dental erosion. The two treatment modalities (conventional versus contemporary) are compared and discussed.

  13. Extrinsic wrist ligaments: prevalence of injury by magnetic resonance imaging and association with intrinsic ligament tears.

    Science.gov (United States)

    Taneja, Atul K; Bredella, Miriam A; Chang, Connie Y; Joseph Simeone, F; Kattapuram, Susan V; Torriani, Martin

    2013-01-01

    The objective of this study was to determine the prevalence of extrinsic wrist ligament injury by magnetic resonance imaging and its association with intrinsic ligament tears. We reviewed conventional magnetic resonance images performed over a 5-year period from adult patients in the setting of wrist trauma. Two musculoskeletal radiologists examined the integrity of wrist ligaments and presence of bone abnormalities. In a cohort of 75 subjects, extrinsic ligament injury was present in 75%, with radiolunotriquetral being most frequently affected (45%). Intrinsic ligament injury was present in 60%. Almost half of subjects had combined intrinsic and extrinsic ligament injury. Bone abnormalities were seen in 69%. The rate of extrinsic injury was higher in subjects with bone injury (P = 0.008). There is high prevalence of extrinsic ligament injury in the setting of wrist trauma, especially in the presence of bone abnormalities, with combined injury of intrinsic and extrinsic ligaments in about half of cases.

  14. Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q

    OpenAIRE

    Marinovic-Terzic, Ivana; Yoshioka-Yamashita, Atsuko; Shimodaira, Hideki; Avdievich, Elena; Hunton, Irina C.; Kolodner, Richard D.; Edelmann, Winfried; Wang, Jean Y. J.

    2008-01-01

    Mismatch repair (MMR) corrects replication errors during DNA synthesis. The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin, a DNA cross-linking agent used in chemotherapy, because of impaired activation of apoptotic pathways. It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53 family of transcrip...

  15. Induction of Non-Apoptotic Cell Death by Activated Ras Requires Inverse Regulation of Rac1 and Arf6

    OpenAIRE

    Bhanot, Haymanti; Young, Ashley M.; Overmeyer, Jean H.; Maltese, William A.

    2010-01-01

    Methuosis is a unique form of non-apoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively active Ras. This study identifies the small GTPases, Rac1 and Arf6, and the Arf6 GTPase-activating-protein, GIT1, as key downstream components of the signaling pathway underlying Ras-induced methuosis. The extent to...

  16. Antiproliferative and apoptotic activities of extracts of Asclepias subulata.

    Science.gov (United States)

    Rascón Valenzuela, Luisa Alondra; Jiménez Estrada, Manuel; Velázquez Contreras, Carlos Arturo; Garibay Escobar, Adriana; Medina Juárez, Luis Angel; Gámez Meza, Nohemi; Robles Zepeda, Ramón Enrique

    2015-01-01

    Asclepias subulata Decne. (Apocynaceae) is a shrub used in the Mexican traditional medicine for the treatment of cancer. The objective of this study was to evaluate the antiproliferative activity of methanol extract of aerial parts of A. subulata and its fractions against different cancer cell lines. Additionally, we analyzed the mechanism of action of the active fractions. Methanol extract fractions were prepared by serial extraction with n-hexane, ethyl acetate, and ethanol. The antiproliferative activity of methanol extract and its fractions was evaluated, against several murine (M12.C3.F6, RAW 264.7, and L929) and human (HeLa, A549, PC-3, LS 180, and ARPE-19) cell lines by the MTT assay, using concentrations of 0.4-400 µg/mL for 48 h. Ethanol and residual fractions were separated using silica gel column. Apoptosis induction of cancer cells was evaluated by Annexin and JC-1 staining using flow cytometry. Methanol extract and its fractions showed antiproliferative activity against all human cancer cell lines tested. Methanol extract had the highest antiproliferative activity on A549 and HeLa cells (IC50 values < 0.4 and 8.7 µg/mL, respectively). Ethanol and residual fractions exerted significant antiproliferative effect on A549 (IC50 < 0.4 µg/mL) and PC3 cells (IC50 1.4 and 5.1 µg/mL). Apoptotic assays showed that CEF7, CEF9, CRF6, and CRF5 fractions induced mitochondrial depolarization in A549 cells, 70, 73, 77, and 80%, respectively. Those fractions triggered the apoptosis mitochondrial pathway. Our data show that A. subulata extracts have potent antiproliferative properties on human cancer cell lines. This plant should be considered an important source of potent anticancer compounds.

  17. faloabi@uniben.edu Antiproliferative and Pro-apoptotic activities

    African Journals Online (AJOL)

    MICHAEL HORSFALL

    Keyword: Persea americana, antiproliferative activity, apoptotic effect, flow ... of the stem bark of Persea americana in MCF-7 cell line by flow cytometer. .... of an electric milling machine. ... Flow Cytometric Measurement Of Cell Proliferation:.

  18. Brucein D, a Naturally Occurring Tetracyclic Triterpene Quassinoid, Induces Apoptosis in Pancreatic Cancer through ROS-Associated PI3K/Akt Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Zheng-Quan Lai

    2017-12-01

    Full Text Available Brucein D (BD, a major active quassinoid in Brucea javanica, has exhibited pronounced anticancer activities. However, the biologic mechanisms have not been fully explored. In this study, BD exhibited more potent cytotoxic effect on pancreatic cancer (PanCa cell lines, while exerted weaker cytotoxic effects on GES-1 cells (non-tumorigenic. BD was shown to elicit apoptosis through inducing both the intrinsic and extrinsic mitochondria-mediated caspase activations. Furthermore, the BD-induced apoptotic effects were dependent on the accumulated reactive oxygen species (ROS and inactivation of PI3K/Akt signaling pathway. Pretreatment with tempol completely prevented the cellular apoptosis induced by BD, and recovered the inactivation of AKT, which suggested ROS essentially involved in BD-elicited apoptosis and down-regulation of PI3K/Akt pathway. In addition, the results obtained from orthotopic xenograft in nude mice were congruent with those of the in vitro investigations. These results support the notion that BD held good potential to be further developed into an effective pharmaceutical agent for the treatment of PanCa.

  19. Text Summarization Evaluation: Correlating Human Performance on an Extrinsic Task with Automatic Intrinsic Metrics

    National Research Council Canada - National Science Library

    President, Stacy F; Dorr, Bonnie J

    2006-01-01

    This research describes two types of summarization evaluation methods, intrinsic and extrinsic, and concentrates on determining the level of correlation between automatic intrinsic methods and human...

  20. Examining extrinsic factors that influence product acceptance: a review.

    Science.gov (United States)

    Li, X E; Jervis, S M; Drake, M A

    2015-05-01

    Drivers of liking (DOL) studies are useful for product development to formulate acceptable products; however, DOL alone are insufficient for understanding why a product is purchased and repurchased, which is ultimately the indication of a successful product. Ultimately sensory attributes drive product success (that is, repeat and continued purchase). However, ignoring the importance of extrinsic factors may neglect the vital product attributes responsible for the initial purchase, which may in turn, affect repeat purchase. The perception of sensory attributes assessed by DOL is mitigated by external perceptions of quality. If the sensory attributes do not deliver based upon the quality cues, the product will not be acceptable. Four key extrinsic factors that affect DOL are the perceived satiety, brand and labeling, price, and the emotional impact to decision making. In order to more thoroughly understand what the DOL for a product is, these 4 product cues should be considered in conjunction with sensory attribute perception to gain a holistic understanding of product acceptance. © 2015 Institute of Food Technologists®

  1. Intrinsic and Extrinsic Science: A Dialectic of Scientific Fame.

    Science.gov (United States)

    Feist, Gregory J

    2016-11-01

    In this article, I argue that scientific fame and impact exists on a continuum from the mundane to the transformative/revolutionary. Ideally, one achieves fame and impact in science by synthesizing two extreme career prototypes: intrinsic and extrinsic research. The former is guided by interest, curiosity, passion, gut, and intuition for important untapped topics. The latter is guided by money, grants, and/or what is being published in top-tier journals. Assessment of fame and impact in science ultimately rests on productivity (publication) and some variation of its impact (citations). In addition to those traditional measures of impact, there are some relatively new metrics (e.g., the h index and altmetrics). If psychology is to achieve consensual cumulative progress and better rates of replication, I propose that upcoming psychologists would do well to understand that success is not equal to fame and that individual career success is not necessarily the same as disciplinary success. Finally, if one is to have a successful and perhaps even famous career in psychological science, a good strategy would be to synthesize intrinsic and extrinsic motives for one's research. © The Author(s) 2016.

  2. The effect of extrinsic attributes on liking of cottage cheese.

    Science.gov (United States)

    Hubbard, E M; Jervis, S M; Drake, M A

    2016-01-01

    Preference mapping studies with cottage cheese have demonstrated that cottage cheese liking is influenced by flavor, texture, curd size, and dressing content. However, extrinsic factors such as package, label claims, and brand name may also influence liking and have not been studied. The objective of this study was to evaluate the role of package attributes and brand on the liking of cottage cheese. A conjoint survey with Kano analysis (n=460) was conducted to explore the effect of extrinsic attributes (brand, label claim, milkfat content, and price) on liking. Following the survey, 150 consumers evaluated intrinsic attributes of 7 cottage cheeses with and without brand information in a 2-d crossover design. Results were evaluated by 2-way ANOVA and multivariate analyses. Milkfat content and price had the highest influence on liking by conjoint analysis. Cottage cheese with 2% milkfat and a low price was preferred. Specific label claims such as "excellent source of calcium (>10%)" were more attractive to consumers than "low sodium" or "extra creamy." Branding influenced overall liking and purchase intent for cottage cheeses to differing degrees. For national brands, acceptance scores were enhanced in the presence of the brand. An all-natural claim was more appealing than organic by conjoint analysis and this result was also confirmed with consumer acceptance testing. Findings from this study can help manufacturers, as well as food marketers, better target their products and brands with attributes that drive consumer choice. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  3. Extrinsic labelling of zinc and calcium in bread

    International Nuclear Information System (INIS)

    Fredlund, Kerstin; Rossander-Hulthen, Lena; Isaksson, Mats; Almgren, Annette; Sandberg, A.-S.

    2002-01-01

    This study investigated the effect of different means of extrinsic administration of 65 Zn and 47 Ca in white wheat flour bread on the measured absorption. Eight healthy subjects were served 80 g of labelled bread as a standardized breakfast after an overnight fast on three occasions. Extrinsic labelling of the meals with 65 Zn and 47 Ca was done in three ways: (a) by adding the isotopes to the bread 16 h before it was served, (b) by adding the isotopes shortly before serving or (c) by adding the isotopes to the water used in dough making. Zinc and calcium chloride corresponding to 3.2 mg (49 μmol) zinc and 275 mg (6.9 mmol) calcium in one portion were added to the dough. Whole-body retention was measured by whole-body counting. The fractional absorption of zinc was (a) 0.243±0.122, (b) 0.217±0.101 and (c) 0.178±0.063 (mean±SD), and the fractional absorption of calcium (expressed as calcium retention on day 7) was (a) 0.351±0.108, (b) 0.357±0.131 and (c) 0.334±0.117 (mean±SD). No significant difference (p>0.05) was seen between the different ways for either zinc nor calcium

  4. Intrinsic and extrinsic influences on children's acceptance of new foods.

    Science.gov (United States)

    Blissett, Jackie; Fogel, Anna

    2013-09-10

    The foods that tend to be rejected by children include those which may have greatest importance for later health. This paper reviews some of the intrinsic and extrinsic influences on preschool children's eating behavior, with particular reference to their acceptance of new foods into their diet. Factors conceptualized as intrinsic to the child in this review include sensory processing, taste perception, neophobia, and temperament. The important extrinsic determinants of children's food acceptance which are reviewed include parental and peer modeling, the family food environment, infant feeding practices including breastfeeding and age at weaning, concurrent feeding practices including restriction, pressure to eat, prompting and reward, and the taste & energy content of foods. Children's willingness to accept new foods is influenced by a wide range of factors that likely have individual and also interactive effects on children's willingness to taste, and then continue to eat, new foods. The literature lacks longitudinal and experimental studies, which will be particularly important in determining interventions most likely to be effective in facilitating children's acceptance of healthy foods. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Extrinsic stretching narrowing and anterior indentation of the rectosigmoid junction

    International Nuclear Information System (INIS)

    Schulman, A.; Fataar, S.

    1979-01-01

    Thirty-five cases of extrinsic narrowing or anterior indentation of the rectosigmoid junction (RSJ) have been studied. The RSJ lies directly behind the pouch of Douglas which is a favoured site for peritoneal metastasis, abscess and endometriosis. Any space-occupying lesion of sufficient size at this site will indent the anterior aspects of the RSJ. Causes include distension or tumour of the ileum or sigmoid colon, gross ascites (when the patient is erect), and tumours below the pelvic peritonium, such as gynaecological neoplasm and internal iliac artery aneurysm. When a desmoplastic metastasis in the pouch of Douglas infiltrates the outer layers of the RSJ, the fibrosis produces an eccentric shortening on its anterior aspect, which in turn causes a pleating of the mucosa with the folds radiating towards the shortened area. This is also seen with primary pelvic carcinomas directly adherent to the rectum, endometriosis with repeated bleeding and increasing eccentric, submucosal fibrosis, and chronic abscess in the pouch of Douglas. Not all extrinsic narrowing of the RSJ are pathological. One case of anterior indentation followed operation for rectal prolapse. Ten additional cases showed narrowing due to a technical artefact air-distended colon rising into the upper abdomen to cause stretching at the RSJ. As with ascites, this narrowing due to 'high-rise sigmoid' disappeared when the patients became recumbent and the colonic air redistributed. (author)

  6. Prevalence and Extrinsic Risk Factors for Dental Erosion in Adolescents.

    Science.gov (United States)

    Mafla, Ana C; Cerón-Bastidas, Ximena A; Munoz-Ceballos, Maria E; Vallejo-Bravo, Diana C; Fajardo-Santacruz, Maria C

    This manuscript examined the prevalence and extrinsic risk factors for dental erosion (DE) in early and middle adolescents in Pasto, Colombia. Dental erosion was evaluated in a random sample of 384 individuals aged 10-15 years attending three primary and high schools in this cross-sectional study. Clinical dental assessment for DE was done using O'Sullivan index. Data on general sociodemographic variables and extrinsic risks factors were obtained. Descriptive and univariate binary logistic regression analyses were performed. Dental erosion was observed in 57.3% of individuals. The univariate binary logistic regression analysis showed that frequency of drinking natural fruit juices (OR 2.670, 95% CI 1.346 - 5.295, P=0.004) and their pH (OR 2.303, 95% CI 1.292 - 4.107, P=0.004) were more associated with the odd of DE in early adolescence. However, a high SES (OR 10.360, 95% CI 3.700 - 29.010, P<0.001) and frequency of snacks with artificial lemon taste (OR 3.659, 95% CI 1.506 - 8.891, P=0.003) were highly associated with the risk of DE in middle adolescence. The results suggest that DE is a prevalent condition in adolescents living in a city in southern Colombia. The transition from early to middle adolescence implies new bio-psychosocial changes, which increase the risk for DE.

  7. WNT signaling controls expression of pro-apoptotic BOK and BAX in intestinal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zeilstra, Jurrit; Joosten, Sander P.J. [Department of Pathology, Academic Medical Center, University of Amsterdam (Netherlands); Wensveen, Felix M. [Department of Experimental Immunology, Academic Medical Center, Amsterdam (Netherlands); Dessing, Mark C.; Schuetze, Denise M. [Department of Pathology, Academic Medical Center, University of Amsterdam (Netherlands); Eldering, Eric [Department of Experimental Immunology, Academic Medical Center, Amsterdam (Netherlands); Spaargaren, Marcel [Department of Pathology, Academic Medical Center, University of Amsterdam (Netherlands); Pals, Steven T., E-mail: s.t.pals@amc.uva.nl [Department of Pathology, Academic Medical Center, University of Amsterdam (Netherlands)

    2011-03-04

    Research highlights: {yields} Intestinal adenomas initiated by aberrant activation of the WNT pathway displayed an increased sensitivity to apoptosis. {yields} Expression profiling of apoptosis-related genes in Apc{sup Min/+} mice revealed the differential expression of pro-apoptotic Bok and Bax. {yields} APC-mutant adenomatous crypts in FAP patients showed strongly increased BAX immunoreactivity. {yields} Blocking of {beta}-catenin/TCF-4-mediated signaling in colon cancer cells reduced the expression of BOK and BAX. -- Abstract: In a majority of cases, colorectal cancer is initiated by aberrant activation of the WNT signaling pathway. Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or {beta}-catenin causes constitutively active {beta}-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to cancer precursor lesions, called dysplastic aberrant crypt foci. Deregulated apoptosis is a hallmark of adenomatous colon tissue. However, the contribution of WNT signaling to this process is not fully understood. We addressed this role by analyzing the rate of epithelial apoptosis in aberrant crypts and adenomas of the Apc{sup Min/+} mouse model. In comparison with normal crypts and adenomas, aberrant crypts displayed a dramatically increased rate of apoptotic cell death. Expression profiling of apoptosis-related genes along the crypt-villus axis and in Apc mutant adenomas revealed increased expression of two pro-apoptotic Bcl-2 family members in intestinal adenomas, Bok and Bax. Analysis of the colon of familial adenomatous polyposis (FAP) patients along the crypt-to-surface axis, and of dysplastic crypts, corroborated this expression pattern. Disruption of {beta}-catenin/TCF-4-mediated signaling in the colorectal cancer cell line Ls174T significantly decreased BOK and BAX expression, confirming WNT-dependent regulation in intestinal epithelial cells. Our results suggest a feedback mechanism by which

  8. WNT signaling controls expression of pro-apoptotic BOK and BAX in intestinal cancer

    International Nuclear Information System (INIS)

    Zeilstra, Jurrit; Joosten, Sander P.J.; Wensveen, Felix M.; Dessing, Mark C.; Schuetze, Denise M.; Eldering, Eric; Spaargaren, Marcel; Pals, Steven T.

