勃起功能障碍基因治疗研究进展

近年来基因治疗被尝试用于勃起功能障碍(ED)治疗的动物实验,许多研究发现基因治疗方案对各种类型的ED均有一定的治疗作用。特别是在左旋精氨酸-一氧化氮-环磷酸鸟苷通路、离子通道、勃起神经和海绵体血管内皮细胞的修复保护等方面的基因治疗研究显示,基因治疗ED有一定的疗效。但应用基因治疗来治疗ED患者,目前仍有较多的困难,暂时无法应用于临床。本综述旨在对该领域的最新研究进展做一个简单的介绍和展望。     

基因及生长因子疗法治疗椎间盘退变研究进展

通过检索复习文献,总结规律,讨论基因及生长因子对治疗椎间盘退变的作用;(检索相关文献)了解基因及生长因子治疗椎间盘退变的研究进展和今后研究的方向之一;从相关文献及研究中提取经验,总结方法,为今后的研究提供参考.通过阅读文献,得出以下结论(1)基因治疗是今后治疗椎间盘退变的重要方向;(2)基因治疗中存在的缺点和不足(生物安全性、表达稳定性差)是基因治疗椎间盘退变需要解决的问题;(3)基因治疗的主要方法,应该是利用基因转染技术,使体细胞表达对椎间盘退变有抑制和逆转作用的生长因子.     

老年性勃起功能障碍的基因治疗

勃起功能障碍(ED)的发病率随着年龄的增长而增高,基因治疗是近年来新兴的一种治疗方法,各种靶基因、不同的载体以及不同的治疗策略用于ED的基因治疗,均取得了一定的治疗效果。本文就老年性ED的基因治疗现状作一综述。     

男性勃起功能障碍的分子生物学研究进展

阴茎勃起功能障碍(ED)是常见的男性疾病,5型磷酸二酯酶(PDE5)抑制剂的问世改善了大部分ED患者的性生活质量,然而其对难治性ED的治疗效果不佳。随着ED分子生物学研究的迅速发展,人们不断地发现新的阴茎勃起相关信号通路,深入阐明各类ED的分子发病机制,并尝试用基因治疗等先进方法,更好地解决甚至从根本上治愈ED。本文将全面综述目前有关ED的分子信号转导通路、常见类型ED的分子发病机制以及ED基因治疗的研究进展。     

阴茎勃起功能障碍的基因治疗进展

50～70岁男性中50%以上患有勃起功能障碍(ED),40岁的男性中有40%的患有不同程度的ED,全球范围内ED患者已超过1亿人,ED已成为困扰全球男性的重要疾病之一。在过去的20年里,对于ED发生机制及治疗有了很大的进展,现有的PDE5抑制剂对大部分ED患者疗效较好,但是对糖尿病性ED、前列腺癌根治术后ED及严重的心血管病变导致的ED疗效欠佳。人们正在寻找更好的治疗ED的方法——基因治疗。本文总结了近年来临床前期基因治疗ED的新进展,即糖尿病ED、老年性ED、神经损伤性ED及血管病变导致的ED的基因治疗。     

下肢动脉硬化闭塞症基因治疗的研究进展

自1994年开始基因治疗缺血性疾病以来,基因治疗下肢动脉硬化症的进展较快,本文对血管内皮生长因子(VEGF)、肝细胞生长因子(HGF)、成纤维生长因子(FGF)、内皮型一氧化氮合酶(eNOS)等基因的临床应用及促血管生成生物学作用机制研究进展作一综述。     

IGF-1基因治疗提高老龄大鼠阴茎海绵体平滑肌密度的研究

目的 观察阴茎海绵体内注射胰岛素样生长因子-1 (IGF-1)基因能否提高老年性大鼠阴茎勃起功能及其对阴茎海绵体平滑肌密度的影响,以探讨IGF-1基因治疗ED的机制.方法 4月龄SD雄性大鼠(青年组)10只;24月龄SD雄性大鼠(老龄组)20只,随机分为2组:PBS对照组、100 μg IGF-1质粒注射组.每组10只注射后8周行电刺激检测大鼠阴茎海绵体内压(ICP)和平均动脉压(MAP),分析比较IGF-1基因治疗的效果,Masson,s三色染色图文定量分析阴茎海绵体平滑肌在海绵体组织中含量的变化.结果 电刺激发现老龄组较青年组ICP/MAP和总ICP明显降低(P＜0.05).IGF-1基因治疗8周后,100 μg IGF-1质粒注射组较PBS对照组ICP/MAP和total ICP均明显提高(P＜0.05);阴茎海绵体平滑肌的含量在老龄组较青年组明显降低(P＜ 0.05);与PBS对照组比较,100μg IGF-1质粒注射组能够明显提高阴茎海绵体平滑肌的含量(P＜0.05).结论 I GF-1基因治疗能够改善老龄大鼠的勃起功能,其作用机制之一可能是通过提高阴茎海绵体平滑肌的含量.     

