Decline In GSH Research Articles

Anticancer effect of propranolol on diethylnitrosamine-induced hepatocellular carcinoma rat model.

Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non-selective β-blocker propranolol demonstrated antiproliferative activity in many cancer types. This investigation aimed to evaluate the anticancer effect of propranolol against DEN-induced HCC in rats. Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks. HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α-fetoprotein (AFP), total- and direct-bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF-1α, IL-8, NF-κB, PGE2, TGF-β1, VEGF, and CD8, but significant decline of GSH, and IL-10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG-3 were up-regulated. Moreover, the protein expression of p-PKC was up-regulated, while that of PD-1 and PD-L1 were down-regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group. Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD-1/PD-L1 and LAG-3 signals participated in the anti-tumor effect of propranolol on HCC.

Therapeutic Potential of Morin Hydrate Against Rifampicin Induced Hepato and Renotoxicity in Albino Wistar Rats: Modulation of Organ Function, Oxidative Stress and Inflammatory Response.

Tuberculosis (TB) is a challenging public health issue, particularly in poor and developing countries. Rifampicin (RIF) is one of the most common first-line anti-TB drugs but it is known for its adverse effects on the hepato-renal system. The present study investigated the efficacy of morin hydrate (MH) in protecting hepato-renal damage inflicted by RIF in rats. RIF (50mg/kg), and a combination of RIF (50mg/kg) and MH (50mg/kg) were administered orally for 4weeks in rats. Silymarin (50mg/kg) was used as a positive control. Increased levels of serological parameters such as AST, ALT, ALP, LDH, GGT, bilirubin, triglyceride, total cholesterol, urea, uric acid, creatinine, TNF-α, IFN-γ, IL-6 along with the decreased level of IL-10, total protein and albumin were used as markers of hepatic and renal injury. Oxidative damage in the tissues was measured by the increase in lipid peroxidation and decline in GSH, SOD and catalase activities. Histopathology of liver slices was used to study hepatic architecture. Four-week RIF treatment produced altered serological parameters with an increase in pro-inflammatory cytokines in serum suggesting hepatotoxicity and nephrotoxicity. The antioxidant status of the liver and kidney (increased lipid peroxidation and decline in GSH, SOD and catalase) was compromised. Cellular damage and necrosis were observed in liver slices. MH supplementation with RIF improved hepato-renal functions by restoring the serum and tissue markers towards normal values. Histological observations authenticated the results. MH supplementation also reduced the production of pro-inflammatory cytokines. Thus, the results revealed that MH provides protection against RIF-induced hepato-renal injury.

Cottonseed oil alleviates ischemic stroke injury by inhibiting ferroptosis.

Ferroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to blood-brain barrier (BBB) disruption followed by secondary iron-loaded transferrin (TF) influx. As a novel and independent cell death pathway, ferroptosis was characterized by iron-dependent lipid peroxidation, decline of GSH, GPX4, and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke-induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats. We conducted the subcutaneous injection of 1.3mL/kg CSO every other day for 3 weeks on rats with middle cerebral artery occlusion-reperfusion (MCAO-R) injury. We used Garcia Test, TTC staining, HE, Nissl and NeuN staining, Evans blue test, 68 Ga-citrate PET, Western blot, immunofluorescence staining, Elisa kits, and transmission electron microscopy to detect the infarct volume, neural injuries, and ferroptosis-related indexes. CSO treatment could significantly ameliorate MCAO-R-induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries; protected BBB integrity; reduced the influx of iron ion, TF, and TF receptors; up-regulated anti-ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down-regulating ferroptosis-related protein ACSL4; increased the activity of GSH and SOD; and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment. CSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.

