类泛素化修饰在脊髓损伤中作用的研究进展

脊髓损伤临床常见且预后大多较差,损伤后病理过程相当复杂。近年来,神经系统疾病中类泛素修饰蛋白(SUMO)的作用越来越受到关注。SUMO是一类最新发现的蛋白质翻译后修饰蛋白,类泛素化修饰在人体中多个生理和病理生理学活动过程中发挥重要作用。研究结果显示脊髓损伤后脊髓水肿、脊髓缺血/再灌注、氧化应激和炎性反应等过程中多种重要的蛋白分子均存在SUMO化修饰调控机制,SUMO相关蛋白的应用亦被证明可调节氧化应激延缓神经元的死亡,其与抗氧化剂等其他脊髓治疗性化合物联合使用有望用于预防缺血性损伤的神经保护,本文拟对脊髓损伤过程中有关SUMO化修饰的最新研究作一综述。     

N6-甲基腺苷修饰与肿瘤相关巨噬细胞关系的研究进展

N6-甲基腺苷(N6-methyladenosine, m⁶A)修饰被认为是真核细胞中最重要的表观遗传学调控之一。m⁶A修饰在多种类型的肿瘤中，被学者们广泛研究。巨噬细胞作为先天免疫系统的吞噬细胞，发挥识别、吞噬、降解抗原和肿瘤细胞的作用。肿瘤相关巨噬细胞(tumor-associated macrophages, TMEs)在不同的肿瘤微环境中发挥着促癌或是抑癌的功能。近年来，已有很多文献报道m⁶A修饰具有通过调控TMEs来调控肿瘤发生发展的能力。该文对m⁶A甲基转移酶、去甲基化酶和甲基化识别蛋白的特征及m⁶A相关蛋白对于TMEs在肿瘤中的作用机制进行了综述。针对m⁶A修饰影响下TMEs的调控机制，提供了新的治疗靶点和研究思路。     

降钙素基因相关肽对心肌缺血/再灌注损伤保护作用信号通路研究进展

背景 降钙素基因相关肽(calcitonin gene-related peptide,CGRP)是一种重要的感觉神经肽,能减轻心肌缺血/再灌注损伤(myocardial ischemia/reperfusion injury,MI/RI). 目的 就CGRP发挥心肌保护作用的信号通路进行综述. 内容 概述CGRP的生物学特征、对MI/RI的影响以及所涉及的信号通路. 趋向 研究CGRP对MI/RI的信号转导机制有助于阐明CGRP对心肌保护的重要性,并提供新的治疗靶点.     

PIAS调控PPARγ的SUMO化修饰在小鼠内毒素性急性肺损伤内源性保护机制中的作用

目的评价小泛素相关修饰物(SUMO) E3连接酶(PIAS)调控过氧化物酶体增殖物激活受体γ(PPARγ)的SUMO化修饰在小鼠内毒素性急性肺损伤(ALI)内源性保护机制中的作用。方法实验Ⅰ清洁级野生型雄性C57BL/6小鼠24只, 6～8周龄, 体质量18～22 g, 采用随机数字表法分为4组(n=6):对照组(C组)、ALI组、ALI+ PPARγ诱导剂TZD组(ALI+T组)、ALI+TZD+SUMO化抑制剂漆树酸组(ALI+T+A组)。尾静脉注射LPS 15 mg/kg制备内毒素性ALI模型。ALI+T+A组注射LPS前1 h时腹腔注射漆树酸5 mg/kg;ALI+T组和ALI+T+A组注射LPS前30 min时腹腔注射TZD 50 mg/kg。给予LPS 12 h后处死小鼠取肺组织, 测定湿重/干重(W/D)比值, 光镜下观察病理学结果, 并行肺损伤评分;分别采用Western blot法和PCR法测定PIAS1、PIAS2、PIAS3和PIASy及其mRNA的表达。实验Ⅱ 体外培养的小鼠肺泡巨噬细胞(MH-S细胞)采用随机数字表法分为4组(n=5):对照组(C组)、LPS...     

