Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis.It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis.Nitazoxanide is an FDA-approved oral antiprot...Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis.It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis.Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile.We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in Hep G2 cells.Gavage administration of nitazoxanide inhibited high-fat diet(HFD)-induced increases of liver weight,blood and liver lipids,and ameliorated HFD-induced renal lipid accumulation in hamsters.Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers.In the hamsters with pre-existing hyperlipidemia and hepatic steatosis,nitazoxanide also showed therapeutic effect.Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet(WD)-induced hepatic steatosis in Apoe-/-mice.The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.展开更多
(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important...(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important compound.Through screening the available carbonyl reductases,we obtained a carbonyl reductase from Novosphingobium aromaticivorans(CBR),which could completely convert 100 g/L of 1a to(S)-1b.Furthermore,a carbonyl reductase from Novosphingobium sp.Leaf2(NoCR)was identified to completely convert 200 g/L of 1a to(S)-1b with excellent enantioselectivity(>99%ee)and 77%isolated yield using FDH/formate system for NADH regeneration.The K_(m) and k_(cat) of recombinant NoCR towards 1a were 0.66 mmol/L and 7.5 s-1,and the catalytic efficiency k_(cat)/K_(m) was 11.3 mmol/s.L.Meanwhile,NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring,indicating that NoCR is a valuable biocatalyst with potential practical applications.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81773725 and 91739102)。
文摘Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis.It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis.Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile.We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in Hep G2 cells.Gavage administration of nitazoxanide inhibited high-fat diet(HFD)-induced increases of liver weight,blood and liver lipids,and ameliorated HFD-induced renal lipid accumulation in hamsters.Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers.In the hamsters with pre-existing hyperlipidemia and hepatic steatosis,nitazoxanide also showed therapeutic effect.Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet(WD)-induced hepatic steatosis in Apoe-/-mice.The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.
基金supported by the National Key R&D Program of China(No.2021YFC2102000)the Strategic Priority Research Program of the Chinese Academy of Sciences,and Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(No.TSBICIPKJGG-009).
文摘(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important compound.Through screening the available carbonyl reductases,we obtained a carbonyl reductase from Novosphingobium aromaticivorans(CBR),which could completely convert 100 g/L of 1a to(S)-1b.Furthermore,a carbonyl reductase from Novosphingobium sp.Leaf2(NoCR)was identified to completely convert 200 g/L of 1a to(S)-1b with excellent enantioselectivity(>99%ee)and 77%isolated yield using FDH/formate system for NADH regeneration.The K_(m) and k_(cat) of recombinant NoCR towards 1a were 0.66 mmol/L and 7.5 s-1,and the catalytic efficiency k_(cat)/K_(m) was 11.3 mmol/s.L.Meanwhile,NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring,indicating that NoCR is a valuable biocatalyst with potential practical applications.
