Omega-3 polyunsaturated fatty acids(n-3 PUFAs),particularly docosahexaenoic acid(22:6n-3,DHA),play crucial roles in the reproductive health of vertebrates,including humans.Nevertheless,the underlying mechanism related...Omega-3 polyunsaturated fatty acids(n-3 PUFAs),particularly docosahexaenoic acid(22:6n-3,DHA),play crucial roles in the reproductive health of vertebrates,including humans.Nevertheless,the underlying mechanism related to this phenomenon remains largely unknown.In this study,we employed two zebrafish genetic models,i.e.,elovl2^(-/-)mutant as an endogenous DHAdeficient model and fat1(omega-3 desaturase encoding gene)transgenic zebrafish as an endogenous DHA-rich model,to investigate the effects of DHA on oocyte maturation and quality.Results show that the elovl2^(-/-)mutants had much lower fecundity and poorer oocyte quality than the wild-type controls,while the fat1 zebrafish had higher fecundity and better oocyte quality than wildtype controls.DHA deficiency in elovl2^(-/-)embryos led to defects in egg activation,poor microtubule stability,and reduced pregnenolone levels.Further study revealed that DHA promoted pregnenolone synthesis by enhancing transcription of cyp11a1,which encodes the cholesterol side-chain cleavage enzyme,thereby stabilizing microtubule assembly during oogenesis.In turn,the hypothalamic-pituitary-gonadal axis was enhanced by DHA.In conclusion,using two unique genetic models,our findings demonstrate that endogenously synthesized DHA promotes oocyte maturation and quality by promoting pregnenolone production via transcriptional regulation of cyp11a1.展开更多
The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic dr...The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.展开更多
As a kind of substrate competition type 5α reductase inhibitor,finasteride is a promising medicine used in the clinical treatment of benign prostatic hyperplasia (BPH).In this paper,a new route for the synthesis of...As a kind of substrate competition type 5α reductase inhibitor,finasteride is a promising medicine used in the clinical treatment of benign prostatic hyperplasia (BPH).In this paper,a new route for the synthesis of finasteride from pregnenolone was proposed.Thus,pregnenolone was converted to finasteride in 10 steps,i.e.,ammoniumation,methoxylation,Oppenauer oxidation,hydrolyzation,cleavage of Δ 4 double bond by oxidation,ring closure by ammonia,hydrogenation of Δ 5 double bond,esterification with methanol,dehydrogenation of 1,2 position in A ring and Bodroux reaction.In this route,expensive reagent 2,2 dipyridyl disulfide commonly used in previous literature was avoided.All of the desired compounds were characterized by MS or/and NMR.The overall yield of finasteride was 13.67% based on pregnenolone.展开更多
Pregna-3,6,20-trioxime and its analog,pregna-6,20-dione-3-oxime were synthesized from pregnenolone by the oxidation of PCC,reduction of NaBH4,oxidation of Jone’s agent and oximation in four-step reaction.Their struct...Pregna-3,6,20-trioxime and its analog,pregna-6,20-dione-3-oxime were synthesized from pregnenolone by the oxidation of PCC,reduction of NaBH4,oxidation of Jone’s agent and oximation in four-step reaction.Their structures were characterized by NMR and IR.展开更多
从滇重楼Paris polyphylla Sm. var. yunnanensis (Fr.) H-M.地上部分分离得到3个甾体皂甙,经光谱测定和化学降解证明其化学结构分别为:偏诺皂甙元3O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4))-β-D-葡萄吡喃糖甙(A);孕甾-5,...从滇重楼Paris polyphylla Sm. var. yunnanensis (Fr.) H-M.地上部分分离得到3个甾体皂甙,经光谱测定和化学降解证明其化学结构分别为:偏诺皂甙元3O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4))-β-D-葡萄吡喃糖甙(A);孕甾-5,16-二烯-3β-醇-20-酮,3β-O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4)〕-β-D-葡萄吡喃糖甙(B);孕甾-5,16-二烯-3β-醇-20-酮,3β-O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4)-α-L-鼠李吡喃糖基(1→4)〕-β-D-葡萄吡喃糖甙(C)。甙A、B和C在滇重楼根中尚未发现,甙C系首次从重楼属植物中获得,而甙A具有止血的活性。展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Precision Seed Design and Breeding,XDA24010108)National Natural Science Foundation of China(31972780&31721005)+1 种基金National Key R&D Program of China(2018YFA0801000)State Key Laboratory of Freshwater Ecology and Biotechnology(2019FBZ05)。
