Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperglycemia, a symptom of diabetes mellitus, induces hyperosmotic responses, including apoptosis, in vascular endothelial cells and leukocytes. Hyperosmotic shock elicits a stress response in mammalian cells, often leading to apoptotic cell death. In a previous report, we showed that hyperosmotic shock induced apoptosis in various mammalian cells. Importantly, apoptotic biochemical changes (i.e., caspase-3 activation and DNA fragmentation) were blocked by antioxidant pretreatment during hyperosmotic shock-induced cell death. In the present study, we report that resveratrol, a phytoalexin present in grapes with known antioxidant and anti-inflammatory properties, attenuates high glucose-induced apoptotic changes, including c-Jun N-terminal kinase (JNK) activation and caspase-3 activation in human leukemia K562 cells. Experiments with the cell permeable dye, 2',7'-dichlorofluorescein diacetate (DCF-DA), an indicator of reactive oxygen species (ROS) generation, revealed that high glucose treatment directly increased intracellular oxidative stress, which was attenuated by resveratrol. In addition, high glucose-treated K562 cells displayed a lower degree of attachment to collagen, the major component of vessel wall subendothelium. In contrast, cells pretreated with resveratrol followed by high glucose exhibited higher affinity for collagen. The results of this report collectively imply the involvement of oxidative stress in high glucose-induced apoptosis and alterations in attachment ability. Moreover, resveratrol blocks these events by virtue of its antioxidant property.
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PMID:Effect of resveratrol on high glucose-induced stress in human leukemia K562 cells. 1572 79

A variety of explanations have been provided to elucidate the requirement of the large islet mass that is essential for a successful treatment of patients with type I diabetes by intrahepatic transplantation. The purpose of this study was to investigate islet cell survival under the effect of prolonged hypoxia and/or nutrient withdrawal, which mimics posttransplantation environment of transplanted islets in the liver. We studied the influence of 24 h of hypoxia (1% O2) in intact isolated human and rat islets as well as the effect of combined oxygen/nutrient deprivation in a mouse insulinoma cell line (MIN6). In intact human islets, 24 h of hypoxia led to central necrosis combined with apoptotic features such as nuclear pyknosis and DNA fragmentation. In the course of hypoxic treatment, ultrastructural analysis demonstrated a gradual transition from an apoptotic to a necrotic morphology particularly pronounced in central areas of large islets. In MIN6 cells, on the other hand, hypoxia led to a twofold (p < 0.01) increase in caspase-3 activity, an indicator of apoptosis, but not to necrosis, as determined by release of lactate dehydrogenase (LDH). Only in combination with nutrient/serum deprivation was a marked increase in LDH release observed (sixfold vs. control, p < 0.01). We therefore conclude that, similar to MIN6 cells, central necrosis in isolated hypoxic islets is the result of the combined effects of hypoxia and nutrient/serum deprivation, most likely due to limited diffusion. Provided that transplanted islets undergo a similar fate as shown in our in vitro study, future emphasis will require the development of strategies that protect the islet graft from early cell death and accelerate the revascularization process.
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PMID:Central necrosis in isolated hypoxic human pancreatic islets: evidence for postisolation ischemia. 1578 64

beta-Cell apoptosis is a key event contributing to the pathogenesis of type 1 diabetes mellitus. In addition to apoptosis being the main mechanism by which beta cells are destroyed, beta-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus through antigen cross-presentation mechanisms that lead to beta-cell-specific T-cell activation. Caspase-3 is the major effector caspase involved in apoptotic pathways. Despite evidence supporting the importance of beta-cell apoptosis in the pathogenesis of type 1 diabetes, the specific role of caspase-3 in this process is unknown. Here, we show that Caspase-3 knockout (Casp3(-/-) mice were protected from developing diabetes in a multiple-low-dose streptozotocin autoimmune diabetes model. Lymphocyte infiltration of the pancreatic islets was completely absent in Casp3(-/-) mice. To determine the role of caspase-3-dependent apoptosis in disease initiation, a defined antigen-T-cell receptor transgenic system, RIP-GP/P14 double-transgenic mice with Casp3 null mutation, was examined. beta-cell antigen-specific T-cell activation and proliferation were observed only in the pancreatic draining lymph node of RIP-GP/P14/Casp3(+/-) mice, but not in mice lacking caspase-3. Together, our findings demonstrate that caspase-3-mediated beta-cell apoptosis is a requisite step for T-cell priming, a key initiating event in type 1 diabetes.
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PMID:Caspase-3-dependent beta-cell apoptosis in the initiation of autoimmune diabetes mellitus. 1583 67

Diabetes leads to vascular leakage, glial dysfunction, and neuronal apoptosis within the retina. The goal of the studies reported here was to determine the role that retinal microglial cells play in diabetic retinopathy and assess whether minocycline can decrease microglial activation and alleviate retinal complications. Immunohistochemical analyses showed that retinal microglia are activated early in diabetes. Furthermore, mRNAs for interleukin-1beta and tumor necrosis factor-alpha, proinflammatory mediators known to be released from microglia, are also increased in the retina early in the course of diabetes. Using an in vitro bioassay, we demonstrated that cytokine-activated microglia release cytotoxins that kill retinal neurons. Furthermore, we showed that neuronal apoptosis is increased in the diabetic retina, as measured by caspase-3 activity. Minocycline represses diabetes-induced inflammatory cytokine production, reduces the release of cytotoxins from activated microglia, and significantly reduces measurable caspase-3 activity within the retina. These results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.
Diabetes 2005 May
PMID:Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. 1585 46