MicroRNAomic profiling of maize root reveals multifaceted mechanisms to cope with Cr (VI) stress

Chromium (Cr) contamination of soil and water poses serious threats to agricultural crop production. MicroRNAs (miRNAs) are conserved, non-coding small RNAs that play pivotal roles in plant growth, development and stress responses through fine-tuning of post-transcriptional gene expression. To better understand the molecular circuit of Cr-responsive miRNAs, two sRNA libraries were prepared from control and Cr (VI) [100 ppm] exposed maize roots. Using deep sequencing, we identified 80 known (1 up and 79 down) and 18 downregulated novel miRNAs from Cr (VI) challenged roots. Gene ontology (GO) analysis reveals that predicted target genes of Cr (VI) responsive miRNAs are potentially involved in diverse cellular and biological processes including plant growth and development (miR159c, miR164d, miR319b-3p and zma_25.145), redox homeostasis (miR528–5p, miR396a-5p and zma_9.132), heavy metal uptake and detoxification (miR159f-5p, 164e-5p, miR408a, miR444f and zma_2.127), signal transduction (miR159f, miR160a-5p, miR393a-5p, miR408–5p and zma_43.158), cell signalling (miR156j, 159c-5p, miR166c-5p and miR398b). Higher accumulation of Cr in maize roots might be due to upregulation of ABC transporter G family member 29 targeted by miR444f. Instead of isolated increase in SOD expression, significant decline in GSH:GSSH ratio and histochemical staining strongly suggest Cr (VI) stress mediated disruption of ROS scavenging machinery thus unbalancing normal cellular homeostasis. Moreover, miR159c-mediated enhanced expression of GAMYB might be a reason for impaired root growth under Cr (VI) stress. In a nutshell, the present microRNAomic study sheds light on the miRNA–target gene regulatory network involved in adaptive responses of maize seedlings to Cr (VI) stress.

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer's Disease Mouse Model.

Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer's disease (AD). To profile the progression of pathology in AD. We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by a pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

PGE2 pathway mediates oxidative stress-induced ferroptosis in renal tubular epithelial cells.

Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H2 O2 , the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin-1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)-1 and COX-2 were up-regulated. Meanwhile, the expression of microsomal prostaglandin E synthase-2 was elevated, whereas the expression of microsomal prostaglandin E synthase-1 and cytosolic prostaglandin E synthase were down-regulated. Furthermore, the expression of 15-hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX-2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E-series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4-methylenedioxyamphetamine, Fe2+ accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress-induced ferroptosis in renal tubular epithelial cells.

Mitochondria-targeted esculetin mitigates atherosclerosis in the setting of aging via the modulation of SIRT1-mediated vascular cell senescence and mitochondrial function in Apoe−/− mice

Background and aimsAge is a dominant and independent risk factor for the development of atherosclerosis, a major cardiovascular disease, and if left untreated leads to myocardial infarction and death. Mitochondria-targeted anti-oxidants are evolving as a new class of compounds that can alter the pathophysiology of age-related diseases, including atherosclerosis, where mitochondrial dysfunction plays a critical role in disease progression. MethodsWe recently synthesized an alkyl TPP + -tagged esculetin (mitochondria-targeted esculetin or Mito-Esc). Apoe−/− mice were chronically (14 months) administered with Mito-Esc to investigate its efficacy in the mitigation of atherosclerosis in the setting of aging. We monitored BP, and performed various biochemical assays, histopathology, immunohistochemistry, inflammatory factors, qPCR, and Western blotting. Simultaneously, human aortic endothelial cells (HAECs) were used as a model system to study the mechanistic aspects. ResultsA chronic low-dose administration of Mito-Esc to Apoe−/− mice greatly prevented alterations in lipid profile, blood pressure, and atherosclerotic plaque formation in the setting of aging. Mito-Esc administration significantly reduced vascular senescence and pro-inflammatory cytokines levels and prevented dysregulation of mitochondrial biogenesis markers in aortic tissue. Further, Mito-Esc treatment prevented replicative and stress-induced premature senescence (SIPS) in HAEC. Importantly, Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. Moreover, Mito-Esc treatment by altering miR-19b and miR-30c via a SIRT1 activation significantly inhibited the increase in PAI-1 levels in HAEC as well as in the serum of Apoe−/− mice. In addition, Mito-Esc treatment improved mitochondrial function in late passage (aged) HAECs by enhancing the oxygen consumption rate (OCR). Furthermore, Mito-Esc administration counteracted the decline in GSH and nitrite levels in Apoe−/− mice and in HAECs. ConclusionsOverall, Mito-Esc alleviates atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function.

