Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance (IR) and its associated metabolic derangements are known complications of advanced chronic kidney disease (CKD). The etiology of IR in CKD is multifactorial with likely contributions from vitamin D deficiency, obesity, metabolic acidosis, inflammation, and accumulation of 'uremic toxins' leading to acquired defects in the insulin-receptor signaling pathway. An important consequence in end-stage renal disease (ESRD) is its role in the pathogenesis of uremic protein energy wasting, a commonly observed state of metabolic derangement characterized by loss of somatic and visceral protein stores not entirely accounted for by inadequate nutrient intake. In the general population, IR has been associated with accelerated protein catabolism. Among ESRD patients, enhanced muscle protein breakdown has been observed in patients with type 2 diabetes mellitus (DM) compared to ESRD patients without DM. In the absence of DM or severe obesity, IR is detectable in dialysis patients and strongly associated with increased muscle protein breakdown, even after controlling for inflammation. This process appears to be mediated by the ubiquitin-proteasome pathway. Given the high prevalence of protein energy wasting in ESRD and its unequivocal association with adverse clinical outcomes, IR may represent an important modifiable target for intervention in the ESRD population.
 ...
PMID:Determinants of insulin resistance and its effects on protein metabolism in patients with advanced chronic kidney disease. 1845 70

Insulin resistance (IR), the reciprocal of insulin sensitivity is a known complication of advanced chronic kidney disease (CKD) and is associated with a number of metabolic derangements. The complex metabolic abnormalities observed in CKD such as vitamin D deficiency, obesity, metabolic acidosis, inflammation, and accumulation of "uremic toxins" are believed to contribute to the etiology of IR and acquired defects in the insulin-receptor signaling pathway in this patient population. Only a few investigations have explored the validity of commonly used assessment methods in comparison to gold standard hyperinsulinemic hyperglycemic clamp technique in CKD patients. An important consequence of insulin resistance is its role in the pathogenesis of protein energy wasting, a state of metabolic derangement characterized by loss of somatic and visceral protein stores not entirely accounted for by inadequate nutrient intake. In the general population, insulin resistance has been associated with accelerated protein catabolism. Among end-stage renal disease (ESRD) patients, enhanced muscle protein breakdown has been observed in patients with Type II diabetes compared to ESRD patients without diabetes. In the absence of diabetes mellitus (DM) or severe obesity, insulin resistance is detectable in dialysis patients and strongly associated with increased muscle protein breakdown, primarily mediated by the ubiquitin-proteasome pathway. Recent epidemiological data indicate a survival advantage and better nutritional status in insulin-free Type II DM patients treated with insulin sensitizer thiazolidinediones. Given the high prevalence of protein energy wasting in ESRD and its unequivocal association with adverse clinical outcomes, insulin resistance may represent an important modifiable target for intervention in the ESRD population.
 ...
PMID:Insulin resistance and protein energy metabolism in patients with advanced chronic kidney disease. 2070 17

Vitamin D deficiency leads to muscle wasting in both animals and humans. A vitamin D-deficient rat model was created using Sprague Dawley male rats. We studied the involvement of the ubiquitin proteasome and other proteolytic pathways in vitamin D deficiency-induced muscle atrophy. To delineate the effect of hypocalcemia that accompanies D deficiency, a group of deficient rats was supplemented with high calcium alone. Total protein degradation in muscle was assessed by release of tyrosine; proteasomal, lysosomal, and calpain enzyme activities were studied using specific substrates by fluorometry, and E2 enzyme expression was assessed by Western blot analysis. Muscle histology was done by myosin ATPase staining method, whereas 3-methylhistidine in the urine was estimated using HPLC. Muscle gene expression was measured by semiquantitative RT-PCR. Total protein degradation in muscle and the level of 3-methylhistidine in urine were increased in the deficient group compared with the control group. Proteasomal enzyme activities, expression of the E2 ubiquitin conjugating enzyme, and ubiquitin conjugates were increased in the deficient group compared with controls. On the other hand, lysosomal and calpain activities were not altered. Type II fiber area, a marker for muscle atrophy, was decreased in the deficient muscle compared with control muscle. Muscle atrophy marker genes and proteasomal subunit genes were up-regulated, whereas myogenic genes were down-regulated in D-deficient muscle. From the results it appears that the ubiquitin proteasome pathway is the major pathway involved in vitamin D deficiency-induced muscle protein degradation and that calcium supplementation alone in the absence of vitamin D partially corrects the changes.
 ...
PMID:Vitamin D deficiency-induced muscle wasting occurs through the ubiquitin proteasome pathway and is partially corrected by calcium in male rats. 2414 94

Vitamin D is known to have a biological role in many extra skeletal tissues in the body including muscle. Vitamin D deficiency has been associated with preferential atrophy of type II fibres in human muscle. Vitamin D at physiological concentrations is known to protect cells against oxidative damage. In this study we examined whether vitamin D deficiency induces muscle oxidative stress in a rat model and further if pre or post treatment of C2C12 muscle cells with vitamin D offers protection against oxidative stress induced muscle proteolysis. Protein carbonylation as a marker of protein oxidation was increased in both the deficient muscle and vehicle-treated C2C12 cells. Vitamin D deficiency led to an increase in activities of the glutathione-dependent enzymes and decrease in SOD and catalase enzymes in the rat muscle. Higher nitrate levels indicative of nitrosative stress were observed in the deficient muscle compared to control muscle. Rehabilitation with vitamin D could reverse the alterations in oxidative and nitrosative stress parameters. Increase in total protein degradation, 20S proteasomal enzyme activity, muscle atrophy gene markers and expression of proteasome subunit genes induced by oxidative stress were corrected both by pre/post treatment of C2C12 muscle cells with vitamin D. Increase in SOD activity in the presence of vitamin D indicates antioxidant potential of vitamin D in the muscle. The data presented indicates that vitamin D deficiency leads to mild oxidative stress in the muscle which may act as a trigger for increased proteolysis in the vitamin D deficient muscle.
...
PMID:Vitamin D treatment protects against and reverses oxidative stress induced muscle proteolysis. 2604 54