Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent clinical trials indicate that the severity of diabetic neuropathy is correlated with the level of patient glycemic control. In the current study, hyperglycemia induces apoptotic changes in dorsal root ganglion neurons and Schwann cells in vivo both in streptozotocin-treated diabetic rats and in rats made acutely hyperglycemic with infused glucose. Typical apoptotic nuclear and cytoplasmic changes are observed. In addition mitochondrial changes recently reported to occur as part of the apoptotic cascade, such as ballooning of mitochondria and disruption of the internal cristae, are seen in diabetic dorsal root ganglion neurons and Schwann cells. Similar changes have been reported in neurons in the presence of oxidative stress. In order to study the neurotoxic effects of high glucose we developed an in vitro model using rat dorsal root ganglion neurons. In dorsal root ganglion cultured in defined medium, addition of moderate glucose levels results in neurite degeneration and apoptosis. These changes are coupled with activation of caspase-3, dependent on the concentration of glucose. The apoptotic changes observed in vitro are similar to those observed in vivo. In contrast, addition of IGF-I, even at physiological concentrations, prevents activation of caspase-3 and neuronal apoptosis in vitro. We suggest that oxidative stress may promote the mitochondrial changes in diabetic animals and lead to activation of programmed cell death caspase pathways. These results imply a new pathogenetic mechanism for diabetic sensory neuropathy.
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PMID:Neurons undergo apoptosis in animal and cell culture models of diabetes. 1052 3

The metabolic effects of hyperglycemia and hypoxia are important in the pathogenesis of diabetic neuropathy. We demonstrated apoptosis in dorsal root ganglion neurons in vitro by employing an oxygen-glucose deprivation model that uses dorsal root ganglia incubated in room air (pO2=150 torr) followed by hypoxic conditions (pO2=7.6 torr). Apoptosis was confirmed by demonstrating caspase-3 activation by immunocytochemistry. Immunocytochemistry and western blot analysis demonstrated an increase in activated p53, suggesting that DNA damage was occurring. Cell cycle disruption was examined by cyclin D1 expression. Neuronal death was associated with up-regulation of markers associated with DNA damage and aberrant entry into G1 of the cell cycle.
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PMID:Hypoxia-induced apoptosis of dorsal root ganglion neurons is associated with DNA damage recognition and cell cycle disruption in rats. 1469 47

Dorsal root ganglia neurons in culture die through programmed cell death when exposed to elevated glucose, providing an in vitro model system for the investigation of the mechanisms leading to diabetic neuropathy. This study examines the time course of programmed cell death induction, regulation of cellular antioxidant capacity, and the protective effects of antioxidants in neurons exposed to hyperglycemia. We demonstrate that the first 2 h of hyperglycemia are sufficient to induce oxidative stress and programmed cell death. Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia. These are followed by caspase-3 activation and DNA fragmentation. Antioxidant potential increases by 3-6 h but is insufficient to protect these neurons. Application of the antioxidant alpha-lipoic acid potently prevents glucose-induced oxidative stress and cell death. This study identifies cellular therapeutic targets to prevent diabetic neuropathy. Since oxidative stress is a common feature of the micro- and macrovascular complications of diabetes, the present findings have broad application to the treatment of diabetic patients.
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PMID:Short-term hyperglycemia produces oxidative damage and apoptosis in neurons. 1567 96

Mild ischemia-reperfusion (IR) injury to diabetic peripheral nerve is known to cause severe ischemic fiber degeneration. Little information is available on its effects on Schwann cell (SC). In this study, we evaluated oxidative stress and apoptosis of SC following mild IR, using immunohistochemistry in streptozotocin (STZ)- induced diabetic rats. Twenty-six rats were divided into four groups according to the duration of diabetes: 1- month STZ-induced diabetic group (n=7) and age-matched control group (n=7); 4-month STZ-induced diabetic group (n=6) and age-matched control group (n=6). Using our established IR model of 3 h of ischemia followed by 7 days of reperfusion, sciatic and tibial nerves were harvested and labeled with 8-hydroxydeoxyguanosine (8-OHdG; oxidative stress marker), caspase-3 (apoptotic executor), and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) activity (apoptotic indicator). Marked positive staining with 8-OHdG, caspase-3, and TUNEL were found in diabetic ischemic nerves (right side) following IR in both 1-month and 4-month groups. Only mild positive staining or no staining was seen in the nonischemic side (left side) of diabetic and age-matched control groups. Co-labeling with S-100 confirmed that the cells labeled with 8-OHdG, caspase3, and TUNEL were SC. SC was susceptible to oxidative injury and apoptosis in experimental diabetic neuropathy when subjected to mild IR injury.
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PMID:Ischemia-reperfusion injury causes oxidative stress and apoptosis of Schwann cell in acute and chronic experimental diabetic neuropathy. 1635 15

