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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maternal diabetes increases the risk for neural tube, and other, structural defects. The mother may have either type 1 or type 2 diabetes, but the diabetes must be existing at the earliest stages of pregnancy, during which organogenesis occurs. Abnormally high glucose levels in maternal blood, which leads to increased glucose transport to the embryo, is responsible for the teratogenic effects of maternal diabetes. Consequently, expression of genes that control essential developmental processes is disturbed. In this review, some of the biochemical pathways by which excess glucose metabolism disturbs neural tube formation are discussed. Research from the author's laboratory has shown that expression of Pax3, a gene required for neural tube closure, is significantly reduced by maternal diabetes, and this is associated with significantly increased neural tube defects (NTD). Pax3 encodes a transcription factor that has recently been shown to inhibit p53-dependent apoptosis. Evidence in support of this model, in which excess glucose metabolism inhibits expression of Pax3, thereby derepressing p53-dependent apoptosis of neuroepithelium and leading to NTD will be discussed.
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PMID:Current perspectives on the causes of neural tube defects resulting from diabetic pregnancy. 1580 Aug 53

The tumor suppressor p53 regulates apoptosis, cell cycle, and oncogenesis. To explore the roles of p53 in autoimmunity, we studied type 1 diabetes and innate immune responses using C57BL/6 mice deficient in p53. We found that p53-deficient mice were more susceptible to streptozotocin-induced diabetes than control mice, and they produced higher levels of interleukin-1, -6, and -12. The innate immune response of p53-/- macrophages to lipopolysaccharides and gamma-interferon was significantly enhanced compared with p53+/+ cells. p53-/- macrophages produced more proinflammatory cytokines and higher levels of total and phosphorylated signal transducer and activator of transcription (STAT)-1. These results indicate that p53 inhibits autoimmune diabetes and innate immune responses through downregulating STAT-1 and proinflammatory cytokines.
Diabetes 2005 May
PMID:Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function. 1585 29

Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link between vanadium and oxidative stress in the etiology of diabetes. The impact of zinc (Zn) on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiology of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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PMID:Metals, toxicity and oxidative stress. 1589 31

IFN-gamma and TNF-alpha are major proinflammatory cytokines implicated in islet beta-cell destruction, which results in type-1 diabetes; however, the underlying mechanism is not clear. Using pancreatic beta-cell line MIN6N8 cells, co-treatment with TNF-alpha and IFN-gamma, but neither cytokine alone, synergistically induced apoptosis, correlated with the activation of the JNK/SAPK, which resulted in the production of reactive oxidative species (ROS) and loss of mitochondrial transmembrane potential (delta psi m). Additionally, cells transfected with wild-type JNK1 became more susceptible to apoptosis induced by TNF-alpha/IFN-gamma through ROS production and loss of delta psi m, while cascading apoptotic events were prevented in dominant-negative JNK1-transfected or JNK inhibitor SP600125-treated cells. As the antioxidant, N-acetyl-cysteine, failed to completely suppress apoptosis induced by TNF-alpha/IFN-gamma, an additional pathway was considered to be involved. The level of p53 was significantly increased through synergistic activation of JNK by TNF-alpha/IFN-gamma. Furthermore, the synergistic effect of TNF-alpha/IFN-gamma on apoptosis and ROS production was further potentiated by the overexpression of wild-type p53, but not with mutant p53. This synergistic activation of JNK/SAPK by TNF-alpha/IFN-gamma was also induced in insulin-expressing pancreatic islet cells, and increased ROS production and p53 level, which was significantly inhibited by SP600125. Collectively, these data demonstrate that TNF-alpha/IFN-gamma synergistically activates JNK/SAPK, playing an important role in promoting apoptosis of pancreatic beta-cell via activation of p53 pathway together with ROS.
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PMID:Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway. 1590 80

Poly(ADP-ribose) polymerase (PARP)-1 is a DNA nick sensor that transforms ADP-ribose from betaNAD+ in the form of polymer to over 40 nuclear proteins, particularly to histones, several transcription factors, and PARP itself, modulating their activities and functions. PARP-1 activated by DNA breaks facilitates transcription, replication, and DNA base excision repair. The last studies indicate that PARP-1 is the new nuclear target for fast signals evoked in cell membranes by depolarization and cholinergic and glutaminergic receptors stimulation. Excessive activation of PARP-1 by peroxynitrate-evoked DNA damage during oxidative stress can cause cell death by NAD+/ATP depletion after ischemia-reperfusion injury, inflammation, and diabetes mellitus. The PARP-1 through interaction with nuclear factor-kappaB, p53, and other transcription factors might significantly modulate cell survival and death and a type of death pathway. The pharmacological modulation of PARP-1 might offer a new effective approach for neuroprotection.
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PMID:Poly(ADP-ribose) polymerase: the nuclear target in signal transduction and its role in brain ischemia-reperfusion injury. 1595 18