Duration of exposure modulates combined effects of arsenic and fluoride on oxidative stress in the liver of rat

Aim: Exposure time dependent combined effects of arsenic (sodium arsenate) and fluoride (sodium fluoride), two major ground water pollutants, have been studied on oxidative stress and antioxidant mechanisms in the liver of female Wistar rats. Methodology: Healthy rats were treated with sodium arsenate (4mg kg-1 b.wt.) and sodium fluoride (4mg kg-1 b.wt.) for three-time intervals, i.e., 30, 60 and 90 days through gavage. Liver tissues of exposed rats were analysed for malonaldehyde (MDA), hydrogen peroxide (H2O2), nitric oxide (NO), reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GPx) and catalase (CAT). Results: Combined exposure of rats to arsenic and fluoride for selected period of exposure viz. 30, 60 and 90 days yielded different results on parameters of oxidative stress in liver. The highest values for malondialdehyde (0.610 nmoles mg-1 protein), hydrogen peroxide (2.31µ moles) and nitric oxide (2.57µ moles) were recorded after 60 days of exposure. Maximum decline in GSH (0.154µ mol g-1 liver) after 30 days of exposure, in GSSG (110µ mol g-1 liver) after 90 days of exposure, GPx (1.03 nmoles NADPH min mg-1 protein) after 30 days of exposure and catalse (74.96 units) after 30 days of exposure were registered. Results showed resistance against oxidative stress after 90 days of combined exposure to arsenic and fluoride. Interpretation: It is hypothesized that internalization of arsenic and fluoride in the hepatic parenchyma leads to the formation of a compound, arsenic trifluoride (AsF3). It was found less toxic than arsenic but more toxic than fluoride. Arsenic-protein interaction is also modulated in the presence of fluoride in the hepatic parenchymal cell.

Siklofosfamid Kaynaklı Toksisite Üzerine Salvia virgata Jacq'ın Hematoprotektif ve Antioksidan Etkilerinin Araştırılması

The present study aims to investigate hematoprotective and antioxidant effects of Salvia virgata (SV) on Cyclophosphamide (CP)-induced toxicity. The rats were divided into 6 groups of 7 members each. These were the Control group, CP Group (150 mg kg-1), 100 and 200 mg kg-1 SV Groups, and CP+100 and CP+200 mg kg-1 SV Groups. All the rats were sacrificed to harvest their blood and bone marrow samples the day after final injections. While some of the blood samples were used for leukocyte and platelet count, the others were used to determine the levels of total antioxidant capacity (TAC), malondialdehyde (MDA), total oxidant status (TOS), glutathione (GSH), and oxidative stress index (OSI). While a decrease was observed in the leukocyte, platelet and bone-marrow nucleated cell counts of the group given CP, apart from a decline in GSH and TAC levels, the MDA and TOC levels of the rats in this group showed an increase. In contrast, CP-induced oxidative stress and myelosuppression reversed in the combined SV Groups (CP+100 and 200 mg kg-1 of SV Groups), although the reversal in the latter group was of more significance. Our experimental results have shown that SV may exert antioxidant and cytoprotective effects upon CP-related peripheral blood and bone marrow toxicities.

Antitumor Activity of Zinc Nanoparticles Synthesized with Berberine on Human Epithelial Colorectal Adenocarcinoma (Caco-2) Cells through Acting on Cox-2/NF-kB and p53 Pathways.

