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)

The cellular redox state is altered in a number of pathological conditions, including various forms of glomerular injury and diabetes. For example, glucose, via the pentose phosphate pathway generates NADPH, which maintains glutathione (GSH) (part of a major intracellular reducing system) in its reduced state. GSH in turn influences the activity of transcription factors on gene expression. We therefore examined whether changes in cellular GSH influence total collagen synthesis and mRNA levels for collagen I, collagen IV and TGF-beta in SV-40 transformed mouse mesangial cells (MC) maintained in either 5 or 25 mM glucose media. Total intracellular GSH was increased by N-acetylcysteine (NAC; 10 mM) or decreased with the GSH synthesis inhibitor buthionine sulfoximine (BSO; 0.2 mM) in MC. NAC increased 3H-proline incorporation into collagenase-sensitive protein while BSO decreased it under both glucose conditions. The presence of BSO did not reverse the increased collagen synthesis seen in the NAC stimulated cells. Northern blot analysis showed increased mRNA levels for collagen I, collagen IV and TGF-beta in cells grown in high glucose (25 mM). NAC increased the mRNA for all three compounds while BSO alone had no effect on these mRNA levels. However, BSO reversed the increased mRNA levels for collagen I, IV and TGF-beta seen in the presence of NAC. These findings suggest that the cellular redox state may influence gene transcription in MC, and may have implications in explaining injury-associated alterations of mesangial matrix generation.
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PMID:Intracellular glutathione influences collagen generation by mesangial cells. 796 50

Reactive oxygen species (ROS) are involved in the destruction of pancreatic beta cells and the development of insulin-dependent diabetes mellitus (IDDM). However, the cellular mechanism responsible for beta cell death is still unclear. We hypothesize that activation of NFkappaB by ROS is the key cellular signal in initiating a cascade of events leading to beta cell death. Thus, enhancement of pancreatic GSH, a known antioxidant and key regulator of NF-kappaB, should protect against IDDM. Weanling CD1 mice (n=5) were injected with alloxan (50 mg/kg i.v.) to induce IDDM. Using EPR spin trapping techniques, we demonstrated that alloxan generated ROS in the pancreas 15 min after administration. Activation of NFkappaB in pancreatic nuclear extracts was observed 30 min after alloxan injection, as assessed by an electrophoretic mobility shift assay. Fasting blood glucose levels were monitored for 14 days. Supplementation with N-acetylcysteine (NAC, 500 mg/kg), a GSH precursor, inhibited alloxan-induced NFkappaB activation and reduced hyperglycemia. Thus, NFkappaB activation by ROS may initiate a sequence of events leading to IDDM. Inhibition of NF-kappaB activation by NAC attenuated the severity of IDDM. This research will contribute to the understanding of the etiology of IDDM and may lead to the development of better strategies for disease prevention.
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PMID:Supplementation of N-acetylcysteine inhibits NFkappaB activation and protects against alloxan-induced diabetes in CD-1 mice. 1050 89

Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.
Diabetes 1999 Dec
PMID:Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity. 1058 Apr 29

The cytotoxic side effects of anti-neoplastic drugs are increased in patients with either type 1 or type 2 diabetes mellitus by a mechanism that is not clearly defined. We report that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). We found that treatment of myeloma cells with the antioxidant N-acetylcysteine completely blocked cisplatin-dependent intracellular GSH oxidation, reactive oxygen species (ROS) generation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Importantly, co-treatment of cells with the reactive carbonyl MGO and cisplatin increased apoptosis by 90% over the expected additive effect of combined MGO and cisplatin treatment. This same synergism was also observed when ROS generation was examined. MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC. Furthermore, rottlerin blocked combined MGO and cisplatin-induced ROS generation and apoptosis. Finally, MGO and cisplatin induced c-Abl activation and c-Abl:PKCdelta association. Rottlerin blocked c-Abl activation, but the c-Abl inhibitor STI-571 increased MGO and cisplatin-induced apoptosis by 50%. Taken together these data indicate that MGO synergistically enhances cisplatin-induced apoptosis through activation of PKCdelta and that PKCdelta is critical to both cell death and cell survival pathways. These findings suggest that in the patient with diabetes mellitus heightened oxidative stress can enhance the cytotoxicity of agents that induce DNA damage.
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PMID:Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta. 1170 30

