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)

Arsenic is a naturally occurring element, but anthropogenic activities can lead to a substantial contamination of the environment. Exposure to arsenic has been associated with a significant number of adverse health effects in humans including: cardiovascular disease, diabetes, hearing loss, developmental abnormalities, anemia, neurologic and neurobehavioral disorder, leukopenia, eosinophilia, fibrosis of the liver and the kidney and various neoplasms. However, the cellular and molecular events associated with arsenic toxicity are poorly understood. Also, the precise mechanisms by which arsenic acts as a carcinogen in humans remain to be elucidated. In the present study, we used human liver carcinoma (HepG2) cells as a model to study the molecular mechanisms of arsenic-induced toxicity and carcinogenesis. We hypothesized that arsenic-induced expression of stress genes and related proteins may play a role in the cellular and molecular events leading to toxicity and tumorigenesis in liver cells. To test this hypothesis, we performed the MTT-assay for cell viability, the CAT-Tox (L) assay for gene induction, and the Western Blot analysis to assess the expression of cellular proteins including c-fos, HMTIIA, HSP70 and p53. Data obtained from the MTT assay indicated a strong dose-response relationship with respect to arsenic trioxide toxicity. Upon 48 hr of exposure, the chemical dose required to cause 50% reduction in cell viability (LD50) was computed to be 8.55 +/- 0.58 microg/ml. The CAT-Tox (L) assay showed statistically significant inductions (p<0.05) of c-fos, HMTIIA, and HSP70. Western blot analysis also demonstrated a dose-response relationship with regard to expression of specific cellular proteins. The p53 protein was expressed in arsenic trioxide-treated cells, however, the densitometric analysis did not show any significant differences (p<0.05) between treated and control cells. The lack of a significant induction of p53 may be due to the potential mitogenic effect of arsenic at low levels of arsenic exposure.
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PMID:Arsenic trioxide-induced transcriptional activation of stress genes and expression of related proteins in human liver carcinoma cells (HepG2). 1468 89

The recent observation that heat shock proteins (HSPs), mostly glucose regulated protein94 (Grp94) and HSP70, are present in plasma of Type 1 diabetic subjects as complexes with immunoglobulins, prompted us to investigate the nature and extent of this association, whether it represents HSP-induced activation of the immune system. Two complementary affinity chromatography procedures followed by immunoprecipitation and immunoblot analyses of HSP-enriched, plasma-purified peaks, revealed that HSPs were inextricably linked with IgG in SDS-resistant complexes from which proteins dissociate partially under reducing treatment. HSP70 was found also closely linked with alpha1-antitrypsin (alpha1AT) in a single protein having the mass of alpha1AT but elution characteristics different from those of normal alpha1AT. Immunoprecipitation with anti-HSP70 antibodies led to co-immunoprecipitation of the alpha1AT species linked to HSP70, thus confirming fusion of the proteins. The additional finding of circulating antibodies against the HSP70-alpha1AT protein supported its immunogenic properties with implications for diabetes and its complications.
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PMID:A heat shock protein70 fusion protein with alpha1-antitrypsin in plasma of type 1 diabetic subjects. 1476 7

A wide range of agents and conditions are known to disrupt the ability of the endoplasmic reticulum (ER) to fold proteins properly, resulting in the onset of ER dysfunction/stress. We and others have shown that ER stress can induce intracellular lipid accumulation through the activation of the sterol responsive element binding proteins (SREBPs) and initiate programmed cell death by activation of caspases. It has been suggested that ER stress-induced lipid accumulation and cell death play a role in the pathogenesis of disorders including Alzheimer's disease, Parkinson's disease, type-1 diabetes mellitus and hepatic steatosis. Here we show that exposure of HepG2 cells to the branch chain fatty acid, valproate, increases cellular resistance to ER stress-induced dysfunction. Two distinctly different potential mechanisms for this protective effect were investigated. We show that exposure to valproate increases the expression of chaperones that assist in the folding of proteins in the ER including GRP78/BiP, GRP94, PDI and calreticulin as well as the cytosolic chaperone, HSP70. However, exposure of HepG2 cells to valproate does not decrease the apparent ER stress response in cells challenged with tunicamycin, A23187 or glucosamine, suggesting that valproate-conferred protection occurs downstream of ER dysfunction. Finally, we demonstrate that valproate directly inhibits the glycogen synthase kinases (GSK)-3alpha/beta. The ability of lithium, another inhibitor of GSK3alpha/beta to protect cells from ER stress-induced lipid accumulation suggests that GSK3 plays a central role in signaling downstream effects of ER stress. Strategies to protect cells from agents/conditions that induce ER stress may have potential in the treatment of the growing number of diseases and disorders linked to ER dysfunction.
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PMID:Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3. 1558 78