Drawbacks and side effects of currently available therapies to colorectal cancer (CRC) have compelled researchers to search for new therapeutic strategies. This study was designed to investigate the effects of zinc nanoparticles biosynthesized with berberine (ZnNPs-BER) on Caco-2 cells compared to 5-Fluorouracil (5-FU) and explore the possible underlying pathways. Caco-2 and Vero cells were treated with 5-FU, BER, or ZnNPs-BER for 24 h. Cell viability was measured by MTT assay. Oxidative stress and apoptotic markers and cell cycle were determined. Additionally, Cox-2 and NF-kB levels were also measured. The IC50 values of 5-FU, BER, and ZnNPs-BER on Caco-2 cells were found to be 34.65 μM, 19.86 μg/ml and 10.49 μg/ml, respectively by MTT assay. The IC50 value for 5-FU in Vero cells was 21.7 μg/ml, however, BER and BER-ZnNPs treatment showed non-toxic effects on the Vero cells. Further, ZnNPs-BER exerted significant induction of ROS besides exhaustion of the antioxidant capacity of tumor cells indicated by a decline in GSH and elevated NO and MDA contents. Marked increments in levels of Bax and caspase-3 were detected together with declines in Bcl- 2 levels in Caco-2 cells subjected to BER-ZnNPs therapy. On the molecular basis, upregulation in mRNA levels of pro-apoptotic genes (Bax, caspase-3, and tumor suppressor gene p53) along with downregulation in the anti-apoptotic gene (Bcl-2) were observed in ZnNPs-BER treated Caco-2 cells. Furthermore, ZnNPs-BER showed more pronounced effects on apoptosis increased cell percentage in the S and subG1 phases. In addition, green synthesis of ZnNPs with BER showed notable induction of Cox2 and NF-kB in Caco-2 cells. Therefore, the antitumor potential of ZnNPs-BER in colon cancer cells may be endorsed for induction of oxidative stress, inflammation, and apoptotic changes in tumor cells. Our study documents the therapeutic potential of Zn nanoparticles conjugated with BER, which may be a new option for combined chemotherapy.

The Neuroprotective Effect of α-Lipoic Acid and/or Metformin against the Behavioral and Neurochemical Changes Induced by Hypothyroidism in Rat.

The present study evaluates the neuroprotective effect of α-lipoic acid (ALA) and/or metformin (MET) on the behavioral and neurochemical changes induced by hypothyroidism. Rats were divided into control, rat model of hypothyroidism induced by propylthiouracil, and rat model of hypothyroidism treated with ALA, MET, or their combination. Behaviorally, hypothyroid rats revealed impaired memory and reduced motor activity as indicated from the novel object recognition test and open-field test, respectively. Hypothyroidism induced a significant increase in lipid peroxidation (malondialdehyde [MDA]) and a significant decrease in reduced glutathione (GSH) and nitric oxide (NO) in the cortex and hippocampus. These were associated with a significant increase in tumor necrosis factor-α (TNF-α) and a significant decrease in brain-derived neurotrophic factor (BDNF). Hypothyroidism decreased significantly the levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and reduced the activities of acetylcholinesterase (AchE) and Na+, K+-ATPase in the cortex and hippocampus. Treatment of hypothyroid rats with ALA and/or MET showed an improvement in memory function and motor activity. Moreover, ALA and/or MET prevented the increase in MDA and TNF-α, and the decline in GSH, NO, BDNF, 5-HT, NE, and DA. It also restored AchE and Na+, K+-ATPase activities in the studied brain regions. ALA and/or MET has a potential neuroprotective effect against the adverse behavioral and neurochemical changes induced by hypothyroidism in rats.

Evaluation of Fractalkine and Migration Inhibitory in the Patient with Atherosclerosis

Atherosclerosis (AS) a is the major underlying clinical mechanism of CVD. Cardiovascular diseases (CVD) are the leading cause of death globally, many factors such as MIF, CX3CL1, GSH and MDA were isociated with atherosclerosis. Materials and method: Sixty back to back patients with conclusion of atherosclerosis along with 30 sound control subjects were enlisted. Venous blood tests were gathered not long before the coronary atheterization methodology (in examination patients). MIF, CX3CL1, GSH and MDA fixation was resolved utilizing financially accessible colorimetric kits. Results: The most elevated value of MIF, MDA, FKN in patient group while decline of GSH in serum level patients. (0.482, 0.512 (ng\ml), 7.28 (μmole/L), respectively; p<0.05). Conclusion: The new data MIF, CX3CL1, GSH and MDA demonstrate a significant job for these components being developed of atherosclerosis, simultaneously these elements information were reveals insight into their job in tweak the safe reaction and irritation in the aortic divider.

Phloridzin ameliorates type 2 diabetes-induced depression in mice by mitigating oxidative stress and modulating brain-derived neurotrophic factor.