This study analyzes the effect of chronic treatment with different antioxidants (N-acetyl-cysteine [NAC], taurine, a combination of NAC and taurine, and oxerutin) on long-term experimental diabetes induced by streptozotocin in rats. Glycoxidative damage was evaluated in the skin; glomerular structural changes were studied with morphometry and immunohistochemistry. Oxerutin treatment and the combined NAC plus taurine treatment resulted in reduced accumulation of collagen-linked fluorescence in skin in comparison with untreated diabetic rats. All treatments except taurine reduced glomerular accumulation of N(epsilon)-(carboxymethyl)lysine and protected against the increase in glomerular volume typical of diabetes; furthermore, the apoptosis rate was significantly decreased and the glomerular cell density was better preserved. Glycoxidative markers in the skin turned out to be good indicators of the glomerular condition. The findings that emerged from our study support the hypothesis that glomerular damage in diabetes can be prevented or at least attenuated by supplementation with specific antioxidants. Treatment with oxerutin and combined treatment with NAC plus taurine gave the most encouraging results, whereas the results of taurine-only treatment were either negligible or negative and therefore suggest caution in the use of this molecule in single-drug treatment courses.
Diabetes 2003 Feb
PMID:Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage in long-term experimental diabetes. 1254 Jun 27

Human LDL were used to study the protective action of four organosulfur compounds (diallyl sulfide, DAS; diallyl disulfide, DADS; S-ethylcysteine, SEC; N-acetylcysteine, NAC) derived from garlic against oxidation and glycation. The four organosulfur compounds significantly inhibited superoxide production by xanthine-xanthine oxidase (P < 0.05) and showed marked copper-chelating capability. DAS and DADS exhibited greater antioxidant activities against copper- and amphotericin B-induced LDL oxidation (P < 0.05) than SEC and NAC. However, SEC and NAC were more effective in sparing LDL alpha-tocopherol (P < 0.05). When oxidation was minimized, SEC was the most powerful agent against LDL glycation (P < 0.05); however, DADS was superior to other agents in suppressing both oxidation and glycation when LDL oxidation occurred simultaneously with glycation. These results suggest that the four organosulfur compounds derived from garlic are potent agents for protecting LDL against oxidation and glycation, and that they may benefit patients with diabetes mellitus or cardiovascular diseases by preventing complications.
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PMID:Protective action on human LDL against oxidation and glycation by four organosulfur compounds derived from garlic. 1278 61

Diabetes mellitus can be looked upon as an array of diseases, all of which exhibit common symptoms. While pathogenesis of IDDM (insulin dependant diabetes mellitus) is well understood, the same is not true for diabetes mellitus type II. In the latter case, relative contribution of the two factors (insulin resistance or decreased insulin secretion) varies individually, being highly increased in peripheral tissues and strictly dependant on insulin for glucose uptake. Moreover, in patients with diabetes mellitus type II, disbalance at the level of regulation of glucose metabolism as well as lipid metabolism has been noted in skeletal muscles. It is normal to assume that in this type of diabetes, these changes are reflected at the level of total activity of enzyme creatine kinase. This experimental work was performed on a group of 80 regular patients of Sarajevo General Hospital. Forty of those patients were classified as patients with diabetes type I and forty as patients with diabetes type II. Each group of patients was carefully chosen and constituted of equal number of males and females. The same was applied for adequate controls. Concentration of glucose was determined for each patient with GOD method, while activity of creatine kinase was determined with CK-NAC activated kit. Statistical analysis of the results was performed with SPSS software for Windows. Obtained results point out highly expressed differences in enzyme activity between two populations examined. Changes in enzyme activity are more expressed in patients with diabetes type II. Positive correlation between concentration of glucose and serum activity of the enzyme is seen in both categories of diabetic patients which is not the case for the patients in control group. At the same time, correlation between age and type of diabetes does exist . This is not followed at the level of enzyme activity or concentration of glucose.
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PMID:Creatine kinase activity in patients with diabetes mellitus type I and type II. 1699 40