NOD样受体热蛋白结构域相关蛋白3炎性体的调控机制研究进展

背景 NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor pyrin domain containing 3,NLRP3)炎性体由NLRP3、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing a CARD,ASC)和酶解活化半胱氨酸蛋白水解酶-1(cysteinyl aspartate specific proteinase-1,caspase-1)相互结合形成,通过活化caspase-1来间接调控IL-1β的成熟和分泌,在细胞质内发挥对外源性微生物或内源性危险信号感受器的作用. 目的 对NLRP3炎性体的调控机制研究进行综述. 内容 分别描述热蛋白结构域(pyrin domains,PYD)、泛素化、一氧化氮(nitric oxide,NO)、干扰素(interferon,IFN)、线粒体、活性氧(reactive oxygen species,ROS)等对NLRP3的调节机制. 趋向 为NLRP3相关疾病的诊疗提供参考.     

PIAS在前列腺癌发生发展中的作用

PIAS(protein inhibitors of activated STAT)是信号转导与转录激活因子(STAT)的特异性抑制蛋白,能够作用于雄激素受体(AR)以及核因子-kappa B(NF-κB)信号通路,且具有小泛素蛋白修饰分子(SUMO)连接酶E3的活性,参与转录因子SUMO化修饰,调控肿瘤细胞周期进程。近年来诸多研究已经证实PIAS与前列腺癌的发生与演变具有密切的关系。本文主要阐述PIAS在前列腺癌发生、发展以及转移等方面的研究进展,为前列腺癌的治疗提供新的理论基础与研究思路。     

组蛋白修饰调节异常在病理性疼痛中的作用

背景 组蛋白修饰是表观遗传学的一项重要内容.近年来研究证实组蛋白修饰调节异常在病理性疼痛的发生发展中起重要作用. 目的 阐述组蛋白修饰调节异常在病理性疼痛产生和维持中作用的研究进展,为病理性疼痛的治疗提供新思路. 内容 讨论组蛋白修饰、组蛋白乙酰化、组蛋白甲基化与病理性疼痛的关系以及组蛋白去乙酰化酶(histonedeacetylase,HDAC)抑制剂对病理性疼痛的治疗作用. 趋向 鉴于组蛋白修饰调节异常在病理性疼痛的重要作用,组蛋白修饰的调节将为病理性疼痛的治疗提供新的策略.     

血红素加氧酶1修饰MSCs的相关研究进展

目的对血红素加氧酶1(Heme oxygenase 1,HO-1)修饰MSCs的相关研究进展进行综述。方法广泛查阅HO-1修饰MSCs的相关研究文献报道,对HO-1修饰MSCs的意义、效应及其相关机制进行总结综述。结果 HO-1修饰MSCs具有重要的研究价值,能够有效增强MSCs移植入体内后在复杂内环境下的抗氧化应激、抗凋亡特性,同时有效增强了MSCs的免疫调节功能,在各种疾病模型及研究领域中提高了MSCs的抗损伤、修复及免疫调控效果。结论 HO-1修饰MSCs的基础研究取得显著进展,有望应用于临床试验,并为干细胞治疗提供一定的理论依据及参考价值。     

组蛋白修饰在破骨细胞分化中的作用

破骨细胞(osteoclast,OC)是来源于造血干细胞的多核巨细胞,是机体内唯一具有骨吸收功能的细胞。OC功能失衡与多种骨代谢疾病的发生发展密切相关,如骨质疏松症、骨关节炎和Paget's病等,常作为骨代谢疾病临床治疗和药物研发的靶细胞。组蛋白(histone,H)是细胞核内序列高度保守的蛋白质,组蛋白修饰是指组蛋白在酶作用下发生甲基化、乙酰化、磷酸化、腺苷酸化和泛素化等修饰的过程,组蛋白修饰通过影响染色质的结构和松弛程度,调控基因转录和翻译,从而影响相关疾病的发展。近年来,越来越多的研究表明组蛋白修饰对于破骨细胞的分化具有重要的调节作用。本文对组蛋白修饰在破骨细胞分化中的作用进行综述,为组蛋白修饰抑制剂在骨代谢相关疾病中的研发和临床运用提供指导。     