Type 2 diabetes (T2D) is linked with depression due to insulin resistance, oxidative stress and disruption of neurotrophic factors. We evaluated potential benefits of phloridzin in ameliorating depressive symptoms in T2D. Adult male Swiss-albino mice (25-30g) on high-fat-diet (HFD) for 2 weeks were administered with streptozotocin (STZ; 35mg/kg, intraperitoneal) to induce T2D. Seven days after STZ administration, diabetic mice on HFD were distributed into different groups. Animals were subjected daily tooral treatment of saline (0.25ml), fluoxetine (10-20mg/kg) or phloridzin (10-20mg/kg) for a period of4 weeks. One hour after last dose, the immobility time of animals was evaluated in forced swim test (FST) and tail suspension test (TST). To further confirm the mechanisms involved in antidepressant effect of phloridzin, biochemical parameters like brain derived neurotropic factor (BDNF), glutathione (GSH), extracellular signal-regulated kinase (ERK), tyrosine receptor kinaseB (TrkB) and cAMP-response element binding protein (CREB) were estimated in the brain. Animals with T2D showed a significant increase in immobility as compared to control in FST and TST. However, 4 weeks administration of fluoxetine or phloridzin attenuated this effect. A significant decline in GSH, BDNF, TrkB, CREB and ERK levels were noticed in the brain of mice with T2D. These changes were alsoattenuated by administration of phloridzin. Phloridzin may ameliorates T2D-induced depression by mitigating the oxidative stress, and up-regulation of neurotrophins in the brain. Therefore, phloridzin can be used as a therapeutic intervention for the management of depression co-morbid with T2D.

Acute Resistance Exercise Reduces Postprandial Lipemia and Oxidative Stress in Resistance-Trained Men

McAllister, MJ, Steadman, KS, Renteria, LI, Case, MJ, Butawan, MB, Bloomer, RJ, and McCurdy, KW. Acute resistance exercise reduces postprandial lipemia and oxidative stress in resistance-trained men. J Strength Cond Res 36(8): 2139-2146, 2022-Acute ingestion of a high-fat meal (HFM) results in significant increases in postprandial triacylglycerols (TAG) and markers of oxidative stress (OS). Combined aerobic and resistance exercise can attenuate postprandial lipemia; however, it is not clear if acute resistance exercise alone can reduce postprandial OS. The purpose of this study was to determine if acute resistance exercise can attenuate postprandial OS and to compare the effects of moderate versus high-intensity resistance exercise in this regard. Nine ( n = 9) moderately resistance-trained individuals completed 3 testing conditions in a randomized order as follows: (a) rest (no exercise), (b) moderate intensity (3 sets of 10 repetitions at 68% 1 repetition maximum [RM]), and (c) high-intensity resistance exercise (4 sets of 6 repetitions at 85% 1RM). Exercises included barbell back squat, bench press, straight leg deadlift, lat pull-down, upright row, and sit-ups. A HFM was ingested 12 hours after each condition. Blood samples were collected immediately before as well as 2 and 4 hours after ingestion and analyzed for TAG, cholesterol (CHOL), insulin, malondialdehyde (MDA), total nitrate/nitrite (NOx), glutathione (GSH), and advanced oxidation protein products (AOPP). When comparing 4 hour area under curve (AUC) data between conditions, AOPP demonstrated a significantly lower AUC after the moderate-intensity condition compared with resting condition. In addition, resistance exercise resulted in significantly higher plasma NOx concentrations as well as lower TAG and CHOL concentrations after HFM ingestion. Resistance exercise also prevented a decline in GSH that was induced by the HFM. These results demonstrate that acute resistance exercise can attenuate postprandial OS.

Testicular dysfunction induced by aluminum oxide nanoparticle administration in albino rats and the possible protective role of the pumpkin seed oil

