Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of CYP2E1 by pyrazole (PY) potentiated the hepatotoxicity induced by TNFalpha in mice. We evaluated the role of nitrosative and oxidative stress and the NF-kappaB activation pathway in this liver injury. The iNOS inhibitor N-(3-aminomethyl)benzylacetamindine (1400W) or the antioxidant N-acetyl-l-cysteine (NAC) prevented this liver injury. TNFalpha plus PY treatment triggered radical stress in the liver with increased lipid peroxidation and decreased glutathione and caused mitochondrial damage as reflected by elevated membrane swelling and cytochrome c release. The radical stress and mitochondrial damage were prevented by 1400W and NAC. TNFalpha plus PY treatment elevated 3-nitrotyrosine adduct formation and induced NOS2 in the liver; 1400W and NAC blocked these changes. A lower extent of liver injury and oxidative stress was found in NOS2(-/-) mice treated with TNFalpha plus PY compared with wild-type controls. Neither 1400W nor NAC modified CYP2E1 activity or protein. Activation of JNK and p38MAPK was weaker in TNFalpha plus PY-treated NOS2(-/-) mice and 1400W and NAC blocked the activation of JNK and p38MAPK in wild-type mice. IKKalpha/beta protein levels were decreased by TNFalpha plus PY treatment, whereas IkappaBalpha and IkappaBbeta protein levels were elevated compared with saline, PY, or TNFalpha alone. NF-kappaB DNA binding activity was increased by TNFalpha alone but lowered by TNFalpha plus PY. All these changes were blocked by 1400W and NAC. NF-kappaB activation products such as Bcl-2, Bcl-X(L), cFLIP(S), cFLIP(L), and Mn-SOD were reduced by TNFalpha plus PY and restored by 1400W or NAC. We conclude that TNFalpha plus CYP2E1 induces oxidative/nitrosative stress, which plays a role in the activation of JNK or p38MAPK and mitochondrial damage. These effects combine with the blunting of the NF-kappaB activation pathways and the synthesis of protective factors to cause liver injury.
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PMID:Role of nitric oxide and nuclear factor-kappaB in the CYP2E1 potentiation of tumor necrosis factor alpha hepatotoxicity in mice. 1906 61

It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel invasion assays, respectively, was done and showed that NO-treated melanoma cells exhibited a higher capacity compared with control, especially metastatic Lu1205 cells. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein and its role in tumor biology has attracted considerable attention. To determine whether APE/Ref-1 plays a role in mediating NO stimulation of melanoma progression, we investigated the effect of DETA/NO on levels of APE/Ref-1 and related downstream targets [activator protein-1 (AP-1)/JunD, matrix metalloproteinase-1 (MMP-1), Bcl-2, and inducible nitric oxide synthase (iNOS)] by Western blot and reverse transcription-PCR analysis. Following DETA/NO treatment, APE/Ref-1 and other downstream molecules were induced. Knockdown of APE/Ref-1 or AP-1/JunD by specific small interfering RNA markedly reversed the induction by NO stress of target proteins. These results present evidence for the existence of a functional feedback loop contributing to progression and metastasis of melanoma cells. Resveratrol has been shown to be an APE/Ref-1 inhibitor and significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels occurred after exposure to resveratrol. This phenolic antioxidant may be an appropriate choice for combining with other compounds that develop resistance by up-regulation of these molecules.
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PMID:Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol. 1907 50

Sildenafil is the first commercially available selective inhibitor of phosphodiesterase-5 (PDE5) and is widely used for the treatment of erectile dysfunction. In recent years, investigations of the role of sildenafil in cardioprotection in animal models have received considerable interest. We evaluated whether sildenafil can attenuate cisplatin-induced nephrotoxicity in a rat experimental model. Male Sprague-Dawley rats were divided into five groups: control rats, sildenafil-control rats, cisplatin-injected rats (5 mg kg(-1) IP, single dose), sildenafil-treated cisplatin-injected rats (0.4 mg kg(-1), daily), and sildenafil+NG-nitro-l-arginine methyl ester hydrochloride (l-NAME)-treated rats. The molecular, functional, and structural parameters of the kidney were measured. At 96 h after cisplatin injection, serum levels of creatinine were lower in rats treated with both sildenafil+cisplatin compared with rats treated with cisplatin alone, and renal iNOS and eNOS expression was significantly higher in sildenafil+cisplatin-treated rats compared with rats treated with cisplatin alone (all P<0.05). Renal Bax gene and protein expression was significantly higher in cisplatin-treated rats compared with control rats, and sildenafil treatment significantly reduced the levels of Bax and increased the renal Bax/Bcl-2 ratio (P<0.05). Sildenafil treatment also reduced renal caspase-3 activation and TUNEL-positive apoptotic cells. These data suggest that sildenafil attenuates experimental cisplatin-induced nephrotoxicity by preventing apoptosis.
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PMID:Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. 1915 27

