Sodium selenite treatment restores long-lasting ovarian damage induced by irradiation in rats: Impact on oxidative stress and apoptosis

The deleterious damage of reproductive function following radiotherapy is of increasing importance. In the present study, we investigated the impact of long-term sodium selenite (SS) treatment on radiotherapy-induced ovarian injury in a rat model. Two-week after radiation exposure vaginal cyclicity was arrested, and serum FSH level was elevated in irradiated female rats. SS significantly ameliorated ovarian and uterine oxidative stress induced by irradiation through decreasing the lipid peroxide level and increasing the glutathione level, and glutathione peroxidase activity. In the presence of SS, ovarian cytochrome c and caspase 3 expressions triggered by radiotherapy were decreased. SS significantly counteracted radiation-induced a widespread loss of ovarian follicles and caused further stimulation of follicular proliferation through enhancing PCNA expression. Despite such alteration in ovarian function, serum estradiol level did not change after irradiation, whereas SS significantly increased it. In conclusion, long-term SS treatment improved reproductive development, which was impaired by radiotherapy.     

Increased oxidative stress and apoptosis in peripheral blood mononuclear cells of fructose-fed rats

BackgroundMeasuring of oxidative stress in peripheral blood mononuclear cells is a suitable model of dietary induced systemic oxidative stress. Thus, we aimed to evaluate whether a chronic high fructose intake could induce oxidative damage in peripheral blood and bone marrow mononuclear cells of rats.MethodsAnimals were randomly assigned to the following groups: Control group (standard rat chow and tap water n = 8), and Fructose group (standard rat chow and a 10% fructose solution in the drinking water n = 8). Reactive oxygen species and cytokines were measure using flow cytometry in peripheral blood and bone-marrow mononuclear cells. Apoptotic cell death and the advanced oxidation protein products (AOPP) were also determined.ResultsWe observed a significant increase in ROS production in peripheral blood mononuclear cells of fructose group as compared to control rats. Apoptosis and the AOPP were higher in those animals underwent high fructose intake. Serum levels of IL-6 and IL-12 were also increased after 12 weeks of high fructose intake.ConclusionWe concluded that fructose intake leads to systemic oxidative stress and pro-inflammatory condition which affect peripheral blood mononuclear cells and bone-marrow mononuclear cells viability.     

Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats

5-Fluorouracil (5-FU) is a potent antineoplastic agent commonly used for the treatment of various malignancies. It has diverse adverse effects such as cardiotoxicity, nephrotoxicity and hepatotoxicity which restrict its wide and extensive clinical usage. It causes marked organ toxicity coupled with increased oxidative stress and apoptosis. Chrysin (CH), a natural flavonoid found in many plant extracts, propolis, blue passion flower. It has antioxidative and anti-cancerous properties. The present study was designed to investigate the protective effects of CH against 5-FU induced renal toxicity in wistar rats using biochemical, histopathological and immunohistochemical approaches.Rats were subjected to prophylactic oral treatment of CH (50 and 100 mg/kg b.wt.) for 21 days against renal toxicity induced by single intraperitoneal administration of 5-FU (150 mg/kg b.wt.). The possible mechanism of 5-FU induced renal toxicity is the induction of oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. However prophylactic treatment of CH decreased serum toxicity markers, increased anti-oxidant armory as well as regulated apoptosis in kidney. Histopathological changes further confirmed the biochemical and immunohistochemical results. Therefore, results of the present finding suggest that CH may be a useful modulator in mitigating 5-FU induced renal toxicity.     

Effects of oxidative stress on apoptosis in manganese-induced testicular toxicity in cocks

Manganese (Mn) is a trace element known to be essential for maintaining the proper function and regulation of many biochemical and cellular reactions. However, little is known about the reproductive toxicity of Mn in birds. To investigate the toxicity of Mn on male reproduction in birds, 50-day-old cocks were fed either a commercial diet or a Mn-supplemented diet containing 600, 900, and 1800 mg/kg MnCl₂. After being treated with Mn for 30, 60, and 90 d, the following were determined: Mn content; histological and ultrastructural changes in the testes, apoptosis; the malondialdehyde (MDA) level; the activities of superoxide dismutase (SOD); the inhibition ability of hydroxyl radicals (OH); the levels of nitric oxide (NO), nitric oxide synthase (NOS), and protein carbonyl in the testes; the DNA–protein crosslinks (DPC); and the activity of the ATP enzyme. Exposure to Mn significantly lowered the activity of SOD and glutathione peroxidase (GPx) and the inhibition ability of OH. Mn exposure also increased the levels of MDA, NO, NOS, DPC, and protein carbonyl; the number of apoptotic cells; and the Mn content and caused obvious histopathological changes in the testes. These findings suggested that Mn exposure resulted in the oxidative damage of cock testicular tissue by altering radical formation, ATP enzyme systems, apoptosis, and DNA damage, which are possible underlying reproductive toxicity mechanisms induced by Mn exposure.     

