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)

Immune-independent diabetes often occurs via pancreatic beta cell dysfunction. However, the role of the tumour suppressor p53 that regulates cellular life and death in multiple tissues, in pancreatic cell death and diabetes has not been clarified. We have therefore utilized an established mouse model for diabetes in which the MHC class I antigen is overexpressed in pancreatic beta cells under the rat insulin promoter, to investigate the role of p53. We show that pancreatic beta cell death, as determined by TUNEL staining, is elevated in transgenic mice compared to wild-type mice. However, there was no increase in immuno-reactivity towards anti-p53 antibodies in the pancreas of transgenic mice over the course of diabetes formation and beta cell death, suggesting that p53 may not be involved in these processes. Interestingly, p53 expression was also not induced in pancreas upon gamma-irradiation, which resulted in a massive increase in the number of TUNEL-positive cells, suggesting that the p53 pathway may not be causally involved in pancreatic cell death. To further confirm these findings, we generated MHC class I transgenic mice lacking p53 expression. Absence of p53 did not result in any significant changes in pancreatic morphology or affect cell death levels. Importantly, p53 absence did not rescue the diabetic phenotype of the transgenic mice. The results therefore demonstrate that p53 may not be causally involved in pancreatic beta cell death, and suggests that the classical cell death pathway dependent on p53 may not be operating in pancreatic beta cells.
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PMID:The tumour-suppressor p53 is not required for pancreatic beta cell death during diabetes and upon irradiation. 1800 84

Loss of retinal pericytes is one of the distinctive features of diabetic retinopathy (DR), which is characterized by retinal capillary obliteration. The matricellular proteins, cysteine-rich protein 61 (Cyr61) and connective tissue growth factor (CTGF), are aberrantly expressed in the retinal vasculature from the early stages of DR, but their effects on retinal pericytes are unknown. We show herein that rat retinal pericytes (RRPs) exposed to advanced glycosylation-end products, an important injurious stimulus of diabetes, express increased levels of both Cyr61 and CTGF, and concomitantly undergo anoikis, a form of apoptosis by loss of cell-matrix interactions. Adenovirus-mediated expression of Cyr61 and/or CTGF conferred an anoikis-prone phenotype to rat retinal pericytes, including decreased phosphotyrosine protein levels at focal adhesion points and formation of cortical actin rings. When used as substrates for pericyte attachment and compared with other matrix proteins (e.g. type IV collagen), recombinant Cyr61 and CTGF proteins exhibited antiadhesive and apoptogenic activities. Phosphatase inhibitors reversed these effects, suggesting that Cyr61 and CTGF promote dephosphorylation events. Furthermore, Cyr61- and CTGF-induced apoptosis was mediated through the intrinsic pathway and involved the expression of genes that have been functionally grouped as p53 target genes. Expression of the matrix metalloproteinase-2 gene, a known target of p53, was increased in pericytes overexpressing either Cyr61 or CTGF. Inhibition of matrix metalloproteinase-2 had, at least in part, a protective effect against Cyr61- and CTGF-induced apoptosis. Taken together, these findings support the involvement of Cyr61 and CTGF in pericyte detachment and anoikis, implicating these proteins in the pathogenesis of DR.
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PMID:Cysteine-rich protein 61 and connective tissue growth factor induce deadhesion and anoikis of retinal pericytes. 1818 44

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy in humans including type I diabetic and normal rats. Tobacco and alcohol, as well as dysregulation of oncogenes and tumor suppressor genes, epigenetic changes and mitochondrial mutations have been implicated in OSCC development. Recent epidemiological studies have incriminated diabetes mellitus as a risk factor for the development of OSCC, as well as oral premalignant lesions. Recently, an animal model was employed to study the influence of diabetes on signal transduction pathways in every stage of oral cancer development, from normal mucosa to hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. Diabetes was induced by streptozotocin and chemical carcinogenesis was induced by the carcinogen 4-nitroquinoline N-oxide. The expression of EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, the tumor suppressor genes p53 and p16, apoptosis markers Bax and Bcl-2, and the cell proliferation marker Ki-67 in the sequential stages of rat oral oncogenesis was investigated. Diabetes seems to promote the activation of the Ras/Raf/MAPK signal transduction pathway mainly by induction of erbB2 and erbB3 receptors, leading to increased cell proliferation, while there was no difference in apoptosis levels during oncogenesis.
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PMID:Diabetes and oral oncogenesis. 1822 90