The diabetogenic major histocompatibility complex (MHC) (H2(g7)) of NOD mice comprises contributions from several class II loci collectively designated as Idd1. Introduction of the H2(gx) haplotype from the related but diabetes-resistant cataract Shionogi (CTS) strain demonstrated an additional MHC-linked locus designated Idd16. The NOD-related alloxan resistant (ALR)/Lt strain is also characterized by the H2(gx) haplotype, which does not differ from H2(g7) from the class I H2-K(d) gene distally through the class II and into the class III region. Polymorphisms distal to the heat shock protein 70 locus (Hspa1b) include a rare H2-D(dx) rather than the H2(g7) encoded D(b) allele. Two differential-length NOD.ALR-H2(gx) congenic stocks (D.R1 and D.R2), both containing H2-D(dx), significantly suppressed diabetogenesis. This protection was lost when ALR alleles between the class III region and H2-D were removed in a shorter interval congenic (D.R3). Because no differences were observed in the ALR-derived interval extending 0.41 mB proximal to H2-K in any of these congenic stocks, a component of what was originally designated "Idd16" was sited to an interval shorter than 7.33 mB, distinguishing D.R2 from D.R3. Evidence supporting the candidacy of the ALR/CTS-shared H2-D(dx) MHC class I variant present in both diabetes-resistant stocks, but not the susceptible stock, is discussed.
Diabetes 2005 May
PMID:Major histocompatibility complex-linked diabetes susceptibility in NOD/Lt mice: subcongenic analysis localizes a component of Idd16 at the H2-D end of the diabetogenic H2(g7) complex. 1585 53

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.
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PMID:Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation. 1615 39

Several groups have reported apoptosis of dorsal root ganglion (DRG) cells as a prominent feature of diabetic polyneuropathy (DPN), although this has been controversial. Here, we examined subacute (4-month) type 1 diabetic BB/Wor rats with respect to sensory nerve functions, DRG and sural nerve morphometry, pro- and antiapoptotic proteins, and the expression of neurotrophic factors and their receptors. Sensory nerve conduction velocity was reduced by 13% and was accompanied by significant hyperalgesia. The numbers of DRG neurons including substance P-and calcitonin gene-related peptide-positive neurons were not altered, although they showed significant atrophy. Sural nerve morphometry showed decreased numbers of myelinated and unmyelinated fibers. Active caspase-3 and Bax expressions were increased, whereas antiapoptotic Bcl-xl and heat shock protein (HSP) 27 expressions in DRGs were increased. Nerve growth factor (NGF) contents in sciatic nerves and the expression of NGF receptor TrkA in DRGs were decreased. Immunohistochemistry showed increased numbers of active caspase-3-, HSP70-, and HSP27-positive neurons. Examinations of DRGs revealed no structural evidence of apoptosis but rather progressive hydropic degenerative changes. We conclude that apoptotic stress is induced in DRGs but is counterbalanced by survival elements in subacute type 1 diabetic BB/Wor rats and that distal nerve fiber loss reflects a dying-back phenomenon caused by impaired neurotrophic support.
Diabetes 2005 Nov
PMID:Apoptotic stress is counterbalanced by survival elements preventing programmed cell death of dorsal root ganglions in subacute type 1 diabetic BB/Wor rats. 1624 57

Human artificial chromosomes (HACs) behave as independent minichromosomes and are potentially useful as a way to achieve safe, long-term expression of a transgene. In this study, we sought to elucidate the potential of HAC vectors carrying the human proinsulin transgene for gene therapy of insulin-dependent diabetes mellitus (IDDM) using non-beta-cells as a host for the vector. To facilitate the production of mature insulin in non-beta-cells and to safely regulate the level of transgene expression, we introduced furin-cleavable sites into the proinsulin coding region and utilized the heat shock protein 70 (Hsp70) promoter. We used Cre-loxP-mediated recombination to introduce the gene cassettes onto 21DeltapqHAC, a HAC vector whose structure is completely defined, present in human fibrosarcoma HT1080 cells. We observed long-term expression and stable retention of the transgene without aberrant translocation of the HAC constructs. As expected, the Hsp70 promoter allowed us to regulate gene expression with temperature, and the production and secretion of intermediates of mature insulin were made possible by the furin-cleavable sites we had introduced into proinsulin. This study can be an initial step on the application of HAC vectors on the gene delivery to non-beta-cells, which might provide a direction for future treatment for diabetes.
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PMID:Heat-regulated production and secretion of insulin from a human artificial chromosome vector. 1640 45

