Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic myocyte cell death, diastolic dysfunction, and progressive deterioration in left ventricular pump function characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG) transmits danger signals in cardiac muscle cells. The growth factor adapter protein p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here we demonstrate that interventions which attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser36) inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes obtained by enzymatic dissociation were transduced with mutant-36 p66ShcA (mu-36) dominant-negative expression vector and plated in serum-free media containing 5 or 25 mM glucose. At HG, adult rat ventricular myocytes exhibit a marked increase in reactive oxygen species production, upregulation of phospho-Ser36, collapse of mitochondrial transmembrane potential, and increased formation of p66ShcA/cytochrome-c complexes. These indexes of oxidative stress were accompanied by a 40% increase in apoptosis and the upregulation of cleaved caspase-3 and the apoptosis-related proteins p53 and Bax. To test whether p66ShcA functions as a redox-sensitive molecular switch in vivo, we examined the hearts of male Akita diabetic nonobese (C57BL/6J) mice. Western blot analysis detected the upregulation of phospho-Ser36, the translocation of p66ShcA to mitochondria, and the formation of p66ShcA/cytochrome-c complexes. Conversely, the correction of HG by recombinant adeno-associated viral delivery of leptin reversed these alterations. We conclude that p66ShcA is a molecular switch whose redox function is turned on by phospho-Ser36 and turned off by interventions that prevent this modification.
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PMID:Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis. 1906 Jan 30

Elevated blood glucose is a key initiator of mechanisms leading to diabetic neuropathy. Increases in glucose induce acute mitochondrial oxidative stress in dorsal root ganglion (DRG) neurons, the sensory neurons normally affected in diabetic neuropathy, whereas Schwann cells are largely unaffected. We propose that activation of an antioxidant response in DRG neurons would prevent glucose-induced injury. In this study, mild oxidative stress (1 microM H2O2) leads to the activation of the transcription factor Nrf2 and expression of antioxidant (phase II) enzymes. DRG neurons are thus protected from subsequent hyperglycemia-induced injury, as determined by activation of caspase 3 and the TUNEL assay. Schwann cells display high basal antioxidant enzyme expression and respond to hyperglycemia and mild oxidative stress via further increases in these enzymes. The botanical compounds resveratrol and sulforaphane activate the antioxidant response in DRG neurons. Other drugs that protect DRG neurons and block mitochondrial superoxide, identified in a compound screen, have differential ability to activate the antioxidant response. Multiple cellular targets exist for the prevention of hyperglycemic oxidative stress in DRG neurons, and these form the basis for new therapeutic strategies against diabetic neuropathy.
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PMID:Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms. 1907 99

Diabetic nephropathy, the leading cause of end-stage renal disease, is characterized by a proapoptotic and prooxidative environment. The mechanisms by which lifestyle interventions, such as exercise, benefit diabetic nephropathy are unknown. We hypothesized that exercise inhibits early diabetic nephropathy via attenuation of the mitochondrial apoptotic pathway and oxidative damage. Type 2 diabetic db/db and normoglycemic wild-type mice were exercised for an hour everyday at a moderate intensity for 7 wk, following which renal function, morphology, apoptotic signaling, and oxidative stress were evaluated. Exercise reduced body weight, albuminuria, and pathological glomerular expansion in db/db mice independent of hyperglycemic status. Changes in renal morphology were also related to reduced caspase-3 (main effector caspase in renal apoptosis), caspase-8 (main initiator caspase of the "extrinsic" pathway) activities, and TNF-alpha expression. A role for the mitochondrial apoptotic pathway was unlikely as both caspase-9 activity (initiator caspase of this pathway) and expression of regulatory proteins such as Bax and Bcl-2 were unchanged. Kidneys from db/db mice also produced higher levels of superoxides and had greater oxidative damage concurrent with downregulation of superoxide dismutase (SOD) 1 and 3. Interestingly, although exercise also increased superoxides, there was also upregulation of multiple SODs that likely inhibited lipid (hydroperoxides) and protein (carbonyls and nitrotyrosine) oxidation in db/db kidneys. In conclusion, exercise can inhibit progression of early diabetic nephropathy independent of hyperglycemia. Reductions in caspase-3 and caspase-8 activities, with parallel improvements in SOD expression and reduced oxidative damage, could underlie the beneficial effects of exercise in diabetic kidney disease.
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PMID:Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. 1914 89

