Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model

BackgroundHyperhomocysteinemia (HHcy) has been reported to be strongly correlated with the occurrence of erectile dysfunction (ED), but the mechanisms are not fully understood. Moreover, whether melatonin could be a potential treatment of HHcy-induced ED needs to be elucidated.AimThe aim of this study was to investigate the effects of melatonin on HHcy-induced ED and the potential mechanisms via modulating oxidative stress and apoptosis.MethodsThe Sprague-Dawley (SD) rat model of HHcy was induced by 7% methionine (Met)-rich diets. 36 male SD rats were randomly distributed into 3 groups (n = 12 per group): control group, 7% Met group, and 7% Met + melatonin (Mel; 10 mg/kg, intraperitoneal injection) treatment group. After 4 weeks, the erectile function of all rats was evaluated by electrical stimulation of the cavernous nerve. Histologic and molecular alterations of the corpus cavernosum were also analyzed by immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, Western blotting, and polymerase chain reaction.OutcomesHHcy-induced ED rat models were successfully established, and Mel could preserve erectile function mainly through inhibiting oxidative stress via the Erk1/2/Nrf2/HO-1 signaling pathway and suppression of apoptosis.ResultsErectile function was significantly reduced in the rats with HHcy compared with that in the control group and was ameliorated in the HHcy rats treated with Mel. Compared with the control group, the rats in the HHcy group showed the following: (1) higher levels of total plasma homocysteine; (2) fewer neuronal nitric oxide synthase-positive cells in the corpus cavernous; (3) higher levels of reactive oxygen species and malondialdehyde, higher expression levels of nicotinamide adenine dinucleotide phosphate oxidase, and lower activities of superoxide dismutase, indicating an overactivated oxidative stress; (4) lower expression levels of Erk1/2/Nrf2/HO-1 signaling pathway components; and (5) higher levels of apoptosis, as determined by the expression levels of Bax, Bcl-2, and caspase 3. Mel treatment improved the erectile response, as well as histologic and molecular alterations.Clinical TranslationOur study on a rodent model of HHcy provided evidence that Mel could be a potential therapeutic method for HHcy-related ED.ConclusionsMel treatment improves erectile function in rats with HHcy probably by potential antioxidative stress activity. This finding provides evidence for a potential new therapy for HHcy-induced ED.Tang Z, Song J, Yu, Z, et al. Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model. J Sex Med 2019;16:1506–1517.     

Association between homocysteine levels and cognitive profile in Alzheimer’s Disease

BackgroundGrowing evidence suggests that hyperhomocysteinemia (HHcy) constitutes a risk factor for Alzheimer’s Disease (AD). The impact of HHcy on cognitive functions has mainly been investigated using screening neuropsychological tests that provide general, unspecific measures of cognitive level. Since an association between HHcy and temporo-mesial atrophy has been documented, we predicted that a fine-grained analysis of neuropsychological performance should show stronger Hcy effects on memory scores than on other cognitive scores.ObjectiveTo determine the influence of Hcy level on cognitive profile evaluated with specific, sensitive neuropsychological tests in a wide AD cohort.Methods323 patients with AD were enrolled in a cross-sectional study and underwent a neuropsychological examination exploring several cognitive domains (memory, language, visuoperception, visuospatial abilities, executive function, constructional praxis, ideomotor praxis). The effects of Hcy levels and other risk factors (including cholesterol, smoking habits, triglycerides, apoEε4 allele) were analysed.ResultsGeneralized Linear Model detected a significant drop in performance with increasing Hcy in 6/19 measures of cognitive functions, namely, in memory performance tasks as well as in Luria’s motor planning test, with effect sizes ranging 1.4%–2.8% (Eta-squared), partialling out effects of other predictors.ConclusionsHHcy was associated with poor performance in short and long-term spatial and verbal memory more than with other cognitive dysfunctions. These results support the hypothesis that medial temporal networks might be vulnerable to HHcy, consistently with data from neuroimaging studies suggesting a link in AD between temporal atrophy and HHcy; the effect on Luria’s motor planning task suggests further involvement of frontal structures.     