We have hypothesized that p75 neurotrophin receptor (p75(NTR))-mediated activation of the pro-apoptotic proteins c-jun, p38 and caspase-3 underlies the neuronal cell loss in dorsal root ganglia (DRG) neurons after axotomy in normal mice, and that this activation is exaggerated in experimental diabetes. To test this hypothesized relationship, we compared the expression of pro-apoptotic proteins in fifth lumbar DRG (L5DRG) neurons of wildtype Balb/c (p75+/+) mice and p75(NTR) knockout (p75-/-) mice, assigned to either non-diabetic control groups or to diabetic (1 month) groups, all with a unilateral sciatic nerve crush produced 10 days before tissue preparation. The absolute number of L5DRG neurons expressing immunoreactivities (IR) for phosphorylated c-jun (P-c-jun-IR), phosphorylated p-38 (P-p38-IR) and cleaved caspase-3 (caspase-3-IR) were estimated in semi-thick sections using the optical fractionator. Nerve crush increased the numbers of P-c-jun-IR and caspase-3-IR neurons in all four groups. On the crush side, diabetes did not exaggerate the increase of P-c-jun-IR or caspase-3-IR neurons in p75+/+ mice, whereas in p75-/- mice diabetes reduced the increase of P-c-jun-IR neurons. Also, in p75-/- mice there was fewer caspase-3-IR cells on the intact and crushed side in comparison with p75+/+ mice independent of the presence of diabetes. This study demonstrates that (1) diabetes of 1 month's duration does not potentiate the expression of three pro-apoptotic markers p38, caspase-3 and P-c-jun neither in intact neurons nor after nerve crush, and that (2) p75(NTR) is required for activation of the pro-apoptosis signal caspase-3 after nerve crush in both diabetic and non-diabetic mice.
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PMID:Differential effect of p75 neurotrophin receptor on expression of pro-apoptotic proteins c-jun, p38 and caspase-3 in dorsal root ganglion cells after axotomy in experimental diabetes. 1585 12

Methylglyoxal (MG) is a reactive dicarbonyl compound endogenously produced mainly from glycolytic intermediates. Elevated MG levels in diabetes patients are believed to contribute to diabetic complications. MG is cytotoxic through induction of apoptosis. Curcumin, the yellow pigment of Curcuma longa, is known to have antioxidant and anti-inflammatory properties. In the present study, we examined the effect of curcumin on apoptotic biochemical events caused by incubation of ESC-B5 cells with MG. Curcumin inhibited the MG-induced DNA fragmentation, caspase-3 activation, cleavage of PARP, mitochondrial cytochrome c release, and JNK activation. Importantly, curcumin also inhibited the MG-stimulated increase of reactive oxygen species (ROS) in these cells. In addition, we demonstrated that curcumin prevented the MG-induced apoptosis of mouse blastocysts isolated from pregnant mice. Moreover, curcumin significantly reduced the MG-mediated impairment of blastocyst development from mouse morulas. The results support the hypothesis that curcumin inhibits MG-induced apoptosis in mouse ESC-B5 cells and blastocysts by blocking ROS formation and subsequent apoptotic biochemical events.
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PMID:Curcumin prevents methylglyoxal-induced oxidative stress and apoptosis in mouse embryonic stem cells and blastocysts. 1588 45

Poly(ADP-ribose)polymerase (PARP-1), a nuclear enzyme activated by DNA strand breaks, is involved in DNA repair, aging, inflammation, and neoplastic transformation. In diabetes, reactive oxygen and nitrogen species occurring in response to hyperglycemia cause DNA damages and PARP-1 activation. Because circulating mononuclear cells (MNCs) are involved in inflammation mechanisms, these cells were chosen as the experimental model to evaluate PARP-1 levels and activity in patients with type 2 diabetes. MNCs were isolated from 25 diabetic patients (18 M, 7 F, age, 63.5 +/- 10.2 years, disease duration 17.7 +/- 8.2 years) and 11 age and sex matched healthy controls. PARP-1 expression and activity were analyzed by semi-quantitative PCR, Western and activity blot, and immunofluorescence microscopy. PARP-1-mRNA expression was increased in MNCs from all diabetic patients versus controls (P < 0.01), whereas PARP-1 content and activity were significantly lower in diabetic patients (P < 0.0001). To verify whether low PARP-1 levels and activity were due to a proteolytic effect of caspase-3 like, the latter activation was measured by a fluorimetric assay. Caspase-3 activity in MNCs was significantly higher in diabetic patients versus control subjects (P < 0.0001). The different PARP-1 behavior in MNCs from patients with type 2 diabetes could therefore be responsible for the abnormal inflammation and infection responses in diabetes.
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PMID:Poly(ADP-ribose)polymerase activity is reduced in circulating mononuclear cells from type 2 diabetic patients. 1589 95

