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)

The nonobese diabetic mouse is a model of spontaneous insulin-dependent diabetes mellitus. The present study made longitudinal observations of renal lesions in the acute-progressive phase of diabetic mice 0, 10, 20, 30, and 40 days after onset of diabetes without insulin therapy. Plasma creatinine and blood urea nitrogen concentrations gradually increased after onset of diabetes. Kidney weight increased and plateaued at day 20. Under electron microscopy the glomeruli demonstrated only mild changes on day 40. In the proximal tubules proliferating cell nuclear antigen-positive nuclei and nuclear divisions were increased on days 10 and 20. On day 40 of diabetes, increased periodic acid-Schiff-positive granules, confirmed as lysosomal dense bodies, increased neuronal nitric oxide synthase (nNOS) positive reaction, and decreased periodic acid-Schiff staining in the brush border were observed in the proximal straight tubules. In the juxtaglomerular apparatus stratified macula densa were decreased with time in diabetes compared with the findings on day 0, and this macula densa positively reacted with nNOS. No changes in renin levels were observed. In addition, apoptotic cells were not detected. In conclusion, this research represents the first thorough characterization of acute changes in nonobese diabetic mouse kidneys. The results demonstrated renal hypertrophy and slight glomerular injury in early stages and structural alteration of the proximal straight tubules at later stages during the acute phase of diabetes. Furthermore, increased nNOS may represent one of the pathogenic factors of diabetic nephropathy.
 ...
PMID:Renal lesions in spontaneous insulin-dependent diabetes mellitus in the nonobese diabetic mouse: acute phase of diabetes. 1263 59

Sexual dysfunction is common in patients with diabetes mellitus. Vascular, neurological and hormonal alterations are involved in this complication. Many studies showed altered endothelium-dependent and neurogenic relaxations in corpus cavernosum from diabetic patients with erectile dysfunction (ED). This finding has been associated with a lack of nitric oxyde (NO) production and a significant increase in NO synthase (NOS) binding sites in penile tissues, induced by diabetes. Advanced glycation endproducts (AGEs) concur to diabetic vascular complications by quenching NO activity and by increasing the expression of mediators of vascular damage such as vascular endothelial growth factor (VEGF), possessing permeabilizing and neoangiogenic effects, and endothelin-1 (ET-1), with vaso-constricting and mitogenic action. Moreover, the differential gene expression for various growth factors in penile tissues may be involved in the pathophysiology of ED associated with diabetes. Neuropathy is also likely to be an important cause of diabetic ED: morphological alterations of autonomic nerve fibers in cavernosal tissue of patients with diabetic ED have been demonstrated. Finally, androgens enhance nNOS gene expression in the penile corpus cavernosum of rats, suggesting that they play a role in maintaining NOS activity. However, sexual dysfunctions in women with diabetes has received less attention in clinical research. Several studies suggest an increased prevalence of deficient vaginal lubrication, making sexual intercourse unpleasant. Sexual dysfunction is associated with lower overall quality of marital relation and more depressive symptoms in diabetic women.
 ...
PMID:Pathophysiology of diabetic sexual dysfunction. 1283 25

This study examined the changes occurring in the pattern of distribution and expression of neuronal nitric oxide synthase (nNOS)-positive nerves in the gastroduodenal tract of streptozotocin-induced diabetic rats. The ganglion cells of the myenteric plexus of the gastric antrum of normal rats contain nNOS. We also observed nNOS-positive neurons and fibres in the myenteric plexus of the duodenum of normal rats. After the onset of diabetes, the number and intensity of staining of nNOS-positive nerve profiles in the gastric antrum and duodenum did not change significantly. However, Western blotting showed a significant increase in the expression of nNOS after the onset of diabetes. In conclusion, diabetes of 4 and 32 weeks duration induced an increase in the tissue content of nNOS in the gastroduodenum of rat. The increase in the level of nNOS in the gastroduodenum of diabetic rats may explain why impaired gastric emptying is common in patients with diabetes.
 ...
PMID:Increase in neuronal nitric oxide synthase content of the gastroduodenal tract of diabetic rats. 1286 83

