Effects of genistein and equol on human and rat testicular 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities

The objective of the present study was to investigate the effects of genistein and equol on 3β-hydroxysteroid de- hydrogenase （3β-HSD） and 17β-hydroxysteroid dehydrogenase 3 （17β-HSD3） in human and rat testis microsomes. These enzymes （3β-HSD and 17β-HSD3）, along with two others （cytochrome P450 side-chain cleavage enzyme and cytochrome P450 17α-hydroxylase/17-20 lyase）, catalyze the reactions that convert the steroid cholesterol into the sex hormone testosterone. Genistein inhibited 3β-HSD activity （0.2 μmol L^-1 pregnenolone） with half-maximal inhibition or a half-maximal inhibitory concentration （IC50） of 87 ± 15 （human） and 636 ± 155 nmol L^-1 （rat）. Genistein＇s mode of action on 3β-HSD activity was competitive for the substrate pregnenolonrge and noncompetitive for the cofactor NAD＋. There was no difference in genistein＇s potency of 3β-HSD inhibition between intact rat Leydig cells and testis microsomes. In contrast to its potent inhibition of 3β-HSD, genistein had lesser effects on human and rat 17β-HSD3 （0.1 μmol L^-1 androstenedione）, with an IC50 〉 100μmol L^-1. On the other hand, equol only inhibited human 3β-HSD by 42%, and had no effect on 3β-HSD and 17β-HSD3 in rat tissues. These observations imply that the ability of soy isoflavones to regulate androgen biosynthesis in Leydig cells is due in part to action on Leydig cell 3β- HSD activity. Given the increasing intake of soy-based food products and their potential effect on blood androgen levels, these findings are greatly relevant to public health.

11β-hydroxysteroid dehydrogenase types 1 and 2. in postnatal development of rat testis： gene express,on, localization and regulation by luteinizing hormone and androgens

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.

Recombinant adenovirus-mediated overexpression of 3β-hydroxysteroid-Δ24 reductase

3β-Hydroxysteroid-△24 reductase （DHCR24） is a multifunctional enzyme that localizes to the endoplasmic reticulum and has neuroprotective and cholesterol-synthesizing activities. DHCR24 overexpression confers neuroprotection against apoptosis caused by amyloid β deposition. The present study aimed to construct two recombinant adenoviruses driving DHCR24 expression specifically in neurons. Two SYN1 promoter DNA fragments were obtained from human （h） and rat （r）. Recombinant Ad-r（h）SYN1-DHCR24 was transfected into AD-293, N2A （mouse neuroblastoma）, and MIN6 （mouse pancreatic carcinoma） cells. Western blot analysis showed DHCR24 was specially expressed in 293 and N2A cells, but no specific band was found in MIN6 cells. This demonstrates that the recombinant adenoviruses successfully express DHCR24, and no expression is observed in non-neuronal cells. TUNEL assay results showed apoptosis was inhibited in adenovirus-transfected neurons. Detecting reactive oxygen species by immunoflu- orescence, we found that adenovirus transfection inhibits apoptosis through scavenging excess reactive oxygen species. Our findings show that the recombinant DHCR24 adenoviruses induce neuron-specific DHCR24 expression, and thereby lay the foundation for further studies on DHCR24 gene therapy for Alzheimer＇s disease.

Interceptive Activities of Some New 3β─Hydroxysteroid Dehydrogenase Inhibitors

Fourteen compounds of azastene and epostane derivatives (from YG101 to YG114) have been studied. Results showed that only YG102 and YG103 wore found to be positive in interceptivo activities, although they were less potent than their parent compound──azastene. Levels ofprogesterone in plasma were decreased significantly after administrstion or YG102, 103 and 106. Only YG107 possessed an interceptive activity approximately as potent as that of its paront compound──epostane. Epostane is a mixture of its enol and keto forms and the percentage of both forms defends on various condions. Since YG107 exists only in one form, we believe this derivative of epostane might be useful in the future work.

Activity of Salivary 11<i>β</i>-Hydroxysteroid Dehydrogenase Type 2 Becomes the Index for the Continuous Strength Exercise to Prevent Locomotive Syndrome in Japan

The Japanese Orthopedic Association proposed a concept called locomotive syndrome (LS) to identify middle-aged and older adults at high risk of requiring health care services because of problems with locomotion-associated lower muscle mass. To prevent LS, it is important to increase muscle mass and muscle strength in middle-age by continuous resistance training. A total of 38 men and women were assessed at baseline and 6 months. Body composition, physical strength and salivary cortisol and cortisone were analyzed. The exercise intervention program was performed by individual muscle endurance level. Body weight, muscle weight and basal metabolism were increased after exercise intervention. The 30-second sit-up test and 3-minute walking were increased, and the 10-time sit-to-stand was decreased significantly. This may be related to increase of leg and abdominal muscular strength. The exercise intervention program increased salivary 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activities significantly. These results suggested that 11β-HDS2 became the index for the increase of muscular strength to prevent LS.