BackgroundEven though the widespread of nanoalumina and their benefits in all fields, its potential impacts on male reproductive system have limited information.ObjectiveThe present study was conducted to investigate the testicular dysfunction of nanoalumina and the protective role of pumpkin seed oil (PSO) against potential adverse impacts induced by alumina nanoparticles (Al2O3-NPs) in male rat.MethodologyAl2O3-NPs were administered to the rat orally at a dose of 70 mg/kg body weight once a day for 28 successive days, while pumpkin seed oil was administered to the rat orally at 4 mL/kg b w before administration of Al2O3-NPs, once a day for 28 successive days. After the administration period, sperm concentration, motility, morphology, and DNA damage, as biomarkers of reproductive toxic effects, were evaluated using sperm analysis and comet assays, and histopathological examination of testis was performed. In addition, level of the serum testosterone hormones were estimated, and the levels of oxidative stress biomarkers that take part in the reproductive pathologies such as catalase, glutathione, and malondialdehyde were estimated.ResultsThe present results revealed that Al2O3-NPs induced DNA damage in testicular cells, marked histopathological alterations, and caused a significant elevation in MDA in testicular tissue. There was a significant decline in GSH and CAT activities. Furthermore, there was a significant decline in serum testosterone level in the testicular tissue of Al2O3-NP-administered rats. In contrast, pumpkin seed oil co-administration alleviated DNA damage and improved the histopathological alterations in the testicular tissues. Moreover, pumpkin seed oil co-administration significantly reduced MDA and improved the antioxidant defenses in testicular tissue.ConclusionThe current study concluded that Al2O3-NPs caused testicular dysfunction by generating oxidative injury. Otherwise, PSO co-administration successfully attenuated the adverse impacts of Al2O3-NPs via suppression of oxidative stress and apoptosis as well as enhancement of the antioxidant defense system.

Lacidipine attenuates reserpine-induced depression-like behavior and oxido-nitrosative stress in mice.

Depression is a serious medical illness displaying high lifetime prevalence, early-age onset that adversely affects socio-economic status. The bidirectional association between oxidative stress and calcium-signaling adversely affects the monoaminergic neuron functions that instigate the pathogenesis of depression. The present study investigates the effect of lacidipine (LCD), L-type Ca2+-channel blocker, on reserpine-induced depression in mice. Separate groups of mice (Swiss albino, 18-25g) were administered lacidipine (0.3, 1 and 3mg/kg, i.p.) daily for 14days and reserpine (5mg/kg, i.p.) was injected on day 14. Rectal temperature, catalepsy, and tail-suspension test (TST) were performed 18h and ptosis scores at 60, 120, 240, 360min post-reserpine treatment. Whole-brain TBARS, GSH, nitrite, and superoxide dismutase (SOD) and catalase activities were estimated. Reserpine elevated the catalepsy, ptosis, hypothermia, and immobility period in TST owing to the marked increase in oxidative-nitrosative stress in the brain of mice. LCD attenuated the reserpine triggered the rise in catalepsy, ptosis scores, hypothermia, and immobility period in mice. LCD pretreatment attenuated the increase in TBARS and nitrite levels, and the decline of GSH, SOD, and catalase activities in the brain of reserpine injected mice. Bay-K8644 (0.5mg/kg, i.p.), Ca2+-channel agonist, attenuated these effects of LCD (3mg/kg) in reserpine-treated mice. It can be inferred that lacidipine (Ca2+ channel antagonist) attenuates depression-like symptoms in reserpine-treated mice. Furthermore, the abrogation of antidepressant-like effects of LCD by Bay-K8644 revealed that modulation of Ca2+-channels might present a potential strategy in the management of depression.

Activin Receptor Ligand Blocking and Cancer Have Distinct Effects on Protein and Redox Homeostasis in Skeletal Muscle and Liver.

Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1–2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1–2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p < 0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 (p < 0.05), phosphorylated eIF2α (p < 0.01) and HSP47 (p < 0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p < 0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-eIF2α, HSP47, p-JNK; p < 0.05) and antioxidant GSH (p < 0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p < 0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p < 0.05), Beclin-1 (p < 0.01), and P62 (p < 0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-eIF2α and GRP78, increased (p < 0.05), whereas ATF4 was strongly decreased (p < 0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.

Naringenin mitigates antituberculosis drugs induced hepatic and renal injury in rats

Tuberculosis is one of the deadly diseases, which can be well treated by antituberculosis drugs (ATDs) i.e. isoniazid, rifampicin, pyrazinamide and ethambutol. These drugs also lead to severe hepatic and renal injury. The present study was designed to investigate efficacy of naringenin against ATDs induced hepato-renal injury. Rats were administered with ATDs for 8 weeks (3 day/week) followed by naringenin at three different doses (10, 20 and 40 mg/kg) conjointly for 8 weeks (3 days/week) orally. Silymarin (50 mg/kg) was used as positive control in the study. Hepatic and renal injury was measured by increased level of serological parameters such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, urea, uric acid and creatinine. The toxic effect of ATDs was also indicated by significant increase in lipid peroxidation along with decline in GSH, catalase and superoxide dismutase activity in liver and kidney tissues. Treatment with naringenin encountered ATDs induced injury as evident by significant reversal of biochemical indices towards their respective control in a dose dependent manner. Histopathological observations also supported biochemical findings. Assessment of TNF-α indicated therapeutic efficacy of naringenin at molecular level. Thus, results of this study clearly showed that naringenin possess protective role against ATDs induced hepato-renal injury and to take naringenin supplementation as food may be worthwhile to reduce ATDs induced hepato-renal injury.

