Effect of liver cirrhosis on erectile function in rats: A study combining bioinformatics analysis and experimental research
Jisheng WangXu CaoSheng DengBin WangJunlong FengFanchao MengHongsheng XuShizhen WangXiaobin ZaoHaisong LiYongan Ye
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To explore the mechanism through which liver cirrhosis (LC) causes erectile dysfunction (ED). Bioinformatic analysis was used to predict the potential signalling pathways in LC-induced ED, and N-nitrosodiethylamine was used to establish a rat model of LC. H&E staining, Western blotting and RT-qPCR were used to detect pathological tissue damage and changes in mRNA and protein expression levels. In addition, the expression levels of sex hormones such as estradiol (E2), prolactin (PRL) and testosterone (T) were measured. The hypoxia-inducible factor (HIF) pathway was an important pathway in our bioinformatics prediction. Pathological damages were detected in the liver and penile tissues of the model rats. Compared with the normal group's serum hormone levels, E2 and PRL were increased in LC rats, while T was decreased (p < 0.01). The mRNA and protein expression results from penis tissues showed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were both downregulated, and HIF-1α was upregulated in the model group compared to the normal group (p < 0.01). These data suggest that LC hinders erectile function and causes histopathological changes in the penis by affecting the expression of HIF-1α, eNOS, iNOS, E2, PRL and T.Red wine polyphenol extracts (RWPE) lead to an increased endothelial nitric oxide synthase (eNOS) activity in EA.hy926 endothelial cells [1]. Trans-resveratrol seems to partly contribute to this effect by inducing eNOS expression [1]. This study aims to identify further major active components by bio-assay guided fractionation.
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زمینه و اهداف: نیتریک اکساید مولکول پیام رسانی است که به وسیلۀ عملکرد آنزیم سنتزکنندۀ نیتریک اکساید (eNOS)، تولید می شود و در تنظیم تعداد زیادی از وقایع تولید مثلی که در لولۀ فالوپ اتفاق می افتد مشارکت دارد. هدف از این مطالعه بررسی بیان eNOS، در سلول های مژک دار و ترشحی اپیتلیوم لومینال لولۀ فالوپ و تغییرات آن در هنگام زایمان می باشد. مواد و روش ها: در این مطالعه موردی-شاهدی تعداد 20 نمونه از بافت لوله های فالوپ دو گروه از زنان شامل: 10 نمونه از زنان غیر حامله که در فاز لوتئال از چرخه قاعدگی بودند و 10 نمونه از زنان حامله سالم ترم، در هنگام زایمان به دست آمد. سپس نمونه ها در فرمالین 10% فیکس شده و مقاطع پارافینی تهیه شده، مورد ارزیابی ایمونوهیستوشیمی قرار گرفتند. یافته ها: مکان یابی پروتئین eNOS در سلول های ترشحی و مژه دار اپیتلیوم لومینال در هر دو گروه مشاهده گردید. با این حال، بیان پروتئین eNOS در سلول های عضله صاف هیچکدام از گروه ها مشاهده نشد. از سوی دیگر، در رابطه با بیان پروتئین eNOS، در اپیتلیوم لومینال لوله فالوپ، بین زنان غیرحامله ای که در فاز لوتئال بودند و زنان حامله سالم، اختلاف معناداری مشاهده نگردید )05/0P>). نتیجه گیری: عدم وجود اختلاف معنادار، در سطح بیان پروتئین eNOS، در سلول های مژکدار و ترشحی اپیتلیوم لومینال زنان حامله ترم در مقایسه با زنان در فاز لوتئال، می تواند نشان دهنده یکسان بودن فعالیت و عملکرد مژک ها در این دو گروه باشد.
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Endothelial nitric oxide (NO) synthase (eNOS) has an indispensable role in the erectile response. In the penis, eNOS activity and endothelial NO bioavailability are regulated by multiple post-translatlonal molecular mechanisms, such as eNOS phosphorylation, eNOS interaction with regulatory proteins and contractile pathways, and actions of reactive oxygen species (ROS). These mechanisms regulate eNOS-mediated responses under physiologic circumstances and provide various mechanisms whereby endothelial NO availability may be altered in states of vasculogenlc erectile dysfunction (ED), in view of the recent advances in the field of eNOS function in the penis and its role in penile erection, the emphasis in this review is placed on the mechanisms regulating eNOS activity and its interaction with the RhoA/Rho-kinase pathway in the physiology of penile erection and the pathophysiology of ED.
