Protective role of sitagliptin against oxidative stress in a kainic acid-induced status epilepticus in rats models via Nrf2/HO-1 pathway

Aim: Sitagliptin (Sita) is a dipeptidyl peptidase-4 inhibitor which has been approved as a curing medicine for Type 2 diabetes (T2D) and has also reported its neuroprotective and antioxidant activity. This article describes the therapeutic effects of Sita on induced rat model of SE by kainic acid (KA) and investigated the antioxidative pathway of sita. Methods: Sprague–Dawley male rats were used randomly divided in four groups: vehicle control, KA and Sita + KA in a 5 and 10 mg/kg doses respectively in further groups. SE in rats was induced by the administration of KA in Phosphate buffered saline (PBS) intraperitoneally (IP) in a dose of 15 mg/kg. Seizure intensity, oxidative stress parameters, TUNEL assay, histopathology, and Nrf2/HO-1 expressions were evaluated. Results: Increment in the latency in SE results in delaying the initiation of disease in the pretreated rats by Sita compared to induce group (KA) as well the percentage of occurrence of SE was decreased. The content of MDA elevates whereas the SOD production decreases on administering the KA at various time intervals. Sita shows protective action against the KA-induced SE by reducing the oxidative stress thus inhibiting the change in SOD and MDA was observed after KA administration prior SE onset. Based on the above results, the study explains possible molecular mechanism of Sita. Sita Pretreatment showed significant elevation in expression of Nrf2 and HO-1 proteins in hippocampus region of the brain. Conclusion: Above parameters defines the potential effect of Sita on brain injury occurred due to SE by anti-oxidative pathway.     

The role of ANXA5 in DBP-induced oxidative stress through ERK/Nrf2 pathway

Di-N-butylphthalate (DBP) have given rise to more and more attention due to its unique endocrine toxicity to male reproductive system. Our previous studies have demonstrated antioxidative Nrf2 (nuclear factor erythroid related factor 2) pathway play a vital role in DBP induced oxidative stress injury. ANXA5 (annexin A5), which is highly expressed in testicular Leydig and Sertoli cells, was found upregulated after DBP stimulation. Mouse Leydig and Sertoli cells were exposed to different concentration of DBP for 24 h to examine the ROS (Reactive oxygen species), MDA (Malondialdehyde), SOD (superoxide dismutase) level and ANXA5, Nrf2, NQO1 (NAD(P)H-quinone oxidoreductase 1), HO-1 (heme oxygenase 1) and ERK/P-ERK protein expression by DHE (Dihydroethidium) staining, ELISA (enzyme-linked immunosorbent assay) and Western blot respectively. Firstly, the oxidative stress injury induced by DBP was re-validated. Then, we confirmed the change of Nrf2 pathway and ANXA5 level after DBP exposure to testicular cells. Additionally, overexpressed ANXA5 could activate Nrf2/HO-1/NQO1 antioxidant pathway and significantly attenuate DBP-induced oxidative stress. Ultimately, we demonstrated ANXA5 could increase ERK phosphorylated level and the activated role of ANXA5 on ERK/Nrf2 pathway could be reversed by ERK inhibitor. Overall, this study illuminated that ANXA5 could defend testicle Leydig and Sertoli cells against DBP-induced oxidative stress injury through ERK/Nrf2 pathway.     

Ginsenoside Rg1 prevents acetaminophen-induced oxidative stress and apoptosis via Nrf2/ARE signaling pathway

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. Ginsenoside Rg1 is a major active ingredient in processed Panax ginseng, which is proved to elicit biological effects. We hypothesized the beneficial effect of Rg1 on APAP-mediated hepatotoxicity was through Nrf2/ARE pathway. The study was conducted in cells and mice, comparing the actions of Rg1. Rg1 significantly improved cell survival rates and promoted the expression of antioxidant proteins. Meanwhile, Rg1 reduced the excessive ROS and the occurrence of cell apoptosis, which were related to Nrf2/ARE pathway. Expression of Nrf2 has a certain cell specificity.

