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Near-infrared-II (NIR-II) photothermal therapy is emerging as a cutting-edge modality for tumor ablation due to its good biosafety, high penetration ability and spatiotemporal controllability. Despite efforts, establishing a link between cellular metabolic regulation and photothermal performance is still promising in synergistic cancer therapy. Herein, we developed a core-shell semiconducting polymer@metal-phenolic network (SP@GFP) nanomotor by assembling diphenol-terminated cisplatin prodrug ligand (cPt-DA) and iron (III) (Fe 3+ ) through metal coordination on SP particles in the presence of GOx and DSPE-PEG-cRGD, for NIR-II-propelled self-propulsion and synergistic cancer therapy. Remotely driving the SP@GFP nanomotor with an NIR-II laser through a thermophoresis mechanism would allow for in-depth penetration and accumulation. The synergistic photothermal effect and continuous Fe 2+ -mediated ROS generation of SP@GFP nanomotor could activate photothermal, chemotherapeutic effects and ferroptosis pathway for cancer cells through reshaping cellular metabolic pathways (HSP and GPX4). By combining the concepts of chemotherapeutic prodrugs, catalytic ROS generation, photothermal response and cellular metabolic regulation, the NIR-II laser-controlled core-shell SP@GFP nanomotor displayed improved outcomes for enhanced cancer therapy through synergistic oxidative stress-photothermo modulation. STATEMENT OF SIGNIFICANCE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background/objective: The effects of fathers' high-fat diet (HFD) on the reproductive health of their male offspring (HFD- F1) remain to be elucidated. Parental obesity is known to have a negative effect on offspring fertility, but there are few relevant studies on the effects of HFD-F1 on reproductive function., Methods: We first succeeded in establishing the HFD model, which provides a scientific basis in the analysis of HFD-F1 reproductive health. Next, we assessed biometric indices, intratesticular cellular status, seminiferous tubules and testicular transcriptomic homeostasis in HFD-F1. Finally, we examined epididymal (sperm-containing) apoptosis, as well as antioxidant properties, motility, plasma membrane oxidation, DNA damage, and sperm-egg binding in the epididymal sperm., Results: Our initial results showed that HFD-F1 mice had characteristics similar to individuals with obesity, including higher body weight and altered organ size. Despite no major changes in the types of testicular cells, we found decreased activity of important genes and noticed the presence of abnormally shaped sperm at seminiferous tubule lumen. Further analysis of HFD-F1 testes suggests that these changes might be caused by increased vulnerability to oxidative stress. Finally, we measured several sperm parameters, these results presented HFD-F1 offspring exhibited a deficiency in antioxidant properties, resulting in damaged sperm mitochondrial membrane potential, insufficient ATP content, increased DNA fragmentation, heightened plasma membrane oxidation, apoptosis-prone and decreased capacity for sperm-oocyte binding during fertilization., Conclusion: HFD- F1 subfertility arises from the susceptibility of the transcriptional network to oxidative stress, resulting in reduced antioxidant properties, motility, sperm-egg binding, and elevated DNA damage. Schematic representation of the HFD-F1 oxidative stress susceptibility to subfertility. Notably, excessive accumulation of ROS surpasses the physiological threshold, thereby damaging PUFAs within the sperm plasma membrane. This oxidative assault affects crucial components such as mitochondria and DNA. Consequently, the sperm's antioxidant defense mechanisms become compromised, leading to a decline in vitality, motility, and fertility., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Ethnopharmacological Relevance: Peucedanum praeruptorum Dunn (PPD) was used to treat gastrointestinal disease in China before the Tang Dynasty, and it was considered a "Top-grade" herb in Shennong Bencaojing, known for its ability to relieve the stomach Qi and indigestion., Aim of the Study: Alcohol consumption can induce severe gastric mucosal injury that lacks effective and safe interventions. We aimed to investigate the gastroprotective effects of Peucedanum praeruptorum Dunn leaf (PPL) after bolting in alcohol-induced gastric damage in mice., Materials and Methods: Mice were orally administered PPL aqueous extract at doses of 2.5, 5, and 10 g/kg for 5 consecutive days prior to the induction of gastric damage model with ethanol. Gastric tissue was stained by hematoxylin and eosin (H&E), and the levels of pro-inflammatory cytokines and oxidative stress indicators were determined using