Increased Expression of 11<i>β</i>-Hydroxysteroid Dehydrogenase Type 1 in Experimental Periodontitis Induced by Lipopolysaccharide from <i>Porphyromonas gingivalis</i>

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.

Edema, Enigma: 11 B-Hydroxysteroid Dehydrogenase Type 2 Inhibition by Sweetener “Stevia”

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.

Expression of 11β-Hydroxysteroid Dehydrogenase mRNA in Rat Leydig Cells

11β-hydroxysteroid dehydrogenase (11β-HSD) in Leydig cells regulates sterodogenesis by controlling intra cellular glucocorticoid (corticosterone, B, in rat) concentration.Prior to the 26th postnatal day, 11β-HSD is absent from rat immature Leydig cells. Asthe Leydig cells are matured, the enzyme is gradually produced. The highest levels of11β-HSD activity are present in adult rat Leydig cells. 11β-HSD controls the intracellular glucocorticoid concentration in Leydig cells and the glucocorticoids at the physiologicallevels also regulate levels of 11β-HSD activity in Leydig cells. The expressions of 11βHSD mRNA in Leydig cells from three different age groups of rats and adrenalectomizedrats (ADX), with and without B replacement were Observed in this study. The steady statelevels of 11β-HSD mRNA could not be detected in Leydig cells from immature rats aged21 days, but this could be detected in those aged 45 days. The highest levels of expressionOf 11β-HSD mRNA were found in adult Leydig cells. The mRNA expression of 11β-HSD was declined in Leydig cells after adrenalectomy, and this decline was prevented byB replacement (the levels were restored to control). The results indicated that 11β-HSDmRNA leVels expressed in three different age groups of rats are parallel with those ofantigen by immunohistochemical analysis and with those of enzyme activity by biochemicalmeasurement in previous studies. Similarly, the effect of B at physiological and endogenous levels on the expressions Of 11β-HSD mRNA corresponded to that on enzyme activity.

Effect of glucocorticoid on promoter of 11β-hydroxysteroid dehydrogenase Ⅱ gene

Objective: To study the effect of glucocorticoid on the promoter of the pre-receptor glucocorticoid metabolizing enzyme llβ-hydroxysteroid dehydrogenase type 1 (llβ-HSD1) gene. Methods: The 1.2 kb length sequence upstream to the transcription start site of the 11 β-HSD1 gene was amplified with polymerase chain reaction (PCR) and then was cloned into pBLCAT6 plasmid carrying chloramphenicol acetyhransferase (CAT) reporter gene. The plasmid pBLCAT6 carrying the promoter and reporter gene was used to transfect HeLa cells to study the regulation of 11 β-HSD1 gene expression by glucocorticoids in terms of reporter gene expression, Results: PCR showed that there was a complete ali^ment of the amplified sequence with the sequence 1.2 kb upstream to the transcription start site of 11 β-HSD1 gene. When cloned into pBLCAT6 plasmid carrying the reporter gene, this part of the promoter is functional in terms of regulation of reporter gene expression upon transfection into HeLa cells. The synthetic glucocorticoid-dexamethasone induced the reporter gene expression in the system described above, which was blocked by glucocorticoid receptor antagonist RU486. Conclusion: Glucocorticoids can modulate the expression of 11 β-HSD1 through a mechanism involving activation of GR and interaction of the promoter of 11 β-HSD1 gene.