The development of type 2 diabetes is accompanied by decreased immune function and the mechanisms are unclear. We hypothesize that oxidative damage and mitochondrial dysfunction may play an important role in the immune dysfunction in diabetes. In the present study, we investigated this hypothesis in diabetic Goto-Kakizaki rats by treatment with a combination of four mitochondrial-targeting nutrients, namely, R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide and biotin. We first studied the effects of the combination of these four nutrients on immune function by examining cell proliferation in immune organs (spleen and thymus) and immunomodulating factors in the plasma. We then examined, in the plasma and thymus, oxidative damage biomarkers, including lipid peroxidation, protein oxidation, reactive oxygen species, calcium and antioxidant defence systems, mitochondrial potential and apoptosis-inducing factors (caspase 3, p53 and p21). We found that immune dysfunction in these animals is associated with increased oxidative damage and mitochondrial dysfunction and that the nutrient treatment effectively elevated immune function, decreased oxidative damage, enhanced mitochondrial function and inhibited the elevation of apoptosis factors. These effects are comparable to, or greater than, those of the anti-diabetic drug pioglitazone. These data suggest that a rational combination of mitochondrial-targeting nutrients may be effective in improving immune function in type 2 diabetes through enhancement of mitochondrial function, decreased oxidative damage, and delayed cell death in the immune organs and blood.
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PMID:Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic Goto-Kakizaki rats. 1841 May 24

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

Folic acid (FA) supplementation has been shown to be extremely effective in reducing the occurrence of neural tube defects (NTDs), one of the most common birth defects associated with diabetic pregnancy. However, the antiteratogenic mechanism of FA in diabetes-induced NTDs is unclear. This study investigated the neuroprotective mechanism of FA in neural stem cells (NSCs) exposed to high glucose in vitro. The undifferentiated or differentiated NSCs were cultured in normal D-glucose concentration (NG) or high D-glucose concentration (HG) with or without FA. FA supplementation significantly decreased apoptosis induced by HG and lowered the expression of p53 in the nucleus of undifferentiated NSCs exposed to HG. Administration of FA in differentiated NSCs did not alter their precocious differentiation induced by HG. The increased mRNA expression levels of the basic helix-loop-helix factors including Neurog1, Neurog2, NeuroD2, Mash1, Id1, Id2, and Hes5 in the presence of HG were not significantly affected by FA. The present results provided a cellular mechanism by which FA supplementation may have a potential role in prevention of NTDs in diabetic pregnancies. On the other hand, FA increased the mRNA expression levels of the above transcription factors and accelerated the differentiation of NSCs in the NG medium, suggesting that it may adversely affect the normal differentiation of NSCs. Therefore, the timing and dose of FA would be critical factors in considering FA supplementation in normal maternal pregnancy.
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PMID:Folic acid supplementation affects apoptosis and differentiation of embryonic neural stem cells exposed to high glucose. 1854 78

Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structures under physiological conditions in vitro. They are highly abundant in nature and their functional repertoire complements the functions of ordered proteins. IDPs are involved in regulation, signaling, and control, where binding to multiple partners and high-specificity/low-affinity interactions play a crucial role. Functions of IDPs are tuned via alternative splicing and posttranslational modifications. Intrinsic disorder is a unique structural feature that enables IDPs to participate in both one-to-many and many-to-one signaling. Numerous IDPs are associated with human diseases, including cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, and diabetes. Overall, intriguing interconnections among intrinsic disorder, cell signaling, and human diseases suggest that protein conformational diseases may result not only from protein misfolding, but also from misidentification, missignaling, and unnatural or nonnative folding. IDPs, such as alpha-synuclein, tau protein, p53, and BRCA1, are attractive targets for drugs modulating protein-protein interactions. From these and other examples, novel strategies for drug discovery based on IDPs have been developed. To summarize work in this area, we are introducing the D2 (disorder in disorders) concept.
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PMID:Intrinsically disordered proteins in human diseases: introducing the D2 concept. 1857 80

