Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury

During cardiac ischemia-reperfusion (IR) injury, excessive generation of reactive oxygen species (ROS) and overload of Ca(2+) at the mitochondrial level both lead to opening of the mitochondrial permeability transition (PT) pore on reperfusion. This can result in the depletion of ATP, irreversible oxidation of proteins, lipids, and DNA within the cardiomyocyte, and can trigger cell-death pathways. In contrast, mitochondria are also implicated in the cardioprotective signaling processes of ischemic preconditioning (IPC), to prevent IR-related pathology. Nitric oxide (NO*) has emerged as a potent effector molecule for a variety of cardioprotective strategies, including IPC. Whereas NO* is most noted for its activation of the "classic" soluble guanylate cyclase (sGC) signaling pathway, emerging evidence indicates that NO can directly act on mitochondria, independent of the sGC pathway, affording acute cardioprotection against IR injury. These direct effects of NO* on mitochondria are the focus of this review.     

Medroxyprogesterone acetate inhibits proliferation of colon cancer cell lines by modulating cell cycle-related protein expression

OBJECTIVE: To investigate the effects of medroxyprogesterone acetate on colon cancer cells in vitro. DESIGN: HT29 and HCT116 human colon cancer cell lines were used in this study. Cell growth and WST-1 assays were performed to investigate the antiproliferative effect of medroxyprogesterone acetate. Cell cycle analysis was performed to investigate the effects of medroxyprogesterone acetate on cell cycle distribution. Western blot, immunoprecipitation, and a cyclin-dependent kinase assay were performed to investigate changes in the levels of cell cycle proteins. RESULTS: Medroxyprogesterone acetate inhibited proliferation of the cancer cells by inducing accumulation in the G0/G1 fraction. Medroxyprogesterone acetate decreased expression of cyclin E, increased expression of p21(WAF1/CIP1), and enhanced interaction of p21(WAF1/CIP1) with cyclin-dependent kinase 2, eventually inhibiting its activity. CONCLUSIONS: Medroxyprogesterone acetate exerts its antiproliferative effect by modulating cell cycle-related protein expression and cyclin-dependent kinase 2 activity. These results should help to elucidate the protective effect of medroxyprogesterone acetate on colon cancer risk.     

子宫缺血再灌注损伤大鼠模型的建立

背景：子宫缺血再灌注损伤可导致能量代谢障碍、大量自由基产生及细胞凋亡等。 目的：建立一种简易、实用、可靠的子宫缺血再灌注损伤大鼠模型。 方法：将50只健康Wistar雌性大鼠随机等分为5组。子宫缺血组(共3组)开腹后采用线栓法分别阻断大鼠子宫动脉45 min、阻断大鼠腹腔动脉30 min或阻断大鼠腹腔动脉45 min进行子宫缺血处理;子宫缺血再灌注组开腹后采用线栓法阻断大鼠腹腔动脉30 min再灌注60 min;假手术组不阻断子宫供血动脉。 结果与结论：子宫动脉纤细,结扎过紧,子宫动脉常常断裂,结扎过松,不能够充分阻断血液,不适宜建立子宫缺血再灌注损伤模型。苏木精-伊红染色显示,阻断大鼠腹腔动脉30 min后子宫细胞及间质肿胀,肌纤维排列尚整齐;阻断大鼠腹腔动脉45 min及子宫缺血再灌注组的子宫细胞及间质明显水肿,渗出增加,肌纤维排列紊乱,有大量中性粒细胞浸润。分光光度计检测显示,阻断大鼠腹腔动脉45 min及子宫缺血再灌注组子宫丙二醛水平升高最明显 (P < 0.01)。提示采用线栓法结扎腹腔动脉30 min后进行再灌注可建立大鼠子宫缺血再灌注损伤模型。     

褪黑激素抗缺血再灌注损伤

缺血再灌注损伤（ischemia-reperfusion injury,IRI）是临床常见的病理过程,其发生发展过程涉及到自由基、钙超载 、白细胞的呼吸爆发等损伤作用。长期以来主要围绕以上几个方面进行对IR损伤的防治。褪黑激素(melatonin,MEL)是由松果体分泌的一种吲哚类激素,能够增强机体多个系统功能,近年来研究发现其通过抗氧化以及在分子水平发挥抗器官IR损伤作用。     