ELISA and RT-qPCR. RNA-seq was used to detect differentially expressed genes (DEGs) in the gastric tissue, while Western blotting was employed to measure the expressions of IL-17, TNF-a, and AKT pathways., Results: Treatment with PPL alleviated alcohol-induced gastric damage in mice, whereas dried root (PPD) and stem (PPS) of Peucedanum praeruptorum Dunn had no gastroprotective function. The content of peucedanocoumarin I was higher in the dried PPL compared to PPD and PPS, with an increase in peucedanocoumarin I content in PPL after boiling. Additionally, PPL administration (5, 10 g/kg) decreased pro-inflammatory factors, such as interleukin-6 (IL-6), IL-8, IL-4, IL-1β, IL-18, and tumor necrosis factor (TNF-a) in alcohol-induced gastric injury mice (p < 0.05), and improved oxidative stress markers, including superoxide dismutase enzymes (SOD), catalase (CAT), and malondialdehyde (MDA) (p < 0.05). RNA-seq data revealed that PPL treatment inhibited alcohol-induced inflammation-related signals, including IL-17 and TNF pathways, and restored alcohol-inhibited gastric digestive and metabolic functions, such as xenobiotics metabolism of cytochrome P450, and protein digestion and absorption pathways. Notably, treatment with PPL downregulated the expressions of IL-17 A, TNF-a, monocyte chemoattractant protein-1 (MCP-1), and AKT-phosphorylation induced by ethanol exposure (p < 0.05). Thus, the aqueous extract of PPL provided protection against alcohol-induced gastric injury by mitigating inflammation and oxidative stress in mice, suggesting a potential novel therapeutic approach for alcohol-induced gastric damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recently, the incidence of NAFLD has exploded globally, but there are currently no officially approved medications for treating the condition. The regulation of NAFLD through plant-derived active substances has become a new area of interest. Quinoa ( Chenopodium quinoa Willd.) has been discovered to contain a large quantity of bioactive compounds. In this study, we established a free fatty acid (FFA)-induced steatosis model and explored the effects of quinoa polyphenol extract (QPE) on the major hallmarks of NAFLD. The results indicated that QPE significantly reduced intracellular triglyceride (TG) and total cholesterol (TC) levels. Additionally, QPE remarkably elevated the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) and lowered levels of malondialdehyde (MDA). Further examination revealed that QPE attenuated intracellular inflammation, which was verified by the reduced levels of pro-inflammatory cytokines. Mechanistically, QPE inhibited fatty acid biosynthesis mainly by targeting de novo lipogenesis (DNL) via the AMPK/SREBP-1c signaling pathway. Moreover, network pharmacology was used to analyze key targets for NAFLD mitigation by ferulic acid (FA), a major component of QPE. Taken together, this study suggests that QPE could ameliorate NAFLD by modulating hepatic lipid metabolism and alleviating oxidative stress and inflammation.

Hypertrophic scar (HS) is characterized by excessive collagen deposition and myofibroblasts activation. Endothelial-to-mesenchymal transition (EndoMT) and oxidative stress were pivotal in skin fibrosis process. Exosomes derived from adipose tissue-derived stem cells (ADSC-Exo) have the potential to attenuate EndoMT and inhibit fibrosis. The study revealed reactive oxygen species (ROS) levels were increased during EndoMT occurrence of dermal vasculature of HS. The morphology of endothelial cells exposure to H 2 O 2, serving as an in vitro model of oxidative stress damage, transitioned from a cobblestone-like appearance to a spindle-like shape. Additionally, the levels of endothelial markers decreased in H 2 O 2 -treated endothelial cell, while the expression of fibrotic markers increased. Furthermore, H 2 O 2 facilitated the accumulation of ROS, inhibited cell proliferation, retarded its migration and suppressed tube formation in endothelial cell. However, ADSC-Exo counteracted the biological effects induced by H 2 O 2 . Subsequently, miRNAs sequencing analysis revealed the significance of mir-486-3p in endothelial cell exposed to H 2 O 2 and ADSC-Exo. Mir-486-3p overexpression enhanced the acceleration of EndoMT, its inhibitors represented the attenuation of EndoMT. Meanwhile, the target regulatory relationship was observed between mir-486-3p and Sirt6, whereby Sirt6 exerted its anti-EndoMT effect through Smad2/3 signaling pathway. Besides, our research had successfully demonstrated the impact of ADSC-Exo and mir-486-3p on animal models. These findings of our study collectively elucidated that ADSC-Exo effectively alleviated H 2 O 2 -induced ROS and EndoMT by inhibiting the mir-486-3p/Sirt6/Smad axis., (© 2024. The Author(s).)

