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

Male Wistar rats were subjected to intraperitoneal (i.p.) streptozotocin (STZ) administration (85 mg/kg) to evoke diabetes. Cerebral ischaemia was produced by injection of 0.03 ml of air into the left carotid followed by bilateral common carotid ligation. We studied the effect of application of two antioxidants--coenzyme Q10 (CoQ10, 10 mg/kg b.w., i.p. for seven days) and lipoic acid (LA, 100 mg/kg b.w., i.p. for seven days) on neurones and on the apoptosis-related enzyme--caspase-3 activity in the hippocampus and dentate gyrus. Ischaemia and diabetes lead to a decrease of nuclear and perikaryon diameters as well as neuronal density in the CA1, CA2, CA3 and dentate gyrus. Application of CoQ10 or LA for seven days improved the mean nucleus area and perikaryon area in almost all investigated structures. Both antioxidants diminished neuronal loss in the diabetes complicated with ischaemia but not in the animals with diabetes only. Activity of one of the key enzymes in apoptotic cell death, caspase-3 (CPP32), increased in hippocampus in the diabetic rats, in the animals with cerebral ischaemia and in the rats with both diabetes and ischaemia by about 80%, 33% and 53%, respectively. Either the CoQ10 or the LA treatment led to a significant decrease of the CPP32 activity in all experimental groups. Our results confirm the presence of neuronal damage and death in the hippocampus and dentate gyrus in the experimental STZ-diabetes and its aggravation by the additional cerebral ischaemia. The effects of the antioxidative treatment support the hypothesis of an important role of oxidative stress and free radicals in neuronal pathology in diabetes and ischaemia. The above results of CPP32 activity suggest an important role of apoptosis as a mechanism of cell death and demonstrate the positive effect of the CoQ10 and the LA treatment.
 ...
PMID:Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. 1177 Jan 25

Exposure of pancreatic beta-cells to cytokines, such as interleukin-1beta (IL-1beta), is thought to contribute to the beta-cell apoptosis that underlies the onset of type 1 diabetes. One important event triggered by IL-1beta is induction of nitric oxide synthase (iNOS), an enzyme that catalyzes intracellular generation of the cytotoxic free radical NO. We recently described a novel requirement for the protein kinase C (PKC) isozyme PKCdelta in this process. Our current aim, therefore, was to assess whether PKCdelta also plays a role in beta-cell apoptosis. As assessed by either annexin V staining or DNA fragmentation, IL-1beta caused INS-1 cells to undergo apoptosis. This was completely blocked by adenoviral overexpression of a dominant-negative, kinase-dead (KD) PKCdelta mutant. The corresponding PKCalpha virus was without effect. However, apoptosis caused by the cytotoxic agent streptozotocin (STZ), which acts independent of iNOS, was also inhibited by overexpression of PKCdeltaKD. STZ was additionally shown to activate the proteolytic enzyme caspase-3, a key biochemical effector of end-stage apoptosis. Moreover, STZ caused a caspase-dependent cleavage of PKCdelta, thereby releasing a COOH-terminal fragment corresponding to the kinase catalytic domain. Thus, proteolytic activation of PKCdelta seems to be important in the distal apoptotic pathway induced by STZ. That IL-1beta also activated caspase-3 and promoted PKCdelta cleavage suggests that this distal pathway also contributes in the apoptotic response to the cytokine. These data therefore support a dual role for PKCdelta in IL-1beta-mediated cell death: it is required for efficient NO generation through regulation of iNOS levels but also contributes to apoptotic pathways downstream of caspase activation.
Diabetes 2002 Feb
PMID:Inhibition of protein kinase C delta protects rat INS-1 cells against interleukin-1beta and streptozotocin-induced apoptosis. 1181 38