Medroxyprogesterone acetate enhances in vivo and in vitro antibody production

In the present study we examine the effects of medroxyprogesterone acetate (MPA) on the specific antibody secretion to T-dependent antigens. Our results show that the in vivo administration of MPA to mice, 7 or 90 days before immunization with sheep red blood cells (SRBC), significantly enhanced both, primary and secondary antibody responses, without affecting delayed-type hypersensitivity (DTH). These effects could be counteracted by the anti-progestin onapristone or ZK 98299 (ZK) suggesting that MPA interacted with progesterone (PRG) receptors to increase B-cell response. To better understand the mechanisms involved in MPA activity we carried out cultures of splenocytes, bone marrow cells or lymph node cells from immunized mice in the presence of MPA, and evaluated the amount of antibody release to supernatants. We found that low doses of MPA (10(-9) M and 10(-10) M) significantly enhanced the in vitro production of specific immunoglobulin G (IgG) antibodies, an effect that appears to involve the interaction of the progestin with PRG receptors, as judged by the inhibition of MPA effects with ZK (10(-8) M) or RU486 (10(-9) M). These receptors were detected by flow cytometry analysis in a proportion of T lymphocytes. Because MPA did not increase the number of immunoglobulin-secreting cells, our findings suggest that MPA enhanced the capacity of individual cells to produce specific immunoglobulin.     

Neuroprotective effect of atorvastatin in spinal cord ischemia-reperfusion injury

OBJECTIVES:

Prevention of the development of paraplegia during the repair of the damage caused by descending thoracic and thoracoabdominal aneurysms remains an important issue. Therefore, we investigated the protective effect of atorvastatin on ischemia-induced spinal cord injury in a rabbit model.

METHOD:

Thirty-two rabbits were divided into the following four equally sized groups: group I (control), group II (ischemia-reperfusion), group III (atorvastatin treatment) and group IV (atorvastatin withdrawal). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the iliac bifurcation. Seventy-two hours postoperatively, the motor function of the lower limbs of each animal was evaluated according to the Tarlov score. Spinal cord and blood samples were obtained for histopathological and biochemical analyses.

RESULTS:

All of the rabbits in group II exhibited severe neurological deficits. Atorvastatin treatment (groups III and IV) significantly reduced the level of motor dysfunction. No significant differences were observed between the motor function scores of groups III and IV at the evaluated time points. Light microscopic examination of spinal cord tissue samples obtained at the 72^nd hour of reperfusion indicated greater tissue preservation in groups III and IV than in group II.

CONCLUSION:

This study demonstrates the considerable neuroprotective effect of atorvastatin on the neurological, biochemical and histopathological status of rabbits with ischemia-induced spinal cord injury. Moreover, the acute withdrawal of atorvastatin therapy following the induction of spinal cord ischemia did not increase the neuronal damage in this rabbit model.     

落新妇甙对肝缺血再灌注损伤的保护作用

背景：肝脏是对缺血再灌注损伤最敏感的器官之一。黄酮类化合物落新妇甙可作为递氢体清除氧自由基,从而可能在减轻肝脏缺血再灌注损伤等方面发挥作用。 目的：观察落新妇甙对肝脏热缺血再灌注损伤的保护作用,对其机制进行初步探讨。 方法：C57BL/6小鼠随机分为4组：假手术组、模型组、小剂量干预组和大剂量干预组。干预组小鼠于缺血前24 h和1 h分别给予10或40 mg/kg的落新妇甙腹腔注射,然后建立70%部分肝缺血再灌注模型。采集血液和肝脏组织样本。检测血清丙氨酸氨基转移酶活性,ELISA测血清肿瘤坏死因子α水平,化学比色法测定肝组织中超氧化物歧化酶、丙二醛含量。肝脏组织病理学检测。Westernblot检测肝组织中肿瘤坏死因子α蛋白含量,RT-PCR检测肿瘤坏死因子α mRNA。 结果与结论：落新妇甙干预能有效降低血清丙氨酸氨基转移酶水平,干预组肝组织丙二醛含量较模型对照组明显下降(P < 0.01);而超氧化物歧化酶含量明显上升(P < 0.01);干预组血清肿瘤坏死因子α含量较模型组对照组明显下降(P < 0.01);小、大剂量干预组肝组织中肿瘤坏死因子α蛋白表达与模型组模型对照组比较渐次降低,与半定量RT-PCR结果相符(小剂量干预组P < 0.05,大剂量干预组P < 0.01)。落新妇甙保护肝脏热缺血再灌注损伤显示出剂量-效应关系趋势。结果提示,落新妇甙干预能减轻小鼠肝脏热缺血再灌注损伤后的炎症反应和脂质过氧化损伤,有效改善肝功能和肝脏病理损害;机制可能在于其能抑制缺血再灌注损伤肝组织中肿瘤坏死因子α的高表达。     

