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Oxidative Medicine and Cellular Longevity publishes research involving cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, metabolism etc.
Chief Editor, Dr Vasquez-Vivar has experience in free radical and redox biology research including the discovery of the role of tetrahydrobiopterin in the regulation of superoxide generation by endothelial and neuronal nitric oxide synthase.
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Ameliorative Effect of Sinapic Acid on Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in Kunming (KM) Mice
Ulcerative colitis is a chronic gastrointestinal disease characterized by intestinal inflammation and serious mucosal damage. As a naturally hydroxycinnamic acid, sinapic acid (SA) has antioxidant, anticancer, and neuroprotective activities. We investigated the anticolitic effect and potential mechanisms of SA in DSS-induced colitis in Kunming (KM) mice. SA treatment significantly reduced body weight loss, colon shortening, and intestinal wall thickening in colitis mice. SA treatment also significantly reduced the histological infiltration of inflammatory cells and decreased myeloperoxidase (MPO) activity in the colons of colitis mice. The administration of SA attenuated oxidative damage by enhancing the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase and reduced the serum and colonic mRNA levels of proinflammatory cytokines in colitis mice. We used qRT-PCR and Western blotting assays and demonstrated that SA reduced the activation of the NLRP3 inflammasome and attenuated intestinal permeability by enhancing the expression of ZO-1, occludin, and claudin-1 in colitis mice. Here, we conclude that SA exhibits great anticolitic activity against DSS-induced colitis by enhancing the activity of antioxidant enzymes, reducing intestinal inflammation, and maintaining the intestinal barrier. Finally, we suggest that SA may be a safe adjuvant for the prevention of clinical colitis.
Overexpression of miR-506-3p Aggravates DBP-Induced Testicular Oxidative Stress in Rats by Downregulating ANXA5 via Nrf2/HO-1 Signaling Pathway
Background. Di-N-butylphthalate (DBP) is a kind of unique endocrine toxicity linked to hormonal disruptions that affects the male reproductive system and has given rise to more and more attention. However, the mechanism of DBP-induced testicular injury remains unclear. Here, the objective of this study was to investigate the potential molecular mechanism of miR-506-3p in DBP-induced rat testicular oxidative stress injury via ANXA5 (Annexin A5)/Nrf2/HO-1 signaling pathway. Methods. In vivo, a total of 40 adolescent male rats were treated from 2 weeks with 800 mg/kg/day of DBP in 1 mL/kg corn oil administered daily by oral gavage. Among them, some rats were also injected subcutaneously with 2 nmol agomir-506-3p and/or 10 nmol recombinant rat ANXA5. The pathomorphological changes of testicular tissue were assessed by histological examination, and the antioxidant factors were evaluated. Subsequently, ANXA5, Nrf2, and its dependent antioxidant enzymes, such as HO-1, NQO1, and GST, were detected by Western blotting or immunohistochemical staining. In vitro, TM3 cells (Leydig cells) were used to detect the cell activity by CCK-8 and the transfection in the DBP-treated group. Results. Differentially expressed miRNAs between the DBP-treated and normal rats were analyzed, and qRT-PCR showed miR-506-3p was highly expressed in testicular tissues of the DBP-treated rats. DBP-treated rats presented severe inflammatory infiltration, increased abnormal germ cells, and missed cell layers frequently existed in seminiferous tubules, resulted in oxidative stress and decreased testicular function. Meanwhile, upregulation of miR-506-3p aggravated the above changes. In addition, miR-506-3p directly bound to ANXA5, and overexpression of miR-506-3p could reduce the ANXA5 expression and also decrease the protein levels of Nrf2/HO-1 signaling pathway. Additionally, we found that recombinant rat ANXA5 reversed the DBP-treated testicular oxidative stress promoting injury of miR-506-3p in rats. In vivo results were reproduced in in vitro experiments. Conclusions. This study provided evidence that miR-506-3p could aggravate the DBP-treated testicular oxidative stress injury in vivo and in vitro by inhibiting ANXA5 expression and downregulating Nrf2/HO-1 signaling pathway, which might provide novel understanding in DBP-induced testicular injury therapy.
TBHQ-Overview of Multiple Mechanisms against Oxidative Stress for Attenuating Methamphetamine-Induced Neurotoxicity
Methamphetamine is a derivative of amphetamines, a highly addictive central stimulant with multiple systemic toxicity including the brain, heart, liver, lung, and spleen. It has adverse effects such as apoptosis and breakdown of the blood-brain barrier. Methamphetamine is a fatal and toxic chemical substance, and its lethal mechanism has been widely studied in recent years. The possible mechanism is that methamphetamine can cause cardiotoxicity and neurotoxicity mainly by inducing oxidative stress so as to generate heat, eliminate people’s hunger and thirst, and maintain a state of excitement so that people can continue to exercise. According to many research, there is no doubt that methamphetamine triggers neurotoxicity by inducing reactive oxygen species (ROS) production and redox imbalance. This review summarized the mechanisms of methamphetamine-induced neurotoxicity including apoptosis and blood-brain barrier breakdown through oxidative stress and analyzed several possible antioxidative mechanisms of tert-butylhydroquinone (TBHQ) which is a kind of food additive with antioxidative effects. As a nuclear factor E2-related factor 2 (Nrf2) agonist, TBHQ may inhibit neurotoxicity caused by oxidative stress through the following three mechanisms: the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, the astrocytes activation, and the glutathione pathway. The mechanism about methamphetamine’s toxic effects and its antioxidative therapeutic drugs would become a research hotspot in this field and has very important research significance.
