11β-Hydroxysteroid dehydrogenase 1(11β-HSD1)represents a promising drug target for metabolic syndrome,includ-ing obesity and type 2 diabetes.Our initial screen of a collection of natural products from Danshen led to...11β-Hydroxysteroid dehydrogenase 1(11β-HSD1)represents a promising drug target for metabolic syndrome,includ-ing obesity and type 2 diabetes.Our initial screen of a collection of natural products from Danshen led to the identi-fication of tanshinones as the potent and selective 11β-HSD1 inhibitors.To improve the druggability and explore the structure-activity relationships(SARs),more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials.More than 10 derivatives exhibited potent in vitro 11β-HSD1 inhibitory activity and good selectivity over 11β-HSD2 across human and mouse species.Based on the biological results,SARs were further discussed,which was also partially rationalized by a molecular docking model of 1 bound to the 11β-HSD1.Remarkably,compounds 1,17 and 30 significantly inhibited 11β-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice,which merits further investigations as anti-diabetic agents.This study not only provides a series of novel selective 11β-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes,but also expands the boundaries of the chemical and biological spaces of tanshinones.展开更多
目的:评估11β-羟基类固醇脱氢酶1(11β-hydroxysteroid dehydrogenase type 1,11β-HSD1)抑制剂BVT.2733对肥胖小鼠骨骼肌、肝脏、肾脏、心肌和脾脏中代谢和炎症相关基因表达的影响。方法:构建高脂饮食诱导的肥胖小鼠模型,分为正常饮...目的:评估11β-羟基类固醇脱氢酶1(11β-hydroxysteroid dehydrogenase type 1,11β-HSD1)抑制剂BVT.2733对肥胖小鼠骨骼肌、肝脏、肾脏、心肌和脾脏中代谢和炎症相关基因表达的影响。方法:构建高脂饮食诱导的肥胖小鼠模型,分为正常饮食组、高脂饮食组和高脂饮食+BVT.2733处理组。采用RT-PCR检测骨骼肌、心肌、肝脏、肾脏和脾脏中的代谢及炎症相关基因的表达。结果:在代谢方面,BVT.2733可促进骨骼肌和心肌的代谢指标UCP2和GLUT4的表达,同时,BVT.2733可抑制肝脏的脂质合成关键酶SREBP和FAS的表达,并可以使肾脏的葡萄糖重吸收蛋白SGLT1和SGLT2表达降低。在炎症方面,BVT.2733可显著抑制脾脏的IFN-γ、IL-13、IL-4和IL-5的表达,同时可减少骨骼肌和心肌炎症因子的表达。结论:BVT.2733对肥胖小鼠的骨骼肌、肝脏、肾脏、心肌和脾脏的代谢及炎症相关基因的表达有显著影响。展开更多
Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis,which is associated with high morbidity and mortality.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1),encoded by Hsd11b1,is a reducta...Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis,which is associated with high morbidity and mortality.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1),encoded by Hsd11b1,is a reductase that can convert inactive cortisone into metabolically active cortisol,but the role of 11β-HSD1 in sepsis-induced myocardial dysfunction remains poorly understood.The current study aimed to investigate the effects of 11β-HSD1 on a lipopolysaccharide(LPS)-induced mouse model,in which LPS(10 mg/kg)was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice.We asscessed cardiac function by echocardiography,performed transmission electron microscopy and immunohistochemical staining to analyze myocardial mitochondrial injury and histological changes,and determined the levels of reactive oxygen species and biomarkers of oxidative stress.We also employed polymerase chain reaction analysis,Western blotting,and immunofluorescent staining to determine the expression of related genes and proteins.To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction,we used LPS to induce lentivirus-infected neonatal rat ventricular cardiomyocytes.We found that knockdown of 11β-HSD1 alleviated LPS-induced myocardial mitochondrial injury,oxidative stress,and inflammation,along with an improved myocardial function;furthermore,the depletion of 11β-HSD1 promoted the phosphorylation of adenosine 5′-monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptor gamma coactivator 1α(PGC-1α),and silent information regulator 1(SIRT1)protein levels both in vivo and in vitro.Therefore,the suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges.展开更多
Hormone Receptor positive (HR+) breast cancer is the most common malignancy in women. New strategies in the treatments have targeted the estrogen biosynthesis pathways including the inhibition of the aromatase and 17...Hormone Receptor positive (HR+) breast cancer is the most common malignancy in women. New strategies in the treatments have targeted the estrogen biosynthesis pathways including the inhibition of the aromatase and 17β-HSD1 enzymes. The present work, describes the study of a new family of 9 hybrid compounds derived from estrone attached to a coumarin fragment, linked through different lengths of hydrocarbon chains. The activity of these compounds was evaluated by molecular docking with two relevant enzymes in breast cancer (HR+). It has been proposed nine compounds as 17β-HSD1 inhibitors and six as aromatase inhibitors. We found important interactions with key amino acids at the orthosteric site of each enzyme and their score values compared to the crystallographic ligand. The in silico analysis showed good score values in the proposed compounds, where the steroidal portion presented important interactions with Met374 and Tyr155 in aromatase and in 17β-HSD1 respectively. Highlighting Compounds 2, 5 and 8 with an aromatic ring at the C4 position of the coumarin moiety, which favored arene-H type interactions essential for protein-ligand recognition. In addition, the results related to the 17β-HSD1 enzyme demonstrated how the length of the linker influences the interaction;the best score was found for derivative 8 with a chain of 8 methylenes.展开更多
Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal ro...Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal role in the progression of estrogen-dependent diseases. N-n-Butyl-N-methyl-ll-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl)undecanamide (EM-139) was previously described as a dual-site inhibitor that can inhibit 17β-HSD1 transforming E1 into E2 and also inhibit estrogen receptor. In the present report, we describe the co-crystallization of EM-139 with 17β-HSD1 as well as the analysis of the three-dimensional structure of the enzyme/inhibitor complex. The crystal is grown under similar condition as native crystals, whereas the space group is changed to I121 never observed in other 17β-HSD1 crystals before. The steroidal moiety of the bound EM-139 molecule has shown a binding pattern similar to E2 in the E2 binary complex. The O-3 of the inhibitor develops hydrogen bonds with residues His221 and Glu282, whereas the O-17 makes hydrogen bonds with Ser142 and Tyr155. The bulky 7α-alkyl moiety of the inhibitor, which is essential for its anti-estrogenic activity but cannot be defined in the electron density, may compromise the inhibitory effect of EM-139 to 17β-HSD1. Moreover, the 16α-Cl atom shows no obvious interaction with surrounding residues. The atomic level understanding of the inhibitory mechanism of EM-139 provides important information for the inhibitor design of 17β-HSD1, which will facilitate future development of more potent and selective inhibitors of the enzyme for therapeutic purposes.展开更多
Objective:To observe the effects of long-snake moxibustion on the hypothalamic-pituitary-adrenocortical(HPA)axis and hepatic 11β-hydroxy steroid dehydrogenase type 1(11β-HSD1)expression in rats with kidney yang defi...Objective:To observe the effects of long-snake moxibustion on the hypothalamic-pituitary-adrenocortical(HPA)axis and hepatic 11β-hydroxy steroid dehydrogenase type 1(11β-HSD1)expression in rats with kidney yang deficiency to provide a basis for later in-depth exploration of the action mechanism of longsnakemoxibustion on suchrats.Methods:Fifteen SPF-grade,male,SD rats were randomly divided into a blank control group,a model group,and a long-snake moxibustion treatment group,with five rats in each group.Hydrocortisone powder(30 mg/kg)was administered by gavage at a volume of 10 mL/kg to prepare the rat model of kidney yang deficiency.After successful modeling,the rats in the long-snake moxibustion treatment group underwent long-snake moxibustion treatment every other day along the governor vessel from Dazhui(GV14)to Shenshu(BL23),for a period of 14 days.The remaining two groups were secured in the same way as the long-snake moxibustion treatment group,although they did not receive any treatment.The body weight,rectal temperature,and spontaneous activity count of the rats,as well as serum levels of corticotropin releasing hormone(CRH)and corticosterone(CORT)were detected by ELISA before modeling,after modeling,and after treatment.The amount of 11β-HSD1 protein in rat liver was determined by immunohistochemistry and Western blot analysis.Results:Compared with the rats in the blank control group,those in the model group exhibited a significant decrease in the trend of body weight growth and in rectal temperature(P<0.05),as well as a slight yet non-significant decrease in spontaneous activity count(P>0.05);compared with the rats in the model group,the rats in the treatment group exhibited a significant increase in rectal temperature(P<0.05)and in spontaneous activity count(P<0.05).Moreover,after 14 days of treatment,compared with the rats in the blank,the rats in the model group exhibited a significant decrease in serum cORT content(P<0.05)and in the expression of 11β-HSD1 in the liver(P<0.05),as well as a slight yet non-significant decrease in serum CRH content(P>0.05);compared with the rats in the model group,the rats in the treatment group exhibited a significant increase in serum CRH content(P<0.05)and in the expression of 11β-HSD1 in the liver(P<0.05),as well as a slight yet non-significant increase in serum CORT content(P>0.05).Conclusion:Long-snake moxibustion can increase the rectal temperature and spontaneous activity count of rats with kidney yang deficiency,improve the function of the HPA axis,and increase the expression of 11β-HSD1 in the liver.展开更多
基金the National Natural Science Foundation of China (No.U1502223)Hunan Provincial Key Research and Development Project (Grant No.2021WK2005 to X.Deng)+1 种基金Natural Science Foundation of Hunan Province (Grant No.2021JJ30894 to X.Deng)the open fund of State Key Laboratory of Phytochemistry and Plant Resource in West China (Grant No.P2020-KF03).