    2011-01-01

    Research highlights: → Intestinal adenomas initiated by aberrant activation of the WNT pathway displayed an increased sensitivity to apoptosis. → Expression profiling of apoptosis-related genes in Apc Min/+ mice revealed the differential expression of pro-apoptotic Bok and Bax. → APC-mutant adenomatous crypts in FAP patients showed strongly increased BAX immunoreactivity. → Blocking of β-catenin/TCF-4-mediated signaling in colon cancer cells reduced the expression of BOK and BAX. -- Abstract: In a majority of cases, colorectal cancer is initiated by aberrant activation of the WNT signaling pathway. Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin causes constitutively active β-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to cancer precursor lesions, called dysplastic aberrant crypt foci. Deregulated apoptosis is a hallmark of adenomatous colon tissue. However, the contribution of WNT signaling to this process is not fully understood. We addressed this role by analyzing the rate of epithelial apoptosis in aberrant crypts and adenomas of the Apc Min/+ mouse model. In comparison with normal crypts and adenomas, aberrant crypts displayed a dramatically increased rate of apoptotic cell death. Expression profiling of apoptosis-related genes along the crypt-villus axis and in Apc mutant adenomas revealed increased expression of two pro-apoptotic Bcl-2 family members in intestinal adenomas, Bok and Bax. Analysis of the colon of familial adenomatous polyposis (FAP) patients along the crypt-to-surface axis, and of dysplastic crypts, corroborated this expression pattern. Disruption of β-catenin/TCF-4-mediated signaling in the colorectal cancer cell line Ls174T significantly decreased BOK and BAX expression, confirming WNT-dependent regulation in intestinal epithelial cells. Our results suggest a feedback mechanism by which uncontrolled epithelial cell proliferation in the

  9. Harnessing Apoptotic Cell Clearance to Treat Autoimmune Arthritis

    Directory of Open Access Journals (Sweden)

    Philippe Saas

    2017-10-01

    Full Text Available Early-stage apoptotic cells possess immunomodulatory properties. Proper apoptotic cell clearance during homeostasis has been shown to limit subsequent immune responses. Based on these observations, early-stage apoptotic cell infusion has been used to prevent unwanted inflammatory responses in different experimental models of autoimmune diseases or transplantation. Moreover, this approach has been shown to be feasible without any toxicity in patients undergoing allogeneic hematopoietic cell transplantation to prevent graft-versus-host disease. However, whether early-stage apoptotic cell infusion can be used to treat ongoing inflammatory disorders has not been reported extensively. Recently, we have provided evidence that early-stage apoptotic cell infusion is able to control, at least transiently, ongoing collagen-induced arthritis. This beneficial therapeutic effect is associated with the modulation of antigen-presenting cell functions mainly of macrophages and plasmacytoid dendritic cells, as well as the induction of collagen-specific regulatory CD4+ T cells (Treg. Furthermore, the efficacy of this approach is not altered by the association with two standard treatments of rheumatoid arthritis (RA, methotrexate and tumor necrosis factor (TNF inhibition. Here, in the light of these observations and recent data of the literature, we discuss the mechanisms of early-stage apoptotic cell infusion and how this therapeutic approach can be transposed to patients with RA.

  10. SIGN-R1 and complement factors are involved in the systemic clearance of radiation-induced apoptotic cells in whole-body irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jin-Yeon; Loh, SoHee; Cho, Eun-hee [Department of Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of); Choi, Hyeong-Jwa [Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, 215-4, 75 Nowon gil Nowon-Gu, Seoul, 139-706 (Korea, Republic of); Na, Tae-Young [College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-741 (Korea, Republic of); Nemeno, Judee Grace E.; Lee, Jeong Ik [Regenerative Medicine Laboratory, Department of Veterinary Medicine, College of Veterinary Medicine, Konkuk University, Seoul, 143-701 (Korea, Republic of); Yoon, Taek Joon [Department of Food and Nutrition, Yuhan College, Bucheon, Gyeonggi-do, 422-749 (Korea, Republic of); Choi, In-Soo [Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of); Lee, Minyoung [Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, 215-4, 75 Nowon gil Nowon-Gu, Seoul, 139-706 (Korea, Republic of); Lee, Jae-Seon [Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 400-712 (Korea, Republic of); Kang, Young-Sun, E-mail: kangys1967@naver.com [Department of Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of); Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of)

    2015-08-07

    Although SIGN-R1-mediated complement activation pathway has been shown to enhance the systemic clearance of apoptotic cells, the role of SIGN-R1 in the clearance of radiation-induced apoptotic cells has not been characterized and was investigated in this study. Our data indicated that whole-body γ-irradiation of mice increased caspase-3{sup +} apoptotic lymphocyte numbers in secondary lymphoid organs. Following γ-irradiation, SIGN-R1 and complements (C4 and C3) were simultaneously increased only in the mice spleen tissue among the assessed tissues. In particular, C3 was exclusively activated in the spleen. The delayed clearance of apoptotic cells was markedly prevalent in the spleen and liver of SIGN-R1 KO mice, followed by a significant increase of CD11b{sup +} cells. These results indicate that SIGN-R1 and complement factors play an important role in the systemic clearance of radiation-induced apoptotic innate immune cells to maintain tissue homeostasis after γ-irradiation. - Highlights: • Splenic SIGN-R1{sup +} macrophages are activated after γ-irradiation. • C3 and C4 levels increased and C3 was activated in the spleen after γ-irradiation. • SIGN-R1 mediated the systemic clearance of radiation-induced apoptotic cells in spleen and liver.

  11. SIGN-R1 and complement factors are involved in the systemic clearance of radiation-induced apoptotic cells in whole-body irradiated mice

    International Nuclear Information System (INIS)

    Park, Jin-Yeon; Loh, SoHee; Cho, Eun-hee; Choi, Hyeong-Jwa; Na, Tae-Young; Nemeno, Judee Grace E.; Lee, Jeong Ik; Yoon, Taek Joon; Choi, In-Soo; Lee, Minyoung; Lee, Jae-Seon; Kang, Young-Sun

    2015-01-01

    Although SIGN-R1-mediated complement activation pathway has been shown to enhance the systemic clearance of apoptotic cells, the role of SIGN-R1 in the clearance of radiation-induced apoptotic cells has not been characterized and was investigated in this study. Our data indicated that whole-body γ-irradiation of mice increased caspase-3 + apoptotic lymphocyte numbers in secondary lymphoid organs. Following γ-irradiation, SIGN-R1 and complements (C4 and C3) were simultaneously increased only in the mice spleen tissue among the assessed tissues. In particular, C3 was exclusively activated in the spleen. The delayed clearance of apoptotic cells was markedly prevalent in the spleen and liver of SIGN-R1 KO mice, followed by a significant increase of CD11b + cells. These results indicate that SIGN-R1 and complement factors play an important role in the systemic clearance of radiation-induced apoptotic innate immune cells to maintain tissue homeostasis after γ-irradiation. - Highlights: • Splenic SIGN-R1 + macrophages are activated after γ-irradiation. • C3 and C4 levels increased and C3 was activated in the spleen after γ-irradiation. • SIGN-R1 mediated the systemic clearance of radiation-induced apoptotic cells in spleen and liver

  12. STAT1, STAT3 and p38MAPK are involved in the apoptotic effect induced by a chimeric cyclic interferon-{alpha}2b peptide

    Energy Technology Data Exchange (ETDEWEB)

    Blank, Viviana C.; Pena, Clara [Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956-C1113AAD Buenos Aires (Argentina); Roguin, Leonor P., E-mail: rvroguin@qb.ffyb.uba.ar [Institute of Biochemistry and Biophysics (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956-C1113AAD Buenos Aires (Argentina)

    2010-02-15

    In the search of mimetic peptides of the interferon-{alpha}2b molecule (IFN-{alpha}2b), we have previously designed and synthesized a chimeric cyclic peptide of the IFN-{alpha}2b that inhibits WISH cell proliferation by inducing an apoptotic response. Here, we first studied the ability of this peptide to activate intracellular signaling pathways and then evaluated the participation of some signals in the induction of apoptosis. Stimulation of WISH cells with the cyclic peptide showed tyrosine phosphorylation of Jak1 and Tyk2 kinases, tyrosine and serine phosphorylation of STAT1 and STAT3 transcription factors and activation of p38 MAPK pathway, although phosphorylation levels or kinetics were in some conditions different to those obtained under IFN-{alpha}2b stimulus. JNK and p44/42 pathways were not activated by the peptide in WISH cells. We also showed that STAT1 and STAT3 downregulation by RNA interference decreased the antiproliferative activity and the amount of apoptotic cells induced by the peptide. Pharmacological inhibition of p38 MAPK also reduced the peptide growth inhibitory activity and the apoptotic effect. Thus, we demonstrated that the cyclic peptide regulates WISH cell proliferation through the activation of Jak/STAT signaling pathway. In addition, our results indicate that p38 MAPK may also be involved in cell growth regulation. This study suggests that STAT1, STAT3 and p38 MAPK would be mediating the antitumor and apoptotic response triggered by the cyclic peptide in WISH cells.

  13. STAT1, STAT3 and p38MAPK are involved in the apoptotic effect induced by a chimeric cyclic interferon-α2b peptide

    International Nuclear Information System (INIS)

    Blank, Viviana C.; Pena, Clara; Roguin, Leonor P.

    2010-01-01

    In the search of mimetic peptides of the interferon-α2b molecule (IFN-α2b), we have previously designed and synthesized a chimeric cyclic peptide of the IFN-α2b that inhibits WISH cell proliferation by inducing an apoptotic response. Here, we first studied the ability of this peptide to activate intracellular signaling pathways and then evaluated the participation of some signals in the induction of apoptosis. Stimulation of WISH cells with the cyclic peptide showed tyrosine phosphorylation of Jak1 and Tyk2 kinases, tyrosine and serine phosphorylation of STAT1 and STAT3 transcription factors and activation of p38 MAPK pathway, although phosphorylation levels or kinetics were in some conditions different to those obtained under IFN-α2b stimulus. JNK and p44/42 pathways were not activated by the peptide in WISH cells. We also showed that STAT1 and STAT3 downregulation by RNA interference decreased the antiproliferative activity and the amount of apoptotic cells induced by the peptide. Pharmacological inhibition of p38 MAPK also reduced the peptide growth inhibitory activity and the apoptotic effect. Thus, we demonstrated that the cyclic peptide regulates WISH cell proliferation through the activation of Jak/STAT signaling pathway. In addition, our results indicate that p38 MAPK may also be involved in cell growth regulation. This study suggests that STAT1, STAT3 and p38 MAPK would be mediating the antitumor and apoptotic response triggered by the cyclic peptide in WISH cells.

  14. Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappaB-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis

    NARCIS (Netherlands)

    Schoemaker, Marieke H.; Ros, Jenny E.; Homan, Manon; Trautwein, Christian; Liston, Peter; Poelstra, Klaas; van Goor, Harry; Jansen, Peter L. M.; Moshage, Han

    2002-01-01

    BACKGROUND/AIMS: In acute liver failure, hepatocytes are exposed to various cytokines that activate both cell survival and apoptotic pathways. NF-kappaB is a central transcription factor in these responses. Recent studies indicate that blocking NF-kappaB causes apoptosis, indicating the existence of

  15. Induction of apoptotic death and retardation of neuronal differentiation of human neural stem cells by sodium arsenite treatment

    International Nuclear Information System (INIS)

    Ivanov, Vladimir N.; Hei, Tom K.

    2013-01-01

    Chronic arsenic toxicity is a global health problem that affects more than 100 million people worldwide. Long-term health effects of inorganic sodium arsenite in drinking water may result in skin, lung and liver cancers and in severe neurological abnormalities. We investigated in the present study whether sodium arsenite affects signaling pathways that control cell survival, proliferation and neuronal differentiation of human neural stem cells (NSC). We demonstrated that the critical signaling pathway, which was suppressed by sodium arsenite in NSC, was the protective PI3K–AKT pathway. Sodium arsenite (2–4 μM) also caused down-regulation of Nanog, one of the key transcription factors that control pluripotency and self-renewal of stem cells. Mitochondrial damage and cytochrome-c release induced by sodium arsenite exposure was followed by initiation of the mitochondrial apoptotic pathway in NSC. Beside caspase-9 and caspase-3 inhibitors, suppression of JNK activity decreased levels of arsenite-induced apoptosis in NSC. Neuronal differentiation of NSC was substantially inhibited by sodium arsenite exposure. Overactivation of JNK1 and ERK1/2 and down-regulation of PI3K–AKT activity induced by sodium arsenite were critical factors that strongly affected neuronal differentiation. In conclusion, sodium arsenite exposure of human NSC induces the mitochondrial apoptotic pathway, which is substantially accelerated due to the simultaneous suppression of PI3K–AKT. Sodium arsenite also negatively affects neuronal differentiation of NSC through overactivation of MEK–ERK and suppression of PI3K–AKT. - Highlights: ► Arsenite induces the mitochondrial apoptotic pathway in human neural stem cells. ► Arsenite-induced apoptosis is strongly upregulated by suppression of PI3K–AKT. ► Arsenite-induced apoptosis is strongly down-regulated by inhibition of JNK–cJun. ► Arsenite negatively affects neuronal differentiation by inhibition of PI3K–AKT

  16. Induction of apoptotic death and retardation of neuronal differentiation of human neural stem cells by sodium arsenite treatment

    Energy Technology Data Exchange (ETDEWEB)

    Ivanov, Vladimir N., E-mail: vni3@columbia.edu [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, NY 10032 (United States); Hei, Tom K. [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, NY 10032 (United States)

    2013-04-01

    Chronic arsenic toxicity is a global health problem that affects more than 100 million people worldwide. Long-term health effects of inorganic sodium arsenite in drinking water may result in skin, lung and liver cancers and in severe neurological abnormalities. We investigated in the present study whether sodium arsenite affects signaling pathways that control cell survival, proliferation and neuronal differentiation of human neural stem cells (NSC). We demonstrated that the critical signaling pathway, which was suppressed by sodium arsenite in NSC, was the protective PI3K–AKT pathway. Sodium arsenite (2–4 μM) also caused down-regulation of Nanog, one of the key transcription factors that control pluripotency and self-renewal of stem cells. Mitochondrial damage and cytochrome-c release induced by sodium arsenite exposure was followed by initiation of the mitochondrial apoptotic pathway in NSC. Beside caspase-9 and caspase-3 inhibitors, suppression of JNK activity decreased levels of arsenite-induced apoptosis in NSC. Neuronal differentiation of NSC was substantially inhibited by sodium arsenite exposure. Overactivation of JNK1 and ERK1/2 and down-regulation of PI3K–AKT activity induced by sodium arsenite were critical factors that strongly affected neuronal differentiation. In conclusion, sodium arsenite exposure of human NSC induces the mitochondrial apoptotic pathway, which is substantially accelerated due to the simultaneous suppression of PI3K–AKT. Sodium arsenite also negatively affects neuronal differentiation of NSC through overactivation of MEK–ERK and suppression of PI3K–AKT. - Highlights: ► Arsenite induces the mitochondrial apoptotic pathway in human neural stem cells. ► Arsenite-induced apoptosis is strongly upregulated by suppression of PI3K–AKT. ► Arsenite-induced apoptosis is strongly down-regulated by inhibition of JNK–cJun. ► Arsenite negatively affects neuronal differentiation by inhibition of PI3K–AKT.

  17. Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage.

    Science.gov (United States)

    Loganes, Claudia; Lega, Sara; Bramuzzo, Matteo; Vecchi Brumatti, Liza; Piscianz, Elisa; Valencic, Erica; Tommasini, Alberto; Marcuzzi, Annalisa

    2017-06-06

    The purpose of this study is to determine if a preventive treatment with curcumin can protect intestinal epithelial cells from inflammatory damage induced by IFNγ. To achieve this goal we have used a human intestinal epithelial cell line (HT29) treated with IFNγ to undergo apoptotic changes that can reproduce the damage of intestinal epithelia exposed to inflammatory cytokines. In this model, we measured the effect of curcumin (curcuminoid from Curcuma Longa ) added as a pre-treatment at different time intervals before stimulation with IFNγ. Curcumin administration to HT29 culture before the inflammatory stimulus IFNγ reduced the cell apoptosis rate. This effect gradually declined with the reduction of the curcumin pre-incubation time. This anti-apoptotic action by curcumin pre-treatment was paralleled by a reduction of secreted IL7 in the HT29 culture media, while there was no relevant change in the other cytokine levels. Even though curcumin pre-administration did not impact the activation of the NF-κB pathway, a slight effect on the phosphorylation of proteins in this inflammatory signaling pathway was observed. In conclusion, curcumin pre-treatment can protect intestinal cells from inflammatory damage. These results can be the basis for studying the preventive role of curcumin in inflammatory bowel diseases.