Background: Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure., Materials and Methods: AC16 cells were treated with 2 µmol/L of doxorubicin (DOX) for 12, 24, and 48 h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry., Results: Increased DUOX1 expression levels were observed after DOX treatment for 24 h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1β, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1β, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors., Conclusion: These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure., (© 2024. The Author(s).)

Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 μM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.

Hypertension caused by a high-salt (HS) diet is one of the major causes of cardiovascular diseases. Underlining pathology includes oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN). This study investigates genistein's (Gen) role in HS-induced hypertension and the underlying molecular mechanism. We placed male Wistar rats on HS (8% NaCl) or normal salt diet (0.3% NaCl). Then, we injected bilateral PVN in rats with Gen, vehicle, or nicotinamide (NAM) for 4 weeks. Tail cuff was used weekly to assess the systolic pressure, diastolic pressure, and mean arterial pressure (MAP). Cardiac hypertrophy was analyzed by heart weight/body weight ratio and wheat germ agglutinin staining. ELISA kits, Western blot, or dihydroethidium staining determined the levels of inflammatory cytokines and oxidative stress markers. Western blot measured protein levels of Sirt1, Ac-FOXO1, Nrf2, NQO-1, HO-1, and gp91 phox . Our result showed that PVN infusion of Gen significantly reduced the increase of systolic pressure, diastolic pressure, and MAP induced by an HS diet. Additionally, there was a decrease in cardiac hypertrophy and the levels of inflammatory cytokines in PVN and plasma. Meanwhile, PVN infusion of Gen notably inhibited the levels of oxidized glutathione and superoxide dismutase and improved the glutathione level and total antioxidant capacities and superoxide dismutase activities. It also decreased the level of reactive oxygen species and gp91 phox expression in PVN. Furthermore, Gen infusion markedly increases the Sirt1, Nrf2, HO-1, and NQO-1 levels and decreases the Ac-FOXO1 level. However, PVN infusion of NAM could significantly block these changes induced by Gen in HS diet rats. Our results demonstrated that PVN infusion of Gen could inhibit the progression of hypertension induced by an HS diet by activating the Sirt1/Nrf2 pathway., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with β-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effects of doxofylline on inflammatory responses and oxidative stress during mechanical ventilation in rats with chronic obstructive pulmonary disease (COPD)., Methods: Eight-week-old male Sprague Dawley rats were selected, and the COPD rat model was constructed. The rats were randomly divided into a model group (group M), a model + normal saline group (group N), a doxofylline group (group D), and a control group fed with conventional chow and given normal oxygen supply (group C) (n = 12 in each group). Tracheal intubation and mechanical ventilation were conducted in the rats in each group after anesthesia. A real-time intravenous infusion with 50 mg/kg of doxofylline was conducted in group D, and there was no drug intervention in groups C, N and M. Pathological manifestations of the pulmonary tissues were observed and compared among the groups. And some indicators were evaluated., Results: (1) The pulmonary tissues of the rats in groups M, N, and D exhibited typical pathological histological changes of COPD. (2) Groups M, N, and D showed increased Ppeak, PaCO 2 , total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue and BALF, and decreased PaO 2 and IL-10 and SOD levels, compared with group C. (3). Group D showed decreased Ppeak, PaCO 2 , total white blood cell count in BALF, and IL-8, TNF-α, and MDA levels in the pulmonary tissue, and increased PaO 2 and IL-10 and SOD levels, compared with group N or M., Conclusion: Doxofylline was shown to improve ventilation and air exchange during mechanical ventilation in rats with COPD, reduce the inflammatory response and oxidative stress, and mitigate the degree of pulmonary tissue injury., (© 2022. The Author(s).)

