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Fenretinide (FEN, also known as N-(4-hydroxyphenyl)retinamide or 4-HPR)) is a synthetic derivative of retinoic acid and has been investigated as a potential therapeutic for metabolic syndrome. In previous studies FEN treatment led to decreased weight gain and adiposity and improved glucose homeostasis and insulin sensitivity in association with decreased accumulation of hepatic triglycerides in high-fat diet fed mice13,14,15,16,17,18. The mechanism of FEN action has been attributed to alterations in retinol homeostasis and retinoic acid signalling and prevention of lipotoxicity by directly inhibiting the elevation of several ceramide species both in vitro19 and in vivo, in adipose14, liver tissue17 and skeletal muscle20. Interestingly, Smpd3 encodes for a type 2-neutral sphingomyelinase (nSMase2) that has been identified as transcriptionally induced by retinoic acid21,22. Smpd3/nSMase2 is key to an alternative ceramide generation pathway (via sphingomyelin hydrolysis) that has recently been linked to atherosclerosis via regulation of serum ceramide levels23.
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