转录因子NF-E2相关因子2-氧化反应元件通路在抗心肌再灌注损伤中的作用

背景 转录因子NF-E2相关因子2(Nf-E2 related factor-2,Nrf2)抗氧化反应元件(antioxidant response element,ARE)通路广泛分布于机体心血管系统中,激活后可上调内源性抗氧化系统减轻心肌的氧化损伤. 目的 阐述Nrf2-ARE通路作为抗心肌缺血/再灌注损伤(ischemia/reperfusion injury,I/RI)的潜在靶点,并探讨其可能的保护机制.内容 Nrf2-ARE通路处于氧化应激、炎症反应的中心地位,介导编码抗氧化蛋白和二项解毒酶基因的基础表达和诱导表达;多种外源性化合物可以激活Nrf2-ARE通路,在转录水平上调节抗氧化蛋白及二项解毒酶基因的表达,增强内源性抗氧化系统的能力从而在减少氧自由基产生、抗炎症反应、减轻钙超载、抗心肌细胞凋亡等方面减轻心肌I/RI.趋向 激活Nrf2-A RE通路可为临床抗I/RI提供新的策略.     

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney–heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.     

丙泊酚对大鼠海马神经元缺氧/复氧损伤中线粒体分裂及其超微结构的影响

目的 探讨丙泊酚在大鼠海马神经元缺氧/复氧损伤模型中对线粒体分裂及其超微结构的影响. 方法 培养原代海马神经元细胞至第8天,氧糖剥夺法建立海马神经元缺氧/复氧模型,按照随机数字表法分为6组(每组6瓶):空白对照组(C组),细胞未给予任何处理;赋形剂组(V组),赋形剂[二甲基亚砜(dimethyl sulfoxide,DMSO),终浓度为0.01％]加入细胞培养基;缺血/再灌注(ischemia/reperfusion,I/R)组(I/R组);I/R+丙泊酚1μmol/L组(P1组)、I/R+丙泊酚10μmol/L组(P10组)、I/R+丙泊酚50 μmol/L组(P5o组),在细胞缺氧/复氧期间分别加入丙泊酚1、10、50 μmol/L.缺氧6h,复氧20 h后,用透射电子显微镜观察线粒体超微结构,激光共聚焦显微镜检测神经元细胞线粒体荧光强度及Drp1与Fis1蛋白的共定位程度,用Western blot检测线粒体分裂相关蛋白Drp1 、Fis1的表达. 结果 与C组比较,I/R组线粒体超微结构破坏明显、线粒体荧光强度(0.079±0.032)明显增高(P＜0.05),蛋白Drp1 (0.756±0.082)与Fis1 (1.164±0.070)的表达及共定位程度(0.815±0.048)明显升高(P＜0.05);与I/R组比较,P1组、P10组、P50组线粒体超微结构破坏减轻、线粒体荧光强度(0.065±0.010、0.056±0.011、0.070±0.024)明显减弱(P＜0.05),蛋白Drp1(0.627±0.005、0.322±0.009、0.696±0.007)与Fis1(0.773±0.012、0.670±0.022、0.796±0.016)的表达及共定位程度(0.649±0.015、0.627±0.008、0.702±0.029)明显降低(P＜0.05). 结论 丙泊酚1、10、50 μmol/L可以抑制体外大鼠海马神经元中线粒体分裂相关蛋白Drp1与Fis1的表达及两者的结合,从而抑制线粒体分裂.     