Allergen-specific immunotherapy (SIT) is the mainstay in the treatment of allergic diseases; its therapeutic efficacy is to be improved. Bacterial flagellin (FGN) has immune regulatory functions. This study investigates the role of FGN in promoting immunotherapy efficacy through modulating oxidative stress in regulatory B cells (Bregs). Blood samples were collected from patients with food allergy (FA) and healthy control (HC) subjects. CD19 + CD5 + Bregs were purified from blood samples by flow cytometry cell sorting. A murine FA model was developed with ovalbumin as the specific antigen. The results showed that peripheral Bregs from FA patients showed lower TLR5-related signals and higher apoptotic activities. The peripheral Breg frequency was negatively correlated with serum FGN levels in FA patients. Exposure to a specific antigen in culture induced antigen-specific Breg apoptosis that was counteracted by the presence of FGN. FGN diminished specific antigen-induced oxidative stress in Bregs. The STAT3/MAPKp38/NF- κ B signal pathway was involved in the FGN/TLR5 signal-promoted superoxide dismutase expression in Bregs. Administration of FGN promotes the SIT efficacy in suppressing experimental FA. In summary, administration of FGN promotes SIT efficacy on FA, suggesting that the combination of FGN and SIT can be a novel therapy that has the translational potential to be employed in the treatment of allergic diseases., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Hao-Tao Zeng et al.)

Background: miR-205 is important for oxidative stress, mitochondrial dysfunction, and apoptosis. The roles of miR-205 in cardiac ischemia/reperfusion (I/R) injury remain unknown. The aim of this research is to reveal whether miR-205 could regulate cardiac I/R injury by focusing upon the oxidative stress, mitochondrial function, and apoptosis., Methods: Levels of miR-205 and Rnd3 were examined in the hearts with I/R injury. Myocardial infarct size, cardiac function, oxidative stress, mitochondria function, and cardiomyocyte apoptosis were detected in mice with myocardial ischemia/reperfusion (MI/R) injury. The primary neonatal cardiomyocytes underwent hypoxia/reoxygenation (H/R) to simulate MI/R injury., Results: miR-205 levels were significantly elevated in cardiac tissues from I/R in comparison with those from Sham. In comparison with controls, levels of Rnd3 were significantly decreased in the hearts from mice with MI/R injury. Furthermore, inhibiting miR-205 alleviated MI/R-induced apoptosis, reduced infarct size, prevented oxidative stress increase and mitochondrial fragmentation, and improved mitochondrial functional capacity and cardiac function. Consistently, overexpression of miR-205 increased infarct size and promoted apoptosis, oxidative stress, and mitochondrial dysfunction in mice with MI/R injury. In cultured mouse neonatal cardiomyocytes, downregulation of miR-205 reduced oxidative stress in H/R-treated cardiomyocytes. Finally, inhibiting Rnd3 ablated the cardioprotective effects of miR-205 inhibitor in MI/R injury., Conclusions: We conclude that inhibiting miR-205 reduces infarct size, improves cardiac function, and suppresses oxidative stress, mitochondrial dysfunction, and apoptosis by promoting Rnd3 in MI/R injury. miR-205 inhibitor-induced Rnd3 activation is a valid target to treat MI/R injury., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Yuerong Xu et al.)