Well-known coronary risk factors such as hyperlipidemia, hypertension, smoking, and diabetes are reported to induce the oxidative stress. Under the oxidative stress, low-density lipoprotein (LDL) is oxidatively modified in the vasculature, and formed oxidized LDL induces endothelial dysfunction, expression of adhesion molecules and apoptosis of vascular smooth muscle cells. It has become evident that these cellular responses induced by oxidized LDL are mediated by lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 was originally identified from cultured aortic endothelial cells as a receptor for oxidized LDL; however, recent investigations revealed that LOX-1 has diverse roles in the host-defense system and inflammatory responses, and it is involved in the pathogenesis of various diseases such as atherosclerosis-based cardiovascular diseases and septic shock. Beside oxidized LDL, LOX-1 recognizes multiple ligands including apoptotic cells, platelets, advanced glycation end products, bacteria, and heat shock proteins (HSPs). The HSPs function as a chaperone to affect protein folding of newly synthesized or denatured proteins. There are accumulating evidences that the HSPs released into the extracellular space have potent biological activities and it may work as a kind of cytokines. It is demonstrated that LOX-1 works as a receptor for HSP70, since it has high affinity for HSP70. The interaction of LOX-1 with HSP70 is involved in the cross-presentation of antigen. Given the potent and wide variety of biological activities, more understanding their interaction provides potential therapeutic strategy for various human diseases.
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PMID:Lectin-like oxidized LDL receptor-1 as extracellular chaperone receptor: its versatile functions and human diseases. 1792 May 18

Diabetes mellitus has been classified as a conformational disease because of changes induced in the structure and function of proteins due to hyperglycemia. In this study, we investigated the effect of high-dose and long-term use of acetyl salicylic acid (ASA) on the streptozotocin-induced diabetic rats as a model of type I diabetes, with consideration on the structure and/or function of proteins. The N-[methylnitrosocarbamoyl]-d-glucosamine (streptozotocin)-induced diabetic rats together with the normal rats were studied for 5 months with and without receiving 100 mg/kg ASA in drinking water. All rats were investigated from different aspects such as heat shock protein (HSP) 70 level, serum glucose and insulin concentration, advanced glycated end product (AGE) and glycated hemoglobin (HbA1c) formation, lipid profile, high-density lipoprotein (HDL) functionality (paraoxonase1 and lecithin cholesterol acyltransferase activities), and the antioxidant system. In addition, the in vitro effect of ASA on the structure of albumin as a model protein was studied in the presence of glucose by spectroscopic techniques such as fluorometry and circular dichroism. The results show that ASA therapy causes a decrease in the glucose level and AGE and HbA1c formation, improves the lipid profile, HDL functionality, and the antioxidant capacity, induces serum HSP70, and overall decreases mortality of diabetic rats in comparison with the group without treatment. The conformation of glycated bovine serum albumin is different from the native form, and ASA retains the conformation of this protein similar to the native. The improving effect of ASA on diabetic rats is mostly due to its role as a chemopreventive agent in the structural conservation and protection of proteins involved in diabetes pathogenesis.
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PMID:Investigation of the mechanisms involved in the high-dose and long-term acetyl salicylic acid therapy of type I diabetic rats. 1800 Jan 61

Ferulic acid (FA) is a polyphenol very abundant in vegetables and maize bran. Several lines of evidence have shown that FA acts as a potent antioxidant in vitro, due to its ability to scavenge free radicals and induce a robust cell stress response through the up-regulation of cytoprotective enzymes such as heme oxygenase-1, heat shock protein 70, extracellular signal-regulated kinase 1/2 and Akt. Furthermore, FA inhibited the expression and/or activity of cytotoxic enzymes including inducible nitric oxide synthase, caspases and cyclooxygenase-2. On this basis, FA has been proposed for the treatment of several age-related diseases such as neurodegenerative disorders, cardiovascular diseases, diabetes and cancer. However, although the great abundance of in vitro data, the real efficacy of FA in humans has not been demonstrated so far. New efforts and resources should be transferred to clinical research for the complete evaluation of the therapeutic potential of FA in chronic diseases.
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PMID:Ferulic acid and its therapeutic potential as a hormetin for age-related diseases. 1865 Dec 37


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