The receptor for advanced glycation end products (RAGE) may promote diabetic vascular and renal disease through the activation of intracellular signaling pathways that promote oxidative stress. Oxidative stress is a mediator of hyperglycemia-induced cell injury and a unifying theme for all mechanisms of diabetic complications, but there are few studies on the expression and potential contribution of RAGE in diabetic neuropathy. The current study demonstrates that dorsal root ganglia neurons express functional RAGE and respond to the RAGE ligand S100 with similar downstream signaling, oxidative stress, and cellular injury as other diabetic complication-prone tissues. RAGE-induced phosphatidylinositol-3 kinase activity is associated with formation of reactive oxygen species, caspase-3 activation, and nuclear DNA degradation. These events are prevented by treatment with the antioxidant alpha-lipoic acid. Our data indicate that therapies aimed at decreasing RAGE ligands, blocking RAGE signaling, or preventing oxidative stress could significantly decrease the development of neuropathy in diabetic patients.
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PMID:Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. 1709 86

Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that overexpression of SOD2 decreases superoxide (O(2)(-)) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Underexpression of SOD2 in dissociated DRG cultures from adult SOD2(+/-) mice results in increased levels of O2-, activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2(+/-) C57BL/6J mice and their SOD2(+/+) littermates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.
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PMID:SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy. 1792 81

The mechanism/s leading to diabetic neuropathy are complex. Transforming growth factor-beta1 (TGF-beta1) has been associated with diabetic nephropathy and retinopathy but not neuropathy. In this study, changes in TGF-beta isoforms were examined in vivo and in vitro. Two groups of animals, streptozotocin diabetic with neuropathy and non-diabetic controls were examined at 4 weeks (n=10/group) and 12 weeks (n=8/group). In diabetic DRG using quantitative real-time PCR (QRT-PCR), TGF-beta1 and TGF-beta2 mRNA, but not TGF-beta3, was increased at 4 and 12 weeks. In sciatic nerve TGF-beta3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-beta formed homo- and hetero-dimers, of which beta(2)/beta(3), beta(1)/beta(1), and beta(1)/beta(3) were significantly increased, while that of the TGF-beta(2)/beta(2) homodimer was decreased, in diabetic compared to non-diabetic rats. In vitro, pretreatment of embryonic DRG with TGF-beta neutralizing antibody prevents the increase in total TGF-beta protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-beta2>beta1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-beta neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in diabetic DRG and nerve, TGF-beta isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-beta neutralizing antibody. These findings implicate upregulation of TGF-beta in experimental diabetic peripheral neuropathy and indicate a novel mechanism of cellular injury related to elevated glucose levels. In combination, these findings indicate a potential new target for treatment of diabetic peripheral neuropathy.
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PMID:Transforming growth factor-beta induces cellular injury in experimental diabetic neuropathy. 1840 5

In the process of glycation, methylglyoxal is a reactive dicarbonyl compound physiologically generated as an intermediate of glycolysis, and is found in high levels in blood or tissue of diabetic models. Biological glycation has been commonly implicated in the development of diabetic microvascular complications of neuropathy. Increasing evidence suggests that neuronal cell cycle regulatory failure followed by apoptosis is an important mechanism in the development of diabetic neuropathy complication. Naturally occurring antioxidants, especially phenolic acids have been recommended as the major bioactive compounds to prevent chronic diseases and promote health benefits. The objective of this study was to investigate the inhibitory abilities of phenolic acids (chlorogenic acid, syringic acid and vanillic acid) on methylglyoxal-induced mouse Neuro-2A neuroblastoma (Neuro-2A) cell apoptosis in the progression of diabetic neuropathy. The data indicated that methylglyoxal induced mouse Neuro-2A neuroblastoma (Neuro-2A) cell apoptosis via alternation of mitochondria membrane potential and Bax/Bcl-2 ratio, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase. Furthermore, the results demonstrated that activation of mitogen-activated protein kinase signal pathways (JNK and p38) participated in the methylglyoxal-induced Neuro-2A cell apoptosis process. Treatment of Neuro-2A cells with phenolic acids markedly suppresses cell apoptosis induced by methylglyoxal, suggesting that phenolic acids possess cytoprotective ability in the prevention of diabetic neuropathy complication.
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PMID:Cytoprotective effects of phenolic acids on methylglyoxal-induced apoptosis in Neuro-2A cells. 1848 34

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


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