Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients admitted to the intensive care unit commonly develop skeletal muscle weakness that can exacerbate illness and complicate their recovery. Beyond the primary disease or aging, weakness is promoted by a variety of prolonged hospitalization-associated conditions. These include altered nutritional status, pharmacologic side effects, physical inactivity, and prolonged bed rest. The two latter conditions (i.e. inactivity and bed rest) are the most ubiquitous, affecting all patients during a prolonged hospitalization. In both cases, skeletal muscle utilization is decreased with a concomitant reduction in fatty acid oxidation. Subsequent fatty acids accumulation converted to ceramides could be a cellular mechanism leading to muscle wasting. Indeed these sphingolipids act as second messengers in several of molecular signaling pathways involved in muscle atrophy. Consequently, the aim of this work is to determine the effects of immobilization on muscle ceramides accumulation, and identify the role of these ectopic lipids in molecular mechanisms involved in skeletal muscle atrophy. For this purpose, male Wistar rats were treated with an inhibitor of de novo synthesis of ceramides (i.e. myriocin) and subjected to hindlimb unloading for 7 days. We found that hindlimb unloading induced skeletal muscle atrophy, in part through proteolysis (i.e. decrease in AKT activation, increase in MuRF1 and polyubiquinated proteins content) and apoptosis activations (i.e. increase in Bax/Bcl-2 ratio and cleaved caspase-3). Myriocin treatment did not prevent skeletal muscle atrophy and concomitant induction of apoptosis and proteolysis. Data concerning muscle ceramides content are being analyzed. Together, these results suggest that de novo synthesis of ceramides is not involved in muscle atrophy induced by a short period of hindlimb unloading.
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PMID:De novo ceramides synthesis is not involved in skeletal muscle atrophy induced by short-term mechanical unloading. 2646 26

Sphingolipids are involved in the regulation of cell proliferation. It has been reported that diacylglycerol and sphingosine-1-phosphate generation, during the synthesis of phospho-sphingolipids, is necessary for both, G1-S transition of cell cycle during the sustained activation of protein kinase C in various cell models (MDCK, Saccharomyces and Entamoeba) and AKT pathway activation. During the estrous cycle of the rat, AKT signaling is the main pathway involved in the regulation of uterine cell proliferation. The aim of the present study was to investigate the role of sphingolipid synthesis during proliferation of uterine cells in the estrous cycle of the rat. On metestrus day, when both luminal and glandular uterine epithelia present the maximal BrdU-labeled cells (S phase cells), there was an increase in the relative abundance of total sphingomyelins, as compared to estrus day. Myriocin, a sphingolipid synthesis inhibitor administered on estrus day, before the new cell cycle of epithelial cells is initiated, decreased the abundance of sphingomyelin, accompanied by proliferation arrest in uterine epithelial cells on metestrus day. In order to study the sphingolipid signaling pathway affected by myriocin, we evaluated the activation of the PKC-AKT-GSK3b-Cyclin D3 pathway. We observed that total and phosphorylated protein kinase C diminished in uterine epithelial cells of myriocin treated animals. Interestingly, cyclin D3 nuclear localization was blocked by myriocin, concomitantly with a decrease in nuclear pRb expression. In conclusion, we demonstrate that sphingolipid synthesis and signaling are involved in uterine epithelial cell proliferation during the estrous cycle of the rat.
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PMID:Sphingolipid synthesis and role in uterine epithelia proliferation. 3005 45

The majority of Merkel cell carcinoma, a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus infection. Polyomavirus binding, internalization, and infection are mediated by glycosphingolipids. Besides receptor function, bioactive sphingolipids are increasingly recognized as potent regulators of several hallmarks of cancer. Merkel cell polyomavirus+ and Merkel cell polyomavirus- cells express serine palmitoyl transferase subunits and sphingosine kinase (SK) 1/2 mRNA. Induced expression of Merkel cell polyomavirus-large tumor antigen in human lung fibroblasts resulted in upregulation of SPTLC1-3 and SK 1/2 expression. Therefore, we exploited pharmacological inhibition of sphingolipid metabolism as an option to interfere with proliferation of Merkel cell polyomavirus+ Merkel cell carcinoma cell lines. We used myriocin (a serine palmitoyl transferase antagonist) and two SK inhibitors (SKI-II and ABC294640). In MKL-1 and WaGa cells myriocin decreased cellular ceramide, sphingomyelin, and sphingosine-1-phosphate content. SKI-II increased ceramide species but decreased sphingomyelin and sphingosine-1-phosphate concentrations. Aberrant sphingolipid homeostasis was associated with reduced cell viability, increased necrosis, procaspase-3 and PARP processing, caspase-3 activity, and decreased AKTS473 phosphorylation. Myriocin and SKI-II decreased tumor size and Ki-67 staining of xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. Our data suggest that pharmacological inhibition of sphingolipid synthesis could represent a potential therapeutic approach in Merkel cell carcinoma.
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PMID:Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation. 3039 62