高血压、高同型半胱氨酸血症与血管性 认知障碍

血管性认知障碍是认知疾病中的常见类型,通常认为导致卒中的血管性危险因素即是血
管性认知障碍的危险因素,其中高血压和高同型半胱氨酸血症不仅是卒中的独立危险因素,也是血
管性认知障碍的重要危险因素。高血压引起血管性认知障碍主要通过小动脉内皮损害及脑内血管
动脉硬化造成;而高同型半胱氨酸血症主要通过对血管损害作用、影响凝血纤溶过程和神经毒性
导致。血管性认知障碍的高发病率、相对可干预性等特点决定了对其早期认识、早期发现的必要性。
本文对高血压、高同型半胱氨酸血症与血管性认知障碍的关系进行了综述,以期为预防血管性痴呆
提供依据。     

Nitrous oxide related behavioral and histopathological changes may be related to oxidative stress

Nitrous oxide (N₂O) toxicity can result in myelin loss and hyperhomocysteinemia similar to cobalamin (Cbl) deficiency. Studies on N₂O exposure can help in understanding the mechanism of demyelination. In view of paucity of studies on N₂O toxicity in rats this study was undertaken. Six male wistar rats were exposed to 1.5 L/min N₂O with 1:1 O₂ for 90 min daily for 1 month. After 1-month exposure blood homocysteine (HCY) and oxidative stress parameters glutathione (GSH) and total antioxidant capacity (TAC) were measured. Brain and spinal cord was subjected to histopathological examination. The neurobehavioral changes, oxidative stress parameters and histopathological changes were correlated with serum B12 and HCY level. After 1-month exposure, the rats appeared sluggish, lethargic and developed predominantly hind limb weakness for 1–1.5 h. In the exposed group, the total distance traveled (2001.66 ± 118.27 cm; p = 0.037), time moving (80.16 ± 5.7 s; p = 0.028), number of rearing (10.33 ± 1.45; p = 0.014) and grip strength (1042.40 ± 51.3 N; p = 0.041) were significantly decreased whereas, resting time significantly increased (219.83 ± 5.7 s; p = 0.030) compared to controls. Serum HCY level was significantly increased (20.56 ± 1.296 μm/ml; p = 0.0007) in the exposed group. However, serum B12 and folic acid levels were not significantly different. GSH significantly decreased (2.21 ± 0.60 mg/dl; p = 0.018) along with TAC (0.76 ± 0.16 Trolox_Eq_mmol/l; p = 0.036). The histopathological studies revealed shrinkage and vacuolation of neurons in cerebral cortex, focal myelin loss, vacuolation in subcortical white matter and spinal cord. N₂O exposure results in behavioral alterations, hyperhomocysteinemia, cortical and spinal cord demyelination which were associated with decrease GSH and TAC highlighting pathophysiological role of oxidative stress.     

高同型半胱氨酸血症对脑小血管病所致认知功能障碍的影响

目的 探讨高同型半胱氨酸血症对脑小血管病所致的认知功能障碍的影响.方法 选取符合脑小血管病诊断标准的病例,进行MoCA评分,分为有认知功能障碍组及无认知功能障碍组,测定同型半胱氨酸的水平,观察两组之间同型半胱氨酸水平的差异,并对不同认知功能受损方面进行评定.结果 有认知功能障碍组明显高于无认知功能障碍组,两组间差异有统计学意义（P＜0.01）.认知功能障碍患者中在语言、视空间及执行功能上有障碍患者的Hyc水平高于无相应障碍者,Hyc水平差异有统计学意义（P＜0.05）.结论 高同型半胱氨酸血症是脑小血管病所致认知功能障碍的影响因素之一,而且对执行功能、视空间功能、语言功能的影响更明显.     