钩藤内生放线菌Streptomyces sp.IMW-B19化学成分研究

目的 研究钩藤内生放线菌Streptomyces sp.IMW-B19发酵产物的次生代谢产物及部分化合物的生物活性。方法 该菌株的发酵产物采用ODS、Sephadex LH-20、半制备HPLC等色谱技术进行分离纯化,并采用ESI-MS和NMR鉴定化合物的化学结构。使用人肝癌HepG2细胞评价化合物1对11β-羟类固醇脱氢酶1活性的影响。结果 共分离得到11个化合物,经多种波谱数据分析和文献对比,分别鉴定为actiphenol(1)、苯甲酸薄荷酯A(2)、cyclo(L-Pro-L-Phe)(3)、胸苷(4)、11-hydroxy-4-amorphen-15-oic acid(5)、3-吲哚甲酸甲酯(6)、苯乙酸(7)、1-(3-ethylphenyl)-ethane-1,2-diol(8)、亚油酸(9)、亚油酸甲酯(10)和2-氨基-4-甲氧基苯甲酸(11)。化合物1对11β-羟类固醇脱氢酶1具有明显的抑制作用,在20 μmol·L^(-1)时,抑制率达到86.01%。结论 从钩藤内生放线菌Streptomyces sp.IMW-B19发酵产物中共分离得到11个化合物,其中化合物4、5、8为首次从链霉菌属的放线菌中分离得到。化合物1对11β-羟类固醇脱氢酶1具有明显的抑制作用。

甾醇脱氢酶的基因挖掘、分子改造及其催化合成熊去氧胆酸

本文介绍近年来利用以甾醇脱氢酶为核心元件的生物合成法制备熊去氧胆酸的研究进展,并提出了该技术进一步发展所面临的挑战和未来的研究方向,旨在为熊去氧胆酸的生物合成研究提供参考。

Xanthomonas maltophilia转化制备熊去氧胆酸及中间产物

以野生型嗜麦芽黄单胞菌(Xanthomonas maltophilia)为出发菌株,鹅去氧胆酸/β-环糊精包合物为反应底物,利用嗜麦芽黄单胞菌在液体发酵过程中产生的7α-羟基类固醇脱氢酶和7β-羟基类固醇脱氢酶,全细胞酶法催化制备熊去氧胆酸及中间产物。对嗜麦芽黄单胞菌形态鉴定,酶活测定并优化,制定产物检测方法。表明嗜麦芽黄单胞菌为杆状、单鞭毛、革兰氏阴性菌。菌株破碎后,SDS-PAGE分析表明在26-33 kDa之间存在蛋白条带,测定7α-羟基类固醇脱氢酶和7β-羟基类固醇脱氢酶酶活分别为79 U/mL、35 U/mL;优化显示,温度为35°C、pH值为9.0、添加30%甲醇时酶的活性提升;转化后UDCA得率为17.2 mg/L,7K-LCA得率为18.2 mg/L。作为一种野生型的底盘转化菌种,该研究为全细胞催化制备熊去氧胆酸及其中间产物提供了新的途径。

Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolicassociated Fatty Liver Disease

Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.

胎盘11β-HSD的表达差异与双胎生长不一致的关系

目的研究胎盘11β-羟基类固醇脱氢酶(11β-hydroxysteroid dehydrogenase,11β-HSD)的表达差异与双胎生长不一致的关系。方法选取2021年1月至2022年12月在嘉兴市妇幼保健分娩的双绒毛膜双胎27对,根据双胎出生体质量差是否在20%及以上,分为双胎生长不一致(discordanttwins,DT)组(实验组)及双胎生长一致(concordant twins,CT)组(对照组)。采用qRT-PCR法检测两组胎儿胎盘组织中11β-HSD1和11β-HSD2 mRNA的表达水平及差异。结果两组胎儿胎盘组织中11β-HSD1 mRNA的表达水平比较,差异无统计学意义(P>0.05);CT组A孩与B孩的11β-HSD2 mRNA表达水平比较,差异无统计学意义(P>0.05),而DT组小孩胎盘11β-HSD2 mRNA的表达水平显著低于DT组大孩的表达水平,差异有统计学意义(P<0.05)。结论胎盘11β-HSD2的表达差异可能与双绒毛膜双胎生长不一致的发生有关。

Transforming growth factor-β1 and epidermal growth factor decrease the expression of 17β-hydroxysteroid dehy-drogenase type 2 in endo-metrial carcinoma cells

Estradiol (E2) is the major molecular form of estrogens. Its biological effects are determined by estrogen receptors and intracellular E2 concentration in target cells. Regulation of intracellular E2 concentration involves the action of 17p-hydroxysteroid dehydrogenase (17HSD) type 2, the enzyme inactivating E2 to estrone. It has been demon-strated that 17HSD type 2 is expressed in normal endo-metrial epithelia and emdometrial carcinoma cells (RL 95-2). However, the regulatory mechanism of 17HSD type 2 expression in emdometrial cancer cells remains unknown. In the present study, the effects of transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF) on 17HSD type 2 expression in RL 95-2 cells have been investigated using enzyme activity assay and Northern blot analysis. After stimulation with TGF-P1 or EGF, the in vivo oxidative 17HSD activity in RL 95-2 cells was significantly decreased. It appeared that the inhibitory effect of TGF-β1 and EGF onthe enzyme activity of 17HSD type 2