Brain Oxidative Stress and Neurodegeneration in the Ketamine Model of Schizophrenia during Antipsychotic Treatment: Effects of N-Acetylcysteine Treatment

We aimed to investigate the effect of N-acetylcysteine (NAC) on brain oxidative stress and on the response to therapy with clozapine or haloperidol in the ketamine model of schizophrenia. Mice received intraperitoneal (i.p.) injections of either saline, ketamine (30 mg/kg), NAC (50 mg/kg), ketamine + NAC, ketamine + clozapine (1.5 mg/kg), ketamine + clozapine + NAC, ketamine + haloperidol (1.5 mg/kg), or ketamine + haloperidol + NAC daily for one week. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, and paraoxonase-1 (PON-1) activity were determined in cerebral cortex and in the rest of the brain tissue. Results indicated that: (i) treatment with only NAC had no significant effects on MDA, GSH, or PON-1 activity, but resulted in a marked decrease in nitric oxide content in both the cortex and the rest of the brain compared to the saline control group; (ii) ketamine caused a significant increase in MDA, while decreasing nitric oxide, and GSH concentrations as well as PON-1activity in both the cerebral cortex and the rest of the brain. These biochemical alterations were alleviated by NAC; (iii) in ketamine-treated mice, either clozapine or haloperidol had no significant effect on MDA or GSH levels. Nitric oxide, however, showed a significant increase by either agent. Meanwhile, PON-1 activity showed a significant increase by clozapine in the cortex but was decreased by haloperidol in both the cortex and the rest of the brain compared with the ketamine only group; (iv) NAC resulted in a significant decrease in MDA in the cortex in ketamine + haloperidol-treated mice, and markedly alleviated the decline in GSH and PON-1 activity in both the cortex and the rest of the brain tissue in ketamine + clozapine- or ketamine + haloperidol-treated groups. NACshowed variable effects on brain nitric oxide in these groups; and (v) ketamine caused neurodegeneration in the cortex and striatum changes in the form of shrunken neurons, pyknotic and apoptotic nuclei, perineuronal vacuolations, and red neurons. These pathological changes were marked after treatment with either clozapine or haloperidol but ameliorated by NAC treatment. These data indicate increased brain oxidative stress in the schizophrenia model induced by ketamine in mice and that treatment with antipsychotics impairs brain antioxidants. The study suggests a potential therapeutic benefit for NACin alleviating brain oxidative stress, lipid peroxidation, and neurodegeneration during antipsychotic drug therapy in schizophrenia.

Role of venlafaxine in prevention of cyclophosphamide-induced lung toxicity and airway hyperactivity in rats

Cyclophosphamide (CP) is a drug used in chemotherapy and management of neoplastic diseases. This study aimed to investigate the prophylactic impacts of venlafaxine against CP-induced lung toxicity in rats. Rats were assigned randomly into 3 groups; control, CP (150 mg/kg) and CP/venlafaxine (50 mg/kg). On the end day, rats were sacrificed then bronchoalveolar fluid (BALF) and lungs were harvested. CP produced significant decrease in animal body weights and significant increase in lung/body weight ratio; levels of LDH, total protein, total and differential cell counts in BALF in comparison with control group. Moreover, significant elevation incontents of MDA, NOx, TNF-α and IL-1β and significant decline in GSH, SOD activities were observed in lung tissues. CP increased the response of tracheal zigzag to ACh. Histopathological results showed that CP increased inflammation and fibrosis in lung tissues. Venlafaxine restored most parameters to the normal levels. This protective effect of venlafaxine could be linked to its ability to reduce oxidative stress and inflammation.