Endothelial Dysfunction
Endothelial NOS
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Previous studies have demonstrated that the polyphenolic compound, reseveratrol (RSV), from the skin of red grapes increases endothelial nitric oxide synthase (eNOS) activity. However, the mechanism by which RSV increases eNOS activity is unknown. Therefore, we have investigated changes in eNOS phosphorylation at Ser1179, Ser635, Thr495 as well as changes in eNOS association with Hsp90, Akt, and cdc37 in bovine aortic endothelial cells (BAECs) treated with varying doses of RSV for 0, 20, 60 min as well as 72 h. Acute RSV treatment (less than 1) resulted in no significant ( P >0.05) changes in eNOS phosphorylation or changes in eNOS association with Hsp90, Akt or cdc37. In contrast, 72h treatment of BAECs at higher concentrations of RSV significantly ( P <0.05) increased eNOS phosphorylation and protein association that was consistent with the increase in eNOS expression. In conclusion, these data suggest that RSV‐induced eNOS activity is primarily due to increased eNOS expression and that acute (less than 1 h) RSV treatment does not alter post‐translational eNOS regulatory mechanisms. Supported by AHA SDG 0430157N (MBH) and William & Mary HHMI Undergraduate Research Program Student Grant (KNS)
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Objective: to study the effects of buyang huanwu decoction on the promotor activity of endothelial nitric oxide synthase (eNOS). Methods: pGL2-eNOS and pEGFP-1-eNOS were constructed by subclone method. The activity of pGL2-eNOS was measured by HTS 7000 Bio assay reader and the expression of pEGFP-1-eNOS was observed by fluorescence microscope. Results: the activity of both pGL2-eNOS and pEGFP-1-eNOS increased after treated by buyang huanwu decoction containing serum and astragalus membranaceus containing serum in ECV304 cells. Conclusion: buyang huanwu decoction increased the activity of the eNOS promotor. It must be the mechanism of buyang huanwu decoction in preventing the endothelial dysfunction.
Decoction
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To investigate the function,function regulation and structure function relationship of endothelial nitric oxide synthase(eNOS),a gene fragment encoding eNOS 801～902 AA residues was cloned by PCR, and inserted into pET 28a(+) expressive vector. The resulted pET 28a/eNOS 2 was transformed into BL 21 host E.coli and expressed by IPTG induction for 4 hour, The expressed protein (14 4 ku) was purified by His Bind TM Sephorose colum and SDS PAGE, thus providing the basis for the selection of the eNOS specific inhibiting peptides and the preparation of the specific antibody against eNOS.
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eNOS is an enzyme that exists in both monomeric and dimeric conformations. The dimeric form catalyzes the rate-limiting step in the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of peroxynitrite (ONOO), a highly reactive oxidant species (ROS). An increase in the monomer form in the hearts of diabetic animals has previously been reported. Chronically elevated ROS exists with diabetes and may be a major underlying cause of many diabetic-related complications. Exercise has been useful in the management of diabetes. Although exercise-induced increased expression of eNOS has been reported, it is unclear if exercise may alter the functional coupling of eNOS. To investigate this question, Goto-Kakizaki (a model of type II diabetes) rats were randomly assigned to a 6-week running program (train) or sedentary (sed) groups. At the end of training, indices of glycemic control were determined prior to sacrifice, and tissues harvested for determination of eNOS conformation, using the low-temperature polyacrylamide gel electrophoresis (LT-PAGE) followed by western blot analysis. Exercise significantly (p<.05) increased plantaris cytochrome oxidase activity (sed: 0.31±0.02; train: 0.39±0.03 nmole/min/mg), and also significantly improved HbA1c (sed: 7.33±0.56%; train: 6.1±0.18%). Exercise increased both total eNOS expression and the ratio of dimer to total eNOS in both LV (sed: 6.4±2.7%; train: 24.8±5.3%) and kidney (sed: 12±2%; train: 20.7±3%). Exercise significantly improved the eNOS functional state; a shift that could serve to decrease diabetic-related oxidative stress and that may serve to lessen diabetic-related complications. Supported in part by NIH PO1HL43023 and the New York Medical College Research Endowment Fund.
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背景氮的氧化物(没有) 由氮的氧化物 synthase (eNOS ) 玩的 endothelial 综合了在两个的一个重要角色 endothelial 功能的规定和血压的控制。直到现在，在那里关于在 eNOS 基因和必要高血压的三临床上相关的多型性(T-786C， intron4b/a 和 G894T ) 之间的协会一直在冲突数据。用北汉汉语，检验三 eNOS 基因多型性的贡献到高血压的发展的方法包括 503hypertensive 盒子和 490 年龄的盒子控制研究 -- ，性 -- ，并且从 InternationalCollaborative 招募的匹配区域的控制在亚洲(InterASIA ) 心血管的疾病学习被进行。Genotyping 被聚合酶链反应(PCR ) 或 PCR 限制碎片长度多型性(RFLP ) 执行。结果 T-786C 和 intron4b/a 多型性在重要连接不平衡被观察(D “ =0.87， P 0.05 ) 。Inaddition，任何一个都显著地没八估计的 haplotypes 增加或减少在为几个已知的风险因素的调整前后的高血压的风险。学习结果的结论建议三 eNOS 基因多型性是不大可能的是为在北汉中国人口的必要高血压的主要基因危险性因素。
Endothelial Dysfunction
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