The advent of a novel oral treatment for erectile dysfunction appears to have reduced the urgency for seeking alternative therapeutic innovations. However, the currently available therapies can be viewed as simply palliative, requiring on-demand access and having a significant failure rate. Therefore, additional approaches for patients unresponsive to any type of medical treatment require investigation. The modulation of the synthesis of nitric oxide (NO), the main mediator of penile erection, is an attractive target for such an approach. Models for human erectile dysfunction related to aging, diabetes and endocrine disorders have been characterized in the rat. The affected animals exhibit a reduced erectile response to electrical stimulation of the cavernosal nerve and/or a loss of spontaneous erectile reflexes. In virtually all cases, the content and/or enzyme activity of penile NOS is significantly reduced, or NO synthesis may be insufficient to overcome the relatively poor compliance of the penile corpora cavernosa smooth muscle (aging). This led to the proposal that the stimulation of penile NO synthesis may be a viable therapy for erectile dysfunction. The upregulation of penile NOS activity may be achieved by: a) increase in NOS substrate concentration, b) stimulation of NOS activity through related pathways or c) blockade of endogenous NOS inhibitors. We have shown that approach a ameliorated the erectile dysfunction of aging rats by elevating intracavernosal NOS substrate through long-term oral administration of high doses of L-arginine. Evidence supporting approach b is based on our recent discovery that the main stimulating pathway for NOS, the NMDA receptor, is present in the penis. However, NMDA receptor antagonists unpredictably trigger cavernosal relaxation in vitro in a NO-independent pathway. Finally, in the case of approach c we have found that a protein inhibitor of NOS (PIN) is expressed in the corpora cavernosa. Penile NOS content may be pharmacologically increased by: d) induction of NOS expression, and e) gene therapy with NOS cDNA. Approach d applied to the penis ameliorated erectile dysfunction in aging rats, but may be clinically unfeasible because of the risk of side effects. Our laboratory cloned the inducible and neuronal NOS isoforms expressed in the penis (PiNOS and PnNOS, respectively), and showed that approach e, based on gene transfer of PiNOS into the rat corpora cavernosa improved the erectile response. Since PnNOS is a nNOS variant different from the one expressed in the CNS, gene therapy with PnNOS is promising in combination with viral vectors and tissue-specific promoters. The aim is to achieve a long-lasting increase in penile NOS that is responsive to sexual stimulation. Following validation in animal models, oral L-arginine, intracavernosal antagonists of NMDA receptor and PIN, and intracavernosal or systemic PnNOS, may eventually translate to clinical trials.
 ...
PMID:Therapeutic stimulation of penile nitric oxide synthase (NOS) and related pathways. 1287 14

Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKCbeta inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKCbeta-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKCbeta and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.
Diabetes 2003 Aug
PMID:Protein kinase Cbeta selective inhibitor LY333531 attenuates diabetic hyperalgesia through ameliorating cGMP level of dorsal root ganglion neurons. 1288 29

The distinction between metabolic and structural changes occurring in autonomic neurons during diabetes has not been fully clarified. Here we demonstrate that nitric oxide synthase-containing (nitrergic) neurons innervating the penis and gastric pylorus of streptozotocin-induced diabetic rats undergo a selective degenerative process in two phases. In the first phase, nitrergic nerve fibers lose some of their neuronal nitric oxide synthase content and function. In the second phase, nitrergic degeneration takes place in the cell bodies in the ganglia, leading to complete loss of nitrergic function. The changes in the first phase are reversible with insulin replacement; however, the neurodegeneration in the second phase is irreversible. Neurodegeneration is due to apoptotic cell death in the ganglia, which is selective for the nitrergic neurones.
Diabetes 2003 Sep
PMID:Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. 1294 76

Angiogenesis is an essential biological process not only in embryogenesis, but also in the progression of several major diseases, including cancer, diabetes, and inflammation. Excessive vascularization can also contribute to some cardiovascular pathologies, such as atherosclerosis, but contradictory reports still prevail regarding its impact on aortic stenosis. Using immunohistochemical techniques, we assessed the vascular density and distribution of angiogenesis (FVIII) and vascular endothelial growth factor (VEGF) expression as well as the expression of 2 VEGF receptors, Flt-1 and Flk-1, in 55 nonrheumatic and 6 control aortic valves. In the light of the fact that the angiogenic effect of VEGF is mediated by sustained formation of nitric oxide, the samples were also immunostained with 3 nitric oxide synthase (eNOS, iNOS, and nNOS) antibodies. The immunohistochemical findings of VEGF and its receptors were verified by immunoblotting techniques. Vascular density was highest in the cases with moderate valve stenosis, and the mean number of FVIII-positive blood vessels was 1.7 +/- 1.9 vessels/mm(2) in the diseased valves, whereas the normal valves contained no blood vessels. Vascular density was significantly higher in the cases showing chronic inflammation (P = 0.007). Interestingly, the patients receiving statin therapy had significantly lower vascular densities than those not receiving such therapy (P = 0.001). Diseased valves showed distinct VEGF, Flt-1, Flk-1, and eNOS positivity of activated endothelial, stromal fusiform myofibroblastic, and histocytic cells. In contrast, immunoreactivity for iNOS and nNOS was seen only in nonendothelial stromal cells, and their expression was weaker. Enhanced vascular density was significantly associated with increased expression of Flk-1 (P = 0.028 for endothelial and P = 0.009 for stromal cells) and with endothelial eNOS expression (P = 0.024). A similar tendency was also observed for VEGF, but not for Flt-1. Our results show a distinct angiogenic response and the presence of angiogenic factors in nonrheumatic aortic valve stenosis, suggesting that angiogenesis may influence on the evolution of this disease.
 ...
PMID:Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis. 1450 35