A total of 20 pancreatic biopsy samples taken from Fibrocalculous Pancreatopathy previously known as Fibro Calculus Pancreatic Diabetes (FCPD) patients, a variant of Malnutrition Related Diabetes Mellitus (MRDM) or under 30 young diabetes attending hepatobiliary, surgical and out patient department of Bangladesh Diabetes, Endocrine and Metabolic (BIRDEM) hospital were processed for light microscopic examination. Four samples were subjected to Immunohistochemistry (IHC) staining using antibodies to T cell marker (CD3), B cell marker (CD20), anti apoptotic markers (bcl-2) and tumour suppressor gene marker p53. Light microscopic findings and IHC indicate an immune mediated injury of pancreatic tissue and increased evidence of apoptosis which possibly results in the development of diabetes in these patients.
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PMID:Histopathological changes of pancreas in patients with fibrocalculous pancreatopathy. 1862 56

Despite diversity in genetic events in oncogenesis, cancer cells exhibit a common set of functional characteristics. Otto Warburg discovered that cancer cells have consistently higher rates of glycolysis than normal cells. The underlying mechanisms leading to the Warburg phenomenon include mitochondrial changes, upregulation of rate-limiting enzymes/proteins in glycolysis and intracellular pH regulation, hypoxia-induced switch to anaerobic metabolism, and metabolic reprogramming after loss of p53 function. The regulation of energy metabolism can be traced to a "triad" of transcription factors: c-MYC, HIF-1 and p53. Oncogenetic changes involve a nonrandom set of gene deletions, amplifications and mutations, and many oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53. Glycolysis in cancer cells has clinical implications in cancer diagnosis, treatment and interaction with diabetes mellitus. Many drugs targeting energy metabolism are in development. Future advances in technology may bring about transcriptome and metabolome-guided chemotherapy.
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PMID:Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. 1876 98

Simvastatin was reported to attenuate platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation by up-regulation of cyclin dependent kinase (CDK) inhibitor p27, but had no effect on p16, p21, p53 expression. We investigate the mechanisms by which simvastatin inhibits vascular smooth muscle cell (VSMC) growth in high glucose conditions to mimic diabetes. Simvastatin was added to A7r5 cells cultured in high glucose (25 mM) medium, mimicking diabetes. We used an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cell viability; flow cytometric analysis for cell counts distribution in the cell cycle; and Western blot, immunoblotting, and immunoprecipitation analyses to evaluate the effects of simvastatin on CDK activity and cell cycle regulatory proteins. Cell counts were significantly increased in G0/G1 phase and significantly decreased in S and G2/M phases. In our study, low dose of simvastatin had no significant inhibitory effect on VSMC growth in normal glucose condition. However, both low and high doses of simvastatin inhibited VSMC growth significantly in a dose-dependent manner in high glucose status. We also found that simvastatin inhibited phosphorylation of Rb, promoted expression of p53, p16, p21, p27 and decreased CDK2/4 activity. In conclusion, simvastatin inhibits VSMC proliferation in high glucose status, mimicking diabetes, inducing a G0/G1 phase cell cycle growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and up-regulation of p53, p21, p16, and p27. We propose that statins may be used more extensively in diabetic patients regardless of lipid status for preventing atherosclerosis and restenosis after PCI.
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PMID:Simvastatin inhibits cell cycle progression in glucose-stimulated proliferation of aortic vascular smooth muscle cells by up-regulating cyclin dependent kinase inhibitors and p53. 1880 36


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