Biomedical subjects
Publications and source records attributed to S R Price.
Dietary practices in India are described and many dietary practices are common throughout the country. The actual foods consumed by different populations depend largely on income, geographical area and whether people are living in an urban or rural setting. Religion and superstition also have some influence.
The oral administration of 1-alpha-acetylmethadol (LAAM) in the mouse was shown to cause a significant elevation in the hepatic LAAM N-demethylase activity. Compared to the self-induction phenomena found with methadone and propoxyphene, LAAM was three and two times more potent, respectively, on a molar basis than these two structurally similar narcotic analogs. Moreover, microsomal induction by LAAM resulted in significant elevations of aminopyrine N-demethylase and aniline hydroxylase activities. These effects were also correlated with a dose related decrement of pentobarbital sleeping time. Thus LAAM appears to be a relatively potent inducer of microsomal metabolism.
Decreased muscle mass in patients with chronic renal failure (CRF) can be caused by mechanisms that activate the ubiquitin-proteasome proteolytic system. This system accelerates the degradation of muscle protein. Concurrent with muscle protein breakdown, there is an increase in transcription of genes encoding components of this pathway, including ubiquitin and subunits of the proteasome. Potential activating signals include metabolic acidosis which stimulates proteolysis in CRF patients and in muscle of rats with CRF by a mechanism involving glucocorticoids. In CRF patients, there is insulin resistance and high circulating levels of tumor necrosis factor and other cytokines. As the ubiquitin-proteasome proteolytic system is activated in acute diabetes and in catabolic conditions associated with high levels of circulating cytokines, these factors could also activate this pathway. Consequently, we examined whether the transcription factor activated by certain cytokines, NF-kappaB, is involved in the transcriptional regulation of subunits of the 26S proteasome complex. The results suggest that cytokines may be involved in the regulation of muscle protein degradation in uremia.
In uremia, accelerated muscle protein degradation results from activation of the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other conditions (e.g., acidosis and diabetes) activate this pathway in rat muscles and are associated with excess glucocorticoids (GC) and impaired insulin action. To define the stimuli responsible for muscle wasting in IDDM, the roles of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ) - induced diabetes were studied. Proteolysis in isolated epitrochlearis muscles from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-injected rats; this increase was eliminated by an inhibitor of the proteasome or by blocking ATP synthesis. In muscles of STZ-diabetic rats, the levels of ubiquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-carrier protein, E2(14k) and the C3, C5 and C9 proteasome subunits were increased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO(3) eliminated acidemia but did not prevent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; physiologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized protein degradation in muscles. In conclusion, reduced insulin together with physiologic levels of glucocorticoids activate the ubiquitin-proteasome pathway by a mechanism that includes enhancing ubiquitin conjugation and proteolysis by the proteasome. The balance between these stimuli could regulate muscle proteolysis in uremia.
Metabolic acidosis and glucocorticoids act in concert to stimulate branched-chain amino acid (BCAA) oxidation in adrenalectomized rats. In muscles of normal rats, metabolic acidosis increases the maximal activity of the rate-limiting enzyme, branched-chain alpha-ketoacid dehydrogenase (BCKAD) and a genetic response to catabolic conditions like uremia is implicated by concurrently higher levels of BCKAD subunit mRNA. To determine if acidification or glucocorticoids increase transcription of BCKAD subunit genes, transfection studies were performed with BCKAD promoter-luciferase reporter minigenes in LLC-PK(1) cells which do not express gluco-corticoid receptors or LLC-PK(1) cells which express a rat glucocorticoid receptor gene (LLC-PK(1)-GR101). Acidification significantly increased luciferase activity in LLC-PK(1) cells and LLC-PK(1)-GR101 cells transfected with reporter plasmids containing 7.0 kb of E2 subunit or 0.8 kb of E1alpha subunit promoter region, respectively. Glucocorticoids in the form of dexamethasone induced transcription of these minigenes but only in LLC-PK(1)-GR101 cells. Using promoter deletion analysis, independent transactivation response elements to acidification or glucocorticoids were localized in the E2 promoter. In summary, catabolic responses to low extracellular pH and glucocorticoids include enhanced expression of genes encoding BCKAD subunits.