  18. Apoptotic activity and gene responses in Drosophila melanogaster S2 cells, induced by azadirachtin A.

    Science.gov (United States)

    Xu, Lin; Li, Sheng; Ran, Xueqin; Liu, Chang; Lin, Rutao; Wang, Jiafu

    2016-09-01

    Azadirachtin has been used as an antifeedant and growth disruption agent for many insect species. Previous investigations have reported the apoptotic effects of azadirachtin on some insect cells, but the molecular mechanisms are still not clear. This study investigated the underlying molecular mechanisms for the apoptotic effects induced by azadirachtin on Drosophila melanogaster S2 cells in vitro. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay demonstrated that azadirachtin exhibited significant cytotoxicity to S2 cells in a time- and dose-dependent manner. The changes in cellular morphology and the DNA fragmentation demonstrated that azadirachtin induced remarkable apoptosis of S2 cells. Expression levels of 276 genes were found to be significantly changed in S2 cells after exposure to azadirachtin, as detected by Drosophila genome array. Among these genes, calmodulin (CaM) was the most highly upregulated gene. Azadirachtin was further demonstrated to trigger intracellular Ca(2+) release in S2 cells. The genes related to the apoptosis pathway, determined from chip data, were validated by the real-time quantitative polymerase chain reaction method. The results showed that azadirachtin-mediated intracellular Ca(2+) release was the primary event that triggered apoptosis in Drosophila S2 cells through both pathways of the Ca(2+) -CaM and EcR/Usp signalling cascade. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  19. Bioactive compounds from crocodile (Crocodylus siamensis) white blood cells induced apoptotic cell death in hela cells.

    Science.gov (United States)

    Patathananone, Supawadee; Thammasirirak, Sompong; Daduang, Jureerut; Chung, Jing Gung; Temsiripong, Yosapong; Daduang, Sakda

    2016-08-01

    Crocodile (Crocodylus siamensis) white blood cell extracts (WBCex) were examined for anticancer activity in HeLa cell lines using the MTT assay. The percentage viability of HeLa cells significantly deceased after treatment with WBCex in a dose- and time-dependent manner. The IC50 dose was suggested to be approximately 225 μg/mL protein. Apoptotic cell death occurred in a time-dependent manner based on investigation by flow cytometry using annexin V-FITC and PI staining. DAPI nucleic acid staining indicated increased chromatin condensation. Caspase-3, -8 and -9 activities also increased, suggesting the induction of the caspase-dependent apoptotic pathway. Furthermore, the mitochondrial membrane potential (ΔΨm ) of HeLa cells was lost as a result of increasing levels of Bax and reduced levels of Bcl-2, Bcl-XL, Bcl-Xs, and XIAP. The decreased ΔΨm led to the release of cytochrome c and the activation of caspase-9 and -3. Apoptosis-inducing factor translocated into the nuclei, and endonuclease G (Endo G) was released from the mitochondria. These results suggest that anticancer agents in WBCex can induce apoptosis in HeLa cells via both caspase-dependent and -independent pathways. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 986-997, 2016. © 2015 Wiley Periodicals, Inc.

  20. Intrinsic, pro-apoptotic effects of IGFBP-3 on breast cancer cells are reversible: Involvement of PKA, Rho and ceramide.

    Directory of Open Access Journals (Sweden)

    Claire M Perks

    2011-05-01

    Full Text Available We established previously that IGFBP-3 could exert positive or negative effects on cell function depending upon the extracellular matrix composition and by interacting with integrin signalling. To elicit its pro-apoptotic effects IGFBP-3 bound to caveolin-1 and the beta 1 integrin receptor and increased their association culminating in MAPK activation. Disruption of these complexes or blocking the beta 1 integrin receptor reversed these intrinsic actions of IGFBP-3. In this study we have examined the signalling pathway between integrin receptor binding and MAPK activation that mediates the intrinsic, pro-apoptotic actions of IGFBP-3. We found on inhibiting protein kinase A(PKA, Rho associated kinase (ROCK and ceramide, the accentuating effects of IGFBP-3 on apoptotic triggers were reversed, such that IGFBP-3 then conferred cell survival. We established that IGFBP-3 activated Rho, the upstream regulator of ROCK and that beta1 integrin and PKA were upstream of Rho activation, whereas the involvement of ceramide was downstream. The beta 1 integrin, PKA, Rho and ceramide were all upstream of MAPK activation. These data highlight key components involved in the pro-apoptotic effects of IGFBP-3 and that inhibiting them leads to a reversal in the action of IGFBP-3.

  1. Molecular interactions of prodiginines with the BH3 domain of anti-apoptotic Bcl-2 family members.

    Directory of Open Access Journals (Sweden)

    Ali Hosseini

    Full Text Available Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.

  2. Creating Rich Portraits: A Mixed-Methods Approach to Understanding Profiles of Intrinsic and Extrinsic Motivations

    Science.gov (United States)

    Corpus, Jennifer Henderlong; Wormington, Stephanie V.; Haimovitz, Kyla

    2016-01-01

    A person-centered, mixed-methods approach (self-report surveys, semistructured interviews, school records) was used to characterize and evaluate profiles of intrinsic and extrinsic motivations among 243 third- through eighth-grade students. Cluster analysis suggested four distinct profiles: high quantity (high intrinsic, high extrinsic), primarily…

  3. Intrinsic and Extrinsic Origins of the Polar Kerr Effect in a Chiral p-WAVE Superconductor

    Science.gov (United States)

    Goryo, Jun

    Recently, the measurement of the polar Kerr effect (PKE) in the quasi two-dimensional superconductor Sr2RuO4, which is motivated to observe the chirality of px + ipy-wave pairing, has been reported. We clarify that the PKE has intrinsic and extrinsic (disorder-induced) origins. The extrinsic contribution would be dominant in the PKE experiment.

  4. Do people differentiate between intrinsic and extrinsic goals for physical activity?

    Science.gov (United States)

    McLachlan, Sarah; Hagger, Martin S

    2011-04-01

    The distinction between intrinsic and extrinsic goals, and between goal pursuit for intrinsically and extrinsically motivated reasons, is a central premise of self-determination theory. Proponents of the theory have proposed that the pursuit of intrinsic goals and intrinsically motivated goal striving each predict adaptive psychological and behavioral outcomes relative to the pursuit of extrinsic goals and extrinsically motivated goal striving. Despite evidence to support these predictions, research has not explored whether individuals naturally differentiate between intrinsic and extrinsic goals. Two studies tested whether people make this differentiation when recalling goals for leisure-time physical activity. Using memory-recall methods, participants in Study 1 were asked to freely generate physical activity goals. A subsample (N = 43) was asked to code their freely generated goals as intrinsic or extrinsic. In Study 2, participants were asked to recall intrinsic and extrinsic goals after making a decision regarding their future physical activity. Results of these studies revealed that individuals' goal generation and recall exhibited significant clustering by goal type. Participants encountered some difficulties when explicitly coding goals. Findings support self-determination theory and indicate that individuals discriminate between intrinsic and extrinsic goals.

  5. Motor memory is encoded as a gain-field combination of intrinsic and extrinsic action representations.

    Science.gov (United States)

    Brayanov, Jordan B; Press, Daniel Z; Smith, Maurice A

    2012-10-24

    Actions can be planned in either an intrinsic (body-based) reference frame or an extrinsic (world-based) frame, and understanding how the internal representations associated with these frames contribute to the learning of motor actions is a key issue in motor control. We studied the internal representation of this learning in human subjects by analyzing generalization patterns across an array of different movement directions and workspaces after training a visuomotor rotation in a single movement direction in one workspace. This provided a dense sampling of the generalization function across intrinsic and extrinsic reference frames, which allowed us to dissociate intrinsic and extrinsic representations and determine the manner in which they contributed to the motor memory for a trained action. A first experiment showed that the generalization pattern reflected a memory that was intermediate between intrinsic and extrinsic representations. A second experiment showed that this intermediate representation could not arise from separate intrinsic and extrinsic learning. Instead, we find that the representation of learning is based on a gain-field combination of local representations in intrinsic and extrinsic coordinates. This gain-field representation generalizes between actions by effectively computing similarity based on the (Mahalanobis) distance across intrinsic and extrinsic coordinates and is in line with neural recordings showing mixed intrinsic-extrinsic representations in motor and parietal cortices.

  6. The Attitudes of Israeli Arab and Jewish High School Students towards Extrinsic and Intrinsic Values

    Science.gov (United States)

    Gross, Zehavit

    2013-01-01

    The aim of this research was to investigate the attitudes of Israeli Arab (n = 259) and Jewish (n = 259) high school students toward extrinsic and intrinsic values. A questionnaire, which consisted of eight value scales in two groups--extrinsic and intrinsic values--was administered. Participants were asked to state whether they agreed or…

  7. Intrinsic and Extrinsic Interlay Factors in Saudi Graduate Students' Perception of Performance and Success

    Science.gov (United States)

    Maguire, Richard K.; Corbin, Thomas Philip, Jr.

    2015-01-01

    The natural symbiotic relationship between intrinsic and extrinsic factors and how they contribute to student success is undeniable. A plethora of work including self-determination, attribution, and social cognitive theories speak about academic achievement by students having a reciprocity relationship between the extrinsic factors that underline…

  8. Intrinsic and Extrinsic Motivational Factors Related to Educators' Pursuit of Doctoral Degrees

    Science.gov (United States)

    George-Reid, Kimberly A.

    2016-01-01

    The purpose of this study was to identify intrinsic and extrinsic motivational factors for professional doctoral degree attainment among educators. The researcher examined the following intrinsic motivating factors: personal attainment, skill and ability enhancement, and goals. The researcher also included the following extrinsic factors:…

  9. Separation of extrinsic and intrinsic plasmon excitations in Ge KLL Auger spectra

    International Nuclear Information System (INIS)

    Berenyi, Z.; Aszalos-Kiss, B.; Csik, A.; Toth, J.; Koever, L.; Varga, D.

    2002-01-01

    The nature of the Ge satellite structure and the contributions from extrinsic and intrinsic processes were investigated using the ESA-31 electron spectrometer. These measurements are providing the first high energy resolution Ge KLL data. The intensity ratio of the plasmon peaks induced by intrinsic and extrinsic excitation processes is found. (R.P.)

  10. Intrinsic and Extrinsic Motivational Orientations in the Classroom: Age Differences and Academic Correlates

    Science.gov (United States)

    Lepper, Mark R.; Corpus, Jennifer Henderlong; Iyengar, Sheena S.

    2005-01-01

    Age differences in intrinsic and extrinsic motivation and the relationships of each to academic outcomes were examined in an ethnically diverse sample of 797 3rd-grade through 8th-grade children. Using independent measures, the authors found intrinsic and extrinsic motivation to be only moderately correlated, suggesting that they may be largely…

  11. Intrinsic and Extrinsic School Motivation as a Function of Age: The Mediating Role of Autonomy Support

    Science.gov (United States)

    Gillet, Nicolas; Vallerand, Robert J.; Lafreniere, Marc-Andre K.

    2012-01-01

    The main purpose of the present research was to investigate school intrinsic and extrinsic motivation, and amotivation as a function of age in a sample of 1,600 elementary and high school students aged 9-17 years. First, results revealed a systematic decrease in intrinsic motivation and self-determined extrinsic motivation from age 9 to 12 years,…

  12. Extrinsic Motivators Affecting Fourth-Grade Students' Interest and Enrollment in an Instrumental Music Program

    Science.gov (United States)

    Vasil, Martina

    2013-01-01

    The purpose of this study was to investigate fourth-grade students' extrinsic motivators for joining and continuing in a school instrumental music program. Three research questions were investigated: (a) What extrinsic motivators have influenced fourth-grade students' initial interest and continuing participation in an instrumental music program?…

  13. Efficacy test of a toothpaste in reducing extrinsic dental stain

    Science.gov (United States)

    Agustanti, A.; Ramadhani, S. A.; Adiatman, M.; Rahardjo, A.; Callea, M.; Yavuz, I.; Maharani, D. A.

    2017-08-01

    This clinical trial compared the external dental stain reduction achieved by tested toothpaste versus placebo in adult patients. In this double-blind, parallel, randomised clinical trial, 45 female volunteers with a mean age of 20 years old were included. All study subjects front teeth were topically applicated with Silver Diamine Fluoride (SDF) to create external dental stains. Subjects were randomized into test (n=22) and control (n=23) groups. Toothpastes were used for two days to analyse the effects of removing external stains on the labial surfaces of all anterior teeth. VITA Easyshade Advance 4.0 was used to measure dental extrinsic stains changes. The analysis showed statistically significant efficacy of the tested toothpaste in reducing external dental stain caused by SDF, comparing to the placebo toothpaste, after one and two days of usage. The tested toothpaste was effective in reducing dental stain.

  14. MATERIAL ELEMENT MODEL FOR EXTRINSIC SEMICONDUCTORS WITH DEFECTS OF DISLOCATION

    Directory of Open Access Journals (Sweden)

    Maria Paola Mazzeo

    2011-07-01

    Full Text Available In a previous paper we outlined a geometric model for the thermodynamic description of extrinsic semiconductors with defects of dislocation.Applying a geometrization technique, within the rationalextended irreversible thermodynamics with internal variables, the dynamical system for simple material elements of these media, the expressions of the entropy function and the entropy 1-form were obtained. In this contribution we deepen the study of this geometric model. We give a detailed description of the defective media under consideration and of the dislocation core tensor, we introduce the transformation induced by the process and, applying the closure conditions for the entropy 1-form, we derive the necessary conditions for the existence of the entropy function. These and other results are new in the paper.The derivation of the relevant entropy 1-form is the starting point to introduce an extended thermodynamical phase space.

  15. Measurement of spin pumping voltage separated from extrinsic microwave effects

    International Nuclear Information System (INIS)

    Iguchi, Ryo; Saitoh, Eiji

    2017-01-01

    Conversions between spin and charge currents are core technologies in recent spintronics. In this article, we provide methods for estimating inverse spin Hall effects (ISHEs) induced by using microwave-driven spin pumping (SP) as a spin-current generator. ISHE and SP induce an electromotive force at the ferromagnetic or spin-wave resonance, which offers a valuable electric method of studying spin physics in materials. At the resonance, a microwave for exciting the magnetization dynamics induces an additional electromotive force via rf-current rectification and thermoelectric effects. We discuss methods of separating the signals generated from such extrinsic microwave effects by controlling sample structures and configurations. These methods are helpful in performing accurate measurements on ISHE induced by SP, enabling quantitative studies on the conversion between spin and charge currents on various kinds of materials. (author)

  16. Scanning gate microscopy on graphene: charge inhomogeneity and extrinsic doping

    International Nuclear Information System (INIS)

    Jalilian, Romaneh; Tian Jifa; Chen, Yong P; Jauregui, Luis A; Lopez, Gabriel; Roecker, Caleb; Jovanovic, Igor; Yazdanpanah, Mehdi M; Cohn, Robert W

    2011-01-01

    We have performed scanning gate microscopy (SGM) on graphene field effect transistors (GFET) using a biased metallic nanowire coated with a dielectric layer as a contact mode tip and local top gate. Electrical transport through graphene at various back gate voltages is monitored as a function of tip voltage and tip position. Near the Dirac point, the response of graphene resistance to the tip voltage shows significant variation with tip position, and SGM imaging displays mesoscopic domains of electron-doped and hole-doped regions. Our measurements reveal substantial spatial fluctuation in the carrier density in graphene due to extrinsic local doping from sources such as metal contacts, graphene edges, structural defects and resist residues. Our scanning gate measurements also demonstrate graphene's excellent capability to sense the local electric field and charges.

  17. Extrinsic and intrinsic motivation at 30: Unresolved scientific issues.

    Science.gov (United States)

    Reiss, Steven

    2005-01-01

    The undermining effect of extrinsic reward on intrinsic motivation remains unproven. The key unresolved issues are construct invalidity (all four definitions are unproved and two are illogical); measurement unreliability (the free-choice measure requires unreliable, subjective judgments to infer intrinsic motivation); inadequate experimental controls (negative affect and novelty, not cognitive evaluation, may explain "undermining" effects); and biased metareviews (studies with possible floor effects excluded, but those with possible ceiling effects included). Perhaps the greatest error with the undermining theory, however, is that it does not adequately recognize the multifaceted nature of intrinsic motivation (Reiss, 2004a). Advice to limit the use of applied behavior analysis based on "hidden" undermining effects is ideologically inspired and is unsupported by credible scientific evidence.

  18. The string model with the extrinsic curvature term

    International Nuclear Information System (INIS)

    Itoi, C.; Kubota, Hiroshi

    1988-01-01

    The string model with the extrinsic curvature is studied which is a gauge invariant field theory with higher order derivatives. We present an equivalent action without any higher order derivatives which keeps the gauge invariance. We point out the difficulty caused by the second class constraints in Dirac's canonical method. Following a new method for dynamical systems with second class constraints, we construct a equivalent model which has no second class constraints but has a new gauge invariance. This gauge invariance guarantees the equivalence between the original model and new one. We show that the model can be quantized in this formalism. In a simple model, we show the nilpotence of the BRST charge under certain conditions, and discuss the unitarity of the theory. (author)

  19. Auditory word recognition: extrinsic and intrinsic effects of word frequency.

    Science.gov (United States)

    Connine, C M; Titone, D; Wang, J

    1993-01-01

    Two experiments investigated the influence of word frequency in a phoneme identification task. Speech voicing continua were constructed so that one endpoint was a high-frequency word and the other endpoint was a low-frequency word (e.g., best-pest). Experiment 1 demonstrated that ambiguous tokens were labeled such that a high-frequency word was formed (intrinsic frequency effect). Experiment 2 manipulated the frequency composition of the list (extrinsic frequency effect). A high-frequency list bias produced an exaggerated influence of frequency; a low-frequency list bias showed a reverse frequency effect. Reaction time effects were discussed in terms of activation and postaccess decision models of frequency coding. The results support a late use of frequency in auditory word recognition.

  20. Extrinsic factors affecting accuracy of ultrasonic flowmeters for LMFBRs

    International Nuclear Information System (INIS)

    Managan, W.W.