Interleukin-10 (IL-10) exerts a wide spectrum of regulatory activities in the immune and inflammatory response. The aim of this study was to investigate the role of endogenous IL-10 on the modulation of the secondary events in mice subjected to spinal cord injury induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. IL-10 wild-type mice developed severe spinal cord damage characterized by oedema, tissue damage and apoptosis (measured by Annexin-V, terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, Bax, Bcl-2, and Fas-L expression). Immunohistochemistry demonstrated a marked increase of localization of TNF-alpha, IL-1beta and S100beta, while western blot analysis shown an increased immunoreactivity of inducible nitric oxide synthase in the spinal cord tissues. The absence of IL-10 in IL-10 KO mice resulted in a significant augmentation of all the above described parameters. We have also demonstrated that the genetic absence of IL-10 worsened the recovery of limb function when compared with IL-10 wild-type mice group (evaluated by motor recovery score). Taken together, our results clearly demonstrate that the presence of IL-10 reduces the development of inflammation and tissue injury events associated with spinal cord trauma.
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PMID:Absence of endogenous interleukin-10 enhances secondary inflammatory process after spinal cord compression injury in mice. 1918 62

Cervical cancer is the most common cancer in Indian females and is associated with infection with high risk Human papillomaviruses (HPVs). Curcumin (Diferuloyl methane), a chemopreventive agent, is a natural compound extracted from Curcuma longa that allows suppression of carcinogenesis. The objective of this study was to identify the molecular mechanism of curcumin induced apoptosis in HPV positive cervical cancer HeLa, SiHa and Ca Ski cells. Curcumin causes distinct inhibition of human telomerase reverse transcriptase (hTERT) the catalytic core of telomerase thereby reducing proliferation of cancer cells. Curcumin mediated apoptosis in these cells appears to be due to upregulation of proapoptotic Bax, AIF, release of cytochrome c and down regulation of antiapoptotic Bcl-2, Bcl-XL in HeLa and SiHa. This was accompanied by an increase in caspase-3 and -9 activity, suggesting the role of mitochondria in curcumin mediated apoptotic cell death. Curcumin acts as an anti-inflammatory and anti-proliferative agent by causing down regulation of COX-2, iNOS and cyclin D1 in all the three cell lines but to different extent.
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PMID:Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells. 1919 Oct 10

Melatonin is a potent antioxidant molecule with a capacity to protect tissues from damage caused by oxidative stress. It reduces cyclosporine A (CsA)-induced cardiotoxicity; this improvement required melatonin's binding to its membrane receptors. This experimental study examined whether melatonin is a useful tool for counteracting CsA-induced apoptosis in the heart of rats. We investigated melatonin's antiapoptotic efficacy in protecting the heart and tested whether this effect was totally dependent on its binding to membrane receptors or also involved radical scavenging. In some animals, solid lipid nanoparticles (SLN) as a melatonin delivery system were used. In one group of rats, melatonin (1 mg/kg/day i.p.) was given concurrently with CsA (15 mg/kg/day s.c.; CsA-MT) for 21 days. In other animals, melatonin loaded in SLN was injected with CsA (CsA-MTSLN). Oxidative stress in heart tissue was estimated using the evaluation of lipid peroxidation and the expression of the isoform of inducible nitric oxide (iNOS). The antiapoptotic effect of melatonin was evaluated using TUNEL staining and Bcl-2 protein family expression. CsA administration produced morphological and biochemical changes in the heart of rats, while melatonin reversed the changes. In particular, since the antiapoptotic melatonin's efficacy is mainly observed when it is loaded in SLN, we suggest that MT1/MT2 pathway is not sufficient for apoptosis antagonism and the additional intracellular effects may be required. Finally, we show that, (i) melatonin significantly reduces CsA cardiotoxicity acting also on apoptotic processes, and (ii) the reduction in CsA-induced cardiotoxicity is mediated mainly by its antioxidant effect.
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PMID:Melatonin delivery in solid lipid nanoparticles: prevention of cyclosporine A induced cardiac damage. 1919 38