2型糖尿病新靶点口服药专利分析

目的 分析2型糖尿病新靶点口服药专利概况,为国内新型糖尿病治疗药物的研发方向和专利布局等提供参考。方法以HimmPat数据库中全球专利数据为基础,从专利申请量及授权量、发展趋势、地域分布、主要申请人等多个角度,对葡萄糖激酶激活剂(GKA)、蛋白酪氨酸磷酸酶1B抑制剂(PTP-1B-IN)、11β-羟基类固醇脱氢酶1抑制剂(11β-HSD1-IN)3类2型糖尿病新靶点口服药相关专利进行统计分析。结果与结论 共检索得到GKA类专利1 649件,PTP-1B-IN类专利709件,11β-HSD1-IN类专利592件。全球主要申请主体为各大药企,其掌握了药物化合物的核心专利;其中GKA类药物的研究更成熟,专利申请量更大,企业布局更全面。国内企业、高校和科研院所在PTP-1B-IN领域具有一定的研究优势。国内企业和研究机构可以发挥传统中药资源优势,提升研究实力,可考虑从核心技术挖掘、工艺路线探索、专利布局、产学研合作、构建专利池等方面提高技术竞争力。

长链非编码RNA H 19调控小鼠睾丸间质细胞功能的机制

目的探讨长链非编码RNA H 19对小鼠睾丸间质细胞(LCs)合成分泌睾酮功能的影响及其可能的机制。方法采用原代小鼠LCs和TM3细胞为研究对象,细胞分为二甲基亚砜(DMSO)组、2-硝基丙烷(2-NP)处理组、si control组、si H19组、si Creb1组、Mimic control组、miR-181c-5p mimic组、Inhibitor control组、miR-181c-5p inhibitor组、si H19+Inhibitor control组和si H19+miR-181c-5p inhibitor组共11组。干扰H 19表达后,ELISA法检测其睾酮分泌水平的变化,CCK8法检测LCs增殖变化;生物信息学分析预测各基因的结合位点。RT-qPCR法和Western-blot检测各组小鼠LCs转染后各相关基因及蛋白表达的变化。结果(1)与si control组比较,si H19组LCs培养液睾酮水平及细胞增殖水平均显著下降(72 h后,P<0.01)。(2)各相关基因之间存在结合位点。(3)与DMSO组比较,2-NP组LCs的p-STAT1表达增加、H 19表达明显升高,而miR-181c-5p表达明显降低(P<0.01)。(4)与si control组比较,si H19处理可显著下调LCs的H 19、Creb1、HSD3B1和HSD3B6 RNA表达水平并显著上调miR-181c-5p表达水平(P<0.01),si Creb1处理可显著下调Creb1、HSD3B1和HSD3B6 mRNA表达水平(P<0.01);si H19组和si Creb1组Creb1、3β-HSD蛋白表达均明显降低(P<0.01);与Mimic control组比较,miR-181c-5p mimic组H 19、Creb1、HSD3B1和HSD3B6 mRNA表达明显降低,miR-181c-5p表达水平明显升高且Creb1、3β-HSD蛋白表达显著降低(P<0.01);与Inhibitor control组比较,miR-181c-5p inhibitor组的各相关基因及蛋白表达呈现与miR-181c-5p mimic组作用相反的效应;与si H19+Inhibitor control组比较,si H19+miR-181c-5p inhibitor组H 19表达显著升高,miR-181c-5p表达水平明显降低,Creb1、HSD的mRNA和蛋白表达均明显升高(P<0.01)。结论H 19低表达可通过抑制细胞增殖、miR-181c-5p表达升高、Creb1蛋白表达降低和3β-HSD蛋白表达降低导致LCs合成分泌睾酮能力降低。STAT1/H 19/miR-181c-5p/Creb1/3β-HSD通路可能在LCs功能调控中发挥重要作用。