    1976-08-01

    Assuming that ultrasonic flowmeters of suitable intrinsic accuracy are feasible, this report explores factors extrinsic to the flowmeter which affect the accuracy such as asymmetric flow profile, regions of high turbulence and thermal stratification. By integrating isovelocity flow profile maps, the predicted performance of various flowmeter configurations may be compared to experimental data. For the two pipe arrangements analyzed, the single diametral path flowmeter results were within 5 percent of true flow rate. Theoretical correction factors could reduce the error for the straight pipe but increased the error for asymmetrical flow. On the same pipe arrangements a four path ultrasonic flowmeter spaced for Gaussian integration gave less than 1 percent error. For more general conclusions a range of flow profiles produced by typical LMFBR piping arrangements must be analyzed

  1. Proprioceptive bimanual test in intrinsic and extrinsic coordinates.

    Science.gov (United States)

    Iandolo, Riccardo; Squeri, Valentina; De Santis, Dalia; Giannoni, Psiche; Morasso, Pietro; Casadio, Maura

    2015-01-01

    Is there any difference between matching the position of the hands by asking the subjects to move them to the same spatial location or to mirror-symmetric locations with respect to the body midline? If the motion of the hands were planned in the extrinsic space, the mirror-symmetric task would imply an additional challenge, because we would need to flip the coordinates of the target on the other side of the workspace. Conversely, if the planning were done in intrinsic coordinates, in order to move both hands to the same spot in the workspace, we should compute different joint angles for each arm. Even if both representations were available to the subjects, the two tasks might lead to different results, providing some cue on the organization of the "body schema". In order to answer such questions, the middle fingertip of the non-dominant hand of a population of healthy subjects was passively moved by a manipulandum to 20 different target locations. Subjects matched these positions with the middle fingertip of their dominant hand. For most subjects, the matching accuracy was higher in the extrinsic modality both in terms of systematic error and variability, even for the target locations in which the configuration of the arms was the same for both modalities. This suggests that the matching performance of the subjects could be determined not only by proprioceptive information but also by the cognitive representation of the task: expressing the goal as reaching for the physical location of the hand in space is apparently more effective than requiring to match the proprioceptive representation of joint angles.

  2. Perceived extrinsic mortality risk and reported effort in looking after health: testing a behavioral ecological prediction.

    Science.gov (United States)

    Pepper, Gillian V; Nettle, Daniel

    2014-09-01

    Socioeconomic gradients in health behavior are pervasive and well documented. Yet, there is little consensus on their causes. Behavioral ecological theory predicts that, if people of lower socioeconomic position (SEP) perceive greater personal extrinsic mortality risk than those of higher SEP, they should disinvest in their future health. We surveyed North American adults for reported effort in looking after health, perceived extrinsic and intrinsic mortality risks, and measures of SEP. We examined the relationships between these variables and found that lower subjective SEP predicted lower reported health effort. Lower subjective SEP was also associated with higher perceived extrinsic mortality risk, which in turn predicted lower reported health effort. The effect of subjective SEP on reported health effort was completely mediated by perceived extrinsic mortality risk. Our findings indicate that perceived extrinsic mortality risk may be a key factor underlying SEP gradients in motivation to invest in future health.

  3. Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts

    Directory of Open Access Journals (Sweden)

    Wen-Hsiung Chan

    2008-05-01

    Full Text Available Caffeine consumption is a risk factor for osteoporosis, but the precise regulatory mechanisms are currently unknown. Here, we show that cell viability decreases in osteoblasts treated with caffeine in a dose-dependent manner. This cell death is attributed primarily to apoptosis and to a smaller extent, necrosis. Moreover, caffeine directly stimulates intracellular oxidative stress. Our data support caffeine-induced apoptosis in osteoblasts via a mitochondria-dependent pathway. The apoptotic biochemical changes were effectively prevented upon pretreatment with ROS scavengers, indicating that ROS plays a critical role as an upstream controller in the caffeine-induced apoptotic cascade. Additionally, p21-activated protein kinase 2 (PAK2 and c-Jun N-terminal kinase (JNK were activated in caffeine-treated osteoblasts. Experiments further found that PAK2 activity is required for caffeine-induced JNK activation and apoptosis. Importantly, our data also show that caffeine triggers cell death via inactivation of the survival signal, including the ERK- and Akt-mediated anti-apoptotic pathways. Finally, exposure of rats to dietary water containing 10~20 μM caffeine led to bone mineral density loss. These results demonstrate for the first time that caffeine triggers apoptosis in osteoblasts via activation of mitochondria-dependent cell death signaling and inactivation of the survival signal, and causes bone mineral density loss in vivo.

  4. Stochasticity in the yeast mating pathway

    International Nuclear Information System (INIS)

    Hong-Li, Wang; Zheng-Ping, Fu; Xin-Hang, Xu; Qi, Ouyang

    2009-01-01

    We report stochastic simulations of the yeast mating signal transduction pathway. The effects of intrinsic and external noise, the influence of cell-to-cell difference in the pathway capacity, and noise propagation in the pathway have been examined. The stochastic temporal behaviour of the pathway is found to be robust to the influence of inherent fluctuations, and intrinsic noise propagates in the pathway in a uniform pattern when the yeasts are treated with pheromones of different stimulus strengths and of varied fluctuations. In agreement with recent experimental findings, extrinsic noise is found to play a more prominent role than intrinsic noise in the variability of proteins. The occurrence frequency for the reactions in the pathway are also examined and a more compact network is obtained by dropping most of the reactions of least occurrence

  5. Effect of extrinsic factors on the production of guaiacol by Alicyclobacillus spp.

    Science.gov (United States)

    Chang, Susen; Park, Sang-Hyun; Kang, Dong-Hyun

    2015-04-01

    Alicyclobacillus spp. is of significance to the fruit juice industry due to the production of guaiacol. Studies on Alicyclobacillus regarding guaiacol focus mainly on novel ways to detect guaiacol or evaluate guaiacol-producing potential of isolated Alicyclobacillus. Basic studies on factors that induce or affect the production of guaiacol and the conversion pathway of vanillic acid to guaiacol are not available. The goal of this study was to evaluate how extrinsic factors can affect the production of guaiacol by Alicyclobacillu s isolates. Guaiacol-producing Alicyclobacillus isolates 1016 and 1101 were used in this study and the effects of temperature (25 to 55 °C), pH (3.0 to 5.5), and oxygen concentration on guaiacol production in laboratory media was investigated. Maximum production of guaiacol by isolate 1016 was detected within 9 h when incubated at 43 °C, pH 4.0, under microaerophilic conditions. Isolate 1101 produced detectable amounts of guaiacol within 8 h at pH 5.0. However, maximum guaiacol production was achieved within 14 h by isolate 1101 when incubated at 50 °C. Our results indicate that the production of guaiacol, contrary to common belief, is a rapid reaction under desirable conditions specific to each isolate. The results of this study can be useful for developing rapid guaiacol monitoring methods for Alicyclobacillus-related spoilage or be applied to more detailed enzyme-related studies.

  6. The role of baculovirus apoptotic suppressors in AcMNPV-mediated translation arrest in Ld652Y cells

    International Nuclear Information System (INIS)

    Thiem, Suzanne M.; Chejanovsky, Nor

    2004-01-01

    Infecting the insect cell line IPLB-Ld652Y with the baculovirus Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) results in global translation arrest, which correlates with the presence of the AcMNPV apoptotic suppressor, p35. In this study, we investigated the role of apoptotic suppression on AcMNPV-induced translation arrest. Infecting cells with AcMNPV bearing nonfunctional mutant p35 did not result in global translation arrest. In contrast, global translation arrest was observed in cells infected with AcMNPV in which p35 was replaced with Opiap, Cpiap, or p49, baculovirus apoptotic suppressors that block apoptosis by different mechanisms than p35. These results indicated that suppressing apoptosis triggered translation arrest in AcMNPV-infected Ld652Y cells. Experiments using the DNA synthesis inhibitor aphidicolin and temperature shift experiments, using the AcMNPV replication mutants ts8 and ts8Δp35, indicated that translation arrest initiated during the early phase of infection, but events during the late phase were required for global translation arrest. Peptide caspase inhibitors could not substitute for baculovirus apoptotic suppressors to induce translation arrest in Ld652Y cells infected with a p35-null virus. However, if the p35-null-AcMNPV also carried hrf-1, a novel baculovirus host range gene, progeny virus was produced and treatment with peptide caspase inhibitors enhanced translation of a late viral gene transcript. Together, these results indicate that translation arrest in AcMNPV-infected Ld652Y cells is due to the anti-apoptotic function of p35, but suggests that rather than simply preventing caspase activation, its activity enhances signaling to a separate translation arrest pathway, possibly by stimulating the late stages of the baculovirus infection cycle

  7. Correlated cone noise decreases rod signal contributions to the post-receptoral pathways.

    Science.gov (United States)

    Hathibelagal, Amithavikram R; Feigl, Beatrix; Zele, Andrew J

    2018-04-01

    This study investigated how invisible extrinsic temporal white noise that correlates with the activity of one of the three [magnocellular (MC), parvocellular (PC), or koniocellular (KC)] post-receptoral pathways alters mesopic rod signaling. A four-primary photostimulator provided independent control of the rod and three cone photoreceptor excitations. The rod contributions to the three post-receptoral pathways were estimated by perceptually matching a 20% contrast rod pulse by independently varying the LMS (MC pathway), +L-M (PC pathway), and S-cone (KC pathway) excitations. We show that extrinsic cone noise caused a predominant decrease in the overall magnitude and ratio of the rod contributions to each pathway. Thus, the relative cone activity in the post-receptoral pathways determines the relative mesopic rod inputs to each pathway.

  8. Macrophages discriminate glycosylation patterns of apoptotic cell-derived microparticles.

    Science.gov (United States)

    Bilyy, Rostyslav O; Shkandina, Tanya; Tomin, Andriy; Muñoz, Luis E; Franz, Sandra; Antonyuk, Volodymyr; Kit, Yuriy Ya; Zirngibl, Matthias; Fürnrohr, Barbara G; Janko, Christina; Lauber, Kirsten; Schiller, Martin; Schett, Georg; Stoika, Rostyslav S; Herrmann, Martin

    2012-01-02

    Inappropriate clearance of apoptotic remnants is considered to be the primary cause of systemic autoimmune diseases, like systemic lupus erythematosus. Here we demonstrate that apoptotic cells release distinct types of subcellular membranous particles (scMP) derived from the endoplasmic reticulum (ER) or the plasma membrane. Both types of scMP exhibit desialylated glycotopes resulting from surface exposure of immature ER-derived glycoproteins or from surface-borne sialidase activity, respectively. Sialidase activity is activated by caspase-dependent mechanisms during apoptosis. Cleavage of sialidase Neu1 by caspase 3 was shown to be directly involved in apoptosis-related increase of surface sialidase activity. ER-derived blebs possess immature mannosidic glycoepitopes and are prioritized by macrophages during clearance. Plasma membrane-derived blebs contain nuclear chromatin (DNA and histones) but not components of the nuclear envelope. Existence of two immunologically distinct types of apoptotic blebs may provide new insights into clearance-related diseases.

  9. Nitric oxide and calcium ions in apoptotic esophageal carcinoma cells induced by arsenite

    Science.gov (United States)

    Shen, Zhong-Ying; Shen, Wen-Ying; Chen, Ming-Hua; Shen, Jian; Cai, Wei-Jie; Yi, Zeng

    2002-01-01

    AIM: To Quantitatively analyze the nitri oxide (NO) and Ca2+ in apoptosis of esophageal carcinoma cells induced by arsenic trioxide (As2O3). METHODS: The cell line SHEEC1, a malignant esophageal epithelial cell induced by HPV in synergy with TPA in our laboratory, was cultured in a serum-free medium and treated with As2O3. Before and after administration of As2O3, NO production in cultured medium was detected quantitatively using the Griess Colorimetric method. Intracellular Ca2+ was labeled by using the fluorescent dye Fluo3-AM and detected under confocal laser scanning microscope (CLSM), which was able to acquire data in real-time enabling Ca2+ dynamics of individual cells in vitro. The apoptotic cells were examined under electron microscopy. RESULTS: Intracellular concentration of Ca2+ increased from 1.00 units to 1.09-1.38 units of fluorescent intensity at As2O3 treatment and NO products subsequently released from As2O3-treated cells increased from 0.98-1.00 × 10-2 μmol·L-1 up to 1.48-1.52 × 10-2 μmol·L-1 and maintained in a high level continuously. Finally apoptosis of cells occurred, chromatin being agglutinated, cells shrunk, nuclei became round and mitochondria swelled. CONCLUSION: Ca2+ and NO increased with cell damage and apoptosis in cells treated by As2O3. The Ca2+ is an initial messenger to the apoptotic pathway. To investigate Ca2+ and NO will be a new direction for studying the apoptotic signaling messenger of the esophageal carcinoma cells induced by As2O3. PMID:11833068

  10. Extrinsic Repair of Injured Dendrites as a Paradigm for Regeneration by Fusion in Caenorhabditis elegans

    Science.gov (United States)

    Oren-Suissa, Meital; Gattegno, Tamar; Kravtsov, Veronika; Podbilewicz, Benjamin

    2017-01-01

    Injury triggers regeneration of axons and dendrites. Research has identified factors required for axonal regeneration outside the CNS, but little is known about regeneration triggered by dendrotomy. Here, we study neuronal plasticity triggered by dendrotomy and determine the fate of complex PVD arbors following laser surgery of dendrites. We find that severed primary dendrites grow toward each other and reconnect via branch fusion. Simultaneously, terminal branches lose self-avoidance and grow toward each other, meeting and fusing at the tips via an AFF-1-mediated process. Ectopic branch growth is identified as a step in the regeneration process required for bypassing the lesion site. Failure of reconnection to the severed dendrites results in degeneration of the distal end of the neuron. We discover pruning of excess branches via EFF-1 that acts to recover the original wild-type arborization pattern in a late stage of the process. In contrast, AFF-1 activity during dendritic auto-fusion is derived from the lateral seam cells and not autonomously from the PVD neuron. We propose a model in which AFF-1-vesicles derived from the epidermal seam cells fuse neuronal dendrites. Thus, EFF-1 and AFF-1 fusion proteins emerge as new players in neuronal arborization and maintenance of arbor connectivity following injury in Caenorhabditis elegans. Our results demonstrate that there is a genetically determined multi-step pathway to repair broken dendrites in which EFF-1 and AFF-1 act on different steps of the pathway. EFF-1 is essential for dendritic pruning after injury and extrinsic AFF-1 mediates dendrite fusion to bypass injuries. PMID:28283540

  11. Chronic MDMA induces neurochemical changes in the hippocampus of adolescent and young adult rats: Down-regulation of apoptotic markers.

    Science.gov (United States)

    García-Cabrerizo, Rubén; García-Fuster, M Julia

    2015-07-01

    While hippocampus is a brain region particularly susceptible to the effects of MDMA, the cellular and molecular changes induced by MDMA are still to be fully elucidated, being the dosage regimen, the species and the developmental stage under study great variables. This study compared the effects of one and four days of MDMA administration following a binge paradigm (3×5 mg/kg, i.p., every 2 h) on inducing hippocampal neurochemical changes in adolescent (PND 37) and young adult (PND 58) rats. The results showed that chronic MDMA caused hippocampal protein deficits in adolescent and young adult rats at different levels: (1) impaired serotonergic (5-HT2A and 5-HT2C post-synaptic receptors) and GABAergic (GAD2 enzyme) signaling, and (2) decreased structural cytoskeletal neurofilament proteins (NF-H, NF-M and NF-L). Interestingly, these effects were not accompanied by an increase in apoptotic markers. In fact, chronic MDMA inhibited proteins of the apoptotic pathway (i.e., pro-apoptotic FADD, Bax and cytochrome c) leading to an inhibition of cell death markers (i.e., p-JNK1/2, cleavage of PARP-1) and suggesting regulatory mechanisms in response to the neurochemical changes caused by the drug. The data, together with the observed lack of GFAP activation, support the view that chronic MDMA effects, regardless of the rat developmental age, extends beyond neurotransmitter systems to impair other hippocampal structural cell markers. Interestingly, inhibitory changes in proteins from the apoptotic pathway might be taking place to overcome the protein deficits caused by MDMA. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Nickel oxide nanoparticles exert cytotoxicity via oxidative stress and induce apoptotic response in human liver cells (HepG2).

    Science.gov (United States)

    Ahamed, Maqusood; Ali, Daoud; Alhadlaq, Hisham A; Akhtar, Mohd Javed

    2013-11-01

    Increasing use of nickel oxide nanoparticles (NiO NPs) necessitates an improved understanding of their potential impact on human health. Previously, toxic effects of NiO NPs have been investigated, mainly on airway cells. However, information on effect of NiO NPs on human liver cells is largely lacking. In this study, we investigated the reactive oxygen species (ROS) mediated cytotoxicity and induction of apoptotic response in human liver cells (HepG2) due to NiO NPs exposure. Prepared NiO NPs were crystalline and spherical shaped with an average diameter of 44 nm. NiO NPs induced cytotoxicity (cell death) and ROS generation in HepG2 cells in dose-dependent manner. Further, ROS scavenger vitamin C reduced cell death drastically caused by NiO NPs exposure indicating that oxidative stress plays an important role in NiO NPs toxicity. Micronuclei induction, chromatin condensation and DNA damage in HepG2 cells treated with NiO NPs suggest that NiO NPs induced cell death via apoptotic pathway. Quantitative real-time PCR analysis showed that following the exposure of HepG2 cells to NiO NPs, the expression level of mRNA of apoptotic genes (bax and caspase-3) were up-regulated whereas the expression level of anti-apoptotic gene bcl-2 was down-regulated. Moreover, activity of caspase-3 enzyme was also higher in NiO NPs treated cells. To the best of our knowledge this is the first report demonstrating that NiO NPs caused cytotoxicity via ROS and induced apoptosis in HepG2 cells, which is likely to be mediated through bax/bcl-2 pathway. This work warrants careful assessment of Ni NPs before their commercial and industrial applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability.