高脂血症对心肌缺血再灌注损伤的影响

高脂血症是诱导缺血性心脏疾病发生发展的主要危险因素之一,除诱导动脉粥样硬化外,高脂血症还能直接导致心肌中氧化应激、炎症、凋亡增加及线粒体功能障碍等负面影响。高脂血症会丧失缺血预适应和后适应心肌保护作用,至少包括一氧化氮合酶功能减低,再灌注挽救激酶信号通路钝化,线粒体KATP开放通道和MPTP调节受损以及凋亡通路激活等参与其中的调节。     

葛根素对肝缺血再灌注损伤的保护作用

近年来 ,有关葛根素改善心脑循环和免疫调节作用的临床研究较多。但葛根素对肝缺血再灌注损伤 (ｈｅｐａｔｉｃｉｓｃｈｅｍｉ ａ ｒｅｐｅｒｆｕｓｉｏｎｉｎｊｕｒｙ ,ＨＩＲＩ)的保护作用的研究 ,国内外未见报道。本研究测定家兔肝缺血前 ,缺血 4 5ｍｉｎ ,再灌 4 5ｍｉｎ的血清及肝组织中乳酸脱氢酶 (ＬＤＨ)活性的变化 ,并观察了葛根素对其影响 ,从而了解葛根素对ＨＩＲＩ的保护作用 ,为ＨＩＲＩ的防治提供理论依据。1　材料和方法1 1　材料 :葛根素注射液 ,陕西安康济仁制药公司产品 ,批号0 10 914 ;全自动生化分析仪 ,日本日立 70 6 …     

己酮可可碱对抗兔肾脏缺血再灌注损伤的实验研究

目的: 研究己酮可可碱对抗兔肾脏缺血再灌注损伤作用。方法: 新西兰兔50只,随机分成5组:假手术组、缺血再灌注组(I/R)、I/R+己酮可可碱组、I/R+低温组、I/R+己酮可可碱+低温组。除假手术组外,其余4组均用动脉夹夹闭左侧肾动脉60min后恢复血流灌注,24h后取左肾分别检测肾组织匀浆的SOD、MDA和BUN、SCr水平的变化,并作病理观察。结果: I/R组肾小管出现水样变性、出血坏死,出血坏死组织中大量炎性细胞浸润,近曲小管上皮细胞线粒体高度肿胀,嵴极其紊乱、模糊、甚至消失;I/R+己酮可可碱组和I/R+低温组损伤减轻;I/R+己酮可可碱+低温组和假手术组形态正常。再灌注24h后I/R组BUN、SCr、MDA水平明显高于其它各组(P＜0.05),SOD活性明显低于其它各组(P＜0.05),I/R+低温组和I/R+己酮可可碱组BUN、SCr、MDA水平明显低于I/R组(P＜0.05),SOD活性明显高于I/R(P＜0.05),低温+己酮可可碱组的上述指标与假手术组无显著差异(P>0.05)。结论: 己酮可可碱有对抗兔肾脏缺血再灌注损伤的作用。     

洋金花总生物碱对犬肠缺血再灌注损伤的实验效应

２４只家犬分３组，用３％戊巴比妥钠（ｉｐ）麻醉。用无创夹阻断犬肠系膜前动脉复制成肠缺血模型。组Ⅰ：假手术对照，未阻断肠系膜前动脉，组Ⅱ：肠缺血１２０ｍｉｎ，再灌注１８０ｍｉｎ；组Ⅲ：肠缺血１２０ｍｉｎ，再灌注１８０ｍｉｎ，在再灌注后的第１０ｍｉｎ静脉注射洋金花总生物碱０．０４ｍｇ／ｋｇ。结果显示：洋金花总生物碱能减轻或改善肠缺血再灌注损伤。表现为再灌注后ＳＯＤ活性提高，ＭＤＡ和乳酸含量降低，组织病理形态改变轻。     