文摘Omega-3 polyunsaturated fatty acids(n-3 PUFAs),particularly docosahexaenoic acid(22:6n-3,DHA),play crucial roles in the reproductive health of vertebrates,including humans.Nevertheless,the underlying mechanism related to this phenomenon remains largely unknown.In this study,we employed two zebrafish genetic models,i.e.,elovl2^(-/-)mutant as an endogenous DHAdeficient model and fat1(omega-3 desaturase encoding gene)transgenic zebrafish as an endogenous DHA-rich model,to investigate the effects of DHA on oocyte maturation and quality.Results show that the elovl2^(-/-)mutants had much lower fecundity and poorer oocyte quality than the wild-type controls,while the fat1 zebrafish had higher fecundity and better oocyte quality than wildtype controls.DHA deficiency in elovl2^(-/-)embryos led to defects in egg activation,poor microtubule stability,and reduced pregnenolone levels.Further study revealed that DHA promoted pregnenolone synthesis by enhancing transcription of cyp11a1,which encodes the cholesterol side-chain cleavage enzyme,thereby stabilizing microtubule assembly during oogenesis.In turn,the hypothalamic-pituitary-gonadal axis was enhanced by DHA.In conclusion,using two unique genetic models,our findings demonstrate that endogenously synthesized DHA promotes oocyte maturation and quality by promoting pregnenolone production via transcriptional regulation of cyp11a1.
基金supported in part by grants from the National Natural Science Foundation of China(Grant Nos.:81973405,82122071,and 82030111)to Dan XuHui Wang,the National Key R&D Program of China(Grant No.:2020YFA0803900)to Hui Wangthe Hubei Provincial Natural Science Foundation Outstanding Youth Found,China(Grant No.:2022CFA083).
文摘The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While pregnane X receptor(PXR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PXR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PXR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.
文摘As a kind of substrate competition type 5α reductase inhibitor,finasteride is a promising medicine used in the clinical treatment of benign prostatic hyperplasia (BPH).In this paper,a new route for the synthesis of finasteride from pregnenolone was proposed.Thus,pregnenolone was converted to finasteride in 10 steps,i.e.,ammoniumation,methoxylation,Oppenauer oxidation,hydrolyzation,cleavage of Δ 4 double bond by oxidation,ring closure by ammonia,hydrogenation of Δ 5 double bond,esterification with methanol,dehydrogenation of 1,2 position in A ring and Bodroux reaction.In this route,expensive reagent 2,2 dipyridyl disulfide commonly used in previous literature was avoided.All of the desired compounds were characterized by MS or/and NMR.The overall yield of finasteride was 13.67% based on pregnenolone.
文摘Pregna-3,6,20-trioxime and its analog,pregna-6,20-dione-3-oxime were synthesized from pregnenolone by the oxidation of PCC,reduction of NaBH4,oxidation of Jone’s agent and oximation in four-step reaction.Their structures were characterized by NMR and IR.
文摘从滇重楼Paris polyphylla Sm. var. yunnanensis (Fr.) H-M.地上部分分离得到3个甾体皂甙,经光谱测定和化学降解证明其化学结构分别为:偏诺皂甙元3O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4))-β-D-葡萄吡喃糖甙(A);孕甾-5,16-二烯-3β-醇-20-酮,3β-O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4)〕-β-D-葡萄吡喃糖甙(B);孕甾-5,16-二烯-3β-醇-20-酮,3β-O-α-L-鼠李吡喃糖基(1→2)〔α-L-鼠李吡喃糖基(1→4)-α-L-鼠李吡喃糖基(1→4)〕-β-D-葡萄吡喃糖甙(C)。甙A、B和C在滇重楼根中尚未发现,甙C系首次从重楼属植物中获得,而甙A具有止血的活性。