    Science.gov (United States)

    Frielink, N; Schuengel, C; Embregts, P

    2017-07-01

    According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and integrated motivation. Although it has been argued theoretically that the different types of motivation are universally applicable, Reid et al. () proposed a dichotomy of broad subtypes of extrinsic motivation for people with intellectual disability (ID) due to their cognitive limitations. The current study challenges this proposal by testing whether the four subtypes of extrinsic motivation can be differentiated among people with ID as well. The subtypes of extrinsic motivation were measured using two adapted versions of the Self-Regulation Questionnaire, one regarding exercise and one regarding support. In total, 186 adults with mild to borderline ID participated in the study. Results supported the distinction between the four subtypes of extrinsic motivation regarding both exercise and support. In addition, the correlation coefficients supported a quasi-simplex pattern of correlations among the subtypes, indicating that adjacent subtypes were more closely related than non-adjacent subtypes. Moreover, the study showed sufficient Cronbach's alphas and test-retest reliabilities for early stage research. Overall, the results of the current study provide initial evidence for the universality of the four subtypes of extrinsic motivation across populations with and without ID. © 2017 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disibilities and John Wiley & Sons Ltd.

  14. Intrinsic and extrinsic motivation among adolescent ten-pin bowlers in kuala lumpur, malaysia.

    Science.gov (United States)

    Teo, Eng-Wah; Khoo, Selina; Wong, Rebecca; Wee, Eng-Hoe; Lim, Boon-Hooi; Rengasamy, Shabesan Sit

    2015-03-29

    Motivation has long been associated with sports engagement. However, to date no research has been performed to understand the domain of motivation among ten-pin bowlers. The purpose of this study was to investigate different types of motivation (i.e., intrinsic vs. extrinsic) based on self-determination theory from the perspective of gender and the bowler type (competitive vs. casual). A total of 240 bowlers (104 male, 136 female; 152 competitive, 88 casual) with a mean age of 16.61 ± 0.78 years were recruited in Kuala Lumpur. The Sport Motivation Scale, a 28-item self-report questionnaire measuring seven subscales (i.e., intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, extrinsic motivation to identify regulation, extrinsic motivation for introjection regulation, extrinsic motivation to external regulation, and amotivation) was administered. Results showed significant differences (t=10.43, df=239, p=0.01) between total scores of intrinsic and extrinsic motivation among ten-pin bowlers. There were significant gender differences with respect to intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, and extrinsic motivation to identify regulation. However, no significant bowler type differences were found for either the intrinsic (t=-1.15, df=238, p=0.25) or extrinsic (t=-0.51, df=238, p=0.61) motivation dimensions. In conclusion, our study demonstrated substantial intrinsic motivation for gender effects, but no bowler type effects among adolescent ten-pin bowlers.

  15. Copper absorption from foods labelled intrinsically and extrinsically with Cu-65 stable isotope.

    Science.gov (United States)

    Harvey, L J; Dainty, J R; Beattie, J H; Majsak-Newman, G; Wharf, S G; Reid, M D; Fairweather-Tait, S J

    2005-03-01

    To determine copper absorption from copper containing foods labelled either intrinsically or extrinsically with a highly enriched Cu-65 stable isotope label. A longitudinal cross-over study. The study was conducted at the Institute of Food Research, Human Nutrition Unit, Norwich, UK. Subjects were recruited locally via advertisements placed around the Norwich Research Park. A total of 10 volunteers (nine female, one male) took part in the study, but not all volunteers completed each of the test meals. A highly enriched Cu-65 stable isotope label was administered to volunteers in the form of a reference dose or in breakfast test meals consisting of red wine, soya beans, mushrooms or sunflower seeds. Faecal monitoring and mass spectrometry techniques were used to estimate the relative quantities of copper absorbed from the different test meals. True copper absorption from the reference dose (54%) was similar to extrinsically labelled red wine (49%) and intrinsically labelled sunflower seeds (52%), but significantly higher than extrinsically labelled mushrooms (35%), intrinsically (29%) and extrinsically (15%) labelled soya beans and extrinsically labelled sunflower seed (32%) test meals. The use of Cu-65 extrinsic labels in copper absorption studies requires validation according to the food being examined; intrinsic and extrinsic labelling produced significantly different results for sunflower seeds.

  16. Bridging the gap between extrinsic and intrinsic motivation in the cognitive remediation of schizophrenia.

    Science.gov (United States)

    Silverstein, Steven M

    2010-09-01

    An important development in cognitive remediation of schizophrenia is a focus on motivation. However, following a distinction between the concepts of intrinsic motivation (IM) and extrinsic motivation, discussions of IM-based methods have downplayed or misrepresented the role that extrinsic rewards can, and actually do, serve to promote positive treatment outcomes in cognitive remediation. Therefore, the purpose of this article is to explore the rationale for using techniques incorporating extrinsic rewards into cognitive treatment of people with schizophrenia. To do this, evidence is presented on each of the following points: (1) there is a long history of research demonstrating that delivery of extrinsic reward is associated with positive outcomes in both behavioral and cognitive rehabilitation; (2) basic human brain systems respond strongly to tangible rewards, and this can directly enhance attention, working memory, and other cognitive functions; (3) nearly all data on the negative effects of extrinsic reward on IM have come from studies of healthy children and adults in school or work settings who have adequate IM for target tasks; these findings do not generalize well to cognitive remediation settings for people with schizophrenia, who often have abnormally low levels of IM and low base rates of attentive behaviors; and (4) in real-world situations, cognitive remediation interventions already utilize a combination of intrinsic and extrinsic reinforcers. Future studies are needed to clarify state and trait factors responsible for individual differences in the extent to which extrinsic rewards are necessary to set the conditions under which IM can develop.

  17. Intrinsic and Extrinsic Motivation Among Adolescent Ten-Pin Bowlers in Kuala Lumpur, Malaysia

    Directory of Open Access Journals (Sweden)

    Teo Eng-Wah

    2015-03-01

    Full Text Available Motivation has long been associated with sports engagement. However, to date no research has been performed to understand the domain of motivation among ten-pin bowlers. The purpose of this study was to investigate different types of motivation (i.e., intrinsic vs. extrinsic based on self-determination theory from the perspective of gender and the bowler type (competitive vs. casual. A total of 240 bowlers (104 male, 136 female; 152 competitive, 88 casual with a mean age of 16.61 ± 0.78 years were recruited in Kuala Lumpur. The Sport Motivation Scale, a 28-item self-report questionnaire measuring seven subscales (i.e., intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, extrinsic motivation to identify regulation, extrinsic motivation for introjection regulation, extrinsic motivation to external regulation, and amotivation was administered. Results showed significant differences (t=10.43, df=239, p=0.01 between total scores of intrinsic and extrinsic motivation among tenpin bowlers. There were significant gender differences with respect to intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, and extrinsic motivation to identify regulation. However, no significant bowler type differences were found for either the intrinsic (t=-1.15, df=238, p=0.25 or extrinsic (t=-0.51, df=238, p=0.61 motivation dimensions. In conclusion, our study demonstrated substantial intrinsic motivation for gender effects, but no bowler type effects among adolescent ten-pin bowlers.

  18. Impact of Antioxidants on Cardiolipin Oxidation in Liposomes: Why Mitochondrial Cardiolipin Serves as an Apoptotic Signal?

    Science.gov (United States)

    Lokhmatikov, Alexey V.; Voskoboynikova, Natalia; Cherepanov, Dmitry A.; Skulachev, Maxim V.; Steinhoff, Heinz-Jürgen; Skulachev, Vladimir P.; Mulkidjanian, Armen Y.

    2016-01-01

    Molecules of mitochondrial cardiolipin (CL) get selectively oxidized upon oxidative stress, which triggers the intrinsic apoptotic pathway. In a chemical model most closely resembling the mitochondrial membrane—liposomes of pure bovine heart CL—we compared ubiquinol-10, ubiquinol-6, and alpha-tocopherol, the most widespread naturally occurring antioxidants, with man-made, quinol-based amphiphilic antioxidants. Lipid peroxidation was induced by addition of an azo initiator in the absence and presence of diverse antioxidants, respectively. The kinetics of CL oxidation was monitored via formation of conjugated dienes at 234 nm. We found that natural ubiquinols and ubiquinol-based amphiphilic antioxidants were equally efficient in protecting CL liposomes from peroxidation; the chromanol-based antioxidants, including alpha-tocopherol, were 2-3 times less efficient. Amphiphilic antioxidants, but not natural ubiquinols and alpha-tocopherol, were able, additionally, to protect the CL bilayer from oxidation by acting from the water phase. We suggest that the previously reported therapeutic efficiency of mitochondrially targeted amphiphilic antioxidants is owing to their ability to protect those CL molecules that are inaccessible to natural hydrophobic antioxidants, being trapped within respiratory supercomplexes. The high susceptibility of such occluded CL molecules to oxidation may have prompted their recruitment as apoptotic signaling molecules by nature. PMID:27313834

  19. Manganese induces mitochondrial dynamics impairment and apoptotic cell death: a study in human Gli36 cells.

    Science.gov (United States)

    Alaimo, Agustina; Gorojod, Roxana M; Miglietta, Esteban A; Villarreal, Alejandro; Ramos, Alberto J; Kotler, Mónica L

    2013-10-25

    Manganese (Mn) is an essential trace element due to its participation in many physiological processes. However, overexposure to this metal leads to a neurological disorder known as Manganism whose clinical manifestations and molecular mechanisms resemble Parkinson's disease. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity being the mitochondria the most affected organelles. The aim of this study was to investigate the possible mitochondrial dynamics alterations in Mn-exposed human astrocytes. Therefore, we employed Gli36 cells which express the astrocytic markers GFAP and S100B. We demonstrated that Mn triggers the mitochondrial apoptotic pathway revealed by increased Bax/Bcl-2 ratio, by the loss of mitochondrial membrane potential and by caspase-9 activation. This apoptotic program may be in turn responsible of caspase-3/7 activation, PARP-1 cleavage, chromatin condensation and fragmentation. In addition, we determined that Mn induces deregulation in mitochondria-shaping proteins (Opa-1, Mfn-2 and Drp-1) expression levels in parallel with the disruption of the mitochondrial network toward to an exacerbated fragmentation. Since mitochondrial dynamics is altered in several neurodegenerative diseases, these proteins could become future targets to be considered in Manganism treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma

    International Nuclear Information System (INIS)

    Del Vecchio, Silvana; Zannetti, Antonella; Aloj, Luigi; Caraco, Corradina; Ciarmiello, Andrea; Salvatore, Marco

    2003-01-01

    Lack of technetium-99m methoxyisobutylisonitrile ( 99m Tc-MIBI) uptake is consistently reported to predict poor response to subsequent chemotherapy in a variety of human malignant tumours. Since 99m Tc-MIBI accumulates within mitochondria, which also play a central role in apoptosis through the integration of death signals by Bcl-2 family members, we tested whether early 99m Tc-MIBI uptake is affected by alterations of the apoptotic pathway. Forty-two breast cancer patients were intravenously injected with 740 MBq of 99m Tc-MIBI and planar images were obtained 10 min post injection with the patients in the prone lateral position. Ten carcinomas failed to accumulate 99m Tc-MIBI and could not be visualised on scintigraphic images despite being larger than 1.8 cm (MIBI negative). Thirty-two of the 42 breast carcinomas showed focal uptake of 99m Tc-MIBI (MIBI positive), and 10 min tumour-to-background ratios (T/B) varied between 1.14 and 6.93. The apoptotic index, the rate of proliferation, and the expression of the anti-apoptotic Bcl-2 protein and pro-apoptotic Bax protein were assessed in surgically excised tumours. All MIBI-negative carcinomas showed a dramatic and statistically significant reduction in the apoptotic index as compared with MIBI-positive lesions (mean±SD, 0.14±0.15 vs 1.28±0.83, P 99m Tc-MIBI in breast carcinomas is affected by alterations of apoptotic pathway. High levels of Bcl-2, despite the stabilisation of mitochondrial membrane potentials, prevent accumulation of 99m Tc-MIBI in tumour cells. In conclusion, absent or reduced early 99m Tc-MIBI uptake in large tumours may indicate a Bcl-2-mediated resistance to chemo- and radiotherapy. (orig.)

  1. Intrinsic and extrinsic motivational orientations in the competitive context: an examination of person-situation interactions.

    Science.gov (United States)

    Abuhamdeh, Sami; Csikszentmihalyi, Mihaly

    2009-10-01

    The current study examined Intrinsic Motivation Orientation and Extrinsic Motivation Orientation (Work Preference Inventory; Amabile, Hill, Hennessey, & Tighe, 1994) as potential trait-level moderators of the way Internet chess players responded to the intrinsic and extrinsic rewards of the chess games they played. On the basis of the defining characteristics of these 2 types of motivational orientations, we predicted that (a) Intrinsic Motivation Orientation would be associated with a stronger curvilinear relationship between challenge and enjoyment and (b) Extrinsic Motivation Orientation would be associated with a heightened affective responsivity to competitive outcome (i.e., winning vs. losing). Results supported the predictions. Implications of the findings are discussed.

  2. Different apoptotic responses to Plasmodium chabaudi malaria in ...

    African Journals Online (AJOL)

    hope&shola

    2010-11-08

    Nov 8, 2010 ... The purpose of this study is to determine whether the apoptotic responses to Plasmodium chabaudi malaria in spleen and liver via mRNA expression of three genes involved in apoptosis (Bax, Bcl-2 and. Caspase-3) are similar or not and to detect if these genes could be a good marker for apoptosis due to.

  3. Growth inhibitory, apoptotic and anti-inflammatory activities ...

    Indian Academy of Sciences (India)

    naturally abundant oleanolic acid, displayed diverse biolog- ical activities ... triterpenoids and natural products. CDDO and its .... ration was determined by treating with anti-BrdU antibody and Texas red ..... apoptotic and necrotic in the tumour tissue. Thus .... Palmer RM, Ashton DS and Moncada S 1988 Vascular endothelial.

  4. Abnormalities in Alternative Splicing of Apoptotic Genes and Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Zodwa Dlamini

    2015-11-01

    Full Text Available Apoptosis is required for normal heart development in the embryo, but has also been shown to be an important factor in the occurrence of heart disease. Alternative splicing of apoptotic genes is currently emerging as a diagnostic and therapeutic target for heart disease. This review addresses the involvement of abnormalities in alternative splicing of apoptotic genes in cardiac disorders including cardiomyopathy, myocardial ischemia and heart failure. Many pro-apoptotic members of the Bcl-2 family have alternatively spliced isoforms that lack important active domains. These isoforms can play a negative regulatory role by binding to and inhibiting the pro-apoptotic forms. Alternative splicing is observed to be increased in various cardiovascular diseases with the level of alternate transcripts increasing elevated in diseased hearts compared to healthy subjects. In many cases these isoforms appear to be the underlying cause of the disease, while in others they may be induced in response to cardiovascular pathologies. Regardless of this, the detection of alternate splicing events in the heart can serve as useful diagnostic or prognostic tools, while those splicing events that seem to play a causative role in cardiovascular disease make attractive future drug targets.

  5. Detection of apoptotic cells using propidium iodide staining

    NARCIS (Netherlands)

    Newbold, Andrea; Martin, Ben P.; Cullinane, Carleen; Bots, Michael

    2014-01-01

    Flow cytometry assays are often used to detect apoptotic cells in in vitro cultures. Depending on the experimental model, these assays can also be useful in evaluating apoptosis in vivo. In this protocol, we describe a propidium iodide (PI) flow cytometry assay to evaluate B-cell lymphomas that have

  6. Effect of Transient Maternal Hypotension on Apoptotic Cell Death in Foetal Rat Brain

    Directory of Open Access Journals (Sweden)

    Hamit Özyürek

    2014-03-01

    Full Text Available Background: Intrauterine perfusion insufficiency induced by transient maternal hypotension has been reported to be associated with foetal brain malformations. However, the effects of maternal hypotension on apoptotic processes in the foetal brain have not been investigated experimentally during the intrauterine period. Aims: The aim of this study was to investigate the effects of transient maternal hypotension on apoptotic cell death in the intrauterine foetal brain. Study Design: Animal experimentation. Methods: Three-month-old female Wistar albino rats were allocated into four groups (n=5 each. The impact of hypoxic/ischemic injury induced by transient maternal hypotension on the 15th day of pregnancy (late gestation in rats was investigated at 48 (H17 group or 96 hours (H19 group after the insult. Control groups underwent the same procedure except for induction of hypotension (C17 and H17 groups. Brain sections of one randomly selected foetus from each pregnant rat were histopathologically evaluated for hypoxic/ischemic injury in the metencephalon, diencephalon, and telencephalon by terminal transferase-mediated dUTP nick end labelling and active cysteine-dependent aspartate-directed protease-3 (caspase-3 positivity for cell death. Results: The number of terminal transferase-mediated dUTP nick end labelling (+ cells in all the areas examined was comparable in both hypotension and control groups. The H17 group had active caspase-3 (+ cells in the metencephalon and telencephalon, sparing diencephalon, whereas the C19 and H19 groups had active caspase-3 (+ cells in all three regions. The number of active caspase-3 (+ cells in the telencephalon in the H19 group was higher compared with the metencephalon and diencephalon and compared with H17 group (p<0.05. Conclusion: Our results suggest that prenatal hypoxic/ischemic injury triggers apoptotic mechanisms. Therefore, blockade of apoptotic pathways, considering the time pattern of the insult, may

  7. Reconstitution of the anti-apoptotic Bcl-2 protein into lipid membranes and biophysical evidence for its detergent-driven association with the pro-apoptotic Bax protein.