Globular adiponectin (gAd), a truncated form of adipocyte-derived cytokine, stimulates RAW 264 cells to produce reactive oxygen species (ROS), which trigger an apoptotic cascade. In this study, we investigated the generation of intracellular and mitochondrial ROS in gAd-stimulated RAW 264 cells. Treatment with gAd efficiently induced the generation of intracellular and mitochondrial ROS, as detected by dichlorodihydrofluorescein diacetate and MitoSOX fluorescence, respectively. Furthermore, gAd treatment significantly increased 8-oxoguanine, a specific indicator of oxidative DNA damage. The transfection of RAW 264 cells with iNOS- and gp91(phox)-specific small interfering RNA reduced markedly the generation of intracellular, but not mitochondrial, ROS. Quantitative PCR revealed that the expression ratio of Bcl-2 to Bax was reduced in a time-dependent manner in gAd-treated RAW 264 cells. The overexpression of Bcl-2 markedly inhibited gAd-induced apoptosis in RAW 264 cells and also reduced both the intracellular and the mitochondrial ROS generation induced by gAd treatment. Moreover, the overexpression of Bcl-2 significantly suppressed gAd-induced NO secretion and NOS activity. In addition, the inhibition of NOS activity partially reduced the oxidative DNA damage induced by gAd. Taken together, these results demonstrate that the gAd-induced apoptotic pathway acting via ROS/RNS generation involves Bcl-2.
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PMID:Globular adiponectin-induced RAW 264 apoptosis is regulated by a reactive oxygen species-dependent pathway involving Bcl-2. 1925 Sep 64

Many natural polyphenolic compounds have been shown to attenuate reactive oxygen/nitrogen species (ROS/RNS) formation and protect against ischemia/reperfusion injury both in vitro and in vivo. 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits antioxidative and anti-inflammatory effects. Here, we used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD-R) and an in vivo ischemic model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of TSG on ischemia/reperfusion brain injury and the related mechanisms. We demonstrated that OGD-R-induced neuronal injury, intracellular ROS generation, and mitochondrial membrane potential dissipation were reversed by TSG. The elevation of H2O2-induced [Ca2+]i was also attenuated by TSG. Inhibition of the c-Jun N-terminal kinase (JNK) and Bcl-2 family-related apoptotic signaling pathway was involved in the neuroprotection afforded by TSG. Meanwhile, TSG inhibited iNOS mRNA expression induced by OGD-R, which may be mediated by the activation of SIRT1 and inhibition of NF-kappaB activation. In vivo studies further demonstrated that TSG significantly reduced the brain infarct volume and the number of positive cells by TUNEL staining in the cerebral cortex compared to the MCAO group. Our study indicates that TSG protects against cerebral ischemia/reperfusion injury through multifunctional cytoprotective pathways.
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PMID:Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. 1927 42

Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). Cotreatment with ERK inhibitor PD98059 abrogated sildenafil-induced protection (31.8 +/- 4.4%). To further evaluate the role of ERK in delayed cardioprotection, mice were treated with sildenafil (ip) 24 h before global ischemia-reperfusion. PD98059 was administered (ip) 30 min before sildenafil treatment. Infarct size was reduced from 27.6 +/- 3.3% in controls to 7.1 +/- 1.5% in sildenafil-treated mice (P < 0.05). The delayed protective effect of sildenafil was also abolished by PD98059 (22.5 +/- 2.3%). Western blots revealed that sildenafil significantly increased phosphorylation of ERK1/2 and GSK-3beta and induced iNOS, eNOS, Bcl-2, and PKG activity in the heart 24 h after treatment. PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.
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PMID:ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice. 1934 60

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
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PMID:Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats. 1947 86


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