     

番茄红素调节Keap1/Nrf2/ARE信号通路对精神分裂大鼠认知障碍和氧化应激反应的影响

目的 探究番茄红素调控Kelch样环氧氯丙烷相关蛋白1(Keap1)/核因子E2相关因子2(Nrf2)/抗氧化反应元件（ARE）通路,影响精神分裂症大鼠的氧化应激反应和认知功能。方法 构建精神分裂症大鼠模型,将大鼠随机分为对照组、氯丙嗪组、模型组以及番茄红素高、低剂量组和番茄红素+Nrf2抑制剂组,每组各10例。Morris水迷宫实验检测各组大鼠认知功能;Tunel染色观察并计算各组大鼠海马组织中神经元凋亡率;酶联免疫吸附测定法（ELISA）检测大鼠血清中过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）、超氧化物歧化酶（SOD）水平;Western blotting法检测各组大鼠海马组织中Keap1、Nrf2和ARE下游抗氧化蛋白HO-1的表达水平。结果 与模型组相比,番茄红素组大鼠水迷宫实验中逃避潜伏期明显缩短（2～5 d）,海马组织细胞凋亡率显著降低,血清CAT、GSH-Px、SOD水平和海马组织Keap1、Nrf2、HO-1蛋白表达量显著升高（P<0.05）;与番茄红素高剂量组相比,番茄红素低剂量组、番茄红素+Nrf2抑制剂组大鼠水迷宫实验中逃避潜伏期明显延长（2～...     

Protective effect of ginsenoside-Re against cerebral ischemia/reperfusion damage in rats

To investigate the protective effect of ginsenoside Re (Re) against cerebral ischemia-reperfusion injury, adult male Wistar rats weighing 250-300 g were subjected to either sham surgery or middle cerebral artery occlusion (MCAO) for 2 h of brain ischemia and 2 h reperfusion. A fluorescence polarization assay was carried out for membrane fluidity of brain mitochondria. Lipid peroxidation [malondiadehyde (MDA) formation], superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) of rat brain were estimated by fluorometric methods. It was observed that Re (5, 10, 20 mg kg-1 p.o. pretreatment for 7 d, once a day) significantly improved the fluidity of mitochondrial membranes as demonstrated by a reduction of average microviscosity, ameliorated lipid peroxidation by raising the activities of SOD and GSH-Px, and reduced the content of MDA in rat brain. This study demonstrated a direct protective effect of Re against cerebral ischemia-reperfusion injury.     

牡荆素通过12/15-LOX信号通路减轻大鼠脑缺血再灌注损伤的研究

目的 探讨牡荆素对大鼠大脑中动脉缺血再灌注损伤的保护作用及可能机制.方法 60只雄性SD大鼠随机分为假手术组、模型组及牡荆素40、80mg/(kg·d)组,每组15只.制作大鼠大脑中动脉缺血(90 min)/再灌注(24 h)损伤模型.术前1周及模型制作前30 min,各组分别ip相应药物,假手术组和模型组给予等量生理...     

Gastrodin protects against glutamate-induced ferroptosis in HT-22 cells through Nrf2/HO-1 signaling pathway

Gastrodin (GAS) is a component of Gastrodia elata Blume, with strong antioxidant activity in neurodegenerative diseases. Ferroptosis is similar to glutamate-induced cell death. This study was designed to explore the protective effects of GAS against glutamate-induced neurotoxicity in mice hippocampal neurons (HT-22) cells. HT-22 cells were cultured with glutamate in the presence or absence of GAS (1, 5, 25 μM). Results showed that GAS inhibited glutamate-induced ferroptosis via Nrf2/HO-1 signaling pathway. Pretreatment of HT-22 cells with GAS significantly decreased glutamate-induced cell death and release of LDH. Ferrostatin-1, liproxstatin-1, and DFO treatments canceled these effect. GAS decreased glutamate-treatment ROS production in HT-22 cells. The concentration of iron ion was analyzed using ICP-MS. Metal analysis showed that GAS pretreatment normalized iron ion concentration in HT-22 cells. We found that GAS increased the nuclear translocation of Nrf2, up-regulated the downstream HO-1 protein expression in HT-22 cells following treatment with glutamate. Nrf2 knockdown greatly decreased glutamate-induced ferroptosis through HO-1. In conclusion, these results show that GAS protects HT-22 cells from the ferroptosis induced by glutamate through a new mechanism of Nrf2/HO-1 signaling pathway.     