Diabetic cardiomyopathy is related directly to hyperglycemia. Cell death such as apoptosis plays a critical role in cardiac pathogenesis. Whether hyperglycemia induces myocardial apoptosis, leading to diabetic cardiomyopathy, remains unclear. We tested the hypothesis that apoptotic cell death occurs in the diabetic myocardium through mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetic mice produced by streptozotocin and H9c2 cardiac myoblast cells exposed to high levels of glucose were used. In the hearts of diabetic mice, apoptotic cell death occurred as detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Correspondingly, caspase-3 activation as determined by enzymatic assay and mitochondrial cytochrome c release detected by Western blotting analysis were observed. Supplementation of insulin inhibited diabetes-induced myocardial apoptosis as well as suppressed hyperglycemia. To explore whether apoptosis in diabetic hearts is related directly to hyperglycemia, we exposed cardiac myoblast H9c2 cells to high levels of glucose (22 and 33 mmol/l) in cultures. Apoptotic cell death was detected by TUNEL assay and DAPI nuclear staining. Caspase-3 activation with a concomitant mitochondrial cytochrome c release was also observed. Apoptosis or activation of caspase-3 was not observed in the cultures exposed to the same concentrations of mannitol. Inhibition of caspase-3 with a specific inhibitor, Ac-DEVD-cmk, suppressed apoptosis induced by high levels of glucose. In addition, reactive oxygen species (ROS) generation was detected in the cells exposed to high levels of glucose. These results suggest that hyperglycemia directly induces apoptotic cell death in the myocardium in vivo. Hyperglycemia-induced myocardial apoptosis is mediated, at least in part, by activation of the cytochrome c-activated caspase-3 pathway, which may be triggered by ROS derived from high levels of glucose.
Diabetes 2002 Jun
PMID:Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. 1203 84

Duration-related cognitive impairment is an increasingly recognized complication of type 1 diabetes. To explore potential underlying mechanisms, we examined hippocampal abnormalities in the spontaneously type 1 diabetic BB/W rat. As a functional assay of cognition, the Morris water maze test showed significantly prolonged latencies in 8-month diabetic rats not present at 2 months of diabetes. These abnormalities were associated with DNA fragmentation, positive TUNEL staining, elevated Bax/Bcl-x(L) ratio, increased caspase 3 activities and decreased neuronal densities in diabetic hippocampi. These changes were not caused by hypoglycemic episodes or reduced weight in diabetic animals. To explore potential mechanisms responsible for the apoptosis, we examined the expression of the IGF system. Western blotting and in situ hybridization revealed significant reductions in the expression of IGF-I, IGF-II, IGF-IR and IR preceding (2 months) and accompanying (8 months) the functional cognitive impairments and the apoptotic neuronal loss in hippocampus. These data suggest that a duration-related apoptosis-induced neuronal loss occurs in type 1 diabetes associated with cognitive impairment. The data also suggest that this is at least in part related to impaired insulin and/or IGF activities.
 ...
PMID:Hippocampal neuronal apoptosis in type 1 diabetes. 1213 25

Injury of endothelial cells has been postulated to be an initial trigger of the progression of atherosclerosis in patients with diabetes. Previously, we demonstrated high D-glucose induced endothelial apoptosis through the bax-caspase pathway and the potential contribution of hepatocyte growth factor (HGF) to the pathogenesis of endothelial dysfunction. In this study, we analyzed the molecular mechanisms of the protective actions of HGF against endothelial cell death under high D-glucose conditions. High concentrations of D-glucose resulted in a significant increase in apoptosis and necrosis. In contrast, HGF attenuated high D-glucose-induced apoptosis and necrosis (P < 0.01). High D-glucose significantly increased bax protein, but not bcl-2, and activated caspase 3-like and 9, whereas HGF significantly increased bcl-2 expression without affecting bax level and attenuated the increase in caspase 3 and 9 activity. Interestingly, high D-glucose resulted in translocation of bax protein from cytosol to the mitochondrial membrane, whereas HGF inhibited the bax translocation. Importantly, this bax translocation was also completely blocked by overexpressed bcl-2. These findings suggest that HGF can activate bcl-2 expression and inhibit translocation of bax protein upstream of the mitochondria, thereby leading to the inhibition of caspase 3 and 9 activation. HGF may be an important factor in the maintenance of endothelial function.
Diabetes 2002 Aug
PMID:Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane. 1214 77