    Directory of Open Access Journals (Sweden)

    Marcus Wallgren

    Full Text Available The anti-apoptotic B-cell CLL/lymphoma-2 (Bcl-2 protein and its counterpart, the pro-apoptotic Bcl-2-associated X protein (Bax, are key players in the regulation of the mitochondrial pathway of apoptosis. However, how they interact at the mitochondrial outer membrane (MOM and there determine whether the cell will live or be sentenced to death remains unknown. Competing models have been presented that describe how Bcl-2 inhibits the cell-killing activity of Bax, which is common in treatment-resistant tumors where Bcl-2 is overexpressed. Some studies suggest that Bcl-2 binds directly to and sequesters Bax, while others suggest an indirect process whereby Bcl-2 blocks BH3-only proteins and prevents them from activating Bax. Here we present the results of a biophysical study in which we investigated the putative interaction of solubilized full-length human Bcl-2 with Bax and the scope for incorporating the former into a native-like lipid environment. Far-UV circular dichroism (CD spectroscopy was used to detect direct Bcl-2-Bax-interactions in the presence of polyoxyethylene-(23-lauryl-ether (Brij-35 detergent at a level below its critical micelle concentration (CMC. Additional surface plasmon resonance (SPR measurements confirmed this observation and revealed a high affinity between the Bax and Bcl-2 proteins. Upon formation of this protein-protein complex, Bax also prevented the binding of antimycin A2 (a known inhibitory ligand of Bcl-2 to the Bcl-2 protein, as fluorescence spectroscopy experiments showed. In addition, Bcl-2 was able to form mixed micelles with Triton X-100 solubilized neutral phospholipids in the presence of high concentrations of Brij-35 (above its CMC. Following detergent removal, the integral membrane protein was found to have been fully reconstituted into a native-like membrane environment, as confirmed by ultracentrifugation and subsequent SDS-PAGE experiments.

  8. Intrinsic and extrinsic rewards in a nonformal environmental education program.

    Science.gov (United States)

    Price, Emily A; Vining, Joanne; Saunders, Carol D

    2009-09-01

    Humans are surrounded by threats to the environment, many of their own making. The severity of environmental problems will not decrease unless action is taken to develop and encourage greater environmentally responsible behavior (ERB) in the general populace. Environmental education (EE) is one method for strengthening precursors to ERB such as knowledge and attitudes, but research on the connection is currently unclear. In this paper we present the results of a study investigating the role played by rewards in encouraging ERB precursors for adults and children involved in a zoo-based Nature Swap program. We used semistructured interviews to question 91 participants, including 38 children, 38 adult guardians, and 15 staff members regarding the importance of rewards in the program. We content analyzed the interviews to identify and describe major themes and then coded them. We found that adult guardians and Play Partners perceived intrinsic and extrinsic rewards as aiding in maintaining motivation and interest in the nonformal Nature Swap program. In addition, both children and adult companion participants in the program mentioned strengthened precursors to ERB. Overall we found that adult companions perceived that children who participated in the program spent more quality time outdoors and had a heightened awareness of their surroundings as a result of program-based rewards. Implications for other EE and conservation education programs are discussed.

  9. Enabling complex genetic circuits to respond to extrinsic environmental signals.

    Science.gov (United States)

    Hoynes-O'Connor, Allison; Shopera, Tatenda; Hinman, Kristina; Creamer, John Philip; Moon, Tae Seok

    2017-07-01

    Genetic circuits have the potential to improve a broad range of metabolic engineering processes and address a variety of medical and environmental challenges. However, in order to engineer genetic circuits that can meet the needs of these real-world applications, genetic sensors that respond to relevant extrinsic and intrinsic signals must be implemented in complex genetic circuits. In this work, we construct the first AND and NAND gates that respond to temperature and pH, two signals that have relevance in a variety of real-world applications. A previously identified pH-responsive promoter and a temperature-responsive promoter were extracted from the E. coli genome, characterized, and modified to suit the needs of the genetic circuits. These promoters were combined with components of the type III secretion system in Salmonella typhimurium and used to construct a set of AND gates with up to 23-fold change. Next, an antisense RNA was integrated into the circuit architecture to invert the logic of the AND gate and generate a set of NAND gates with up to 1168-fold change. These circuits provide the first demonstration of complex pH- and temperature-responsive genetic circuits, and lay the groundwork for the use of similar circuits in real-world applications. Biotechnol. Bioeng. 2017;114: 1626-1631. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  10. Rethinking the extrinsic incubation period of malaria parasites.

    Science.gov (United States)

    Ohm, Johanna R; Baldini, Francesco; Barreaux, Priscille; Lefevre, Thierry; Lynch, Penelope A; Suh, Eunho; Whitehead, Shelley A; Thomas, Matthew B

    2018-03-12

    The time it takes for malaria parasites to develop within a mosquito, and become transmissible, is known as the extrinsic incubation period, or EIP. EIP is a key parameter influencing transmission intensity as it combines with mosquito mortality rate and competence to determine the number of mosquitoes that ultimately become infectious. In spite of its epidemiological significance, data on EIP are scant. Current approaches to estimate EIP are largely based on temperature-dependent models developed from data collected on parasite development within a single mosquito species in the 1930s. These models assume that the only factor affecting EIP is mean environmental temperature. Here, we review evidence to suggest that in addition to mean temperature, EIP is likely influenced by genetic diversity of the vector, diversity of the parasite, and variation in a range of biotic and abiotic factors that affect mosquito condition. We further demonstrate that the classic approach of measuring EIP as the time at which mosquitoes first become infectious likely misrepresents EIP for a mosquito population. We argue for a better understanding of EIP to improve models of transmission, refine predictions of the possible impacts of climate change, and determine the potential evolutionary responses of malaria parasites to current and future mosquito control tools.

  11. European Educational Research Quality Indicators (EERQI): A first prototype framework of intrinsic and extrinsic indicators

    NARCIS (Netherlands)

    Mooij, Ton

    2011-01-01

    Mooij, T. (2011, 15-16 March). European Educational Research Quality Indicators (EERQI): A first prototype framework of intrinsic and extrinsic indicators. Paper presented at the final EERQI conference, Brussels, University Foundation.

  12. Consolidation power of extrinsic rewards: reward cues enhance long-term memory for irrelevant past events.

    Science.gov (United States)

    Murayama, Kou; Kitagami, Shinji

    2014-02-01

    Recent research suggests that extrinsic rewards promote memory consolidation through dopaminergic modulation processes. However, no conclusive behavioral evidence exists given that the influence of extrinsic reward on attention and motivation during encoding and consolidation processes are inherently confounded. The present study provides behavioral evidence that extrinsic rewards (i.e., monetary incentives) enhance human memory consolidation independently of attention and motivation. Participants saw neutral pictures, followed by a reward or control cue in an unrelated context. Our results (and a direct replication study) demonstrated that the reward cue predicted a retrograde enhancement of memory for the preceding neutral pictures. This retrograde effect was observed only after a delay, not immediately upon testing. An additional experiment showed that emotional arousal or unconscious resource mobilization cannot explain the retrograde enhancement effect. These results provide support for the notion that the dopaminergic memory consolidation effect can result from extrinsic reward.

  13. The detrimental effects of extrinsic reinforcement on “Intrinsic motivation”

    Science.gov (United States)

    Dickinson, Alyce M.

    1989-01-01

    Extrinsic consequences have been criticized on the grounds that they decrease intrinsic motivation or internally initiated behavior. Two popular rationales for this criticism, Lepper's overjustification hypothesis (1981) and Deci's motivational theory (Deci & Ryan, 1985), are reviewed and the criticism is then redefined behaviorally. “Intrinsically controlled” behavior is defined as behavior maintained by response-produced reinforcers, and the question concerning extrinsic consequences is thus restated as follows: When behavior is maintained by response-produced stimuli, does extrinsic reinforcement decrease the reinforcing value of those stimuli? The empirical support for this detrimental effect is summarized briefly, and several possible explanations for the phenomenon are offered. Research results that reflect on the effect's generality and social significance are discussed next, with the conclusion that the effect is transient and not likely to occur at all if extrinsic rewards are reinforcing, noncompetitive, based on reasonable performance standards, and delivered repetitively. PMID:22478013

  14. Self-Perception of Intrinsic and Extrinsic Motivation: Effects on Institutionalized Mentally Retarded Adolescents

    Science.gov (United States)

    Lee, Dong Yul; And Others

    1977-01-01

    The self-perception theory which predicts that the introduction of extrinsic rewards for behavior that was intrinsically rewarding may decrease overall motivation was tested on 44 mildly retarded institutionalized adolescents. (Author/CL)

  15. Withaferin A Suppresses Anti-apoptotic BCL2, Bcl-xL, XIAP and ...

    African Journals Online (AJOL)

    apoptotic ... Quantitative real-time polymerase chain reaction (qPCR) was performed using Taq PCR Master ... Keywords: Anti-apoptotic genes, Cervical cancer, Apoptosis, Cell viability, BCL2, .... polyclonal anti-rabbit immunoglobulin HRP-linked.

  16. Reanalysis of the EMC charm production data with extrinsic and intrinsic charm at NLO

    International Nuclear Information System (INIS)

    Harris, B.W.; Vogt, R.

    1996-01-01

    A calculation of the next-to-leading order exclusive extrinsic charm quark differential distributions in deeply inelastic electroproduction has recently been completed. Using these results we compare the NLO extrinsic contributions to the charm structure function F 2 (x,Q 2 ,m c 2 ) with the corresponding NLO intrinsic contributions. The results of this analysis are compared with the EMC DIS charm quark data and evidence for an intrinsic charm component in the proton is found. (orig.)

  17. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability

    OpenAIRE

    Frielink, N.; Schuengel, C.; Embregts, P.J.C.M.

    2017-01-01

    Background According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and integrated motivation. Although it has been argued theoretically that the different types of motivation are universally applicable, Reid et al. (2009) proposed a dichotomy of broad subtypes of extrins...

  18. A comparison of South African and German extrinsic and intrinsic motivation

    OpenAIRE

    Snelgar, Robin; Shelton, Stacy A.; Giesser, Anne

    2017-01-01

    Background: Various researchers have identified a trend of individuals shifting their preference from extrinsic to intrinsic motivation. The authors aimed to research this phenomenon specifically within the context of two different cultures as to date, this had not been done. This research explored the differing levels of extrinsic and intrinsic motivation in Germans and South Africans. Aim: The main objective of this study was to investigate similarities and differences concerning extrins...

  19. A validity generalization procedure to test relations between intrinsic and extrinsic motivation and influence tactics.

    Science.gov (United States)

    Barbuto, John E; Moss, Jennifer A

    2006-08-01

    The relations of intrinsic and extrinsic motivation with use of consultative, legitimating, and pressure influence tactics were examined using validity generalization procedures. 5 to 7 field studies with cumulative samples exceeding 800 were used to test each relationship. Significance was found for relation between agents' intrinsic motivation and their use of consultative influence tactics and agents' extrinsic motivation and their use of legitimating influence tactics.

  20. The relationship between extrinsic motivation, job satisfaction and life satisfaction amongst employees in a public organisation

    OpenAIRE

    Mafini, Chengedzai; Dlodlo, Nobukhosi

    2014-01-01

    Orientation: There is much research on extrinsic motivation, job satisfaction and life satisfaction in organisations. However, empirical evidence on how such factors affect employees in public organisations in developing countries is lacking. Research purpose: To examine the relationships between extrinsic motivation, job satisfaction and life satisfaction amongst employees in a public organisation. Motivation for the study: Labour strife is an endemic phenomenon in South Africa’s publ...

  1. The Effect Of Extrinsic Motivation On Adversity Quotient In Patients With HIV/AIDS

    OpenAIRE

    Nursalam, Nursalam; Misutarno, Misutarno; Puspitawati, Yulia Dewi

    2017-01-01

    Introduction: Patients with HIV/AIDS may have various types of psychological responses. It was very difficult situation for them. Difficulty can measured by using Adversity Quotient. As a nurse, we can give extrinsic motivation to bring back the patient HIV/AIDS’s quality of life. The objective of this study was to identify the presence effect of extrinsic motivation on Adversity Quotient in patients with HIV/AIDS in Infectious Disease Intermediateatery Treatment Unit, Dr. Soetomo Hospital, S...

  2. The Effect of Extrinsic Motivation on Adversity Quotient in Patients with Hiv/aids

    OpenAIRE

    Nursalam, Nursalam; Misutarno, Misutarno; Puspitawati, Yulia Dewi

    2008-01-01

    Introduction: Patients with HIV/AIDS may have various types of psychological responses. It was very difficult situation for them. Difficulty can measured by using Adversity Quotient. As a nurse, we can give extrinsic motivation to bring back the patient HIV/AIDS’s quality of life. The objective of this study was to identify the presence effect of extrinsic motivation on Adversity Quotient in patients with HIV/AIDS in Infectious Disease Intermediateatery Treatment Unit, Dr. Soetomo Hospital, S...

  3. The detrimental effects of extrinsic reinforcement on “Intrinsic motivation”

    OpenAIRE

    Dickinson, Alyce M.

    1989-01-01

    Extrinsic consequences have been criticized on the grounds that they decrease intrinsic motivation or internally initiated behavior. Two popular rationales for this criticism, Lepper's overjustification hypothesis (1981) and Deci's motivational theory (Deci & Ryan, 1985), are reviewed and the criticism is then redefined behaviorally. “Intrinsically controlled” behavior is defined as behavior maintained by response-produced reinforcers, and the question concerning extrinsic consequences is thu...

  4. Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q.

    Science.gov (United States)

    Marinovic-Terzic, Ivana; Yoshioka-Yamashita, Atsuko; Shimodaira, Hideki; Avdievich, Elena; Hunton, Irina C; Kolodner, Richard D; Edelmann, Winfried; Wang, Jean Y J

    2008-09-16

    Mismatch repair (MMR) corrects replication errors during DNA synthesis. The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin, a DNA cross-linking agent used in chemotherapy, because of impaired activation of apoptotic pathways. It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53 family of transcription factors with proapoptotic activity. The human PMS2 is highly polymorphic, with at least 12 known nonsynonymous codon changes identified. We show here that the PMS2(R20Q) variant is defective in activating p73-dependent apoptotic response to cisplatin. When expressed in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic response to cisplatin. Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of cisplatin measured by clonogenic survival. Because PMS2(R20Q) lacks proapoptotic activity, this polymorphic allele may modulate tumor responses to cisplatin among cancer patients.

  5. The interplay of intrinsic and extrinsic bounded noises in biomolecular networks.

    Directory of Open Access Journals (Sweden)

    Giulio Caravagna

    Full Text Available After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a biomolecular network. The influence of intrinsic and extrinsic noises on biomolecular networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: (i the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, (ii a model of enzymatic futile cycle and (iii a genetic toggle switch. In (ii and (iii we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possible functional role of bounded noises.

  6. Influential Effects of Intrinsic-Extrinsic Incentive Factors on Management Performance in New Energy Enterprises.

    Science.gov (United States)

    Wang, Ping; Lu, Zhengnan; Sun, Jihong

    2018-02-08

    Background : New energy has become a key trend for global energy industry development. Talent plays a very critical role in the enhancement of new energy enterprise competitiveness. As a key component of talent, managers have been attracting more and more attention. The increase in job performance relies on, to a certain extent, incentive mechanism. Based on the Two-factor Theory, differences in influences and effects of different incentives on management performance have been checked in this paper from an empirical perspective. Methods : This paper selects the middle and low level managers in new energy enterprises as research samples and classifies the managers' performance into task performance, contextual performance and innovation performance. It uses manager performance questionnaires and intrinsic-extrinsic incentive factor questionnaires to investigate and study the effects and then uses Amos software to analyze the inner link between the intrinsic-extrinsic incentives and job performance. Results : Extrinsic incentives affect task performance and innovation performance positively. Intrinsic incentives impose active significant effects on task performance, contextual performance, and innovation performance. The intrinsic incentive plays a more important role than the extrinsic incentive. Conclusions : Both the intrinsic-extrinsic incentives affect manager performance positively and the intrinsic incentive plays a more important role than the extrinsic incentive. Several suggestions to management should be given based on these results.

  7. The interplay of intrinsic and extrinsic bounded noises in biomolecular networks.

    Science.gov (United States)

    Caravagna, Giulio; Mauri, Giancarlo; d'Onofrio, Alberto

    2013-01-01

    After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a biomolecular network. The influence of intrinsic and extrinsic noises on biomolecular networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: (i) the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, (ii) a model of enzymatic futile cycle and (iii) a genetic toggle switch. In (ii) and (iii) we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possible functional role of bounded noises.