The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway

BackgroundOxidative stress and inflammation play a key role in the development of hepatic ischemia reperfusion (HIR)-induced injury. Nuclear factor-erythroid 2-related factor-2 (Nrf-2) is a main regulator of numerous genes, encoding cytoprotective molecules including heme oxygenase-1 (HO-1). Sitagliptin (Sit) is an incretin enhancer acting via inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme. This study was undertaken to investigate the ability of Sit to prevent the hepatic pathological changes of HIR induced injury and to modify Nrf-2 and its target HO-1.MethodsPringle's maneuver was used to induce total HIR in adult male rats that were randomly assigned into 4 groups. Group1 (sham-operated control), Group 2 (sham-operated + Sit-control group), Group 3 (HIR non-treated), and Group 4 (HIR + Sit). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities together with hepatic contents of malondialdhyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) and superoxide dismutase (SOD) activity were evaluated. Hepatic tissue mRNA of Nrf-2 and protein content of HO-1 along with histopathological examination and scoring of hepatic injury were performed.ResultsSit caused a significant reduction in ALT and AST activities together with attenuation of HIR-induced histopathological liver injury. Effect of Sit was associated with decreased hepatic level of MDA and NO with increased GSH level and SOD activity. Non-treated rats with HIR showed an increase in Nrf-2 mRNA expression and HO-1 content in hepatic tissue which was further increased by Sit treatment.ConclusionsThese results indicate that hepatoprotective activity of Sit against HIR is attributed at least in part to modulation of Nrf-2/ HO-1 signaling pathway.     

Protective effect of agmatine on ischemia/reperfusion-induced renal injury in rats

Enhanced renal sympathetic nerve activity (RSNA) during ischemic period and the renal venous norepinephrine (NE) overflow after reperfusion play important roles in the development of ischemic/reperfusion (I/R)-induced acute renal failure (ARF) in rats. This study evaluated whether agmatine, which is known to reduce sympathetic nerve activity and NE overflow by electrical stimulation, would prevent the I/R-induced renal dysfunction. Ischemic ARF was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Intravenous (IV) injection of agmatine (100 and 300 micromol/kg) to ischemic ARF rats dose-dependently suppressed the enhanced RSNA and attenuated the I/R-induced renal dysfunction and histological damage. Intracerebroventricular (ICV) injection of agmatine (600 nmol/kg) to ischemic ARF rats suppressed the enhanced RSNA during the ischemic period and attenuated the I/R-induced renal injury. Furthermore, both IV and ICV injection of agmatine significantly suppressed the renal venous NE overflow after the reperfusion. These results indicate that agmatine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppression of the enhanced RSNA during ischemic period and NE overflow from renal sympathetic nerve endings.     

巴曲酶对缺血性眩晕大鼠及其脑组织Nrf2/HO-1信号通路的影响

目的 探讨巴曲酶对缺血性眩晕大鼠眩晕症状、抗氧化指标、炎症因子、血液流变学指标及脑组织NF-E2-相关因子2/血红素氧合酶1(Nrf2/HO-1)信号通路的影响.方法 40只SD大鼠随机分为假手术组、模型组、巴曲酶组(尾iv 1 BU/kg)、NRF2抑制剂(ML385)组(ip 30 mg/kg)、巴曲酶+ML385...     

Protective effects of Forsythia suspensa extract against oxidative stress induced by diquat in rats

Forsythia suspensa extract has been proved as a potential antioxidant in the recent years. The present study was undertaken to obtain the optimal antioxidant fraction in vitro and examine its antioxidative potential against diquat-induced oxidative stress in male Sprague Dawley rats in vivo. In vitro, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiment indicated that the CH₂Cl₂ fraction of F. suspensa (FSC) exerted the strongest scavenging activities; forsythoside A, forythialan A and phillygenin from it might be the major antioxidant constituents. In vivo, pretreatment of rats with different doses of FSC (25, 50 and 100 mg/kg bw) and vitamin C (100 mg/kg bw, positive control) for 15 days significantly lowered the tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in plasma compared to the negative control group. Also, FSC significantly increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of glutathione (GSH) in plasma, liver and kidney whereas it decreased the levels of malondialdehyde (MDA) in plasma and kidney. Moreover, the protective effect of FSC (100 mg/kg bw) was better than vitamin C. These results revealed that FSC exerted a protective effect against diquat-induced oxidative stress and is worthy of becoming a potential dietary antioxidant.     