Protective effect of dapsone against renal ischemia-reperfusion injury in rat

Abstract

Background: Ischemia/reperfusion can cause injury to tissues and compromise functionality of organs due to inflammatory processes. Significantly, development of these effects in kidney tissue has been a challenging issue that leads to acute renal injury. In this study, anti-inflammatory, anti-oxidative, and protective features of dapsone on kidney ischemia/reperfusion injury were investigated.

Material and methods: Renal ischemia was induced in rats by bilateral renal arteries clamping for 45?min followed by 24?h reperfusion phase. The effects of different doses of dapsone (1, 3, 10?mg/kg) on ischemia/reperfusion injury in kidney tissue were investigated by targeting BUN, Creatinine, LDH, MDA, MPO, IL-1β, TNF-α, and NFκB. In addition histopathological examination was performed by H&E staining method.

Results and discussion: Comparing the findings of this study showed significant reduction in BUN and LDH in 10?mg/kg dapsone received groups, and Cr, MDA, and MPO in 3?mg/kg dapsone received groups. The serum level of TNF-α was significantly decreased with both doses of 3 and 10?mg/kg dapsone. The same results were observed in the serum level of IL-1β and NFκB. Besides, remarkable improvement in histological damages was also observed with dapsone treatment.

Conclusion: These results support the hypothesis that the positive effects of dapsone on the renal ischemia/reperfusion injury are mediated by modulating inflammatory cascades.     

缺血预处置对大鼠肢体缺血再灌注损伤的影响

目的和方法在大鼠肢体缺血再灌注（ＩＲ）损伤模型上观察了缺血预处置（ｐｒｅｃｏｎｄｉｔｉｏｎｉｎｇ，ＰＣ）的影响。结果：发现ＰＣ可以明显减轻ＩＲ引起的血压降低，血浆乳酸脱氢酶、组织蛋白酶Ｄ活性及脂质过氧化产物丙二醛含量的升高；并抑制骨骼肌组织水肿及骨骼肌细胞线粒体钙超载的发生。同时还观察到，ＰＣ对ＩＲ时肢体微血管通透性升高、中性粒细胞浸润及血浆内皮素水平增高均有抑制作用。结论：ＰＣ对大鼠ＩＲ肢体有保护作用，其保护机理之一与其对血管床的保护作用有关。     

地奥心血康对心肌缺血再灌注损伤的抗脂质过氧化作用的研究

目的:揭示地奥心血康(DK)对心肌缺血再灌注损伤的抗氧化作用与机制。方法:用成年杂种犬复制心肌缺血再灌注损伤模型。多道生理记录仪监测心功能指标;酶法测定AST、CK、LDH含量;荧光法测血清与心肌细胞膜MDA含量;电子自旋共振(ESR)记录微分谱线进行体外羟自由基捕捉实验。结果:①生理盐水对照(NS)组随着缺血再灌注时间的延长,LVSP,±dp/dt_max呈进行性下降;而DK组缺血再灌注后LVSP和±dp/dt_max虽有下降,但显著高于NS组(P＜0.05);②血清中AST,CK,LDH含量随缺血/再灌时间延长均增高,于再灌120min后DK显著低于NS组(P＜0.05);③血清MDA含量于再灌注240min时DK组显著低于NS组(P＜0.05);④DK组心肌细胞膜MDA含量也显著地低于NS组(P＜0.05);⑤在DK浓度为0.71%、1.43%和2.14%时,羟自由基强度分别减少66%、80%和100%。结论:DK对心肌缺血再灌注损伤犬的心功能和心肌细胞膜有明显的保护作用,其很强的清除羟自由基的功能是实现这种保护效应的重要机制。     

氢在治疗缺血再灌注损伤的研究进展

缺血再灌注(IR)损伤在临床上较为常见,自由基引起的细胞氧化应激是产生损伤的重要因素。近年来,氢被报道能选择性地清除动物体内羟自由基,对缺血再灌注损伤有一定的治疗作用。由于氢在人体内扩散简单,容易穿透各种屏障,且毒副作用小,有望成为一种理想的治疗缺血再灌注损伤的抗氧化剂应用于临床。     