Primary human cells enter senescence after a characteristic number of population doublings (PDs). In the current study, human skin fibroblasts were propagated in culture under 5.5mM glucose (normoglycemia); addition of 16.5mM D-glucose to a concentration of 22 mM (hyperglycemia); and addition of 16.5mM L-glucose (osmotic control). Hyperglycemia induced premature replicative senescence after 44.42+/-1.5 PDs compared to 57.9+/-3.83 PDs under normoglycemia (p<0.0001). L-Glucose had no effect, suggesting that the effect of hyperglycemia was not attributed to hyperosmolarity. Activated caspase-3 measurement showed a significantly higher percentage of apoptotic cells in high glucose medium. Telomerase overexpression circumvented the effects of hyperglycemia on replicative capacity and apoptosis. The "point of no return," beyond which hyperglycemia resulted in irreversible progression to premature replicative senescence, occurred after exposure to hyperglycemia for as few as 20 PDs. These results may provide a biochemical basis for the relationship between hyperglycemia and those complications of diabetes, which are reminiscent of accelerated senescence.
 ...
PMID:High glucose-induced replicative senescence: point of no return and effect of telomerase. 1214 32

Poly (ADP-ribose) polymerase is a zinc-finger DNA-binding enzyme which detects and signals DNA strand breaks generated either directly during base excision repair, or indirectly by genotoxic agents such as oxygen radicals. In response to genotoxic injury, PARP catalyses the synthesis of poly (ADP-ribose), from its substrate beta-NAD+ and this polymer is covalently attached to several nuclear proteins and PARP itself. As a result, PARP converts DNA breaks into intracellular signals which activate DNA repair programs or cell death options. Several studies have also shown that PARP is involved in either necrosis and subsequent inflammation or apoptosis. Although this enzyme is not indispensable during the latter cell death program, it has been demonstrated that PARP plays a facilitating role in this process. PARP is activated at an intermediate stage of apoptosis and is then cleaved and inactivated at a late stage by apoptotic proteases, namely caspase-3/CPP-32/Yama/apopain and caspase-7. This cleavage prevents necrosis during apoptosis, avoiding inflammation. All these functions, and the observation that PARP is an abundant and highly conserved enzyme, suggest that this enzyme plays a pivotal role, particularly in the maintenance of genomic DNA stability, apoptosis and in the response to oxidative stress. Since these situations are found in cancer, inflammation, autoimmunity (such as diabetes), myocardial dysfunction, certain infections, ageing and radiation/chemical exposure, attempts have been made to modulate PARP activity. With regard to the increasing interest towards PARP, the aim of this review is to explain the cellular role of PARP and the advantages of modulating its activity in diverse preventive or therapeutic strategies.
 ...
PMID:Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. 1216 82

Renal proximal tubular epithelial cells (PTEC) are target for LPS during sepsis and renal infections. In the present study, we evaluated whether stimulation of human PTEC by LPS is modulated through the soluble or the membrane form of the LPS receptor CD14. We found that PTEC lacked expression of the membrane form of CD14 and did not release soluble CD14 (sCD14). sCD14 was detected in the urine of normal subjects and it was increased in patients with renal sepsis or with proteinuria. In the presence of sCD14 and LPS binding protein (LBP), PTEC were 10 to 100-fold more sensitive to LPS activation, resulting in cytokine production (IL-6, IL-8 and TNF-alpha) and NO release. We found that sCD14 purified from urine was biologically active on PTEC. Moreover, the presence of sCD14 and LBP was required for cytotoxicity induced by low concentrations of LPS (1-10 ng/ml) in PTEC. Cell death showed the characteristics of both necrosis and apoptosis, as demonstrated by LDH release and by TUNEL and acridine orange staining and caspase-3 activation. Whereas the LPS alone was sufficient to induce necrosis, sCD14 and LBP were required for apoptosis. Our results suggest that sCD14 excreted in urine may participate with endotoxin in the activation and injury of renal proximal tubules. In particular, sCD14 may contribute to the tubulo-interstitial injury in clinical settings characterised by proteinuria and enhanced susceptibility to infections such as in diabetes.
 ...
PMID:Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS. 1223 91

