Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sperm motility is regulated by protein phosphorylation. We have shown that the signaling kinase, glycogen synthase kinase-3 alpha (GSK-3 alpha), is present in spermatozoa. In somatic cells, GSK-3 is regulated by serine and tyrosine phosphorylation. In this report, we document that both GSK-3 alpha and GSK-beta isoforms are present in spermatozoa, with GSK-3 alpha being the predominant isoform. The relationship between GSK-3 serine phosphorylation and motility was investigated. Serine phosphorylation of GSK-3 increases significantly in spermatozoa during their passage through the epididymis. Initiation and stimulation of motility in vitro by isobutyl-methyl-xanthine, 2-chloro-2'-deoxy-adenosine, and calyculin A lead to a dramatic increase in GSK-3 serine phosphorylation. The concentration-dependent induction of motility by calyculin A is closely associated with GSK-3 serine phosphorylation. Immunoprecipitation of GSK-3 alpha and GSK-3 beta shows that both of the GSK-3 isoforms are more active in caput than in caudal spermatozoa. Calyculin A treatment decreased the activity of both isoforms. Column chromatography was used to purify inactive GSK-3 alpha from the caudal sperm extracts. This GSK-3 alpha species was phosphorylated at amino acid residues serine 21 and tyrosine 214. Inactive GSK-3 alpha is present in caudal but not in caput epididymal spermatozoa. The enzymes protein kinase B (PKB; also known as cAkt) and phosphoinositide 3-kinase (PI3-kinase), the upstream signaling proteins involved in GSK-3 phosphorylation, are both present in spermatozoa. Fluorescence immunocytochemistry showed that GSK-3 is present in the head and tail regions of sperm. Our work suggests a novel role for the signaling system involving GSK-3 in the regulation of sperm motility.
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PMID:Changes in sperm glycogen synthase kinase-3 serine phosphorylation and activity accompany motility initiation and stimulation. 1522 49

Epidemiological and experimental studies have demonstrated that early postnatal nutrition has been associated with long-term effects on glucose homeostasis in adulthood. Recently, our group demonstrated that undernutrition during early lactation affects the expression and activation of key proteins of the insulin signaling cascade in rat skeletal muscle during postnatal development. To elucidate the molecular mechanisms by which undernutrition during early life leads to changes in insulin sensitivity in peripheral tissues, we investigated the insulin signaling in adipose tissue. Adipocytes were isolated from epididymal fat pads of adult male rats that were the offspring of dams fed either a normal or a protein-free diet during the first 10 days of lactation. The cells were incubated with 100 nM insulin before the assays for immunoblotting analysis, 2-deoxyglucose uptake, immunocytochemistry for GLUT4, and/or actin filaments. Following insulin stimulation, adipocytes isolated from undernourished rats presented reduced tyrosine phosphorylation of IR and IRS-1 and increased basal phosphorylation of IRS-2, Akt, and mTOR compared with controls. Basal glucose uptake was increased in adipocytes from the undernourished group, and the treatment with LY294002 induced only a partial inhibition both in basal and in insulin-stimulated glucose uptake, suggesting an involvement of phosphoinositide 3-kinase activity. These alterations were accompanied by higher GLUT4 content in the plasma membrane and alterations in the actin cytoskeleton dynamics. These data suggest that early postnatal undernutrition impairs insulin sensitivity in adulthood by promoting changes in critical steps of insulin signaling in adipose tissue, which may contribute to permanent changes in glucose homeostasis.
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PMID:Maternal protein restriction during early lactation induces GLUT4 translocation and mTOR/Akt activation in adipocytes of adult rats. 1855 80

Insulin resistance is central to the pathogenesis of type 2 diabetes mellitus. Previous studies have demonstrated that compounds that cause adipogenesis and improve glucose uptake in 3T3-L1 cells are potential insulin sensitizers. Therefore, we evaluated one such compound, 18F9, for (1) adipogenesis in human subcutaneous preadipocyte (SQ) cells, (2) glucose uptake in human skeletal muscle myotubes and SQ cells, and (3) antidiabetic activity in db/db mice. We also investigated its effect on ex vivo glucose uptake in soleus muscle isolated from continuously treated db/db mice. Gene expression profiling in soleus muscle and epididymal fat of db/db mice was performed to understand its effect on glucose metabolism, lipid metabolism, and thermogenesis. 18F9 enhanced adipogenesis in SQ cells and increased glucose uptake in SQ and human skeletal muscle myotubes cells. In db/db mice, 18F9 exhibited dose-dependent reduction in plasma glucose and insulin level. Interestingly, 18F9 was as efficacious as rosiglitazone but did not cause body weight gain and hepatic adverse effects. In addition, 18F9 demonstrated no change in plasma volume in Wistar rats. Furthermore, it enhanced ex vivo glucose uptake in soleus muscles in these mice, which substantiates our in vitro findings. Human peroxisome proliferator activated receptor-gamma transactivation assay revealed a weak peroxisome proliferator activated receptor-gamma transactivation potential (44% of rosiglitazone at 10 mumol/L) of 18F9. Gene expression profiling indicated that 18F9 increased insulin sensitivity mainly through a phosphoinositide 3-kinase-dependent mechanism. 18F9 also up-regulated genes involved in lipid transport and synthesis at par with rosiglitazone. Unlike rosiglitazone, 18F9 elevated the expression of Pdk4. In addition, 18F9 elevated the expression of glycogen synthase and adiponectin significantly higher than rosiglitazone. Taken together, these observations suggest that 18F9 is a safer and potent insulin sensitizer that demonstrates promising antidiabetic activity and is worth further development.
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PMID:18F9 (4-(3,6-bis (ethoxycarbonyl)-4,5,6,7-tetrahydrothieno (2,3-c) pyridin-2-ylamino)-4-oxobutanoic acid) enhances insulin-mediated glucose uptake in vitro and exhibits antidiabetic activity in vivo in db/db mice. 1960 7

Inonotus obliquus has been traditionally used for treatment of metabolic diseases; however, the mechanism remains to be elucidated. In this study, we found that the water-soluble melanin complex extracted from I. obliquus improved insulin sensitivity and reduced adiposity in high fat (HF)-fed obese mice. When the melanin complex was treated to 3T3-L1 adipocytes, insulin-stimulated glucose uptake was increased significantly, and its phosphoinositide 3-kinase-dependent action was proven with wortmannin treatment. Additionally, dose-dependent increases in Akt phosphorylation and glucose transporter 4 translocation into the plasma membrane were observed in melanin complex-treated cells. Adiponectin gene expression in 3T3-L1 cells incubated with melanin complex increased which was corroborated by increased AMP-activated protein kinase phosphorylation in HepG2 and C2C12 cells treated with conditioned media from the 3T3-L1 culture. Melanin complex-treated 3T3-L1 cells showed no significant change in expression of several lipogenic genes, whereas enhanced expressions of fatty acid oxidative genes were observed. Similarly, the epididymal adipose tissue of melanin complex-treated HF-fed mice had higher expression of fatty acid oxidative genes without significant change in lipogenic gene expression. Together, these results suggest that the water-soluble melanin complex of I. obliquus exerts antihyperglycemic and beneficial lipid-metabolic effects, making it a candidate for promising antidiabetic agent.
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PMID:Insulin-sensitizing and beneficial lipid-metabolic effects of the water-soluble melanin complex extracted from Inonotus obliquus. 2461 48