羟基类固醇脱氢酶基因家族单核苷酸多态性与指长比的关联性

目的探讨羟基类固醇脱氢酶基因家族8个单核苷酸多态性(SNPs)与人类指长比(2D∶4D)的关联性。方法随机选取808名在校大学生(男性400名,女性408名)为研究对象,拍摄双手掌面照片后利用电脑图像软件测量并计算左、右手各指长比;多重PCR法对11β-羟基类固醇脱氢酶(HSD11B)和17β-羟基类固醇脱氢酶(HSD17B)基因家族8个SNPs位点(rs1000283,rs2236903,rs5479,rs56303414,rs676387,rs4445895,rs2066474,rs8190478)进行基因分型;单因素方差分析法分析不同基因型与2D∶4D的关联。结果宁夏大学生女性左手(L)2D∶3D,L2D∶4D、L3D∶4D、右手(R)2D∶4D、R2D∶5D均显著高于男性(P<0.05);rs2236903(HSD11B1)的基因型频率在男女间的差异具有统计学意义(P<0.05);HSD11B1基因的rs1000283-rs2236903及HSD11B2基因rs5479-rs56303414存在强关联,但其频率在男女两性间差异均无统计学意义(P>0.05);不论男性还是女性,8个SNPs位点基因型频率与指长比(2D∶4D)无显著关联(P>0.05)。结论宁夏汉族大学生群体的指长比性别差异存在显著性,然而,其与HSD11B和HSD17B基因家族8个SNPs位点基因多态性无关联性,提示其可能与人类指长比的形成无关。

知母山楂饮对大鼠非酒精性脂肪肝的治疗作用及可能机制的研究

目的研究知母山楂饮对非酒精性脂肪性肝病(NAFLD)大鼠的治疗作用。方法2021年6—12月,在沧州医学高等专科学校实验中心将55只雄性SD大鼠(其中5只大鼠用于判断是否造模成功)经过适应性喂养后,按照随机数字表法分为正常组(基础饲料喂养)、模型组(高脂饲料喂养进行NAFLD模型造模)、阳性对照组(造模成功后给予普罗布考500 mg/kg)、低剂量给药组(造模成功后给予知母山楂饮2.5 g/kg)、高剂量给药组(造模成功后给予知母山楂饮5 g/kg),每组10只。造模后培养8周,对各组大鼠称体质量,同时进行胰岛素耐量试验,以及测定各组大鼠血清中总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、谷草转氨酶(AST)、谷丙转氨酶(ALT)、超氧化物歧化酶(SOD)、丙二醛(MDA)。之后,各组的大鼠被处死,剖取各组大鼠肝脏组织。计算肝脏指数后,经HE染色、油红O染色后观察组织病理形态学变化。并测定肝脏组织的SOD、MDA、肿瘤坏死因子α(TNF-α)和白细胞介素-6(IL-6)。对肝脏组织11β-羟基类固醇脱氢酶1(11β-HSD1)、髓样分化因子初次应答基因88(myd88)、Toll样受体4(TLR4)和核因子κB(NF-κB)mRNA表达及蛋白表达检测。结果低剂量给药组大鼠体质量(515.72±20.55)g明显低于模型组(595.26±27.88)g(P<0.01),其中低剂量给药组肝脏指数变化(2.65±0.05)%明显低于模型组(3.05±0.09)%(P<0.01);累积糖耐量低剂量给药组(14.63±1.05)mmol·L^(-1)·h^(-1)明显低于模型组(17.95±1.09)mmol·L^(-1)·h^(-1)(P<0.05),可改善胰岛素抵抗;很好改善大鼠血清中TC、TG、LDL-C、AST、ALT、MDA水平,升高HDL-C、SOD水平(P<0.05);降低肝脏组织组织中11β-HSDl、MyD88、TLR4B和NF-κB表达水平(P<0.05);并且高剂量给药组效果明显。结论知母山楂饮可以很好地改善高脂饲料引发的大鼠非酒精性肝损伤。

11β-HSD1在炎性反应、肝癌的发生发展与免疫中作用的研究进展

11β-羟基类固醇脱氢酶1(11β-HSD1)在与代谢有关的炎性疾病,以及免疫中可通过调节糖皮质激素(GC)的合成发挥抗炎或促炎作用。11β-HSD1的整体表达和活性可受促炎细胞因子的诱导,这一过程依赖于NF-κB信号通路并由其基因(HSD11B1)P1和P2启动子的利用水平最终决定。此外,11β-HSD1在肝细胞癌中通过降低葡萄糖摄入和糖酵解抑制肝细胞癌的增殖,并通过调节GC的水平参与胸腺中T细胞的发育和血管生成。了解11β-HSD1在炎性疾病、癌的发生发展、免疫中的分子调控机制有利于探究相关疾病的发生发展。