The circulatory inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is increased in pathological conditions, such as diabetes, which initiate or exacerbate vascular endothelial injury. Both nitric oxide (NO) and reactive oxygen species may play a dual role (i.e., inhibiting or promoting) in TNF-alpha-induced endothelial cell apoptosis. We investigated the effects of the antioxidant N-acetylcysteine on TNF-alpha-induced apoptosis in human vascular endothelial cell (cell line ECV304) apoptosis, NO production and lipid peroxidation. Cultured vascular endothelial cell (ECV304) were either not treated (control), or treated with TNF-alpha (40 ng/ml) alone or TNF-alpha in the presence of N-acetylcysteine at 30 mmol/l or 1 mmol/l, respectively, for 24 h. Cell viability was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was assessed by flow cytometry. TNF-alpha-induced endothelial cell apoptosis was associated with increased inducible NO synthase but reduced endothelial NO synthase (eNOS) protein expression. NO production and the levels of the lipid peroxidation product malondialdehyde were concomitantly increased. Treatment with NAC at 30 mmol/l restored eNOS expression and further increased NO production as compared to TNF-alpha alone, resulting in improved cell viability and reduced apoptosis. This was accompanied by increased superoxide dismutase activity, increased glutathione peroxidase production and reduced malondialdehyde levels. N-acetylcysteine at 1 mmol/l, however, did not have significant effects on TNF-alpha-induced endothelial cell apoptosis and cell viability despite it slightly enhanced glutathione peroxidase production. N-acetylcysteine attenuation of TNF-alpha-induced human vascular endothelial cell apoptosis is associated with the restoration of eNOS expression.
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PMID:N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression. 1702 86

We studied whether angiotensin II (ANG II) via superoxide may contribute to retinal leukostasis and thus to the pathogenesis of retinopathies. We studied: 1) whether intravitreal ANG II induces retinal leukostasis that is altered by antioxidants or by apocynin, a NAD(P)H oxidase inhibitor and 2) whether retinal leukostasis induced by diabetes in rats is also altered by these treatments. Rats were injected intravitreally with ANG II (20 microg in 2 microl), and divided into the following three groups: 1) untreated; 2) treated with tempol doses ( approximately 3 mM/day) and N-acetylcysteine (NAC; approximately 1 g.kg(-1).day(-1)); and 3) treated with apocynin ( approximately 2 mM/day), both in the drinking water. Rats with streptozotocin-induced diabetes were similarly treated. Leukostasis was evaluated 48 h after ANG II or 2 wk after diabetes induction. ANG II increased retinal leukostasis from 0.3 +/- 0.5 to 3.7 +/- 0.4 leukocytes/ mm(2) (P < 0.01), and these changes were markedly decreased by treatment with tempol + NAC or apocynin, and also by a blocking antibody against vascular endothelial growth factor given intravitreally (P < 0.01). In addition, incubation of dihydroethidium-loaded retina sections with ANG II caused marked increase in superoxide formation. Compared with normal controls, retinal leukostasis in diabetic rats markedly increased from 0.2 +/- 0.3 to 3.8 +/- 0.1 leukocytes/mm(2) (P < 0.01). Diabetic retinal leukostasis was also decreased by treatment with tempol-NAC and normalized by apocynin. Thus increases in intravitreal ANG II can induce retinal leukostasis, which appears to be mediated via increasing superoxide generation by NAD(P)H oxidase, and by VEGF. The activity of NAD(P)H oxidase is required for leukostasis to occur in the diabetic retina.
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PMID:Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. 1765 61

We studied the effects of advanced glycation end products (AGEs), which are known to accumulate in patients with diabetes, autoimmune diseases, or those who smoke, on embryonal development. Pronuclear (PN) embryos were obtained by flushing the fallopian tubes of rats after superovulation and mating. The cleavage rate and blastocyst yield were evaluated at 24, 72, 96, and 120 h of culture. Glyoxal, an AGE-forming aldehyde, suppressed embryonal development at every stage from PN to blastocyst in a concentration-dependent manner. The cleavage rate of the embryo was also signifi cantly decreased by treatment with glyoxal at concentrations of 1 mM or higher. The blastocyst yield was significantly decreased by treatment with glyoxal at concentrations of 0.5 mM or higher. N-acetyl-L-cysteine (L-NAC) at 1 mM significantly suppressed the glyoxal-induced embryonal toxicity. BSA-AGEs at 5 microg/ml or higher concentration signifi cantly reduced the cleavage rate and blastocyst yield compared to those for BSA-treated embryos. L-NAC at 1 mM significantly suppressed BSAAGE-induced embryonal toxicity. Because AGEs are embryo-toxic, AGE contamination may influence the pregnancy rate of in vitro fertilization and embryo transfer. AGEs, which are increased in women under pathological conditions, may also be involved in their infertility.
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PMID:Adverse effects of advanced glycation end products on embryonal development. 1846 85


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