Lactotroph cell death is increased in streptozotocin-induced diabetic rats. To determine the mechanism involved, cell death proteins were accessed in pituitaries of diabetic (streptozotocin at 65 mg/kg, 2 months evolution) and control male rats by Western blot analysis and double immunohistochemistry. The intact and cleaved forms of caspase 9 were increased in diabetic rat pituitaries compared with controls. Although the proforms of caspases 3, 6, and 7 were increased in diabetic rat pituitaries, their activated forms were either unchanged or decreased. Activation of these effector caspases may be blocked by the increased expression of X-chromosome-linked inhibitor of apoptosis protein (XIAP) in diabetic rat pituitaries. However, in diabetic rats, XIAP expression in lactotrophs was decreased, suggesting that this cell type is not protected. Caspase 8, p53, and nuclear factor kappaB were more highly activated in diabetic rat pituitaries, with caspase 8 colocalization in lactotrophs being increased. These results suggest that, in the pituitaries of diabetic rats, the cascades of normal cell turnover are partially inhibited, possibly via XIAP, and this may be cell specific. Furthermore, activation of the extrinsic cell-death pathway, including activation of caspase 8, may underlie the diabetes-associated increase in lactotroph death.
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PMID:Activation of caspase 8 in the pituitaries of streptozotocin-induced diabetic rats: implication in increased apoptosis of lactotrophs. 1597 52

Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
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PMID:Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. 1602 17

Pentoxifylline (Ptx), a hemorrheologic methylxanthine derivative, is of interest in radiation oncology for several reasons. First, improvement of tumor perfusion might result in better oxygenation and thus radiosensitivity. In addition, the drug also influences cytokine-mediated inflammation. The role of cytokines in the progression of radiation reactions in both tumor and normal tissues therefore provides further opportunities to combine Ptx with ionising radiation in order to improve the therapeutic ratio. This review summarizes preclinical and clinical data in both tumor and normal tissues. Regarding radiosensitization of tumors, a large body of evidence suggests that Ptx improves tumor oxygenation and sensitizes p53 mutant tumors. However, these findings have not translated into positive clinical studies to date. None of three published clinical trials attempting to enhance the effectiveness of radiotherapy with Ptx had a satisfactory design. There is also little evidence to prove that Ptx reduces acute side effects of radiotherapy. The only possible exception is a small randomized trial of lung radiotherapy. Regarding established late sequelae, numerous non-randomized clinical trials described healing of soft tissue necrosis and improvement of trismus and fibrosis after several weeks of Ptx or Ptx plus vitamin E. However, is not unequivocally clear that the combination with vitamin E indeed is superior. The literature data suggest that radiation necrosis can be treated more effectively than fibrosis and that certain improvements might be functional and transient, with less influence on the chronic structural damage induced by ionising radiation. The ultimate individual outcome might depend, for example, on the stage of fibrosis progression, the size of the lesion and comorbid conditions such as diabetes and arteriosclerosis. Some of these factors will influence the actual amount of drug available in the targeted region. It is therefore necessary to evaluate Ptx in larger clinical trials with less baseline variation and to improve the recording of long-term results.
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PMID:The role of pentoxifylline as a modifier of radiation therapy. 1622 96

The mRNA coding for FGF-2 (fibroblast growth factor 2), a major angiogenic factor, is translated by an IRES (internal ribosome entry site)-dependent mechanism. We have studied the role of the IRES in the regulation of FGF-2 expression in vivo, under pathophysiological conditions, by creating transgenic mice lines expressing bioluminescent bicistronic transgenes. Analysis of FGF-2 IRES activity indicates strong tissue specificity in adult brain and testis, suggesting a role of the IRES in the activation of FGF-2 expression in testis maturation and brain function. We have explored translational control of FGF-2 mRNA under diabetic hyperglycaemic conditions, as FGF-2 is implied in diabetes-related vascular complications. FGF-2 IRES is specifically activated in the aorta wall in streptozotocin-induced diabetic mice, in correlation with increased expression of endogenous FGF-2. Thus, under hyperglycaemic conditions, where cap-dependent translation is blocked, IRES activation participates in FGF-2 overexpression, which is one of the keys of diabetes-linked atherosclerosis aggravation. IRES activation under such pathophysiological conditions may involve ITAFs (IRES trans-acting factors), such as p53 or hnRNP AI (heterogeneous nuclear ribonucleoprotein AI), recently identified as inhibitory or activatory ITAFs respectively for FGF-2 IRES.
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PMID:IRES-dependent regulation of FGF-2 mRNA translation in pathophysiological conditions in the mouse. 1624 70

Protein tyrosine phosphatase 1B (PTP1B) is involved in multiple signaling pathways by down-regulating several tyrosine kinases. For example, gene-targeting studies in mice have established PTP1B as a critical physiologic regulator of metabolism by attenuating insulin signaling. PTP1B is an important target for the treatment of diabetes, because the PTP1B null mice are resistant to diet-induced diabetes and obesity. On the other hand, despite the potential for enhanced oncogenic signaling in the absence of PTP1B, PTP1B null mice do not develop spontaneous tumors. Because the majority of human cancers harbor mutations in p53, we generated p53/PTP1B double null mice to elucidate the role of PTP1B in tumorigenesis. We show that genetic ablation of PTP1B in p53 null mice decreases survival rate and increases susceptibility towards the development of B lymphomas. This suggested a role for PTP1B in lymphopoiesis, and we report that PTP1B null mice have an accumulation of B cells in bone marrow and lymph nodes, which contributed to the increased incidence of B lymphomas. The mean time of tumor development and tumor spectrum are unchanged in p53-/-PTP1B+/- mice. We conclude that PTP1B is an important determinant of the latency and type of tumors in a p53-deficient background through its role in the regulation of B-cell development.
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PMID:Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development. 1626 35


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