Roles of AKAP1 in high-glucose induced mitochondrial fission in podocytes

Objective To investigate the roles of A kinase anchoring protein1(AKAP1)in high-glucose induced mitochondrial fission in podocytes. Methods Conditionally immortalized human podocytes were cultured in serum-free medium for 24 hours, and then exposed to different glucose concentration conditions in different time periods. The protein expressions of AKAP1 were observed by immunofluorescence, and AKAP1, dynamin related protein1 (Drp1) and phospho Ser 637-Drp1 (p-Drp1) were analyzed by Western blotting. AKAP1 siRNA was transfected to block AKAP1 expression.Podocytes were then divided into normal control group (5 mmol/L glucose), hypertonic group (30 mmol/L mannitol+5 mmol/L glucose), high glucose group (35 mmol/L glucose), and high glucose+AKAP1 siRNA group. Mitochondrial morphological changes were assessed by mitotracker red staining. Podocyte apoptosis was assessed by flow cytometry. Results Compared with normal group, high-glucose induced more podocytes apoptosis (P＜0.05), more mitochondrial fission with decreased aspect ratio and form factor (all P＜0.05). Upregulated AKAP1 protein level, and increased ratio of p-Drp1/Drp1 (all P＜0.05) in time and concentration dependent manners were also observed. Compared with high glucose group, transfection of AKAP1 siRNA showed less apoptosis (P＜0.05), less mitochondrial fission with increased aspect ratio and form factor (all P＜0.05), and down-regulated AKAP1 protein level as well as p-Drp1/Drp1 ratio (all P＜0.05). Conclusion High glucose induced mitochondrial fission might be induced through AKAP1-Drp1 pathway.     

Drp1-Mediated Mitochondrial Abnormalities Link to Synaptic Injury in Diabetes Model

Diabetes has adverse effects on the brain, especially the hippocampus, which is particularly susceptible to synaptic injury and cognitive dysfunction. The underlying mechanisms and strategies to rescue such injury and dysfunction are not well understood. Using a mouse model of type 2 diabetes (db/db mice) and a human neuronal cell line treated with high concentration of glucose, we demonstrate aberrant mitochondrial morphology, reduced ATP production, and impaired activity of complex I. These mitochondrial abnormalities are induced by imbalanced mitochondrial fusion and fission via a glycogen synthase kinase 3β (GSK3β)/dynamin-related protein-1 (Drp1)-dependent mechanism. Modulation of the Drp1 pathway or inhibition of GSK3β activity restores hippocampal long-term potentiation that is impaired in db/db mice. Our results point to a novel role for mitochondria in diabetes-induced synaptic impairment. Exploration of the mechanisms behind diabetes-induced synaptic deficit may provide a novel treatment for mitochondrial and synaptic injury in patients with diabetes.     

Rhein Protects Pancreatic β-Cells From Dynamin-Related Protein-1–Mediated Mitochondrial Fission and Cell Apoptosis Under Hyperglycemia