双苯氟嗪对大鼠全脑缺血再灌注损伤的保护作用

目的研究双苯氟嗪(D ip)对大鼠急性全脑缺血再灌注损伤的保护作用,并初步探讨其作用机制。方法采用Pu lsinelli等的四动脉结扎法(4-VO)造成大鼠全脑缺血再灌注损伤模型,观察大鼠全脑缺血再灌注损伤后早期脑组织水分的变化、生化指标的改变,再灌注后期行为学和组织形态学的改变。结果缺血30 m in再灌注1 h脑组织水分及丙二醛(MDA)含量升高,乳酸脱氢酶(LDH)和超氧化物歧化酶(SOD)活性下降;缺血20 m in再灌注5 d后海马CA1区椎体细胞层破裂,胞核固缩或溶解,间质也变得疏松。行为学实验表明大鼠记忆力明显受损。D ip可不同程度地抑制上述变化,能对抗自由基损伤和脑水肿,并能保护海马CA1区神经元免受缺血损伤,提高大鼠对空间辨别的记忆能力。结论D ip对大鼠全脑缺血再灌注早期损伤有明显的保护作用,并能保护海马CA1区神经元免受缺血损伤,提高大鼠对空间辨别的记忆能力,对迟发性神经元死亡有一定的保护作用。这可能与其抗脂质过氧化产物产生有关。     

葡萄籽原花青素联合亚低温通过ERK/Nrf2/HO-1通路对脑缺血再灌注损伤大鼠的保护作用

目的基于ERK/Nrf2/HO-1通路探讨葡萄籽原花青素(GSP)联合亚低温(MHT)对脑缺血再灌注损伤大鼠的脑保护作用。方法大鼠随机分为假手术组、模型组、MHT组、GSP组、MHT+GSP组。采用线栓法建立脑缺血再灌注损伤大鼠模型。评估各组大鼠神经功能缺损评分(NDS),TTC法观察并计算脑梗死面积,尼氏染色观察脑组织病理学变化,TUNEL法计算细胞凋亡指数,酶联免疫吸附法检测脑组织丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)水平,Westernblotting检测Bax、Bcl-2、p-ERK1/2、Nrf2和HO-1蛋白表达。结果与假手术组比较,模型组大鼠NDS、脑梗死面积、AI、脑组织MDA水平、Bax、p-ERK1/2、胞质和胞核Nrf2、HO-1蛋白表达均显著升高(P<0.05),SOD、GSH-Px活力和Bcl-2蛋白表达显著降低(P<0.05)。与模型组比较,MHT组、GSP组和MHT+GSP组大鼠NDS、脑梗死面积、AI、脑组织MDA水平、Bax和胞质Nrf2蛋白显著降低(P<0.05),SOD、GSH-Px活力、Bcl-2、p-ERK1/2、胞核Nrf2、HO-1蛋白表达显著升高(P<0.05)。且MHT+GSP组的治疗疗效高于MHT组和GSP组。结论 MHT和GSP联合作用可能通过激活ERK/Nrf2/HO-1通路,上调p-ERK1/2、胞核Nrf2和HO-1蛋白表达,抑制氧化应激,发挥脑保护作用。     

