11β-hydroxysteroid dehydrogenase type 1 （11β-HSD1） and type 2 （11β-HSD2） are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and lo...11β-hydroxysteroid dehydrogenase type 1 （11β-HSD1） and type 2 （11β-HSD2） are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone （LH） and androgens, mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day （PND） 7, 14, 21, 35, and 90, and from rats treated with LH, 7α.methyl-19-nortestosterone （MENT） and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.展开更多
Intrduction: Edema, Hypertension and Hypokalemia occur with inhibition of 11 B-Hydroxysteroid Dehydrogenase Type 2 (11B-HSD2) by chronic Licorice ingestion. However, a similar presentation following a chronic use of a...Intrduction: Edema, Hypertension and Hypokalemia occur with inhibition of 11 B-Hydroxysteroid Dehydrogenase Type 2 (11B-HSD2) by chronic Licorice ingestion. However, a similar presentation following a chronic use of another commonly used sweetener “Stevia” is not reported. Objective: To document a first case report of a subject presenting with Edema, Prehypertension and Hypokalemia induced by 11B-HSD2 inhibition induced by chronic ingestion of sweetener stevia. Case Report: 32 year old Caucasian woman presented with generalized edema (feet, hands and face) of over 6 months. She was noted to also manifest Prehypertension (138/88 mmHg) and Hypokalemia (3.4 mM/l). Laboratory tests revealed decline in serum aldosterone and plasma renin activity, an increase in plasma cortisol/cortisone ratio. On persistent interrogation, patient admitted to daily consumption of sweetener stevia for over 9 months. All the presenting manifestations resolved with normalization of the laboratory tests on withdrawal of stevia. Conclusion: This case report indicates that chronic ingestion of sweetener stevia may induce edema, hypertension and hypokalemia via reduced conversion of cortisol into cortisone by inhibition of 11 B-Hydroxysteroid Dehydrogenase Type 2.展开更多
It has been proposed that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which activates glucocorticoids, plays a role in chronic inflammatory diseases including metabolic diseases, rheumatoid arthritis, and ul...It has been proposed that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which activates glucocorticoids, plays a role in chronic inflammatory diseases including metabolic diseases, rheumatoid arthritis, and ulcerative colitis. We have recently reported that the expression of 11β-HSD1 is increased in the gingiva of patients with chronic periodontitis and in that of rats with ligature-induced periodontitis. In this study, to further demonstrate the involvement of 11β-HSD1 in chronic periodontitis, the expression of 11β-HSD1 was investigated in another rat model of experimental periodontitis induced by intragingival injection of lipopolysaccharide from Porphyromonas gingivalis (LPS-PG). Alveolar bone loss was observed two weeks after intragingival injection of LPS-PG. The level of 11β-HSD1 mRNA assessed by real-time reverse transcriptase-polymerase chain reaction was significantly elevated in LPS-PG-induced periodontitis compared with controls. The expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates glucocorticoids, was not significantly different between control and LPS-PG-induced periodontitis. The expression of 11β-HSD1 was significantly correlated with that of TNF in LPS-PG-induced periodontitis. The increased expression of 11β-HSD1 protein in LPS-PG-induced periodontitis was confirmed by immunohistochemistry using anti-11β-HSD1 antibody. These results further suggest a role for 11β-HSD1 in the pathogenesis of chronic periodontitis.展开更多
目的研究原发性高血压(essential hypertension,EH)患者11β-类固醇脱氢酶2(11 beta-hydroxysteroid dehydrogenase type 2,11β-HSD2)基因甲基化表达,探讨原发性高血压的发病机制。方法选取2018年1月至2019年6月在佳木斯医学院第一附...目的研究原发性高血压(essential hypertension,EH)患者11β-类固醇脱氢酶2(11 beta-hydroxysteroid dehydrogenase type 2,11β-HSD2)基因甲基化表达,探讨原发性高血压的发病机制。方法选取2018年1月至2019年6月在佳木斯医学院第一附属医院未经治疗的EH患者71例为EH组,选取我院体检的50例健康志愿者为正常对照组,应用甲基化特异性PCR(methylation specific PCR,MSP)方法检测所有入选研究对象11β-HSD2基因甲基化表达。结果EH组和对照组11β-HSD2基因甲基化表达比较,差异具有统计学意义(P<0.05)。结论11β-HSD2基因甲基化参与EH的发生。展开更多
Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide vari...Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.展开更多
The metabolic syndrome, one of the most common clinical conditions in recent times, represents a combination of cardiometabolic risk determinants, including central obesity, glucose intolerance, insulin resistance, dy...The metabolic syndrome, one of the most common clinical conditions in recent times, represents a combination of cardiometabolic risk determinants, including central obesity, glucose intolerance, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease and hypertension. Prevalence of the metabolic syndrome is rapidly increasing worldwide as a consequence of common overnutrition and consequent obesity. Although a unifying picture of the pathomechanism is still missing, the key role of the pre-receptor glucocorticoid activation has emerged recently. Local glucocorticoid activation is catalyzed by a triad composed of glucose-6-phosphate-transporter, hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum. The elements of this system can be found in various cell types, including adipocytes and hepatocytes. While the contribution of glucocorticoid activation in adipose tissue to the pathomechanism of the metabolic syndrome has been well established, the relative importance of the hepatic process is less understood. This review summarizes the available data on the role of the hepatic triad and its role in the metabolic syndrome, by confronting experimental findings with clinical observations.展开更多
目的探讨心房颤动患者心房肌组织盐皮质激素受体(MR)和赋予 MR 特异性的关键酶11β-羟基类固醇脱氢酶Ⅱ(11βHSD2)的 mRNA 和蛋白表达改变。方法入选进行人工心脏瓣膜置换术的风湿性心脏病患者25例,其中窦性心律12例,慢性心房颤动(心房...目的探讨心房颤动患者心房肌组织盐皮质激素受体(MR)和赋予 MR 特异性的关键酶11β-羟基类固醇脱氢酶Ⅱ(11βHSD2)的 mRNA 和蛋白表达改变。方法入选进行人工心脏瓣膜置换术的风湿性心脏病患者25例,其中窦性心律12例,慢性心房颤动(心房颤动时程≥6月)13例。术前进行经胸超声心动图检查,所有患者在术前均签订知情同意书,于手术时取左右心房侧壁组织。用实时荧光定量 PCR 检测 MR 和11βHSD2的 mRNA 水平,Western 印迹检测 MR 和11βHSD2的蛋白表达改变。结果心房颤动组比窦性心律组左房内径显著扩大(P<0.01);房颤组患者 MR mRNA表达(右房:5.37±1.15 vs 2.67±1.09,左房:5.19±1.14 vs 2.70±0.82 P 均<0.01)和11βHSD2mRNA 表达(右房:0.86±0.14 vs 0.33±0.12,左房:0.95±0.15 vs 0.37±0.10 P 均<0.01)均明显增加;同时房颤组患者 MR 和11βHSD2蛋白表达也较窦性心律者明显增加,MR 分别为右房:1.65±0.72 vs 0.86±0.33(P<0.01);左房:1.72±0.62 vs 0.97±0.37(P<0.05)。11βHSD2分别为右房:-1.18±0.64 vs 0.71+0.21(P<0.01);左房:1.36±0.58 vs 0.85±0.15(P<0.05);但在左右心房之间无论是在窦性心律或心房颤动时,MR 和11βHSD2二者在 mRNA 水平和蛋白表达水平差异均无统计学意义(P>0.05)。结论心房颤动时心房肌组织 MR 和11βHSD2表达增加,醛固酮受体拮抗剂将可能对心房颤动发挥治疗作用。展开更多
Inhibition of 11βHSD1 （11-beta-hydroxysteroid dehydrogenase 1） is a promising strategy in drug treatment of diabetes. Several 11βHSDI inhibitors have been proposed; however, their selectivity to 11βHSD1 over its ...Inhibition of 11βHSD1 （11-beta-hydroxysteroid dehydrogenase 1） is a promising strategy in drug treatment of diabetes. Several 11βHSDI inhibitors have been proposed; however, their selectivity to 11βHSD1 over its isozyme 11βHSD2 （11-beta-hydroxysteroid dehydrogenase 2） has not been fully reported. The authors sought to provide a short list of top potent and selective compounds along with their detailed binding modes and pharmacophore models, Molecular docking was used for initial screening of a set of 23 potent inhibitors reported by previous experimental studies. After that, selected promising entries were reassessed by molecular dynamics simulations, followed by hydrogen bond analysis. Pharmacophore models of all drug candidates and binding modes of some selected drugs were analyzed. Among the 23 compounds, only four inhibitors were identified as potent and selective drug candidates. Binding energies, 3D pharmacophores and binding modes of the four compounds with 11βHSDI are also discussed in detail in this study.展开更多
文摘11β-hydroxysteroid dehydrogenase type 1 （11β-HSD1） and type 2 （11β-HSD2） are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone （LH） and androgens, mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day （PND） 7, 14, 21, 35, and 90, and from rats treated with LH, 7α.methyl-19-nortestosterone （MENT） and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.