针对磷酸二酯酶基因治疗勃起功能障碍的研究进展

阴茎勃起功能障碍(erectile dysfunction,ED)是影响男性健康的一种常见疾病,其患病率大约是20%～45%。近年来,ED的治疗取得了很大的进展,尤其是高选择性磷酸二酯酶5型(phosphodiesterase V,PDE_5)抑制剂西地那非的问世,使ED的治疗发生了根本性的改变。然而选择性PDE_5抑制剂需长期服药,治疗费用昂贵,加之头痛、面部潮红、消化不良、鼻炎、视觉异常等副作用,从而限制了临床上的应用。近年来,基因治疗ED的研究取得了一些可喜的成果,展示了美好的前景。ED的基因治疗有很多优势：(1)阴茎是体表器官,能准确定位；(2)治疗时在阴茎根部扎止血带,能局限目的基因,减少不良反应；(3)阴茎海绵体细胞间存在缝隙连接,少量细胞转染目的基因即可有效；(4)阴茎平滑肌细胞更新较慢,可使目     

高脂血症与男性勃起功能障碍

勃起功能障碍(ED)是男性,尤其是老年男性的常见病。高脂血症是引起男性ED的重要危险因子之一,流行病学研究发现高密度脂蛋白(HDL)水平的下降和总胆固醇/高密度脂蛋白比值(TC/HDL)的上升与ED有明显相关性。目前研究显示高脂血症引起的动脉狭窄和闭塞可能只是高脂血症引起ED的晚期机制。高脂血症早期即可影响阴茎的内皮细胞、平滑肌细胞及支配阴茎勃起的外周神经而使阴茎勃起功能受损。对高脂血症所致ED的治疗除针对高脂血症的饮食治疗和药物治疗外,针对ED的中药治疗和基因治疗有望成为治疗高脂血症所致ED的重要方法。     

阴茎勃起功能障碍基础研究新动向

阴茎勃起功能障碍(ED)是指阴茎不能达到或维持充分勃起,以完成满意的性交。据文献报道,全球约有一亿多ED患者,40～70岁的男性中,约有52％的男性有不同程度的阴茎勃起功能障碍。因此,ED是一种影响男性健康的常见疾病。近20年来,人们对ED的发病基础作了大量的研究,通过利用各种ED动物模型,筛选安全有效的、增强阴茎海绵体平滑肌松弛作用的药物,为ED的治疗提供了光明的前景。其中一氧化氮-环磷酸鸟苷(NO-cGMP)通路、离子通道、细胞间通讯、基因治疗是近年来研究的新热点,本文将较详细阐述ED基础研究最新动向。     

Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction （ED）. Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.     

Serum from patients with erectile dysfunction inhibits circulating angiogenic cells from healthy men: relationship with cardiovascular risk, endothelial damage and circulating angiogenic modulators

Erectile dysfunction (ED) is an early manifestation of arteriosclerosis associated with endothelial damage/dysfunction and to a blunted ability of cultured mononuclear circulating cells (MNCs) to differentiate circulating angiogenic cells (CACs), putatively involved in endothelial damage repair. Here we explored effects of human serum (HS) from patients with ED and cardiovascular risk factors (VRFs) but no clinical atherosclerosis, on cultured MNCs of healthy men to differentiate CACs and to form colonies. Effect of HS on number of CACS and of colony forming units (CFUs) was correlated with circulating markers of endothelial damage and with angiogenic modulators. MNCs from healthy men were cultured in standard conditions or with 20% HS from 35 patients with ED and from 10 healthy men. CACs were identified after 7?days of culture by uptake of acetylated low-density lipoprotein with concomitant binding of Ulex europaeus agglutinin I. CFUs were counted after 5?days of culture. Enzyme-linked immunosorbent assays assessed plasmatic soluble (s) form of E-selectin, Endothelin (ET)-1, tissue type plasminogen activator (tPA), vascular endothelial growth factor (VEGF)(165) and sVEGF receptor (R)-1. The number of CACs and of CFUs from healthy men was reduced after culturing MNCs with HS compared to standard medium. The inhibitory effect was significantly higher with HS from ED patients with higher or lower VRF exposure compared to healthy men. Inhibition was positively correlated with VRFs exposure, with ED severity, with common carotid artery intima media thickness measured using B-mode ultrasound, and to a lesser extent with plasmatic sE-Selectin, sET-1 and sVEGFR-1. Dysfunction of cells involved in vascular homoeostasis is induced by soluble factors still unknown and already present in a very initial systemic vascular disease in men with ED and VRFs.     