Honokiol Alleviates Methionine-Choline Deficient Diet-Induced Hepatic Steatosis and Oxidative Stress in C57BL/6 Mice by Regulating CFLAR-JNK Pathway
Background. Honokiol (HNK) has been reported to possess various beneficial effects in the context of metabolic disorders, including fatty liver, insulin resistance, and oxidative stress which are closely related to nonalcoholic steatohepatitis (NASH), however with no particular reference to CFLAR or JNK. Methods. C57BL/6 mice were fed methionine-choline-deficient (MCD) diet and administered simultaneously with HNK (10 and 20 mg/kg once a day, ig) for 6 weeks, and NCTC1469 cells were pretreated, respectively, by oleic acid (OA, 0.5 mmol/L) plus palmitic acid (PA, 0.25 mmol/L) for 24 h, and adenovirus-down Cflar for 24 h, then exposed to HNK (10 and 20 μmol/L) for 24 h. Commercial kits, H&E, MT, ORO staining, RT-qPCR, and Western blotting were used to detect the biomarkers, hepatic histological changes, and the expression of key genes involved in NASH. Results. The in vivo results showed that HNK suppressed the phosphorylation of JNK (pJNK) by activating CFLAR; enhanced the mRNA expression of lipid metabolism-related genes Acox, Cpt1α, Fabp5, Gpat, Mttp, Pparα, and Scd-1; and decreased the levels of hepatic TG, TC, and MDA, as well as the levels of serum ALT and AST. Additionally, HNK enhanced the protein expression of oxidative stress-related key regulatory gene NRF2 and the activities of antioxidases HO-1, CAT, and GSH-Px and decreased the protein levels of prooxidases CYP4A and CYP2E1. The in vivo effects of HNK on the expression of CLFAR, pJNK, and NRF2 were proved by the in vitro experiments. Moreover, HNK promoted the phosphorylation of IRS1 (pIRS1) in both tested cells and increased the uptake of fluorescent glucose 2-NBDG in OA- and PA-pretreated cells. Conclusions. HNK ameliorated NASH mainly by activating the CFLAR-JNK pathway, which not only alleviated fat deposition by promoting the efflux and β-oxidation of fatty acids in the liver but also attenuated hepatic oxidative damage and insulin resistance by upregulating the expression of NRF2 and pIRS1.
Mitochondrial Dysfunction in Intervertebral Disc Degeneration: From Pathogenesis to Therapeutic Target
Mitochondria are cytosolic organelles essential for cellular function and survival. The function of mitochondria is maintained by mitochondrial quality control systems including mitochondrial fission and fusion to adapt the altered environment and mitophagy for removal of damaged mitochondria. Mitochondrial dysfunction is closely involved in aging-related diseases. Intervertebral disc (IVD) degeneration, an aging-associated process, is the major contributor to low back pain. Growing evidence has suggested that the mitochondrial function in IVD cells is severely compromised during the degenerative process of IVD, and dysfunctional mitochondria along with impaired mitochondrial dynamics and mitophagy cause a series of cascade reactions that have been implicated in increased oxidative stress, senescence, matrix catabolism, and apoptosis of IVD cells, thereby contributing to the degeneration of IVD. Accordingly, therapies that target mitochondrial dysfunction and related mechanisms, such as ROS generation, mitophagy, and specific molecules and signaling, hold great promise. The present review summarizes the current state of the role of mitochondrial dysfunction in the pathophysiology of IVD degeneration and potential therapeutic strategies that could be developed.
Metabolomic Analysis of the Ameliorative Effect of Enhanced Proline Metabolism on Hypoxia-Induced Injury in Cardiomyocytes
Background. Coronary heart disease is currently the leading cause of death in humans. Its poor prognosis and high mortality are associated with myocardial ischemia, which leads to metabolic disorder-related cardiomyocyte apoptosis and reactive oxygen species (ROS) production. Previous cardiovascular metabolomics studies in humans and mice have shown that proline metabolism is severely altered after cardiomyocyte hypoxia. Proline dehydrogenase (PRODH) is located on the inner mitochondrial membrane and is an enzyme that catalyzes the first step of proline catabolism, which plays an important role in improving the cellular redox state. In vitro oxygen-glucose deprivation can mimic in vivo myocardial ischemic injury. This study is aimed at investigating whether enhancing proline metabolism by overexpressing PRODH can ameliorate hypoxia-induced injury in cardiomyocytes and to reveal the related altered metabolites and mechanistic pathway via untargeted metabolomics analysis. Methods and Results. First, through public database analysis and RT-qPCR and western blot analyses in a cardiomyocyte hypoxia model, we found that the expression of the proline-degrading enzyme PRODH was downregulated after myocardial infarction and hypoxia exposure. Second, LDH assays, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), DHE staining, flow cytometric apoptosis analysis with DCFH and Annexin V-FITC/PI, and western blot analysis were used to assess the injury level in cardiomyocytes. Enhanced proline metabolism induced by PRODH overexpression reduced the levels of reactive oxidative stress and apoptosis, whereas PRODH knockdown had the opposite effects. Third, untargeted metabolomics analysis revealed that the protective effect was associated with significant changes in metabolism linked to sphingolipid signaling pathways, unsaturated fatty acid biosynthesis, phosphocreatine, glutathione disulfide, aminoacyl-tRNA biosynthesis, and ABC transporters. Conclusions. Our study demonstrated a protective effect of enhanced proline metabolism in cardiomyocytes under hypoxia, providing a novel strategy for exploring new treatments for coronary heart disease.