文摘11β-Hydroxysteroid dehydrogenase 1(11β-HSD1)represents a promising drug target for metabolic syndrome,includ-ing obesity and type 2 diabetes.Our initial screen of a collection of natural products from Danshen led to the identi-fication of tanshinones as the potent and selective 11β-HSD1 inhibitors.To improve the druggability and explore the structure-activity relationships(SARs),more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials.More than 10 derivatives exhibited potent in vitro 11β-HSD1 inhibitory activity and good selectivity over 11β-HSD2 across human and mouse species.Based on the biological results,SARs were further discussed,which was also partially rationalized by a molecular docking model of 1 bound to the 11β-HSD1.Remarkably,compounds 1,17 and 30 significantly inhibited 11β-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice,which merits further investigations as anti-diabetic agents.This study not only provides a series of novel selective 11β-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes,but also expands the boundaries of the chemical and biological spaces of tanshinones.
文摘目的:评估11β-羟基类固醇脱氢酶1(11β-hydroxysteroid dehydrogenase type 1,11β-HSD1)抑制剂BVT.2733对肥胖小鼠骨骼肌、肝脏、肾脏、心肌和脾脏中代谢和炎症相关基因表达的影响。方法:构建高脂饮食诱导的肥胖小鼠模型,分为正常饮食组、高脂饮食组和高脂饮食+BVT.2733处理组。采用RT-PCR检测骨骼肌、心肌、肝脏、肾脏和脾脏中的代谢及炎症相关基因的表达。结果:在代谢方面,BVT.2733可促进骨骼肌和心肌的代谢指标UCP2和GLUT4的表达,同时,BVT.2733可抑制肝脏的脂质合成关键酶SREBP和FAS的表达,并可以使肾脏的葡萄糖重吸收蛋白SGLT1和SGLT2表达降低。在炎症方面,BVT.2733可显著抑制脾脏的IFN-γ、IL-13、IL-4和IL-5的表达,同时可减少骨骼肌和心肌炎症因子的表达。结论:BVT.2733对肥胖小鼠的骨骼肌、肝脏、肾脏、心肌和脾脏的代谢及炎症相关基因的表达有显著影响。
基金supported by grants from the National Natural Science Youth Foundation of China(Grant No.81501201)the National Natural Science Youth Foundation of Jiangsu Province(Grant No.BK20151032)Min Huang,and the project of Critical Care Medicine of the Key Clinical Specialty of Jiangsu Province.
文摘Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis,which is associated with high morbidity and mortality.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1),encoded by Hsd11b1,is a reductase that can convert inactive cortisone into metabolically active cortisol,but the role of 11β-HSD1 in sepsis-induced myocardial dysfunction remains poorly understood.The current study aimed to investigate the effects of 11β-HSD1 on a lipopolysaccharide(LPS)-induced mouse model,in which LPS(10 mg/kg)was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice.We asscessed cardiac function by echocardiography,performed transmission electron microscopy and immunohistochemical staining to analyze myocardial mitochondrial injury and histological changes,and determined the levels of reactive oxygen species and biomarkers of oxidative stress.We also employed polymerase chain reaction analysis,Western blotting,and immunofluorescent staining to determine the expression of related genes and proteins.To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction,we used LPS to induce lentivirus-infected neonatal rat ventricular cardiomyocytes.We found that knockdown of 11β-HSD1 alleviated LPS-induced myocardial mitochondrial injury,oxidative stress,and inflammation,along with an improved myocardial function;furthermore,the depletion of 11β-HSD1 promoted the phosphorylation of adenosine 5′-monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptor gamma coactivator 1α(PGC-1α),and silent information regulator 1(SIRT1)protein levels both in vivo and in vitro.Therefore,the suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges.