Erectile dysfunction in hemodialysis patients with diabetes mellitus: Association with age and hemoglobin A1c levels

Abstract Aim: Erectile dysfunction (ED) is common in patients with diabetes mellitus (DM) as well as those undergoing hemodialysis (HD). The purpose of this study is to investigate the frequency and severity of ED in HD patients with DM and those without DM. In addition, we examined the relationship between erectile function and several risk factors, including presence of DM and hemoglobin A1c levels in HD patients. Methods: This study involved 180 patients on HD, including 66 HD patients with DM (DM‐HD) and 114 patients without DM (non‐DM‐HD). We evaluated erectile function using an abridged five‐item version of the international index of erectile function (IIEF‐5). Logistic regression analysis was used to investigate the relationship between presence of ED and several risk factors. Results: The total score of IIEF‐5 in DM‐HD patients (9.5 ± 4.2) was significantly lower than in non‐DM‐HD patients (13.5 ± 5.7). The prevalence of severe ED was 42.4% and 18.4% in DM‐HD patients and non‐DM‐HD patients, respectively. Age, cardiovascular disease history, and DM were identified as independent risk factors for the presence of ED. Furthermore, age and elevated hemoglobin A1c levels were identified as independent risk factors for the presence of severe ED. Conclusion: DM‐HD patients are more likely to have ED, and particularly severe forms of ED, than non‐DM‐HD patients. DM and elevated hemoglobin A1c levels were associated with the presence of ED or severe ED, respectively. Aging was identified as an independent factor in both ED and severe ED.     

Traumatic arteriogenic erectile dysfunction: a rat model

We developed a rat model of traumatic arteriogenic erectile dysfunction (ED) for the study of vasculogenic ED. Bilateral ligation of the internal iliac artery was performed on 30 three-month old male Sprague-Dawley rats as an experimental group. The control group consisted of 12 rats which underwent dissection of the internal iliac artery without ligation. Before their euthanization at 3 days, 7 days, and 1 month (10 rats in the experimental group and four rats in the control group at each time point), erectile function was assessed by electrostimulation of the cavernous nerves. Penile tissues were collected for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining, trichrome staining, electron microscopy and RT-PCR for transforming growth factor beta (TGF-beta1), insulin like growth factor-I (IGF-I) and fibroblast growth factors (FGF) mRNA expression. Electrostimulation of the cavernous nerves revealed a highly significant declining of the intracavernous pressure after 3 and 7 days. No significant recovery of erectile function was noted at 1 month. Histology showed degeneration of the dorsal nerve fibers in all experimental rats. There was little decrease in the bulk of intracavernous smooth muscle in the experimental rats euthanazed 7 and 30 days. NADPH diaphorase staining revealed a significant decrease in nitric oxide synthase (NOS) containing nerve fibers in the dorsal and intracavernosal nerves in all rats in the experimental group. Electron microscopy showed a variety of changes such as collapse of sinusoids, increased cell debris, fibroblast and myofibroblast loss, intracellular deposition of fat and collagen and fatty degeneration. RT-PCR revealed up-regulation of TGF-beta1 after 3 days but not after 7 days or 1 month. There is no significant difference in IGF-I or FGF expression between the experimental and control group. Bilateral ligation of internal iliac arteries produces a reliable animal model for traumatic arteriogenic ED. Further studies are needed to investigate the molecular mechanism of ED in this model.     

阴茎勃起相关基因的研究进展

勃起功能障碍 (ED)的分子生物学研究近 10年来已取得了较大的进展 ,阴茎勃起是在神经内分泌调节下的阴茎动脉 ,阴茎海绵体及阴茎静脉回流等一系列血流动力学的变化过程。在阴茎海绵体平滑肌松弛过程中 ,一氧化氮 3’,5 ’ 单磷酸环鸟苷酸 (NO cGMP)通路起着重要的调控作用 ,对与勃起有关的一氧化氮合酶 (NOS)、磷酸二酯酶(PDEs)、K+ 通道、胰岛素样生长因子 (IGF)、血红素氧合酶 (HO)、血管内皮生长因子 (VEGF)、cGMP依赖性激酶Ⅰ (cGKⅠ )、血管紧张素转换酶 (ACE)、生长因子 (GF)等相关基因的深入研究 ,为ED的临床治疗提供了理论基础     