白藜芦醇对脑缺血/再灌注氧化应激损伤保护机制的研究进展

白藜芦醇是一种广泛存在于植物中的多酚类化合物,具有广泛的生物学活性。该文主要从白藜芦醇的性质以及在脑缺血/再灌注氧化应激损伤中的保护作用及其机制作一综述。     

前列腺素E1对大鼠移植肺再灌注损伤的保护作用

目的:探讨前列腺素E1(PGE1)对大鼠移植肺再灌注损伤的保护作用及机制。方法:SD大鼠36只随机分为3组,每组12只,即对照组、肺移植组和肺移植加PGE1处理组,观察受体大鼠肺移植前后注射PGE1对移植肺再灌注损伤的保护作用。肺功能指标包括肺湿干重比、肺通透性指数、支气管肺泡灌洗液(BALF)中白细胞计数和分类。比色法检测各组肺组织超氧化物歧化酶(SOD)和丙二醛(MDA)含量。ELISA法检测受体大鼠血清中肿瘤坏死因子α(TNFα)含量。结果:肺移植术后1 h,肺湿干重比、肺通透指数、BALF中中性粒细胞百分比和MDA含量显著高于对照组(P<0.01),肺组织中SOD活性明显低于对照组(P<0.01);给予受体大鼠静脉注射PGE1可明显改善上述指标(P<0.01);肺移植组血清TNFα含量较对照组显著升高(P<0.01),PGE1可明显降低血清TNFα水平(P<0.01)。结论:PGE1对移植肺缺血／再灌注损伤有显著的保护作用,与其抗氧化自由基损伤、抑制中性白细胞激活和炎性因子TNFα分泌有关。     

Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats.

Oxidative stress is a major contributor to the development of vascular dysfunction found in various pathological conditions. Quercetin, one of the potent antioxidant bioflavonoid compounds, has been shown to alleviate oxidative injury by modulation of gene expression leading to suppression of production of reactive oxygen and nitrogen species and conferring an antiapoptotic activity. The aim of the present study was to investigate the protective effects of quercetin in a model of phenylhydrazine (PHZ)-induced oxidant stress, vascular dysfunction and hemodynamic disturbance in rats. Male Sprague-Dawley rats were administered quercetin orally (25 or 50mg/kg/day) for 6 days. On day four, all animals except those in the normal control group, were administered PHZ intraperitoneally. The results showed that PHZ induced severe hemolysis. The mean arterial pressure and hindlimb vascular resistance of PHZ-control rats were markedly decreased compared to normal controls. Treatment with quercetin significantly improved arterial blood pressure and peripheral vascular resistance. Vascular responsiveness to bradykinin, acetylcholine, and phenylephrine in PHZ-control rats was dramatically suppressed and quercetin restored these responses in a dose-dependent manner. Quercetin partially protected blood glutathione, suppressed plasma malondialdehyde levels, and largely suppressed nitric oxide metabolites and superoxide anion production. These results provide the first evidence for the role of the flavonoid, quercetin, in the alleviation of vascular dysfunction in an animal model of PHZ-induced oxidant stress.     

Schisandrin A protects against lipopolysaccharide-induced mastitis through activating Nrf2 signaling pathway and inducing autophagy

Schisandrin A (Sch A), a dibenzocyclooctadiene lignan extracted from Schisandra chinensis (Turcz.) Baill., has anti-oxidant and anti-inflammatory effects, but the effect on masitits has not been studied. Therefore, we investigated the effect of Sch A in cell and mouse models of lipopolysaccharide (LPS)-induced mastitis. Studies in vivo showed that Sch A reduced LPS-induced mammary injury and the production of pro-inflammatory mediators. Sch A also decreased the levels of pro-inflammatory mediators and activated nuclear factor-E2 associated factor 2 (Nrf2) signaling pathway in mouse mammary epithelial cells (mMECs). The Nrf2 inhibitor partially abrogated the downregulation of Sch A on LPS-induced inflammatory response. In addition, LPS stimulation suppressed autophagy, while both Sch A and the autophagy inducer rapamycin activated autophagy in mMECs, which down-regulated inflammatory response. Sch A also restrained LPS-induced phosphorylation of mammalian target of rapamycin (mTOR) and activated AMP-activated protein kinase (AMPK) and unc-51 like kinase 1 (ULK1). In summary, these results suggest that Sch A exerts protective effects in LPS-induced mastitis models by activating Nrf2 signaling pathway and inducing autophagy and the autophagy is initiated by suppressing mTOR signaling pathway and activating AMPK-ULK1 signaling pathway.