Apoptosis of pericytes (PCs) is an early event in diabetic retinopathy. It is generally thought to be a consequence of sustained hyperglycemia. In keeping with this, long-term (>7 days) incubation of cultured PCs in a high-glucose media has been shown to increase apoptosis. We examine here whether the saturated free fatty acid palmitate, the concentration of which is often elevated in diabetes, has similar effects on cultured PCs. Incubation with 0.4 mmol/l palmitate for 24 h induced both oxidant stress and apoptosis, as evidenced by a sixfold increase in DCF fluorescence and a twofold increase in caspase-3 activation, respectively. NAD(P)H oxidase appeared to be involved in these responses, since overexpression of dominant-negative subunits of NAD(P)H oxidase, such as phox47(DN), diminished oxidant stress, and phox67(DN) and N-17 RAC1(DN) prevented the increase in caspase-3 activity. Likewise, overexpression of vRAC, a constitutively active RAC1, increased caspase-3 activity to the same extent as palmitate alone. The effects of vRAC and palmitate were not additive. In parallel with the increases in oxidative stress, the redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB) was activated in cells incubated with 0.4 mmol/l palmitate. Furthermore, inhibition of NF-kappaB activation by various means inhibited caspase-3 activation. Finally, incubation with palmitate increased the cellular content of ceramide, a molecule linked to apoptosis and increases in oxidative stress and NF-kappaB activation in other cells. In keeping with such a role, in PCs both coincubation with fumonisin B1 (a ceramide synthase inhibitor) and overexpression of ceramidase I reversed the proapoptotic effect of palmitate. On the other hand, they increased rather than decreased DCF fluorescence. In conclusion, the results suggest that palmitate-induced apoptosis in PCs is associated with activation of NAD(P)H oxidase and NF-kappaB and an increase in ceramide. The precise interactions between these molecules in causing apoptosis and the importance of oxidant stress as a contributory factor remain to be determined.
Diabetes 2005 Jun
PMID:Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P)H oxidase, oxidant stress, and ceramide. 1591 7

High-fat diet intake often leads to obesity, insulin resistance and hypertension, which present a common and detrimental health problem. However, precise mechanism underlying tissue damage due to high-fat diet-induced obesity has not been carefully elucidated. The present study was designed to examine the effect of high-fat diet intake on visceral advanced glycation end products (AGEs) formation, nuclear O-Glc-NAc modification and apoptosis in heart, liver and kidney. Adult male Sprague-Dawley weight-matched rats were fed for 12 weeks with a high-fat diet (45% kcal from fat) or an isocaloric low-fat diet (10% kcal from fat). High-fat diet feeding significantly elevated body weight. Blood pressure and heart rate were comparable between the two rat groups. Competitive enzyme-linked immunosorbent assay showed significantly elevated serum AGE levels, visceral AGE formation, caspase-3 activation and cytoplasmic DNA fragmentation in heart and liver but not kidney samples of high-fat diet fed rats compared with those from low-fat diet fed group. Western blot analysis further revealed that high-fat diet feeding induced overt nuclear O-Glc-NAc modification and p38 mitogen-activated protein kinase activation in heart and liver although not in kidney samples of the high-fat diet-fed rats. Collectively, our results indicated that high-fat diet intake is associated with obesity accompanied by elevated serum and visceral AGEs, visceral post-translational nuclear O-Glc-NAcylated modification and apoptosis, which may contribute to high-fat diet-induced tissue damage.
Diabetes Obes Metab 2005 Jul
PMID:High-fat diet enhances visceral advanced glycation end products, nuclear O-Glc-Nac modification, p38 mitogen-activated protein kinase activation and apoptosis. 1595 32

Methylglyoxal (MG) is a reactive dicarbonyl compound endogenously produced mainly from glycolytic intermediates. Elevated MG levels in diabetes patients are believed to contribute to diabetic complications. MG is cytotoxic through induction of apoptosis. Curcumin, the yellow pigment of Curcuma longa, is known to have antioxidant and anti-inflammatory properties. In the present study, we investigated the effect of curcumin on MG-induced apoptotic events in human hepatoma G2 cells. We report that curcumin prevented MG-induced cell death and apoptotic biochemical changes such as mitochondrial release of cytochrome c, caspase-3 activation, and cleavage of PARP (poly [ADP-ribose] polymerase). Using the cell permeable dye 2',7'-dichlorofluorescein diacetate (DCF-DA) as an indicator of reactive oxygen species (ROS) generation, we found that curcumin abolished MG-stimulated intracellular oxidative stress. The results demonstrate that curcumin significantly attenuates MG-induced ROS formation, and suggest that ROS triggers cytochrome c release, caspase activation, and subsequent apoptotic biochemical changes.
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PMID:Curcumin inhibits ROS formation and apoptosis in methylglyoxal-treated human hepatoma G2 cells. 1596 83


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