Coronary artery risk factors in patients with erectile dysfunction

PURPOSE: We evaluated the risk factors of coronary artery disease in patients with erectile dysfunction (ED). MATERIALS AND METHODS: A total of 417 male patients with ED were enrolled in this study. Patients were interviewed for ED using the International Index of Erectile Function. All patients were also screened for sociodemographic data and risk factors for ischemic heart disease (IHD), including age, smoking, diabetes, hypertension, dyslipidemia and psychological disorders. Patients underwent routine laboratory investigation plus testosterone and prolactin assessment. All patients were referred to a cardiologist for IHD evaluation. RESULTS: Mean age +/- SD was 59.1 +/- 10.3 years. Of the patients 27.3% were younger than 50 years, 37.2% were current or former smokers, and 27.6% had mild, 30% had moderate and 42.4% had severe ED. Of the patients 26.9% had different degrees of IHD, of whom 84.8% were older than 50 years. There was a significant association between age and IHD (p <0.05). There were significant associations between IHD, and the increased severity and progressive course of ED (each p <0.05). Furthermore, higher degrees of IHD were significantly associated with severe ED. Diabetes, hypertension, dyslipidemia and psychological disorders were present in 75.1%, 39.3%, 45.6% and 8.2% of the patients, respectively. Overall 92.1% of the patients with ED had 1 or more coronary artery risk factors. The presence of at least 1 risk factor is significantly associated with ED in patients with IHD (p <0.05). CONCLUSIONS: Coronary artery risk factors are significantly associated with erectile dysfunction. A significant association between higher degrees of IHD and the increased severity of ED was detected.     

Loss of TGFbeta, Apoptosis, and Bcl-2 in Erectile Dysfunction and Upregulation of p53 and HIF-1alpha in Diabetes-Associated Erectile Dysfunction

Vasculogenic erectile dysfunction (ED) is associated with collagen replacement of the cavernosal smooth muscle, mediated by an increase in transforming growth factor (TGF)-production secondary to hypoxemia. We tested the hypothesis that human ED is the result of an increase in apoptosis of the cavernosal smooth muscle cells with replacement by collagen, mediated by the TGFbeta upregulation. We also examined the tissue for proteins associated with apoptosis. Human cavernosal tissue was procured from impotent men at the time of prosthesis insertion. Normal corpous cavernosum served as a control. The TUNEL assay was used to assess apoptosis. Immunohistochemistry staining was used to detect TGFbeta and Bcl-2 expression, while Western blot analysis was used to detect expression of Bcl-2, p53, and hypoxia-inducible factor (HIF)-1a. Immunohistochemistry showed downregulation of TGFbeta protein expression in the corpus cavernosum of men with ED. Apoptotic nuclei were noted in cavernosal smooth muscle from a potent man but were not found in cavernosal tissue from men with ED. To gain insight into the possible mechanism of apoptosis in men with ED, the proto-oncogene Bcl-2, a potential inhibitor of apoptosis, was examined. Both immunohistochemistry and Western analysis revealed the presence of Bcl-2 in the cavernosal nerve of a potent man but its absence in cavernosal tissue from men with ED. Thus, loss of Bcl-2 expression correlated with the loss of apoptosis. In contrast, Western blotting demonstrated upregulation of p53 and HIF-1a expression in the cavernosal tissues from the men with ED and diabetes. Male ED follows an active process characterized by a loss of TGFb expression, apoptosis, and Bcl-2 expression. However, there is upregulation of p53 and HIF-1a in men with diabetes. These data support the possibility of hypoxia-mediated ED in diabetes via upregulation of p53 and HIF-1a but does not substantiate a role for TGFbeta in ED.     

The etiology of erectile dysfunction and contributing factors in different age groups in Turkey

BACKGROUND: The aim of the present study was to determine the pathophysiological factors which cause erectile dysfunction (ED), as well as the risk factors in different age groups in Turkey. METHODS: A total of 948 patients with ED who were admitted to three andrology clinics were evaluated in terms of etiological factors. They underwent a multidisciplinary diagnostic evaluation. Erectile dysfunction was classified as primarily organic, primarily psychogenic, mixed or unknown in etiology. RESULTS: Psychogenic ED was diagnosed in 65.4% of the patients and organic ED was diagnosed in 34.6% of patients overall. In patients under 40 years, the rate of psychogenic ED was 83% and the rate of organic ED was 17%, but in the patients over 40 years, the rate of psychogenic ED was 40.7% and the rate of organic ED was 59.3%. The causes of organic ED were identified as arteriogenic ED, 40.5%; cavernosal factor (venogenic) ED, 10%; neurogenic ED, 12.5%; endocrinologic ED, 1.8%; mixed type ED, 11.8%; and drug induced ED, 4.5%. CONCLUSION: Our data represent a higher ratio of ED in patients under 40, which are mostly psychogenic, This finding potentially results from local social and cultural differences.