脑小血管病患者外周血同型半胱氨酸水平与认知功能的相关性研究

目的 HHcy是脑血管病和认知功能障碍的危险因素之一。本文拟明确脑小血管病（small vessel disease，SVD）患者外周血Hcy水平与早期认知功能损害的相关性及其机制。 方法 连续入组缺血性卒中后门诊随访的非痴呆SVD患者，登记人口社会学、血管危险因素等资 料，进行全面认知评估。入组1周内采集空腹静脉血检测Hcy，根据血浆Hcy水平将SVD患者分为HHcy组 （Hcy＞15 μmmol/L）和正常Hcy（normal Hcy，NHcy）组（Hcy≤15 μmmol/L）。2周内行多模式头颅MRI检 查。对2组患者的认知评分及影像特点进行比较，并与Hcy水平进行相关性分析。 结果 ①研究共纳入81例SVD患者，平均年龄（64.3±7.4）岁；男性65例，占80.2%；轻度认知障 碍50例，占61.7%。②HHcy组30例（37.0%），NHcy组51例（63.0%）。HHcy组吸烟比例高于NHcy组。 ③HHcy组执行功能中交替连线测验B（trail making test B，TMT-B）耗时数高于NHcy组（P =0.016），数 字符号转换测验（digital symbol substitution test，DSST）（P =0.013）、数字广度测验（digital span test， DS）顺背（P =0.029）得分低于NHcy组。④HHcy组较NHcy组中重度脑室旁白质病变（63.3% vs 39.2%， P =0.018）、深部白质病变（60.0% vs 37.3%，P =0.036）和多发微出血（36.7% vs 17.3%，P =0.047）的 比例更高，且Hcy水平与脑室旁白质病变评分显著相关（r =0.227，P =0.041）。⑤经脑室旁白质病变评 分校正后，Hcy水平与TMT-B耗时数（r =0.278，P =0.013）正相关，与DSST（r =-0.354，P =0.004）和DS 顺背（r =-0.366，P =0.001）得分负相关。 结论 SVD患者外周血Hcy水平与执行注意以及脑室旁白质病变严重程度显著相关，外周血Hcy水平 可能是SVD早期认知功能障碍的生物标志物之一。     

儿童脓毒症相关性脑病发生的危险因素分析

目的 分析脓毒症病儿发生脓毒症相关性脑病(SAE)的危险因素.方法 选取2018年1月至2020年2月入住徐州市儿童医院的脓毒症病儿158例,其中符合SAE诊断标准病儿57例,未发生SAE病儿101例,通过单因素分析和多因素回归等方法,研究脓毒症病儿发生SAE的危险因素.结果 SAE组病儿死亡率(29.8％)高于非SAE组(9.9％),差异有统计学意义(P<0.05).凝血功能障碍、高同型半胱氨酸血症、高尿酸血症是儿童SAE发生的独立危险因素,差异有统计学意义(P<0.05).结论 凝血功能障碍、高同型半胱氨酸血症、高尿酸血症对脓毒症病儿是否发生SAE有一定预测价值.     

Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model

Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is associated with numerous pathological conditions. A number of nutritional and hormonal factors have been shown to influence circulating homocysteine concentrations; however, the impact of exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was that exercise represents an effective means to prevent hyperhomocysteinemia in a folate-independent manner. The purpose of this study was to determine the influence of exercise on homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate hyperhomocysteinemia. Female outbred mice (12 weeks old) were assigned to either a sedentary or free-access wheel exercise group. Following a 4-week acclimation period, half of the mice in each group were provided a folate-restricted diet for 7-weeks prior to euthanasia and tissue collection. As expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total homocysteine concentrations; however, exercise completely prevented the increase in circulating homocysteine concentrations. Moreover, exercise reduced plasma homocysteine concentrations 36% within the group fed only the control diet. The prevention of hyperhomocysteinemia by exercise appears, at least in part, to be the result of increased folate-independent homocysteine remethylation owing to a 2-fold increase in renal betaine homocysteine S-methyltransferase. To our knowledge, this is the first report demonstrating the prevention of hyperhomocysteinemia by exercise in a dietary folate-restriction model. Future research will be directed at determining if exercise can have a positive impact on other nutritional, hormonal, and genetic models of hyperhomocysteinemia relevant to humans.