  8. Intrinsic to extrinsic phonon lifetime transition in a GaAs–AlAs superlattice

    International Nuclear Information System (INIS)

    Hofmann, F; Garg, J; Chen, G; Maznev, A A; Nelson, K A; Jandl, A; Bulsara, M; Fitzgerald, E A

    2013-01-01

    We have measured the lifetimes of two zone-center longitudinal acoustic phonon modes, at 320 and 640 GHz, in a 14 nm GaAs/2 nm AlAs superlattice structure. By comparing measurements at 296 and 79 K we separate the intrinsic contribution to phonon lifetime determined by phonon–phonon scattering from the extrinsic contribution due to defects and interface roughness. At 296 K, the 320 GHz phonon lifetime has approximately equal contributions from intrinsic and extrinsic scattering, whilst at 640 GHz it is dominated by extrinsic effects. These measurements are compared with intrinsic and extrinsic scattering rates in the superlattice obtained from first-principles lattice dynamics calculations. The calculated room-temperature intrinsic lifetime of longitudinal phonons at 320 GHz is in agreement with the experimentally measured value of 0.9 ns. The model correctly predicts the transition from predominantly intrinsic to predominantly extrinsic scattering; however the predicted transition occurs at higher frequencies. Our analysis indicates that the ‘interfacial atomic disorder’ model is not entirely adequate and that the observed frequency dependence of the extrinsic scattering rate is likely to be determined by a finite correlation length of interface roughness. (paper)

  9. Extrinsic response enhancement at the polymorphic phase boundary in piezoelectric materials

    Energy Technology Data Exchange (ETDEWEB)

    Ochoa, Diego A.; García, José E., E-mail: jose.eduardo.garcia@upc.edu [Department of Physics, Universitat Politècnica de Catalunya - BarcelonaTech, Barcelona 08034 (Spain); Esteves, Giovanni; Jones, Jacob L. [Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina 27696 (United States); Rubio-Marcos, Fernando; Fernández, José F. [Department of Electroceramics, Instituto de Cerámica y Vidrio - CSIC, Madrid 28049 (Spain)

    2016-04-04

    Polymorphic phase boundaries (PPBs) in piezoelectric materials have attracted significant interest in recent years, in particular, because of the unique properties that can be found in their vicinity. However, to fully harness their potential as micro-nanoscale functional entities, it is essential to achieve reliable and precise control of their piezoelectric response, which is due to two contributions known as intrinsic and extrinsic. In this work, we have used a (K,Na)NbO{sub 3}-based lead-free piezoceramic as a model system to investigate the evolution of the extrinsic contribution around a PPB. X-ray diffraction measurements are performed over a wide range of temperatures in order to determine the structures and transitions. The relevance of the extrinsic contribution at the PPB region is evaluated by means of nonlinear dielectric response measurements. Though it is widely appreciated that certain intrinsic properties of ferroelectric materials increase as PPBs are approached, our results demonstrate that the extrinsic contribution also maximizes. An enhancement of the extrinsic contribution is therefore also responsible for improving the functional properties at the PPB region. Rayleigh's law is used to quantitatively analyze the nonlinear response. As a result, an evolution of the domain wall motion dynamics through the PPB region is detected. This work demonstrates that the extrinsic contribution at a PPB may have a dynamic role in lead-free piezoelectric materials, thereby exerting a far greater influence on their functional properties than that considered to date.

  10. Intrinsic to extrinsic phonon lifetime transition in a GaAs-AlAs superlattice.

    Science.gov (United States)

    Hofmann, F; Garg, J; Maznev, A A; Jandl, A; Bulsara, M; Fitzgerald, E A; Chen, G; Nelson, K A

    2013-07-24

    We have measured the lifetimes of two zone-center longitudinal acoustic phonon modes, at 320 and 640 GHz, in a 14 nm GaAs/2 nm AlAs superlattice structure. By comparing measurements at 296 and 79 K we separate the intrinsic contribution to phonon lifetime determined by phonon-phonon scattering from the extrinsic contribution due to defects and interface roughness. At 296 K, the 320 GHz phonon lifetime has approximately equal contributions from intrinsic and extrinsic scattering, whilst at 640 GHz it is dominated by extrinsic effects. These measurements are compared with intrinsic and extrinsic scattering rates in the superlattice obtained from first-principles lattice dynamics calculations. The calculated room-temperature intrinsic lifetime of longitudinal phonons at 320 GHz is in agreement with the experimentally measured value of 0.9 ns. The model correctly predicts the transition from predominantly intrinsic to predominantly extrinsic scattering; however the predicted transition occurs at higher frequencies. Our analysis indicates that the 'interfacial atomic disorder' model is not entirely adequate and that the observed frequency dependence of the extrinsic scattering rate is likely to be determined by a finite correlation length of interface roughness.

  11. Influential Effects of Intrinsic-Extrinsic Incentive Factors on Management Performance in New Energy Enterprises

    Directory of Open Access Journals (Sweden)

    Ping Wang

    2018-02-01

    Full Text Available Background: New energy has become a key trend for global energy industry development. Talent plays a very critical role in the enhancement of new energy enterprise competitiveness. As a key component of talent, managers have been attracting more and more attention. The increase in job performance relies on, to a certain extent, incentive mechanism. Based on the Two-factor Theory, differences in influences and effects of different incentives on management performance have been checked in this paper from an empirical perspective. Methods: This paper selects the middle and low level managers in new energy enterprises as research samples and classifies the managers’ performance into task performance, contextual performance and innovation performance. It uses manager performance questionnaires and intrinsic-extrinsic incentive factor questionnaires to investigate and study the effects and then uses Amos software to analyze the inner link between the intrinsic-extrinsic incentives and job performance. Results: Extrinsic incentives affect task performance and innovation performance positively. Intrinsic incentives impose active significant effects on task performance, contextual performance, and innovation performance. The intrinsic incentive plays a more important role than the extrinsic incentive. Conclusions: Both the intrinsic-extrinsic incentives affect manager performance positively and the intrinsic incentive plays a more important role than the extrinsic incentive. Several suggestions to management should be given based on these results.

  12. Resistance to abrasion of extrinsic porcelain esthetic characterization techniques.

    Science.gov (United States)

    Chi, Woo J; Browning, William; Looney, Stephen; Mackert, J Rodway; Windhorn, Richard J; Rueggeberg, Frederick

    2017-01-01

    groups. In this study, the novel external characterization technique (stain+LFP: Group SL) did not significantly enhance the wear resistance against toothbrush abrasion. Instead, the average wear of the applied extrinsic porcelain was 2 to 3 times more than Group S (stain only) and Group GS (glaze over stain). Application of a glaze layer over the colorants (Group GS) showed a significant improvement on wear resistance. Despite its superior physical properties, the leucite reinforced ceramic core (Group C) showed 2 to 4 times more wear when compared with other test groups. A conventional external esthetic characterization technique of applying a glaze layer over the colorants (Group GS) significantly enhanced the surface wear resistance to toothbrush abrasion when compared with other techniques involving application of colorants only (Group S) or mixture of colorant and LFP (Group SL). The underlying core ceramic had significantly less wear resistance compared with all externally characterized specimens. The novel esthetic characterization technique showed more wear and less color stability, and is thus not advocated as the "best" method for surface characterization. Application of a glaze layer provides a more wear-resistant surface from toothbrush abrasion when adjusting or extrinsically characterizing leucite reinforced ceramic restorations. Without the glaze layer, the restoration is subjected to a 2 to 4 times faster rate and amount of wear leading to possible shade mismatch.

  13. Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation

    Directory of Open Access Journals (Sweden)

    Yoon TH

    2012-03-01

    , Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.Keywords: TiO2, reactive oxygen species, apoptotic cell death, Fas upregulation, Bax activation, mitochondrial membrane potential loss, caspase activation

  14. Extrinsic Calibration for Vehicle-based Mobile Mapping System

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    SHI Limei

    2015-01-01

    Full Text Available Having the advantage of 360° imaging and rotation invariance, panoramic camera has gradually been used in mobile mapping systems(MMS. Calibration is an essential requirement to make sure that MMS can get high quality geo-information. This paper presents a way to address the extrinsic calibration for vehicle-based MMS composed of panoramic camera and Position and Orientation System (POS. Firstly, control points in the natural scene are set up, whose spatial coordinates are measured with high precision. Secondly, a panoramic spherical model is constructed and panoramic image can be projected to this model by means of spherical reverse transformation projection. Then, localize and select the control points in 3D spherical panoramic view but not in panoramic distorted image directly, the spherical coordinates of control points in panoramic image are gotten. After points correspondence is established, make use of direct geo-reference positioning equation and coordinate transformation, the translation and rotation parameters of panoramic camera relative to POS are computed. Experiments are conducted separately in space city calibration site located in Beijing and the Binhai New Area in Tianjin using our approach. Test results are listed as follows. When the GPS signal are of good quality, absolute positioning mean square error of a point is 10.3 cm in two-dimension plane and 16.5 cm in height direction; Otherwise, it is 35.4 cm in two-dimension plane and 54.8 cm in height direction. The max relative error of distance measurement is about 5 cm over a short distance (distance<3 km, which is not obviously affected by the GPS signal quality.

  15. Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function.

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    Maria Sophia Mackroth

    2016-11-01

    Full Text Available In acute Plasmodium falciparum (P. falciparum malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4+ T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1+CTLA4+CD4+ T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1+CTLA4+CD4+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1+CTLA4+CD4+ T cells suppressed the proliferation of the total CD4+ population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1+CTLA4+CD4+ Teffector cells that coproduce IFNγ and IL10, and inhibit other CD4+ T cells. Transient induction of regulatory Teffector cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections.

  16. Ultrastructural apoptotic lesions induced in rat thymocytes after borax ingestion.

    Science.gov (United States)

    Sylvain, I C; Berry, J P; Galle, P

    1998-01-01

    Apoptosis has gained increasing attention in recent years. Several chemical compounds induce apoptotic lesions in the thymus. Male Wistar rats received 2000 ppm of borax (Na2B4O7.10H2O) in their food for 16 days. The rats were sacrificed 2, 5, 9, 12, 19, 21, 26 and 28 days after the beginning of treatment. Thymus samples of all rats were taken. A Philips EM 300 electron microscopy was used to study the ultrastructural morphology. Serious nuclear and cytoplasmic lesions were observed. Moreover, numerous macrophages containing apoptotic cells were present in the thymus. The alterations were observed from the 2nd to the 28th day. The extent of damage was much more important in the rats sacrificed 21, 26 and 28 days after borax ingestion.

  17. Macrophage Clearance of Apoptotic Cells: A Critical Assessment

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    Siamon Gordon

    2018-01-01

    Full Text Available As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and dendritic cells play a central role in discriminating among viable, apoptotic, and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self-ligands on potential targets, mediating their eventual uptake, disposal, and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process.

  18. Phosphatidylserine-Liposomes Promote Tolerogenic Features on Dendritic Cells in Human Type 1 Diabetes by Apoptotic Mimicry

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    Silvia Rodriguez-Fernandez

    2018-02-01

    Full Text Available Type 1 diabetes (T1D is a metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow β-cell recovery has become vital. Relying on the inherent ability of apoptotic cells to induce immunological tolerance, we demonstrated that liposomes mimicking apoptotic β-cells arrested autoimmunity to β-cells and prevented experimental T1D through tolerogenic dendritic cell (DC generation. These liposomes contained phosphatidylserine (PS—the main signal of the apoptotic cell membrane—and β-cell autoantigens. To move toward a clinical application, PS-liposomes with optimum size and composition for phagocytosis were loaded with human insulin peptides and tested on DCs from patients with T1D and control age-related subjects. PS accelerated phagocytosis of liposomes with a dynamic typical of apoptotic cell clearance, preserving DCs viability. After PS-liposomes phagocytosis, the expression pattern of molecules involved in efferocytosis, antigen presentation, immunoregulation, and activation in DCs concurred with a tolerogenic functionality, both in patients and control subjects. Furthermore, DCs exposed to PS-liposomes displayed decreased ability to stimulate autologous T cell proliferation. Moreover, transcriptional changes in DCs from patients with T1D after PS-liposomes phagocytosis pointed to an immunoregulatory prolife. Bioinformatics analysis showed 233 differentially expressed genes. Genes involved in antigen presentation were downregulated, whereas genes pertaining to tolerogenic/anti-inflammatory pathways were mostly upregulated. In conclusion, PS-liposomes phagocytosis mimics efferocytosis and leads to phenotypic and functional changes in human DCs, which are accountable for tolerance induction. The herein reported results reinforce the potential of this novel immunotherapy to re-establish immunological

  19. Histopathological, Ultrastructural and Apoptotic Changes in Diabetic Rat Placenta

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    Mehmet Gül

    2015-09-01

    Full Text Available Background: The exchange of substances between mother and fetus via the placenta plays a vital role during development. A number of developmental disorders in the fetus and placenta are observed during diabetic pregnancies. Diabetes, together with placental apoptosis, can lead to developmental and functional disorders. Aims: Histological, ultrastructural and apoptotic changes were investigated in the placenta of streptozotocin (STZ induced diabetic rats. Study Design: Animal experimentation. Methods: In this study, a total of 12 female Wistar Albino rats (control (n=6 and diabetic (n=6 were used. Rats in the diabetic group, following the administration of a single dose of STZ, showed blood glucose levels higher than 200 mg/dL after 72 hours. When pregnancy was detected after the rats were bred, two pieces of placenta and the fetuses were collected on the 20th day of pregnancy by cesarean incision under ketamine/xylazine anesthesia from in four rats from the control and diabetic groups. Placenta tissues were processed for light microscopy and transmission electron microscopy (TEM. Hematoxylin-eosin (HE and periodic acid Schiff-diastase (PAS-D staining for light microscopic and caspase-3 staining for immunohistochemical investigations were performed for each placenta. Electron microscopy was performed on thin sections contrasted with uranyl acetate and lead nitrate. Results: Weight gain in the placenta and fetuses of diabetic rats and thinning of the decidual layer, thickening of the hemal membrane, apoptotic bodies, congestion in intervillous spaces, increased PAS-D staining in decidual cells and caspase-3 immunoreactivity were observed in the diabetic group. After the ultrastructural examination, the apoptotic appearance of the nuclei of trophoblastic cells, edema and intracytoplasmic vacuolization, glycogen accumulation, dilation of the endoplasmic reticulum and myelin figures were observed. In addition, capillary basement membrane thickening

  20. Membrane Protected Apoptotic Trophoblast Microparticles Contain Nucleic Acids

    Science.gov (United States)

    Orozco, Aaron F.; Jorgez, Carolina J.; Horne, Cassandra; Marquez-Do, Deborah A.; Chapman, Matthew R.; Rodgers, John R.; Bischoff, Farideh Z.; Lewis, Dorothy E.

    2008-01-01

    Microparticles (MPs) that circulate in blood may be a source of DNA for molecular analyses, including prenatal genetic diagnoses. Because MPs are heterogeneous in nature, however, further characterization is important before use in clinical settings. One key question is whether DNA is either bound to aggregates of blood proteins and lipid micelles or intrinsically associated with MPs from dying cells. To test the latter hypothesis, we asked whether MPs derived in vitro from dying cells were similar to those in maternal plasma. JEG-3 cells model extravillous trophoblasts, which predominate during the first trimester of pregnancy when prenatal diagnosis is most relevant. MPs were derived from apoptosis and increased over 48 hours. Compared with necrotic MPs, DNA in apoptotic MPs was more fragmented and resistant to plasma DNases. Membrane-specific dyes indicated that apoptotic MPs had more membranous material, which protects nucleic acids, including RNA. Flow cytometry showed that MPs derived from dying cells displayed light scatter and DNA staining similar to MPs found in maternal plasma. Quantification of maternal MPs using characteristics defined by MPs generated in vitro revealed a significant increase of DNA+ MPs in the plasma of women with preeclampsia compared with plasma from women with normal pregnancies. Apoptotic MPs are therefore a likely source of stable DNA that could be enriched for both early genetic diagnosis and monitoring of pathological pregnancies. PMID:18974299

  1. Cell shape and organelle modification in apoptotic U937 cells

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    MR Montinari

    2009-12-01

    Full Text Available U937 cells induced to apoptosis, progressively and dramatically modified their cell shape by intense blebbing formation, leading to the production of apoptotic bodies. The blebs evolved with time; milder forms of blebbing involving only a region or just the cortical part of the cytoplasm were observed within the first hour of incubation with puromycin; blebbing involving the whole cell body with very deep constrictions is the most frequent event observed during late times of incubation. The ultrastructural analysis of apoptotic cells revealed characteristic features of nuclear fragmentation (budding and cleavage mode and cytoplasmatic modifications. The cytoplasm of blebs does not contain organelles, such as ribosomes or mitochondria. Scarce presence of endoplasmic reticulum can be observed at the site of bleb detachment. However, blebbing is a dispensable event as evaluated by using inhibitor of actin polymerization. In the present study, the progressive modifications of the nucleus, mitochondria, nuclear fragmentation, cytoplasmic blebs formation and production of apoptotic bodies in U937 monocytic cells induced to apoptosis by puromycin (an inhibitor of protein synthesis were simultaneously analyzed.