We examined the effect of type 2 diabetes on stroke-induced Alzheimer's disease-like pathological and behavioral changes in rats. Rats were treated for 2 months with high fat diet (HFD) followed by streptozotocin (STZ) injection to induce type 2 diabetes (HFD-STZ model). Middle cerebral artery occlusion (MCAO) was used to induce cerebral focal ischemia. Animals were divided into four groups: Sham-NPD, Sham-HFD-STZ, MCAO-NPD and MCAO-HFD-STZ. The results showed that HFD-STZ treatment induced obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia and insulin resistance, characteristics of type 2 diabetes. The performance of rats in the Morris water maze test was impaired in MCAO-NPD and Sham-HFD-STZ rats, indicating cognitive deficits. Hippocampal caspase-3+ and beta amyloid (Abeta+) cell numbers, as well as beta-site amyloid precursor protein-cleaving enzyme (BACE1) levels and activity, increased in both groups. Moreover, HFD-STZ treatment exacerbated stroke-induced cognitive deficits, additively increased MCAO-induced activation of caspase-3, and increased levels of BACE1, C99 and Abeta. However, the level of insulin decreased in MCAO-HFD-STZ rats. These results suggested that type 2 diabetes deteriorated stroke-induced brain damage and cognitive impairment, which might be associated with increased Abeta generation and cytotoxicity. We concluded that type 2 diabetes exacerbated poststroke dementia possibly due to brain injury and synergistic generation of Abeta via activation of BACE1.
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PMID:Exacerbation of poststroke dementia by type 2 diabetes is associated with synergistic increases of beta-secretase activation and beta-amyloid generation in rat brains. 1937 2

Hyperglycemia, which occurs under the diabetic condition, is widely recognized as the causal link between diabetes and its serious complications. Diabetic neuropathies, which are among the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. The exact molecular mechanisms of high glucose-induced toxicity on neuronal cells, is still unclear. We previously reported that high glucose can induce apoptosis in PC12 cells, as evidenced by DNA fragmentation and high Bax/Bcl-2 ratio. The present study examined the involvement of caspase-3, the executioner, and two initiators of apoptosis, caspase-8 and caspase-9, during high glucose-induced apoptosis in PC12 cells, a neuronal cell line. Cells were exposed to high glucose with or without z-VAD-fmk, a pan-caspase inhibitor. Cell viability was measured by MTT assay. Caspase activity was determined spectrophotometrically using enzyme specific substrates. To correlate and confirm the caspase activity with changes in protein expression, procaspase-8, -9, and -3 were evaluated by Western blot analysis. The DNA-fragmentation was determined by DNA ladder using gel electrophoresis. The PC12 cell viability on high glucose exposure was decreased compared to controls, which was reversed by z-VAD-fmk. The activities of caspase-8, -9, and -3 were significantly increased in treated cells compared to controls. Moreover, high glucose exposure induced a significant decrease in protein levels of procaspases, indicating conversion of pro-form into the mature caspases. Finally, DNA fragmentation (Ladder) was shown in treated cells by high glucose. Based on the current data, it could be concluded that high glucose-induced apoptosis in PC12 cells is mediated, in part, by activation of caspase-8, -9, and -3 dependent pathways.
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PMID:Involvement of caspase-8, -9, and -3 in high glucose-induced apoptosis in PC12 cells. 1946 86

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. Reactive oxygen/nitrogen species, cytokines and apoptosis are implicated in the pathogenesis of diabetic neuropathy. The aim of the present study was to explore the effect of tocotrienol on thermal and mechanical hyperalgesia, allodynia, oxidative-nitrosative stress, inflammation and apoptosis in streptozotocin-induced experimental diabetes. Diabetic rats developed neuropathy which was evident from a marked hyperalgesia and allodynia associated with enhanced nitrosative stress, release of inflammatory mediators (TNF-alpha, IL-1beta, TGF-1beta) and caspase-3. Chronic treatment with tocotrienol (25, 50 and 100 mg/kg body weight; p.o.) for 4 weeks starting from the 4th week of streptozotocin injection significantly attenuated behavioral, biochemical and molecular changes associated with diabetic neuropathy. Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced beneficial effect as compared to their per se groups. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, combination with tocotrienol not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release and caspase-3 in the diabetic rats and thus it may find clinical application to treat neuropathic pain in the diabetic patients.
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PMID:Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. 1955 1

Hyperglycemia-induced oxidative stress has been suggested as a mechanism underlying diabetic complications. Oxidative stress triggers cell death in various cell types, including glomerular mesangial cells which play important roles in diabetic nephropathy. In the present study, we investigated the potential cytoprotective effect of erigeroflavanone, a novel flavanone derivative from the flowers of Erigeron annuus, in cultured mouse mesangial cells using hydrogen peroxide (H2O2) as an oxidative stress inducer. Our data show that hydrogen peroxide induced a decrease in cell viability that was attenuated by erigeroflavanone. Hydrogen peroxide treatment increased formation of dichlorofluorescein (DCF)-sensitive intracellular reactive oxygen species (ROS). This enhanced ROS formation was significantly reduced by pretreatment with erigeroflavanone in a dose-dependent manner. Hydrogen peroxide treatment also induced phosphorylation of the mitogen-activated protein kinases (MAPKs), c-Jun terminal kinase (JNK), extracellular-regulated kinase (ERK) and p38, and activated caspase-3. Pretreatment with erigeroflavanone inhibited hydrogen peroxide-induced activation of MAPKs and caspase-3. From these data we conclude that erigeroflavanone provides a protective effect against oxidative stress-induced cell death in mesangial cells that is associated with its antioxidant action and inhibition of MAPKs and caspase-3. These results suggest that erigeroflavanone has potential as a therapeutic agent in the treatment of renal diabetic complications.
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PMID:Cytoprotection against hydrogen peroxide-induced cell death in cultured mouse mesangial cells by erigeroflavanone, a novel compound from the flowers of Erigeron annuus. 1955 77