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.
 ...
PMID:Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model. 1456 36

Erectile dysfunction (ED) is commonly experienced in men with diabetes mellitus. Vascular endothelial growth factor (VEGF) has been extensively documented for its pathogenic significance in different complications of diabetes. We hypothesized that expressions of VEGF, its receptors and its signaling pathway Akt may be drastically altered in diabetic penile tIssues and their alterations may modulate penile expression of the molecules that are believed to play a role in diabetic ED. Otsuka Long-Evans Fatty (OLETF) rats, a type II (non-insulin-dependent) diabetes mellitus, were used at the insulin-resistant stage of type II diabetes (20 weeks of age). We determined protein and mRNA expressions of VEGF, its receptors, Akt, nitric oxide synthase isoforms, and apoptosis-related molecules in the penis using immunohistochemistry, Western blotting, in situ hybridization, and real-time quantitative PCR analyses. The penile sections were also submitted to the Tdt-mediated dUTP nick end labeling assay for apoptosis. OLETF rats showed marked reductions in penile expression of VEGF, its two receptors and Akt. In OLETF rat penises, endothelial and neuronal nitric oxide synthase isoforms were expressed less abundantly. Furthermore, while anti-apoptotic markers, Bcl-2 and phosphorylated Bad, were down-regulated, pro-apoptotic markers, active caspase-3 and Bax, were up-regulated, resulting in the appearance of apoptotic cells in the penile tIssues of OLETF rats. The VEGF signaling system would work less well in diabetic penile tIssues as a result of the reduced expression, leading to diminished endothelial production of nitric oxide and apoptosis-related erectile tIssue damage. We propose that the abnormalities of the VEGF signaling system in the penis may play a role in the pathophysiology of diabetic ED.
 ...
PMID:Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes. 1466 2

Mitochondria play a central role in cell life and cell death. An increasing number of studies place mitochondrial dysfunction at the heart of disease, most notably in the heart and the central nervous system. In this article, I review some of the key features of mitochondrial biology and focus on the pathways of mitochondrial calcium accumulation. Substantial evidence now suggests that the accumulation of calcium into mitochondria may play a key role as a trigger to mitochondrial pathology, especially when that calcium uptake is accompanied by another stressor, in particular nitrosative or oxidative stress. The major process involved is the opening of the mitochondrial permeability transition pore, a large conductance pore that causes a collapse of the mitochondrial membrane potential, leading to ATP depletion and necrotic cell death or to cytochrome c release and apoptosis, depending on the rate of ATP consumption. I discuss two models in particular in which these processes have been characterized. The first is a model of oxidative stress in cardiomyocytes, in which reperfusion after ischemia causes mitochondrial calcium overload, and oxidative stress. Recent experiments suggest that cardioprotection by hypoxic preconditioning or exposure to the ATP-dependent K(+) channel opener diazoxide increases mitochondrial resistance to oxidative injury. In a second model, of calcium overload in neurons, the neurotoxicity of glutamate depends on mitochondrial calcium uptake, but the toxicity to mitochondria also requires the generation of nitric oxide. Glutamate toxicity after activation of N-methyl-D-aspartate (NMDA) receptors results from the colocalization of NMDA receptors with neuronal nitric oxide synthase (nNOS). The calcium increase mediated by NMDA receptor activation is thus associated with nitric oxide generation, and the combination leads to the collapse of mitochondrial membrane potential followed by cell death.
Diabetes 2004 Feb
PMID:Roles of mitochondria in health and disease. 1474 73


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