Taurine reverses endosulfan-induced oxidative stress and apoptosis in adult rat testis

The present study was aimed to investigate the mechanistic aspect of endosulfan toxicity and its protection by taurine in rat testes. Pre-treatment with taurine (100 mg/kg/day) significantly reversed the decrease in testes weight, and the reduction in sperm count, motility, viability and daily sperm production in endosulfan (5 mg/kg/day)-treated rats. Sperm chromatin integrity and epididymal L-carnitine were markedly decreased by endosulfan treatment. Endosulfan significantly decreased the level of serum testosterone and testicular 3β-HSD, 17β-HSD, G6PDH and LDH-X. Sperm Δψm and mitochondrial cytochrome c content were significantly decreased after endosulfan. Testicular caspases-3, -8 and -9 activities were significantly increased but taurine showed significant protection from endosulfan-induced apoptosis. Oxidative stress was induced by endosulfan treatment as evidenced by increased H₂O₂ level and LPO and decreased the antioxidant enzymes SOD, CAT and GPx activities and GSH content. These alterations were effectively prevented by taurine pre-treatment.In conclusion, endosulfan decreases rat testes weight, and inhibits spermatogenesis and steroidogenesis. It induces oxidative stress and apoptosis by possible mechanisms of both mitochondria and non-mitochondria pathways. These data provide insight into the mode of action of endosulfan-induced toxicity and the beneficial role provided by taurine to counteract endosulfan-induced oxidative stress and apoptosis in rat testis.     

Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes

Background

Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells.

Methods

Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1 μM), propofol (1 μM), or propofol plus doxorubicin (given 1 h post propofol). After 24 h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted.

Results

Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced by doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-δ was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment.

Conclusions

Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application.     

Ascorbic acid attenuates cognitive impairment and brain oxidative stress in ovariectomized mice

Background

Menopause is associated with increased oxidative stress and memory impairment. Based on the antioxidant property of ascorbic acid (AA), It’s effect on cognitive function, the serum level of the brain-derived neurotrophic factor (BDNF) and the activity of antioxidant enzymes within the brain in ovariectomized (OVX) mice was investigated.

Modulation of cadmium induced alterations in murine thymocytes by piperine: oxidative stress, apoptosis, phenotyping and blastogenesis

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use in Indian medicine. It is known to exhibit a variety of biological activities which include anti-pyretic, anti-inflammatory, anti-depressant, hepatoprotective and antitumor. Its immunomodulatory role has so far been limited to humoral response. The influence of piperine on murine thymocytes, immunocompromised by cadmium has been reported by us in this investigation. The various biochemical parameters such as oxidative stress markers (ROS and GSH), Bcl-2 protein expression, mitochondrial membrane potential, caspase-3 activity, DNA damage, blastogenesis and T lymphocyte phenotypes were determined. Cadmium (25 microM) induced apoptosis earliest at 6 h. Alterations in ROS and GSH preceded mitochondrial membrane depolarization and caspase-3 activation followed by apoptosis. The phenotypic changes occurred at 18 h and blastogenesis at 72 h. Various conc. of piperine (1, 10 and 50 microg/ml) when added along with Cd (25 microM) from 1.5 to 72 h, caused a dose and time dependent amelioration in all the cellular events mentioned above. Modulation of oxidative stress has earlier been reported to reduce Cd induced apoptosis in murine lymphocytes. Inhibition of the ROS production and replenishment of GSH by piperine, may in part be responsible for the suppression of downstream cascade of events, i.e. apoptosis, blastogenesis and T lymphocyte phenotyping. The study clearly demonstrated the anti-oxidative, anti-apoptotic, and restorative ability against cell proliferative mitogenic response and phenotypic alterations by piperine, suggesting its therapeutic usefulness in immunocompromised conditions.     