Diabetic nephropathy is a common cause for end-stage renal disease. Present study investigated the beneficial role of arjunolic acid (AA) against streptozotocin (STZ) induced diabetic nephropathy in rats. Diabetic renal injury was associated with increased kidney weight to body weight ratio, glomerular area and volume, blood glucose (hyperglycemia), urea nitrogen and serum creatinine. This nephro pathophysiology increased the productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS), enhanced lipid peroxidation, protein carbonylation and decreased intracellular antioxidant defense in the kidney tissue. In addition, hyperglycemia activates polyol pathway by increasing aldose reductase (AR) with a concomitant reduction in Na+-K+-ATPase activity. Investigating the oxidative stress responsive signaling cascades, we found the activation of PKCdelta, PKCvarepsilon, MAPKs and NF-kappaB (p65) in the renal tissue of the diabetic animals. Furthermore, hyperglycemia disturbed the equilibrium between the pro and anti-apoptotic members of Bcl-2 family of proteins as well as reduced mitochondrial membrane potential, elevated the concentration of cytosolic cytochrome C and caspase-3 activity. Treatment of AA effectively ameliorated diabetic renal dysfunctions by reducing oxidative as well as nitrosative stress and deactivating the polyol pathways. Histological studies also support the experimental findings. Results suggest that AA might act as a beneficial agent against the renal dysfunctions developed in STZ-induced diabetes.
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PMID:Prophylactic role of arjunolic acid in response to streptozotocin mediated diabetic renal injury: activation of polyol pathway and oxidative stress responsive signaling cascades. 1968 44

Diabetic heart disease contributes to the high mortality in diabetics, although effective clinical management is lacking. The protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) was reported to protect the hearts against ischemic injury. This study examined the role of UCF-101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF-101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF-101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr(172) of catalytic alpha-subunit, which was restored by UCF-101. Neither diabetes nor UCF-101 affected the expression of HtrA2/Omi and XIAP or caspase-3 activity. The AMPK activator resveratrol mimicked the UCF-101-induced beneficial effect against diabetic cardiac dysfunction. Mechanical properties in cardiomyocytes from the AMPK-kinase-dead (KD) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF-101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiac dysfunction, possibly through AMPK signaling.
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PMID:UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK. 1969 68

Hyperglycemia induces p38 MAPK-mediated renal proximal tubular cell (RPTC) apoptosis. The current study hypothesized that alteration of the Akt signaling pathway by hyperglycemia may contribute to p38 MAPK activation and development of diabetic nephropathy. Immunoblot analysis demonstrated a hyperglycemia-induced increase in Akt phosphorylation in diabetic kidneys at 1 mo, peaking at 3 mo, and dropping back to baseline by 6 mo. Immunohistochemical staining with anti-pAkt antisera localized Akt phosphorylation to renal tubules. Maximal p38 MAPK phosphorylation was detected concomitant with increase in terminal uridine deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity in 6-mo diabetic kidneys. Exposure of cultured RPTCs to high glucose (HG; 22.5 mM) significantly increased Akt phosphorylation at 3, 6, and 9 h, and decreased thereafter. In contrast, p38 MAPK phosphorylation was detected between 9 and 48 h of HG treatment. Increased p38 MAPK activation at 24 and 48 h coincided with increased apoptosis, demonstrated by increased caspase-3 activity at 24 h and increased TUNEL-positive cells at 48 h of HG exposure. Blockade of p38 cascade with SB203850 inhibited HG-induced caspase-3 activation and TUNEL-positive cells. Overexpression of constitutively active Akt abrogated HG-induced p38 MAPK phosphorylation and RPTC apoptosis. In addition, blockade of the phosphatidylinositol-3 kinase/Akt pathway with LY294002 and silencing of Akt expression with Akt small interfering RNA induced p38 MAPK phosphorylation in the absence of HG. These results collectively suggest that downregulation of Akt activation during long-term hyperglycemia contributes to enhanced p38 MAPK activation and RPTC apoptosis. Mechanism of downregulation of Akt activation in 6-mo streptozotocin diabetic kidneys was attributed to decreased Akt-heat shock protein (Hsp) 25, Akt-p38 interaction, and decreased PTEN activity. Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK-mediated diabetic complications.
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PMID:Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy. 1972 50


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