α-硫辛酸对大鼠肾缺血再灌注损伤的影响

目的： 探讨硫辛酸（LA）对大鼠肾缺血再灌注损伤(RIRI)的作用及其机制。方法: 采用夹闭双侧肾动、静脉45 min后松夹再灌的方法制作RIRI模型，测定血清肌酐（Scr）、丙二醛(MDA)、一氧化氮(NO)及尿NAG酶(UNAG)浓度，放射免疫和免疫组化法对肾皮质内皮素-1（ET-1）的表达做定位和定量分析，肾组织病理学观察和流式细胞术检测肾损伤程度和肾皮质细胞凋亡率。结果： 缺血再灌注后，大鼠肾功能和肾小管上皮细胞明显受损，Scr、MDA和UNAG含量均明显高于sham组(P<0.01)，血清NO含量与sham组相比无明显差异；肾皮质ET-1含量明显高于sham组(P<0.01)，肾小管ET-1表达明显强于sham组，ET-1免疫反应阳性颗粒主要分布于近曲小管上皮细胞；肾皮质细胞凋亡率明显高于sham组(P<0.01)。尾静脉注射α-硫辛酸可明显降低RIRI大鼠Scr、MDA和UNAG水平，肾小管上皮细胞内ET-1免疫反应阳性颗粒明显少于IR组，肾皮质细胞凋亡率明显低于IR组(P<0.05)。结论： ET-1在大鼠RIRI的发生发展中起着十分重要的作用；LA可通过拮抗ET-1的生物学效应，减轻氧自由基损伤而对RIRI大鼠肾脏产生一定的保护作用。     

牛磺酸对大鼠脑缺血再灌注损伤时细胞凋亡的影响

目的：研究牛磺酸对脑缺血再灌注损伤中细胞凋亡的影响。方法：建立大鼠全脑缺血再灌注模型，使用ＤＮＡ片段原位末端标记和流式细胞仪观察了Ｔａｕ治疗后细胞凋亡的变化。结论：Ｔａｕ对脑缺血再灌汪损伤中神经细胞的保护作用可能部分由于降低细胞凋亡的发生。     

刺五加在心肌细胞缺血再灌注损伤中的保护作用

目的：研究刺五加注射液对缺血再灌注损伤(ischemia-reperfusion,I/R)心肌细胞的保护作用。方法：体外培养心肌细胞并计数;721可见光分光光度计测量培养液中的乳酸脱氢酶(LDH)、丙二醛(MDA)和超氧化物歧化酶(SOD)的含量;激光扫描共聚焦显微镜观察细胞内钙离子荧光染色。结果：中药刺五加注射液各剂量组与I/R组相比,细胞存活率升高,LDH、MDA水平降低,SOD水平升高,荧光像素值及阳性染色面积降低,有统计学意义。结论：中药刺五加注射液对缺血再灌注损伤心肌细胞有保护作用,可能与其保护细胞膜、清除氧自由基和减少钙离子内流等机制有关,其最佳浓度为40%。     

锌对肝缺血再灌注损伤的对抗作用及其机制研究

目的:观察外源性锌对缺血再灌注肝脏(HIR)的防护作用并探讨其机制,包括对粘附分子表达的影响。方法:复制大鼠HIRI模型,灌胃给锌,观察实验动物肝组织形态、血清转氨酶活性、血清丙二醛(MDA)含量及粘附分子表达的改变。结果:在肝脏缺血30min,再灌注90min时,大鼠血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)活性增高,肝细胞结构受损,血清MDA含量升高,肝组织中细胞间粘附分子-1(ICAM-1)和血管细胞粘附分子-1(VCAM-1)两种粘附分子表达增强;锌+缺血再灌注组大鼠血清GPT、GOT活性及血清MDA含量均明显低于缺血再灌注组,肝组织粘附分子表达亦较弱,肝细胞的结构基本正常。结论:外源给锌可以明显减轻肝脏缺血再灌注损伤,抗脂质过氧化和抑制粘附分子表达是其作用的重要机制。