文摘Intrduction: Edema, Hypertension and Hypokalemia occur with inhibition of 11 B-Hydroxysteroid Dehydrogenase Type 2 (11B-HSD2) by chronic Licorice ingestion. However, a similar presentation following a chronic use of another commonly used sweetener “Stevia” is not reported. Objective: To document a first case report of a subject presenting with Edema, Prehypertension and Hypokalemia induced by 11B-HSD2 inhibition induced by chronic ingestion of sweetener stevia. Case Report: 32 year old Caucasian woman presented with generalized edema (feet, hands and face) of over 6 months. She was noted to also manifest Prehypertension (138/88 mmHg) and Hypokalemia (3.4 mM/l). Laboratory tests revealed decline in serum aldosterone and plasma renin activity, an increase in plasma cortisol/cortisone ratio. On persistent interrogation, patient admitted to daily consumption of sweetener stevia for over 9 months. All the presenting manifestations resolved with normalization of the laboratory tests on withdrawal of stevia. Conclusion: This case report indicates that chronic ingestion of sweetener stevia may induce edema, hypertension and hypokalemia via reduced conversion of cortisol into cortisone by inhibition of 11 B-Hydroxysteroid Dehydrogenase Type 2.
文摘It has been proposed that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which activates glucocorticoids, plays a role in chronic inflammatory diseases including metabolic diseases, rheumatoid arthritis, and ulcerative colitis. We have recently reported that the expression of 11β-HSD1 is increased in the gingiva of patients with chronic periodontitis and in that of rats with ligature-induced periodontitis. In this study, to further demonstrate the involvement of 11β-HSD1 in chronic periodontitis, the expression of 11β-HSD1 was investigated in another rat model of experimental periodontitis induced by intragingival injection of lipopolysaccharide from Porphyromonas gingivalis (LPS-PG). Alveolar bone loss was observed two weeks after intragingival injection of LPS-PG. The level of 11β-HSD1 mRNA assessed by real-time reverse transcriptase-polymerase chain reaction was significantly elevated in LPS-PG-induced periodontitis compared with controls. The expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates glucocorticoids, was not significantly different between control and LPS-PG-induced periodontitis. The expression of 11β-HSD1 was significantly correlated with that of TNF in LPS-PG-induced periodontitis. The increased expression of 11β-HSD1 protein in LPS-PG-induced periodontitis was confirmed by immunohistochemistry using anti-11β-HSD1 antibody. These results further suggest a role for 11β-HSD1 in the pathogenesis of chronic periodontitis.
文摘目的研究原发性高血压(essential hypertension,EH)患者11β-类固醇脱氢酶2(11 beta-hydroxysteroid dehydrogenase type 2,11β-HSD2)基因甲基化表达,探讨原发性高血压的发病机制。方法选取2018年1月至2019年6月在佳木斯医学院第一附属医院未经治疗的EH患者71例为EH组,选取我院体检的50例健康志愿者为正常对照组,应用甲基化特异性PCR(methylation specific PCR,MSP)方法检测所有入选研究对象11β-HSD2基因甲基化表达。结果EH组和对照组11β-HSD2基因甲基化表达比较,差异具有统计学意义(P<0.05)。结论11β-HSD2基因甲基化参与EH的发生。
文摘Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.