Rhein, an anthraquinone compound isolated from rhubarb, has been shown to improve glucose metabolism disorders in diabetic mice. The mechanism underlying the protective effect of rhein, however, remains unknown. Here, we demonstrate that rhein can protect the pancreatic β-cells against hyperglycemia-induced cell apoptosis through stabilizing mitochondrial morphology. Oral administration of rhein for 8 or 16 weeks in db/db mice significantly reduced fasting blood glucose (FBG) level and improved glucose tolerance. Cell apoptosis assay using both pancreatic sections and cultured pancreatic β-cells indicated that rhein strongly inhibited β-cell apoptosis. Morphological study showed that rhein was mainly localized at β-cell mitochondria and rhein could preserve mitochondrial ultrastructure by abolishing hyperglycemia-induced mitochondrial fission protein dynamin-related protein 1 (Drp1) expression. Western blot and functional analysis confirmed that rhein protected the pancreatic β-cells against hyperglycemia-induced apoptosis via suppressing mitochondrial Drp1 level. Finally, mechanistic study further suggested that decreased Drp1 level by rhein might be due to its effect on reducing cellular reactive oxygen species. Taken together, our study demonstrates for the first time that rhein can serve as a novel therapeutic agent for hyperglycemia treatment and rhein protects pancreatic β-cells from apoptosis by blocking the hyperglycemia-induced Drp1 expression.Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is an anthraquinone compound isolated from rhubarb that has been used for more than 2,000 years in China to treat constipation, gastrointestinal hemorrhage, and ulcers (1). In our previous work, we found that rhein could improve glucose metabolism disorders in diabetic mice, and its effect on reducing blood glucose level was even stronger than rosiglitazone and benazepril (2,3). Moreover, rhein also inhibited apoptosis of islet cells and protected islet function (4). Using mouse nonalcoholic fatty liver disease as an animal model associated with obesity, insulin resistance, and inflammatory disorders, Sheng et al. (5) reported that rhein could ameliorate fatty liver disease in diet-induced obese mice via negative energy balance, hepatic lipogenous regulation, and immunomodulation. Recent antihyperglycemic study by Chatterjee et al. (6) suggests that rhein, as well as other natural inhibitors such as aloins and capparisine, may be a foundation for a better antidiabetic therapy. However, the mechanism underlying these protective effects of rhein remains unclear.Increasing evidence suggests that β-cell failure is the mainstay of the pathogenesis of type 2 diabetes (7). Although the precise mechanisms underlying the β-cell dysfunction in type 2 diabetes are not fully understood, hyperglycemia has been shown as a major factor to cause the β-cell apoptosis. Once hyperglycemia develops, the pancreatic β-cell is exposed to increased metabolic flux and associated cellular stress, leading to impairment of β-cell function and survival, a process called glucotoxicity (8,9). In type 2 diabetes, hyperglycemia is commonly associated with deregulation of lipid metabolism and elevation of free fatty acids, which also contribute to β-cell dysfunction (8,10). Moreover, high levels of glucose can also amplify lipotoxicity (10). The thiazolidinedione peroxisome proliferator–activated receptor-γ activator drugs, rosiglitazone and pioglitazone, have been widely used to suppress insulin resistance in type 2 diabetic patients (11). Although rhein shows a similar or even better effect on reducing mouse blood glucose level than rosiglitazone, the underlying mechanism remains unclear. It has been known that mitochondrial fission and fusion modulators, dynamin-related protein 1 (Drp1) (12), optic atrophy protein 1 (Opa1) (13), prohibitin (14), and mitofusin (15), collectively control the dynamic balance of mitochondria fission and fusion processes and consequent mitochondria functions. Previous studies have demonstrated that Drp1 plays an important role in promoting hyperglycemia-induced apoptosis of β-cells and neurons (12,16,17). Drp1 expression was increased drastically in islet β-cells under hyperglycemia conditions. Estaquier and Arnoult (18) further demonstrated that inhibiting Drp1-mediated mitochondrial fission could selectively prevent the release of cytochrome c, a mediator of apoptosis, from mitochondria. In contrast to the mitochondria fission modulators, which are upregulated or activated by stress factors such as high concentration of glucose (HG), mitochondria fusion modulators are generally reduced when cells are challenged with proapoptotic insults. Recent studies by Kushnareva et al. (19) and Leboucher et al. (15) showed that stress-induced loss of Opa1 and mitofusin can facilitate mitochondrial fragmentation and cell apoptosis. However, it remains to be determined whether rhein executes its protective role in pancreatic β-cells through regulating the expression or activation of these mitochondria fission/fusion modulators.In the current study, we used db/db mice and a pancreatic β-cell line (NIT-1) to study the protective effect of rhein. Our results showed that rhein largely localized at mitochondria in the β-cells and that it strongly protected pancreatic β-cells from hyperglycemia-induced apoptosis through suppressing Drp1 activation and Drp1-mediated mitochondria fission.     

Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress

Mitochondria are the essential eukaryotic organelles that produce most cellular energy. The energy production and supply by mitochondria appear closely associated with the continuous shape change of mitochondria mediated by fission and fusion, as evidenced not only by the hereditary diseases caused by mutations in fission/fusion genes but also by aberrant mitochondrial morphologies associated with numerous pathologic insults. However, how morphological change of mitochondria is linked to their energy-producing activity is poorly understood. In this study, we found that perturbation of mitochondrial fission induces a unique mitochondrial uncoupling phenomenon through a large-scale fluctuation of a mitochondrial inner membrane potential. Furthermore, by genetically controlling mitochondrial fission and thereby inducing mild proton leak in mice, we were able to relieve these mice from oxidative stress in a hyperglycemic model. These findings provide mechanistic insight into how mitochondrial fission participates in regulating mitochondrial activity. In addition, these results suggest a potential application of mitochondrial fission to control mitochondrial reactive oxygen species production and oxidative stress in many human diseases.     

Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency

Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. BACKGROUND: Little is known about the prevalence of cardiovascular disease (CVD) and associated risk factors in individuals with mild renal insufficiency (RI). Furthermore, the long-term outcomes associated with mild RI in the community have not been described. METHODS: Serum creatinine (SCr) was measured in 6233 adult participants of the Framingham Heart Study (mean age 54 years, 54% women). Mild RI was defined as SCr 136 to 265 micromol/liter (1.5 to 3.0 mg/dl) in men and 120 to 265 micromol/liter (1.4 to 3.0 mg/dl) in women. The lower limits for mild RI were defined by the sex-specific 95th percentile SCr values in a healthy subgroup of our sample. The upper limit for mild RI was chosen to exclude those subjects with more advanced renal failure. Cox proportional hazards analyses were used to determine the relationship of baseline RI to CVD and all-cause mortality. RESULTS: At baseline, 8.7% of men (N = 246) and 8.0% of women (N = 270) had mild RI. Nineteen percent of the subjects with mild RI had prevalent CVD. During 15 years of follow-up, there were 1000 CVD events and 1406 deaths. In women, mild RI was not associated with increased risk for CVD events [hazards ratio (HR) 1.04, 95% CI, 0.79 to 1.37] or all-cause mortality (HR 1.08, 95% CI, 0.87 to 1.34). In men, mild RI showed no significant associations with CVD events (HR 1.17, 95% CI, 0.88 to 1.57), but it was associated with all-cause mortality in age-adjusted (HR 1.42, 95% CI, 1.12 to 1.79) and multivariable adjusted (HR 1.31, 95% CI, 1.02 to 1.67) analyses. CONCLUSION: Mild RI in the community is common and is associated with a high prevalence of CVD. The association of RI with risk for adverse outcomes is strongly related to coexisting CVD and CVD risk factors.     

线粒体动态网络在脓毒症相关性脑病中的研究进展

线粒体是能量代谢中心,通过不断的分裂、融合和转运形成高度互联的线粒体动态网络。均衡的融合/分裂比和精确的分布定位与线粒体自身及神经元生理活动的稳定性密不可分。脓毒症相关性脑病(sepsis associated encephalopathy,SAE)为脓毒症的严重并发症之一,其发病机制复杂,目前尚无确切诊断和治疗方法。近来研究表明线粒体动态网络失衡是SAE进程中的关键病理机制。基于上述研究背景探讨SAE时线粒体动态网络的构成形式和介导的关键分子表达变化以及针对线粒体动态网络治疗SAE的研究进展,以期为SAE诊治提供新思路,为靶向线粒体疗法治疗中枢系统疾病提供新方向。文章主要阐述参与构成线粒体动态网络的3种形式——融合、分裂和转运,以及介导的关键分子,并进一步说明线粒体动态网络稳定及关键分子表达水平对神经元发挥生理功能的意义。     

Levosimendan in rats decreases acute kidney injury after cardiopulmonary resuscitation by improving mitochondrial dysfunction