文摘Hormone Receptor positive (HR+) breast cancer is the most common malignancy in women. New strategies in the treatments have targeted the estrogen biosynthesis pathways including the inhibition of the aromatase and 17β-HSD1 enzymes. The present work, describes the study of a new family of 9 hybrid compounds derived from estrone attached to a coumarin fragment, linked through different lengths of hydrocarbon chains. The activity of these compounds was evaluated by molecular docking with two relevant enzymes in breast cancer (HR+). It has been proposed nine compounds as 17β-HSD1 inhibitors and six as aromatase inhibitors. We found important interactions with key amino acids at the orthosteric site of each enzyme and their score values compared to the crystallographic ligand. The in silico analysis showed good score values in the proposed compounds, where the steroidal portion presented important interactions with Met374 and Tyr155 in aromatase and in 17β-HSD1 respectively. Highlighting Compounds 2, 5 and 8 with an aromatic ring at the C4 position of the coumarin moiety, which favored arene-H type interactions essential for protein-ligand recognition. In addition, the results related to the 17β-HSD1 enzyme demonstrated how the length of the linker influences the interaction;the best score was found for derivative 8 with a chain of 8 methylenes.
文摘Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of the most potent natural estrogen 17β-estradiol (E2) from estrone (E1) in the ovary and peripheral tissues, playing a pivotal role in the progression of estrogen-dependent diseases. N-n-Butyl-N-methyl-ll-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl)undecanamide (EM-139) was previously described as a dual-site inhibitor that can inhibit 17β-HSD1 transforming E1 into E2 and also inhibit estrogen receptor. In the present report, we describe the co-crystallization of EM-139 with 17β-HSD1 as well as the analysis of the three-dimensional structure of the enzyme/inhibitor complex. The crystal is grown under similar condition as native crystals, whereas the space group is changed to I121 never observed in other 17β-HSD1 crystals before. The steroidal moiety of the bound EM-139 molecule has shown a binding pattern similar to E2 in the E2 binary complex. The O-3 of the inhibitor develops hydrogen bonds with residues His221 and Glu282, whereas the O-17 makes hydrogen bonds with Ser142 and Tyr155. The bulky 7α-alkyl moiety of the inhibitor, which is essential for its anti-estrogenic activity but cannot be defined in the electron density, may compromise the inhibitory effect of EM-139 to 17β-HSD1. Moreover, the 16α-Cl atom shows no obvious interaction with surrounding residues. The atomic level understanding of the inhibitory mechanism of EM-139 provides important information for the inhibitor design of 17β-HSD1, which will facilitate future development of more potent and selective inhibitors of the enzyme for therapeutic purposes.
基金Supported by National Natural Science Foundation of China:81960900。
文摘Objective:To observe the effects of long-snake moxibustion on the hypothalamic-pituitary-adrenocortical(HPA)axis and hepatic 11β-hydroxy steroid dehydrogenase type 1(11β-HSD1)expression in rats with kidney yang deficiency to provide a basis for later in-depth exploration of the action mechanism of longsnakemoxibustion on suchrats.Methods:Fifteen SPF-grade,male,SD rats were randomly divided into a blank control group,a model group,and a long-snake moxibustion treatment group,with five rats in each group.Hydrocortisone powder(30 mg/kg)was administered by gavage at a volume of 10 mL/kg to prepare the rat model of kidney yang deficiency.After successful modeling,the rats in the long-snake moxibustion treatment group underwent long-snake moxibustion treatment every other day along the governor vessel from Dazhui(GV14)to Shenshu(BL23),for a period of 14 days.The remaining two groups were secured in the same way as the long-snake moxibustion treatment group,although they did not receive any treatment.The body weight,rectal temperature,and spontaneous activity count of the rats,as well as serum levels of corticotropin releasing hormone(CRH)and corticosterone(CORT)were detected by ELISA before modeling,after modeling,and after treatment.The amount of 11β-HSD1 protein in rat liver was determined by immunohistochemistry and Western blot analysis.Results:Compared with the rats in the blank control group,those in the model group exhibited a significant decrease in the trend of body weight growth and in rectal temperature(P<0.05),as well as a slight yet non-significant decrease in spontaneous activity count(P>0.05);compared with the rats in the model group,the rats in the treatment group exhibited a significant increase in rectal temperature(P<0.05)and in spontaneous activity count(P<0.05).Moreover,after 14 days of treatment,compared with the rats in the blank,the rats in the model group exhibited a significant decrease in serum cORT content(P<0.05)and in the expression of 11β-HSD1 in the liver(P<0.05),as well as a slight yet non-significant decrease in serum CRH content(P>0.05);compared with the rats in the model group,the rats in the treatment group exhibited a significant increase in serum CRH content(P<0.05)and in the expression of 11β-HSD1 in the liver(P<0.05),as well as a slight yet non-significant increase in serum CORT content(P>0.05).Conclusion:Long-snake moxibustion can increase the rectal temperature and spontaneous activity count of rats with kidney yang deficiency,improve the function of the HPA axis,and increase the expression of 11β-HSD1 in the liver.