We investigated the effect of a chronic exposure to high levels of free fatty acid (FFA; 2 mmol/L oleate/palmitate 2:1) or glucose (16.7 mmol/L) on islet cell apoptosis. Apoptosis was detected using 4 different methods: (1) cell staining with annexin-V fluorescien isothiocyanate (FITC) conjugate and propidium iodide (PI); (2) quantification of cytoplasmatic DNA fragments by an enzyme-linked immunosorbent assay (ELISA); (3) assay of caspase 3 activity; and (4) TdT-mediated dUTP nick-end labeling (TUNEL). Islet cells were also costained with an anti-insulin antibody to identify apoptotic beta cells. We also evaluated by reverse-transcriptase polymerase chain reaction (RT-PCR) the expression of bax, bcl-2, and caspas 3, genes involved in apoptosis. In islets cultured for 7 days in the presence of high FFA or for 3 days in the presence of high glucose levels, we observed: (1) a 2- to 3-fold increase of apoptotic cells conjugated with annexin-V FITC and PI; (2) a 4- to 6-fold increase of cytoplasmatic DNA fragments; (3) a 3- to 4-fold increase of caspase 3 activity; and (4) a significant increase of insulin positive apoptotic cells as detected with the TUNEL method. RT-PCR analysis indicated in islets exposed to high FFA or glucose levels an increase of bax (proapoptotic gene), a reduction of bcl-2 (antiapoptotic gene), and a slight (although not significant) increase in caspase 3 expression. Western blot analysis also showed an increase of Bax protein levels in islets exposed to high FFA or glucose. The simultaneous presence of both metabolic abnormalities did not further increase the amount of apoptotic cells, although the time-course of the cellular damage induced by FFA was accelerated by the contemporary presence of high glucose. To elucidate the mechanism by which FFA and glucose may induce pancreatic beta-cell damage, we examined whether nicotinamide prevents apoptosis in pancreatic islets cultured for 7 days with high FFA or for 3 days with high glucose. Nicotinamide was able to prevent beta-cell damage by significantly reducing apoptosis in both experimental conditions. Also, the increase of Bax protein level was prevented by nicotinamide. These data indicate that chronic exposure to elevated FFA or glucose levels increases apoptosis in rat pancreatic islets and these cytotoxic effects could be mediated by oxidative stress. This may contribute to the beta-cell failure that occurs in most in type 2 diabetic patients few years after clinical diabetes onset.
 ...
PMID:Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress. 1237 Aug 56

A constant remodeling of islet cell mass mediated by proliferative and apoptotic stimuli ensures a dynamic response to a changing demand for insulin. In this study, we investigated the effect of glucagon-like peptide-1 (GLP-1) in Zucker diabetic rats, an animal model in which the onset of diabetes occurs when the proliferative potential and the rate of beta-cell apoptosis no longer compensate for the increased demand for insulin. We subjected diabetic rats to a 2-d infusion of GLP-1 and tested their response to an ip glucose tolerance test. GLP-1 produced a significant increase of insulin secretion, which was paralleled by a decrease in plasma glucose levels (P < 0.001 and P < 0.01, respectively). Four days after the removal of the infusion pumps, rats were killed and the pancreas harvested to study the mechanism by which GLP-1 ameliorated glucose tolerance. Ex vivo immunostaining with the marker of cell proliferation, Ki-67, showed that the metabolic changes observed in rats treated with GLP-1 were associated with an increase in cell proliferation of the endocrine and exocrine component of the pancreas. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, a marker of cellular apoptosis, indicated a reduction of apoptotic cells within the islet as well in the exocrine pancreas in GLP-1-treated rats. Double immunostaining for the apoptotic marker caspase-3 and for insulin showed a significant reduction of caspase-3 expression and an increase in insulin content in GLP-1-treated animals. Finally, staining of pancreatic sections with the nuclear dye 4,6-Diaminidino-2-phenyl-dihydrochloride demonstrated a marked reduction of fragmented nuclei in the islet cells of rats treated with GLP-1. Our findings provide evidence that the beneficial effects of GLP-1 in Zucker diabetic rats is mediated by an increase in islet cell proliferation and a decrease of cellular apoptosis.
 ...
PMID:Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. 1239 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>