Taxifolin prevents diabetic cardiomyopathy in vivo and in vitro by inhibition of oxidative stress and cell apoptosis

Diabetic cardiomyopathy has been increasingly recognized as an important cause of heart failure in diabetic patients. Excessive oxidative stress has been suggested to play a critical role in the development of diabetic cardiomyopathy. The objective of this study was to investigate the potential protective effects and mechanisms of taxifolin on cardiac function of streptozotocin-induced diabetic mice and on hyperglycemia-induced apoptosis of H9c2 cardiac myoblasts. In vivo study revealed that taxifolin improved diastolic dysfunction, ameliorated myocardium structure abnormality, inhibited myocyte apoptosis and enhanced endogenous antioxidant enzymes activities. Interestingly, taxifolin reduced angiotensin II level in myocardium, inhibited NADPH oxidase activity, and increased JAK/STAT3 activation. In vitro investigation demonstrated that taxifolin inhibited 33 mM glucoseinduced H9c2 cells apoptosis by decreasing intracellular ROS level. It also inhibited caspase-3 and caspase-9 activation, restored mitochondrial membrane potential, and regulated the expression of proteins related to the intrinsic pathway of apoptosis, thus inhibiting the release of cytochrome c from mitochondria into the cytoplasm. In conclusion, taxifolin exerted cardioprotective effects against diabetic cardiomyopathy by inhibiting oxidative stress and cardiac myocyte apoptosis and might be a potential agent in the treatment of diabetic cardiomyopathy.     

Effects of benzo[a]pyrene exposure on oxidative stress and apoptosis of gill cells of Chlamys farreri in vitro

As a common pollutant in marine environment, benzo[a]pyrene (B[a]P) has high toxicity to economic shellfish. In order to explore the mechanism of oxidative stress and apoptosis, the effects of 0, 2, 4, 8 μg/mL B[a]P on gill cells of C. farreri at 12 and 24 h were studied. The results showed that B[a]P decreased the activity of gill cells, increased the content of reactive oxygen species (ROS) and the expression of antioxidant defense genes. Besides, B[a]P could induce oxidative damage to nucleus and mitochondria. The gene expression and enzyme activity of apoptosis pathway related factors were changed. In conclusion, these results showed that B[a]P could cause oxidative stress and oxidative damage in gill cells of C. farreri, and mediate gill cell apoptosis through mitochondrial pathway and death receptor pathway. This article provides a theoretical basis for clarifying the molecular mechanism of PAHs-included oxidative stress and apoptosis in bivalves.     

芍药苷通过调控硫氧还蛋白结合蛋白表达对脂多糖诱导的肾小球系膜细胞氧化应激及凋亡的影响

目的 探讨芍药苷对脂多糖(LPS)诱导的肾小球系膜细胞氧化应激及凋亡的影响及其作用机制.方法 研究起止时间为2018年1月至2019年7月,体外培养人肾小球系膜细胞(HMCL),用不同浓度的(5、10、20μmol/L)芍药苷处理LPS诱导的HMCL细胞.采用流式细胞仪检测细胞凋亡率;应用试剂盒检测细胞中丙二醛(MDA)量及超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性;实时荧光定量聚合酶链反应(qRT-PCR)与蛋白质迹法(Western blotting)分别检测硫氧还蛋白结合蛋白(Thioredoxin-interacting protein,TXNIP)表达;观察干扰TXNIP的表达对LPS诱导的HMCL细胞氧化应激与凋亡的影响.结果 与对照组(Con)比较,LPS组细胞凋亡率升高[(6.58±0.66)％比(28.41±2.83)％](P<0.05),MDA含量增加[(1.26±0.13)nmol/L比(5.06±0.49)nmol/L](P<0.05),SOD[(26.41±2.31)U/mL比(12.46±1.21)U/mL]、GSH-Px[(45.61±4.13)U/mL比(8.12±0.83)U/mL]活性下降(P<0.05),TXNIP信使RNA(mRNA)及蛋白表达升高[(1.02±0.09)vs(2.54±0.25);(0.42±0.04)比(0.87±0.05)](P<0.05);与LPS组比较,芍药苷不同剂量组细胞凋亡率降低[(28.41±2.83)％比(22.16±2.17)/(16.48±1.03)/(11.25±1.12)％](P<0.05),MDA含量下降[(5.06±0.49)nmol/L比(4.12±0.41)/(2.94±0.29)/(1.68±0.17)nmol/L](P<0.05),SOD[(12.46±1.21)U/mL比(15.46±1.52)/(18.24±1.63)/(22.54±2.03)U/mL]、GSH-Px[(8.12±0.83)U/mL比(17.62±1.74)/(26.14±2.63)/(39.44±3.25)U/mL]活性升高(P<0.05),TXNIP mRNA及蛋白表达降低[(2.54±0.25)比(2.13±0.21)/(1.84±0.17)/(1.46±0.15);(0.87±0.05)比(0.72±0.05)/(0.61±0.04)/(0.49±0.03)](P<0.05);干扰TXNIP的表达可减轻LPS诱导的HMCL细胞氧化应激损伤,降低细胞凋亡率;TXNIP过表达可逆转芍药苷对LPS诱导的HMCL细胞氧化应激及凋亡的作用.结论 芍药苷可通过抑制TXNIP的表达对LPS诱导的HMCL细胞氧化应激发挥保护作用,抑制细胞凋亡.     

PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation

Cardiovascular disease (CVD) is a leading cause of death and disabilities worldwide. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists possess potent anti-inflammatory actions and have recently emerged as potential therapeutic agents for CVD. Here we show that H₂O₂ induced apoptosis in cardiomyocytes with a marked down-regulation of Bcl-2 protein. The PPARγ agonist rosiglitazone protected cardiomyocytes from oxidative stress and apoptosis. Cardiomyocytes constitutively overexpressing PPARγ were resistant to oxidative stress-induced apoptosis and protected against impairment of mitochondrial function. On the contrary, cells expressing a dominant negative mutant of PPARγ were highly sensitive to oxidative stress. Cells overexpressing PPARγ exhibited an almost 3 fold increase in Bcl-2 protein content; whereas, in PPARγ dominant negative expressing cells, Bcl-2 was barely detected. Bcl-2 knockdown by siRNA in cells overexpressing PPARγ results in increased sensitivity to oxidative stress, suggesting that Bcl-2 up-regulation mediated the protective effects of PPARγ. These data suggest that, in oxidative stress-induced cardiomyocyte apoptosis, PPARγ protects cells from oxidative stress through upregulating Bcl-2 expression. These findings provide further support for the use of PPARγ agonists in ischemic cardiac disease.     

Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol

Rationale

Clinical and experimental evidence have demonstrated that alcohol consumption during pregnancy can disrupt brain development, leading to a variety of behavioral alterations including hyperactivity, motor dysfunction, and cognitive deficits in offsprings. Alcohol-induced neurocognitive deficits are associated with activation of oxidative-inflammatory cascade coupled with extensive apoptotic neurodegeneration in different brain regions.

Objectives

The present study was designed with an aim to investigate the protective effect of curcumin, a principal curcuminoid present in the Indian spice turmeric, against alcohol-induced cognitive deficits, neuroinflammation, and neuronal apoptosis in rat pups postnatally exposed to ethanol.

Methods and results

Male Wistar rat pups were administered ethanol (5?g/kg, 12?% v/v) by intragastric intubation on postnatal days (PD) 7, 8, and 9 and were treated with curcumin (30 and 60?mg/kg) from PD 6 to 28. Performance of ethanol-exposed pups that did not receive curcumin was significantly impaired as evaluated in both Morris water maze and elevated plus maze tasks recorded by using computer tracking. Cognitive deficit was associated with enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-??, IL-1??, and TGF-??1), and neuronal apoptosis (NF-??? and caspase 3) in both cerebral cortex and hippocampus of ethanol-exposed pups. Chronic treatment with curcumin significantly ameliorated all the behavioral, biochemical, and molecular alterations in different brain regions of ethanol-exposed pups.

Conclusions

The current study demonstrates the possible involvement of oxidative-inflammatory cascade-mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure and points towards the neuroprotective potential of curcumin in mitigating alcohol-induced behavioral, biochemical, and molecular deficits.     

The protective effects of selenium on cadmium-induced oxidative stress and apoptosis via mitochondria pathway in mice kidney

Selenium, an essential trace element, showed the significant protective effects against kidney damage induced by some heavy metals. Our previous research have found that the protection effects of selenium on ROS mediated-apoptosis by mitochondria dysfunction in cadmium (Cd)-induced LLC-PK1 cells. The present study as a continuation of our earlier one to investigate the protective effects and mechanism of selenium on Cd-induced apoptosis of kidney in vivo. Cadmium exposure increased the production of reactive oxygen species (ROS) and altered the levels of oxidative stress related biomarkers in kidney tissue. A concomitant by the loss of mitochondrial membrane potential, cytochrome c release and regulation of VDAC, Bcl-2 and Bax were observed. Apoptotic nature of cell death is confirmed by activation of caspase-3, which is also supported by histological examination. During the process, selenium played a beneficial role against Cd-induced renal damage. Pretreatment with selenium partially blocked Cd-induced ROS generation, inhibited Cd induced mitochondrial membrane potential collapse, prevented cytochrome c release, inhibited caspase activation and changed the level of VDAC, Bcl-2 and Bax. Combining all, results suggest that selenium has an ability to inhibit mitochondrial apoptotic pathway in oxidative stress mediated kidney dysfunction caused by cadmium.     

Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons

The mechanisms underlying the neurotoxicity of endemic fluorosis still remain unknown. To investigate the expression level of neural cell adhesion molecules (NCAM), oxidative stress, and apoptosis induced by fluoride, the primary rat hippocampal neurons were incubated with 20, 40, and 80 mg/l sodium fluoride for 24 h in vitro. The results showed that the cell survival rate in the 80 mg/l fluoride-treated group was significantly lower than that of the control group. Forty and 80 mg/l of fluoride induced significantly increased lactate dehydrogenase release, intracellular reactive oxygen species, and the percentage of apoptosis. Compared with control group, the malondialdehyde levels were significantly elevated while glutathione levels and glutathione peroxidase activities were decreased in all fluoride-treated groups, accompanied by the markedly reduced superoxide dismutase activity in 80 mg/l fluoride-treated group. With respect to NCAM mRNA expression levels, a significant dose-dependent decrease was observed in 40 and 80 mg/l fluoride-treated groups against the control group. In addition, as compared to the control group, the protein expression levels of NCAM-180 in 40 and 80 mg/l fluoride-treated groups, NCAM-140 in all fluoride-treated groups, and NCAM-120 in the 80 mg/l fluoride-treated group were significantly decreased. Our study herein suggested that fluoride could cause oxidative stress, apoptosis, and decreased mRNA and protein expression levels of NCAM in rat hippocampal neurons, contributing to the neurotoxicity induced by fluoride.     

Obesity-induced testicular oxidative stress,inflammation and apoptosis: Protective and therapeutic effects of orlistat

Obesity has been reported to induce oxidative stress, inflammation and apoptosis in the testis. The objective of this study was to determine the effects of the anti-obesity drug orlistat, on testicular oxidative stress, inflammation and apoptosis in high-fat diet (HFD)-fed rats. Twenty-four adult male Sprague Dawley rats weighing 250−300 g were randomized into four groups (n = 6/group), namely; normal control (NC), high-fat diet (HFD), HFD plus orlistat (10 mg/kg body weight/day administered concurrently for 12 weeks) (HFD + Opr) and HFD plus orlistat (10 mg/kg body weight/day administered 6 weeks after induction of obesity) (HFD + Ot) groups. Antioxidant enzymes activities were significantly decreased, while mRNA levels of pro-apoptotic markers (p53, Bax/BCl-2, caspase-9, caspase-8 and caspase-3) were significantly increased in the testis of HFD group relative to NC group. Furthermore, the mRNA levels of pro-inflammatory markers (nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis factor alpha and interleukin (IL)-1β increased significantly, while anti-inflammatory marker (IL-10) decreased significantly in the testis of the HFD group relative to NC group. However, in both models of orlistat intervention (protective and treatment models) up-regulated antioxidant enzymes, down-regulated inflammation and apoptosis were observed in the testis of HFD-fed rats. Orlistat ameliorated testicular dysfunction by attenuating oxidative stress, inflammation and apoptosis in HFD-fed rats, suggesting its potential protective and therapeutic effects in the testis compromised by obesity.     

DL0410 attenuates oxidative stress and neuroinflammation via BDNF/TrkB/ERK/CREB and Nrf2/HO-1 activation