基金Supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences to Csala M
文摘The metabolic syndrome, one of the most common clinical conditions in recent times, represents a combination of cardiometabolic risk determinants, including central obesity, glucose intolerance, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease and hypertension. Prevalence of the metabolic syndrome is rapidly increasing worldwide as a consequence of common overnutrition and consequent obesity. Although a unifying picture of the pathomechanism is still missing, the key role of the pre-receptor glucocorticoid activation has emerged recently. Local glucocorticoid activation is catalyzed by a triad composed of glucose-6-phosphate-transporter, hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum. The elements of this system can be found in various cell types, including adipocytes and hepatocytes. While the contribution of glucocorticoid activation in adipose tissue to the pathomechanism of the metabolic syndrome has been well established, the relative importance of the hepatic process is less understood. This review summarizes the available data on the role of the hepatic triad and its role in the metabolic syndrome, by confronting experimental findings with clinical observations.
文摘目的探讨心房颤动患者心房肌组织盐皮质激素受体(MR)和赋予 MR 特异性的关键酶11β-羟基类固醇脱氢酶Ⅱ(11βHSD2)的 mRNA 和蛋白表达改变。方法入选进行人工心脏瓣膜置换术的风湿性心脏病患者25例,其中窦性心律12例,慢性心房颤动(心房颤动时程≥6月)13例。术前进行经胸超声心动图检查,所有患者在术前均签订知情同意书,于手术时取左右心房侧壁组织。用实时荧光定量 PCR 检测 MR 和11βHSD2的 mRNA 水平,Western 印迹检测 MR 和11βHSD2的蛋白表达改变。结果心房颤动组比窦性心律组左房内径显著扩大(P<0.01);房颤组患者 MR mRNA表达(右房:5.37±1.15 vs 2.67±1.09,左房:5.19±1.14 vs 2.70±0.82 P 均<0.01)和11βHSD2mRNA 表达(右房:0.86±0.14 vs 0.33±0.12,左房:0.95±0.15 vs 0.37±0.10 P 均<0.01)均明显增加;同时房颤组患者 MR 和11βHSD2蛋白表达也较窦性心律者明显增加,MR 分别为右房:1.65±0.72 vs 0.86±0.33(P<0.01);左房:1.72±0.62 vs 0.97±0.37(P<0.05)。11βHSD2分别为右房:-1.18±0.64 vs 0.71+0.21(P<0.01);左房:1.36±0.58 vs 0.85±0.15(P<0.05);但在左右心房之间无论是在窦性心律或心房颤动时,MR 和11βHSD2二者在 mRNA 水平和蛋白表达水平差异均无统计学意义(P>0.05)。结论心房颤动时心房肌组织 MR 和11βHSD2表达增加,醛固酮受体拮抗剂将可能对心房颤动发挥治疗作用。
文摘Inhibition of 11βHSD1 （11-beta-hydroxysteroid dehydrogenase 1） is a promising strategy in drug treatment of diabetes. Several 11βHSDI inhibitors have been proposed; however, their selectivity to 11βHSD1 over its isozyme 11βHSD2 （11-beta-hydroxysteroid dehydrogenase 2） has not been fully reported. The authors sought to provide a short list of top potent and selective compounds along with their detailed binding modes and pharmacophore models, Molecular docking was used for initial screening of a set of 23 potent inhibitors reported by previous experimental studies. After that, selected promising entries were reassessed by molecular dynamics simulations, followed by hydrogen bond analysis. Pharmacophore models of all drug candidates and binding modes of some selected drugs were analyzed. Among the 23 compounds, only four inhibitors were identified as potent and selective drug candidates. Binding energies, 3D pharmacophores and binding modes of the four compounds with 11βHSDI are also discussed in detail in this study.