  2. Intrinsic and extrinsic spin-orbit torques from first principles

    International Nuclear Information System (INIS)

    Geranton, Guillaume

    2017-01-01

    This thesis attempts to shed light on the microscopic mechanisms underlying the current-induced magnetic torques in ferromagnetic heterostructures. We have developed first principles methods aiming at the accurate and effcient calculation of the so-called spin-orbit torques (SOTs) in magnetic thin films. The emphasis of this work is on the impurity-driven extrinsic SOTs. The main part of this thesis is dedicated to the development of a formalism for the calculation of the SOTs within the Korringa-Kohn-Rostoker (KKR) method. The impurity-induced transitions rates are obtained from first principles and their effect on transport properties is treated within the Boltzmann formalism. The developed formalism provides a mean to compute the SOTs beyond the conventional constant relaxation time approximation. We first apply our formalism to the investigation of FePt/Pt and Co/Cu bilayers in the presence of defects and impurities. Our results hint at a crucial dependence of the torque on the type of disorder present in the films, which we explain by a complex interplay of several competing Fermi surface contributions to the SOT. Astonishingly, specific defect distributions or doping elements lead respectively to an increase or a sign change of the torque, which can not be explained on the basis of simple models. We also compute the intrinsic SOT induced by electrical and thermal currents within the full potential linearized augmented plane-wave method. Motivated by recent experimental works, we then investigate the microscopic origin of the SOT in a Ag_2Bi-terminated Ag film grown on ferromagnetic Fe(110). We find that the torque in that system can not be explained solely by the spin-orbit coupling in the Ag_2Bi alloy, and instead results from the spin-orbit coupling in all regions of the film.Finally, we predict a large SOT in Fe/Ge bilayers and suggest that semiconductor substrates might be a promising alternative to heavy metals for the development of SOT-based magnetic

  3. Intrinsic and extrinsic spin-orbit torques from first principles

    Energy Technology Data Exchange (ETDEWEB)

    Geranton, Guillaume

    2017-09-01

    This thesis attempts to shed light on the microscopic mechanisms underlying the current-induced magnetic torques in ferromagnetic heterostructures. We have developed first principles methods aiming at the accurate and effcient calculation of the so-called spin-orbit torques (SOTs) in magnetic thin films. The emphasis of this work is on the impurity-driven extrinsic SOTs. The main part of this thesis is dedicated to the development of a formalism for the calculation of the SOTs within the Korringa-Kohn-Rostoker (KKR) method. The impurity-induced transitions rates are obtained from first principles and their effect on transport properties is treated within the Boltzmann formalism. The developed formalism provides a mean to compute the SOTs beyond the conventional constant relaxation time approximation. We first apply our formalism to the investigation of FePt/Pt and Co/Cu bilayers in the presence of defects and impurities. Our results hint at a crucial dependence of the torque on the type of disorder present in the films, which we explain by a complex interplay of several competing Fermi surface contributions to the SOT. Astonishingly, specific defect distributions or doping elements lead respectively to an increase or a sign change of the torque, which can not be explained on the basis of simple models. We also compute the intrinsic SOT induced by electrical and thermal currents within the full potential linearized augmented plane-wave method. Motivated by recent experimental works, we then investigate the microscopic origin of the SOT in a Ag{sub 2}Bi-terminated Ag film grown on ferromagnetic Fe(110). We find that the torque in that system can not be explained solely by the spin-orbit coupling in the Ag{sub 2}Bi alloy, and instead results from the spin-orbit coupling in all regions of the film.Finally, we predict a large SOT in Fe/Ge bilayers and suggest that semiconductor substrates might be a promising alternative to heavy metals for the development of SOT

  4. Recollection and unitization in associating actors with extrinsic and intrinsic motions.

    Science.gov (United States)

    Kersten, Alan W; Earles, Julie L; Berger, Johanna D

    2015-04-01

    Four experiments provide evidence for a distinction between 2 different kinds of motion representations. Extrinsic motions involve the path of an object with respect to an external frame of reference. Intrinsic motions involve the relative motions of the parts of an object. This research suggests that intrinsic motions are represented conjointly with information about the identities of the actors who perform them, whereas extrinsic motions are represented separately from identity information. Experiment 1 demonstrated that participants remembered which actor had performed a particular intrinsic motion better than they remembered which actor had performed a particular extrinsic motion. Experiment 2 replicated this effect with incidental encoding of actor information, suggesting that encoding intrinsic motions leads one to automatically encode identity information. The results of Experiments 3 and 4 were fit by Yonelinas's (1999) source-memory model to quantify the contributions of familiarity and recollection to memory for the actors who carried out the intrinsic and extrinsic motions. Successful performance with extrinsic motion items in Experiment 3 required participants to remember in which scene contexts an actor had appeared, whereas successful performance in Experiment 4 required participants to remember the exact path taken by an actor in each scene. In both experiments, discrimination of old and new combinations of actors and extrinsic motions relied strongly on recollection, suggesting independent but associated representations of actors and extrinsic motions. In contrast, participants discriminated old and new combinations of actors and intrinsic motions primarily on the basis of familiarity, suggesting unitized representations of actors and intrinsic motions. (c) 2015 APA, all rights reserved).

  5. Bimanual motor coordination controlled by cooperative interactions in intrinsic and extrinsic coordinates.

    Science.gov (United States)

    Sakurada, Takeshi; Ito, Koji; Gomi, Hiroaki

    2016-01-01

    Although strong motor coordination in intrinsic muscle coordinates has frequently been reported for bimanual movements, coordination in extrinsic visual coordinates is also crucial in various bimanual tasks. To explore the bimanual coordination mechanisms in terms of the frame of reference, here we characterized implicit bilateral interactions in visuomotor tasks. Visual perturbations (finger-cursor gain change) were applied while participants performed a rhythmic tracking task with both index fingers under an in-phase or anti-phase relationship in extrinsic coordinates. When they corrected the right finger's amplitude, the left finger's amplitude unintentionally also changed [motor interference (MI)], despite the instruction to keep its amplitude constant. Notably, we observed two specificities: one was large MI and low relative-phase variability (PV) under the intrinsic in-phase condition, and the other was large MI and high PV under the extrinsic in-phase condition. Additionally, using a multiple-interaction model, we successfully decomposed MI into intrinsic components caused by motor correction and extrinsic components caused by visual-cursor mismatch of the right finger's movements. This analysis revealed that the central nervous system facilitates MI by combining intrinsic and extrinsic components in the condition with in-phases in both intrinsic and extrinsic coordinates, and that under-additivity of the effects is explained by the brain's preference for the intrinsic interaction over extrinsic interaction. In contrast, the PV was significantly correlated with the intrinsic component, suggesting that the intrinsic interaction dominantly contributed to bimanual movement stabilization. The inconsistent features of MI and PV suggest that the central nervous system regulates multiple levels of bilateral interactions for various bimanual tasks. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and

  6. Distinct neural control of intrinsic and extrinsic muscles of the hand during single finger pressing.

    Science.gov (United States)

    Dupan, Sigrid S G; Stegeman, Dick F; Maas, Huub

    2018-06-01

    Single finger force tasks lead to unintended activation of the non-instructed fingers, commonly referred to as enslaving. Both neural and mechanical factors have been associated with this absence of finger individuality. This study investigates the amplitude modulation of both intrinsic and extrinsic finger muscles during single finger isometric force tasks. Twelve participants performed single finger flexion presses at 20% of maximum voluntary contraction, while simultaneously the electromyographic activity of several intrinsic and extrinsic muscles associated with all four fingers was recorded using 8 electrode pairs in the hand and two 30-electrode grids on the lower arm. The forces exerted by each of the fingers, in both flexion and extension direction, were recorded with individual force sensors. This study shows distinct activation patterns in intrinsic and extrinsic hand muscles. Intrinsic muscles exhibited individuation, where the agonistic and antagonistic muscles associated with the instructed fingers showed the highest activation. This activation in both agonistic and antagonistic muscles appears to facilitate finger stabilisation during the isometric force task. Extrinsic muscles show an activation independent from instructed finger in both agonistic and antagonistic muscles, which appears to be associated with stabilisation of the wrist, with an additional finger-dependent modulation only present in the agonistic extrinsic muscles. These results indicate distinct muscle patterns in intrinsic and extrinsic hand muscles during single finger isometric force pressing. We conclude that the finger specific activation of intrinsic muscles is not sufficient to fully counteract enslaving caused by the broad activation of the extrinsic muscles. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Intrinsic and Extrinsic Motivation Among Adolescent Ten-Pin Bowlers in Kuala Lumpur, Malaysia

    Science.gov (United States)

    Teo, Eng-Wah; Khoo, Selina; Wong, Rebecca; Wee, Eng-Hoe; Lim, Boon-Hooi; Rengasamy, Shabesan Sit

    2015-01-01

    Motivation has long been associated with sports engagement. However, to date no research has been performed to understand the domain of motivation among ten-pin bowlers. The purpose of this study was to investigate different types of motivation (i.e., intrinsic vs. extrinsic) based on self-determination theory from the perspective of gender and the bowler type (competitive vs. casual). A total of 240 bowlers (104 male, 136 female; 152 competitive, 88 casual) with a mean age of 16.61 ± 0.78 years were recruited in Kuala Lumpur. The Sport Motivation Scale, a 28-item self-report questionnaire measuring seven subscales (i.e., intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, extrinsic motivation to identify regulation, extrinsic motivation for introjection regulation, extrinsic motivation to external regulation, and amotivation) was administered. Results showed significant differences (t=10.43, df=239, p=0.01) between total scores of intrinsic and extrinsic motivation among ten-pin bowlers. There were significant gender differences with respect to intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, and extrinsic motivation to identify regulation. However, no significant bowler type differences were found for either the intrinsic (t=−1.15, df=238, p=0.25) or extrinsic (t=−0.51, df=238, p=0.61) motivation dimensions. In conclusion, our study demonstrated substantial intrinsic motivation for gender effects, but no bowler type effects among adolescent ten-pin bowlers. PMID:25964827

  8. THE EFFECT OF EXTRINSIC MOTIVATION ON ADVERSITY QUOTIENT IN PATIENTS WITH HIV/AIDS

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    Nursalam Nursalam

    2017-07-01

    Full Text Available Introduction: Patients with HIV/AIDS may have various types of psychological responses. It was very difficult situation for them. Difficulty can measured by using Adversity Quotient. As a nurse, we can give extrinsic motivation to bring back the patient HIV/AIDS’s quality of life. The objective of this study was to identify the presence effect of extrinsic motivation on Adversity Quotient in patients with HIV/AIDS in Infectious Disease Intermediateatery Treatment Unit, Dr. Soetomo Hospital, Surabaya. Method: This study was used a quasy experimental purposive sampling design. The population was taken from ambulatory patients. There were 16 respondents who met to the inclusion criteria. The independent variable was extrinsic motivation and dependent variable was Adversity Quotient. Data were collected by using questionnaire and interview, then analyzed by using Wilcoxon Signed Rank Test and Mann Whitney U Test with significance level p=0.05. Result: The result revealed that there was an effect of extrinsic motivation on Adversity Quotient of patients with HIV/AIDS (p=0.017. The extrinsic motivation was found to have an effect on control response (p=0.027 and origin response (p=0.028, there was no influence of extrinsic motivation on ownership response (p=0.334, reach (p=0.129 and endurance (p=0.161. Discussion: It can be concluded that the extrinsic motivation with intervention of social support has a positive effect on the improvement of Adversity Quotient in patients with HIV/AIDS. Further studies should measure the effectiveness of Adversity Quotient training on acceptance response in patients with HIV/AIDS.

  9. Temporal activation of anti- and pro-apoptotic factors in human gingival fibroblasts infected with the periodontal pathogen, Porphyromonas gingivalis: potential role of bacterial proteases in host signalling

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    Takehara Tadamichi

    2006-03-01

    Full Text Available Abstract Background Porphyromonas gingivalis is the foremost oral pathogen of adult periodontitis in humans. However, the mechanisms of bacterial invasion and the resultant destruction of the gingival tissue remain largely undefined. Results We report host-P. gingivalis interactions in primary human gingival fibroblast (HGF cells. Quantitative immunostaining revealed the need for a high multiplicity of infection for optimal infection. Early in infection (2–12 h, P. gingivalis activated the proinflammatory transcription factor NF-kappa B, partly via the PI3 kinase/AKT pathway. This was accompanied by the induction of cellular anti-apoptotic genes, including Bfl-1, Boo, Bcl-XL, Bcl2, Mcl-1, Bcl-w and Survivin. Late in infection (24–36 h the anti-apoptotic genes largely shut down and the pro-apoptotic genes, including Nip3, Hrk, Bak, Bik, Bok, Bax, Bad, Bim and Moap-1, were activated. Apoptosis was characterized by nuclear DNA degradation and activation of caspases-3, -6, -7 and -9 via the intrinsic mitochondrial pathway. Use of inhibitors revealed an anti-apoptotic function of NF-kappa B and PI3 kinase in P. gingivalis-infected HGF cells. Use of a triple protease mutant P. gingivalis lacking three major gingipains (rgpA rgpB kgp suggested a role of some or all these proteases in myriad aspects of bacteria-gingival interaction. Conclusion The pathology of the gingival fibroblast in P. gingivalis infection is affected by a temporal shift from cellular survival response to apoptosis, regulated by a number of anti- and pro-apoptotic molecules. The gingipain group of proteases affects bacteria-host interactions and may directly promote apoptosis by intracellular proteolytic activation of caspase-3.

  10. β3 integrin promotes chemoresistance to epirubicin in MDA-MB-231 through repression of the pro-apoptotic protein, BAD

    Energy Technology Data Exchange (ETDEWEB)

    Nair, Madhumathy G.; Desai, Krisha; Prabhu, Jyothi S.; Hari, P.S.; Remacle, Jose; Sridhar, T.S., E-mail: tssridhar@sjri.res.in

    2016-08-01

    Resistance to anthracycline based chemotherapy is a major limitation in the treatment of breast cancer, particularly of the triple negative sub-type that lacks targeted therapies. Resistance that arises from tumor-stromal interaction facilitated by integrins provides the possibility of targeted disruption. In the present study, we demonstrate that integrin β3 signaling inhibits apoptosis induced by a DNA-damaging chemotherapeutic agent, epirubicin, in MDA-MB-231 breast cancer cells. Drug efflux based mechanisms do not contribute to this effect. We show that integrin β3 employs the PI3K-Akt and the MAPK pathway for enabling cell survival and proliferation. Further, our results indicate that integrin β3 helps inhibit epirubicin induced cytotoxicity by repression of the pro-apoptotic protein BAD, thus promoting an anti-apoptotic response. Myristoylated RGT peptide and a monoclonal antibody against integrin β3 brought about a reversal of this effect and chemosensitized the cells. These results identify β3 integrin signaling via repression of BAD as an important survival pathway used by breast cancer cells to evade chemotherapy induced stress. - Highlights: • Integrin β3 signaling promotes chemoresistance to epirubicin in breast cancer cells. • Integrin β3 promotes cell survival and proliferation in drug treated cells through the PI3K and MAPK pathways. • Integrin signaling helps evade drug induced cytotoxicity by repression of pro-apoptotic molecule; BAD.

  11. Breviscapine ameliorates CCl4‑induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation.

    Science.gov (United States)

    Liu, Yu; Wen, Pei-Hao; Zhang, Xin-Xue; Dai, Yang; He, Qiang

    2018-05-02

    Acute liver injury is characterized by fibrosis, inflammation and apoptosis, leading to liver failure, cirrhosis or cancer and affecting the clinical outcome in the long term. However, no effective therapeutic strategy is currently available. Breviscapine, a mixture of flavonoid glycosides, has been reported to have multiple biological functions. The present study aimed to investigate the effects of breviscapine on acute liver injury induced by CCl4 in mice. C57BL/6 mice were subjected to intraperitoneal injection with CCl4 for 8 weeks with or without breviscapine (15 or 30 mg/kg). Mice treated with CCl4 developed acute liver injury, as evidenced by histological analysis, Masson trichrome and Sirius Red staining, accompanied with elevated levels of alanine aminotransferase and aspartate aminotransferase. Furthermore, increases in pro‑inflammatory cytokines, chemokines and apoptotic factors, including caspase‑3 and poly(ADP ribose) polymerase‑2 (PARP‑2), were observed. Breviscapine treatment significantly and dose‑dependently reduced collagen deposition and the fibrotic area. Inflammatory cytokines were downregulated by breviscapine through inactivating Toll‑like receptor 4/nuclear factor-κB signaling pathways. In addition, co‑administration of breviscapine with CCl4 decreased the apoptotic response by enhancing B‑cell lymphoma-2 (Bcl‑2) levels, while reducing Bcl‑2‑associated X protein, apoptotic protease activating factor 1, caspase‑3 and PARP activity. Furthermore, CCl4‑induced oxidative stress was blocked by breviscapine through improving anti‑oxidants and impeding mitogen‑activated protein kinase pathways. The present study highlighted that breviscapine exhibited liver‑protective effects against acute hepatic injury induced by CCl4 via suppressing inflammation and apoptosis.

  12. Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia.

    Science.gov (United States)

    Minutoli, Letteria; Rinaldi, Mariagrazia; Marini, Herbert; Irrera, Natasha; Crea, Giovanni; Lorenzini, Cesare; Puzzolo, Domenico; Valenti, Andrea; Pisani, Antonina; Adamo, Elena B; Altavilla, Domenica; Squadrito, Francesco; Micali, Antonio

    2016-08-11

    Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targets either the static component of BPH, including finasteride and dutasteride, or the dynamic component of BPH, including α-adrenoceptor antagonists such as tamsulosin and alfuzosin. Both these classes of drugs significantly interfere with the apoptosis machinery. Furthermore, phytotherapic supplements and new drugs may also modulate several molecular steps of apoptosis.

  13. Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia

    Science.gov (United States)

    Minutoli, Letteria; Rinaldi, Mariagrazia; Marini, Herbert; Irrera, Natasha; Crea, Giovanni; Lorenzini, Cesare; Puzzolo, Domenico; Valenti, Andrea; Pisani, Antonina; Adamo, Elena B.; Altavilla, Domenica; Squadrito, Francesco; Micali, Antonio

    2016-01-01

    Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targets either the static component of BPH, including finasteride and dutasteride, or the dynamic component of BPH, including α-adrenoceptor antagonists such as tamsulosin and alfuzosin. Both these classes of drugs significantly interfere with the apoptosis machinery. Furthermore, phytotherapic supplements and new drugs may also modulate several molecular steps of apoptosis. PMID:27529214

  14. Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia

    Directory of Open Access Journals (Sweden)

    Letteria Minutoli

    2016-08-01

    Full Text Available Benign prostatic hyperplasia (BPH is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl-2 associated X protein (Bax expression. Inhi