Oxidative stress and neuroinflammation have been deeply associated with Alzheimer’s disease. DL0410 is a novel acetylcholinesterase inhibitor with potential anti-oxidative effects in AD-related animal models, while the specific mechanism has not been fully clarified. In this study, DL0410 was predicted to be related to the modification of cell apoptosis, oxidation-reduction process, inflammatory response and ERK1/ERK2 cascade by in silico target fishing and GO enrichment analysis. Then the possible protective effects of DL0410 were evaluated by hydrogen peroxide (H₂O₂)-induced oxidative stress model and lipopolysaccharides (LPS)-induced neuroinflammation model H₂O₂ decreased the viability of SH-SY5Y cells, induced malondialdehyde (MDA) accumulation, mitochondrial membrane potential (Δψm) loss and cell apoptosis, which could be reversed by DL0410 dose-dependently, indicating that DL0410 protected SH-SY5Y cells against H₂O₂-mediated oxidative stress. Western blot analysis showed that DL0410 increased the H₂O₂-triggered down-regulated TrkB, ERK and CREB phosphorylation and the expression of BDNF. In addition, TrkB inhibitor ANA-12, ERK inhibitor SCH772984 and CREB inhibitor 666-15 eliminated the inhibition of DL0410 on MDA accumulation and Δψm loss. Furthermore, DL0410 attenuates inflammatory responses and ROS production in LPS-treated BV2 cells, which is responsible for Nrf2 and HO-1 up-regulation. The present study demonstrates that DL0410 is a potential activator of the BDNF/TrkB/ERK/CREB and Nrf2/HO-1 pathway and may be a potential candidate for regulating oxidative stress and neuroinflammatory response in the brain. Together, the results showed that DL0410 is a promising drug candidate for treating AD and possibly other nervous system diseases associated with oxidative stress and neuroinflammation.     

Involvement of oxidative stress in simvastatin-induced apoptosis of murine CT26 colon carcinoma cells

Recent studies have suggested that oxidative stress may play a role in the cytotoxic activity of statins against cancer cells. The objective of this study was to elucidate the role of oxidative stress in the cytotoxicity of simvastatin in murine CT26 colon carcinoma cells and B16BL6 melanoma cells. We found that CT26 cells were more sensitive to simvastatin than B16BL16 cells. Interestingly, exposure to simvastatin causes significant apoptotic cell death and perturbations in parameters indicative of oxidative stress in CT26 cells. Moreover, the increase in oxidative stress parameters and cell death were suppressed by isoprenoids including mevalonolactone, farnesyl pyrophosphate ammonium salt, geranylgeranyl pyrophosphate ammonium salt, and coenzyme Q10, and by antioxidants including N-acetyl cysteine, reduced glutathione, superoxide dismutases (SOD), and catalase (CAT) alone or in combination, but were promoted by an inhibitor of glutathione synthesis, L-buthionine-sulfoximine. The signaling pathway induced by simvastatin breaks down the antioxidant defense system by suppressing the expression of reactive oxygen species scavengers, particularly Mn-SOD, CAT, GPx1, and SESN 3, thereby inducing oxidative stress and apoptotic cell death. Collectively, our results demonstrate that simvastatin induces colon cancer cell death at least in part by increasing intracellular oxidative stress and inducing apoptosis.     

Dioscin alleviates dimethylnitrosamine-induced acute liver injury through regulating apoptosis,oxidative stress and inflammation

In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future.     

褪黑素对心力衰竭大鼠心肌细胞凋亡及氧化应激的影响

目的：观察褪黑素（melatonin,MT）对心力衰竭大鼠的心肌细胞凋亡及氧化应激的影响,并初步探讨其影响机制。方法：将52只雄性SD大鼠随机分为3组。MT组及异丙肾上腺素组（ISO组）各20只,对照组12只。MT组及ISO组给予ISO皮下多点注射ISO建立心衰模型,造模成功后MT组给予MT治疗,ISO组不给予MT治疗;对照组不给予任何处置。8周后,随机从各组选取存活大鼠各10只,进行心脏超声检查,并测定心肌组织SOD、GSH-PX活性及MDA的含量;原位末端标记法（TUNEL）检测心肌细胞凋亡指数。结果：与对照组大鼠比较,ISO组及MT组大鼠LVEDD、LVESD明显扩大（P〈0.05或P〈0.01）,LVEF、FS明显降低（P〈0.01）,心肌细胞凋亡指数升高（P〈0.01）,心肌组织MDA含量升高（P〈0.01）,SOD、GSH-Px活性均有显著性下降（P〈0.05或0.01）;与ISO组大鼠比较,MT组大鼠LVEDD、LVESD明显减小（P〈0.05）,LVEF、FS明显增加（P〈0.05）,心肌细胞凋亡指数减低（P〈0.01）,心肌组织MDA含量下降（P〈0.05）,SOD、GSH-Px活性亦有明显升高（P〈0.05）。结论：MT能够改善心力衰竭大鼠心肌组织的氧化应激反应及心肌细胞凋亡,并具有改善心脏功能的作用。