BackgroundAcute kidney injury (AKI), the most common complication after cardiac resuscitation, is highly prevalent and harmful. There is increasing evidence that levosimendan can improve cardiac output, increase renal blood flow, and prevent AKI. As a novel calcium sensitizer, levosimendan may exert its protective effect via mitochondria.MethodsRat models of asphyxia-induced cardiac arrest and cardiopulmonary resuscitation (CPR) were set up. Thirty healthy adult male SD rats were randomly divided into CPR group (CPR group, n=10), levosimendan-treated group (levo group, n=10), and sham-operated group (sham group, n=10). Twelve hours after CPR, serum renal function indicators were measured, the kidney injury and mitochondrial morphological changes were observed. Oxygen uptake of the mitochondria, mitochondrial adenosine triphosphate (ATP) and mitochondrial free Ca²⁺ concentration were measured. Oxidative stress-related indicator levels in rat kidney tissues were further detected to analyze the differences in apoptosis rates among these three groups. Mitochondrial optic atrophy 1 (Opa1), dynamin-related protein 1 (Drp1), and apoptosis-related proteins were detected using Western blotting.ResultsCompared with the sham group, the CPR group had a significant increase in renal tissue damage. PAS staining and HE stains confirmed that CPR led to renal histopathological damage and destruction of the mitochondrial structure. Levosimendan improved the histopathological and ultrastructural damages of kidneys. Further analysis revealed that mitochondrial ATP content, NADH dehydrogenase, succinate dehydrogenase/cytochrome C oxidase, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (CSH-Px) decreased. Free Ca²⁺ concentration and malondialdehyde (MDA) significantly increased (all P<0.05) in the kidney tissues of rats in the CPR group. However, mitochondrial ATP content, NADH dehydrogenase, succinate dehydrogenase/cytochrome C oxidase, SOD, CAT, and CSH-Px increased, whereas free Ca²⁺ concentration and MDA decreased (all P<0.05) in the levo group. The apoptosis rate increased in the CPR group. There were significantly increased levels of Drp1 protein levels, and significantly decreased Opa1 expression (all P<0.05). However, the levo group showed the opposite effects (all P<0.05).ConclusionsLevosimendan can alleviate AKI following CPR, which may be achieved by improving mitochondrial dysfunction and suppressing the mitochondrial apoptosis pathway.     

Correlation of invasive Doppler flow wire with renal duplex ultrasonography in the evaluation of renal artery stenosis: the Renal Artery Stenosis Invasive Doppler (RAIDER) study

OBJECTIVE: Determining renal resistive index (RI) in the setting of renal artery stenosis may predict which patients benefit from revascularization. Renal duplex ultrasonography (RDUS) is the traditional method of assessing RI, but it is not available in most invasive endovascular laboratories. Conversely, endovascular techniques to assess RI are available but not well validated. The primary goal was to determine if an invasive approach using an endovascular Doppler flow wire correlates with RI assessment using traditional noninvasive RDUS. METHODS: In a single-center prospective trial, patients were enrolled if they had known or suspected renovascular disease. A Doppler flow wire was placed in multiple segments of the renal artery, and peak (PSV) and end-diastolic velocities (EDV) were measured. RI was calculated using the formula: RI = [1 - (EDV/PSV)] x 100. Similarly, RI was also derived using standard RDUS. All patients underwent both RI techniques before any revascularization procedure. Secondary end points included assessing the correlation for pole-to-pole renal length assessment and PSV and EDV velocities using both invasive and noninvasive techniques. Pearson correlation coefficient calculations were used to determine degree of correlation. RESULTS: The study enrolled 20 patients, and 35 renal arteries were studied. Overall, Pearson correlation coefficient for invasive vs noninvasive RI assessment was 0.86 (95% confidence interval [CI], 0.73 to 0.93). The r values were 0.43 (95% CI, 0.11 to 0.67) for pole-to-pole renal length, 0.66 (95% CI, 0.54 to 0.76) for PSV, and 0.61 (95% CI, 0.48 to 0.72) for EDV determination. No major complications occurred during this study. Average time to perform invasive Doppler assessment was 10.4 +/- 7.4 minutes per artery. CONCLUSIONS: Invasive RI assessment using an endovascular flow wire technique correlates well with traditional noninvasive RDUS. A moderate statistical correlation also exists for pole-to-pole renal length, PSV, and EDV determinations. The procedure is safe and can be performed rapidly.