Objective: To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo., Methods: Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes., Results: Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups., Interpretation: NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Hypertension, as one of the major risk factors for cardiovascular disease, significantly affects human health. Prostaglandin E 2 (PGE 2 ) and the E3-class prostanoid (EP3) receptor have previously been demonstrated to modulate blood pressure and hemodynamics in various animal models of hypertension. The PGE2-evoked pressor and biochemical responses can be blocked with the EP3 receptor antagonist, L-798106 (N-[(5-bromo-2methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl) phenyl]-2-propenamide). In the hypothalamic paraventricular nucleus (PVN), sympathetic excitation can be introduced by PGE2, which can activate EP3 receptors located in the PVN. In such a case, the central knockdown of EP3 receptor can be considered as a potential therapeutic modality for hypertension management. The present study examined the efficacy of the PVN infusion of L-798106, by performing experiments on spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The rats were administered with chronic bilateral PVN infusion of L-798106 (10 μg/day) or the vehicle for 28 days. The results indicated that the SHRs had a higher mean arterial pressure (MAP), an increased Fra-like (Fra-LI) activity in the PVN, as well as a higher expression of gp 91phox , mitogen-activated protein kinase (MAPK), and proinflammatory cytokines in the PVN compared with the WKYs. Additionally, the expression of Cu/Zn-SOD in the PVN of the SHRs was reduced compared with the WKYs. The bilateral PVN infusion of L-798106 significantly reduced MAP, as well as plasma norepinephrine (NE) levels in the SHRs. It also inhibited Fra-LI activity and reduced the expression of gp 91phox , proinflammatory cytokines, and MAPK, whereas it increased the expression of Cu/Zn-SOD in the PVN of SHRs. In addition, L-798106 restored the balance of the neurotransmitters in the PVN. On the whole, the findings of the present study demonstrate that the PVN blockade of EP3 receptor can ameliorate hypertension and cardiac hypertrophy partially by attenuating ROS and proinflammatory cytokines, and modulating neurotransmitters in the PVN.

The toxicity of Cr(VI) was widely investigated, but the defense mechanism against Cr(III) in bacteria are seldom reported. Here, we found that Cr(III) inhibited bacterial growth and induced reactive oxygen species (ROS). After exposure to Cr(III), loss of sodA not only led to the excessive generation of ROS, but also enhanced the level of lipid peroxidation and reduced the GSH level, indicating that the deficiency of Mn-SOD decreased the bacterial resistance ability against Cr(III). The adverse effects of oxidative stress caused by Cr(III) could be recovered by the rescue of Mn-SOD in the sodA-deficient strain. Besides the oxidative stress, Cr(III) could cause the bacterial morphology variation, which was distinct between the wild-type and the sodA-deficient strains due to the differential expressions of Z-ring division genes. Moreover, Mn-SOD might prevent Cr(III) from oxidation on the bacterial surface by combining with Cr(III). Taken together, our results indicated that the Mn-SOD played a vital role in regulating the stress resistance, expression of cell division-related genes, bacterial morphology, and chemistry valence state of Cr. Our findings firstly provided a more in-depth understanding of Cr(III) toxicity and bacterial defense mechanism against Cr(III)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Hepatic ischemia-reperfusion injury (IRI) is the main leading cause of morbidity and mortality of patients after liver surgery and transplantation. Fisetin, a kind of flavonoid, has been reported to protect against myocardial and cerebral IRI. However, the effects of fisetin on liver IRI were poorly investigated., Methods: C57BL/6 mice were used to establish the liver IRI model in vivo. Intraperitoneal injection of fisetin was performed one hour before IR treatment (1 h ischemia and 6h reperfusion). In vitro experimental study was conducted using AML-12 hepatocytes with 1 h hypoxia and 12 h reoxygenation (HR) treatment. Tissue damage was evaluated through serum AST and ALT levels and hematoxylin-eosin (HE) staining. Cell apoptosis was assessed by TUNEL staining and protein levels of Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP. Oxidative stress was evaluated by ROS and MDA levels and the activity of SOD and GSH-Px. Immunohistochemistry and immunofluorescence assay were performed to observe the translocation of Nrf2 from the cytoplasm into the nucleus., Results: The histopathological assessment showed that fisetin attenuated IR-induced liver damage obviously. Besides, fisetin served a protective role in IR liver to alleviate cell apoptosis and oxidative stress in vivo and in vitro. Introduction of high concentration of fisetin promoted the translocation of Nrf2 from the cytoplasm into the nucleus, increasing protein expression of its downstream elements, at least HO-1 in IR liver tissues and hepatocytes after HR. Inhibition of Nrf2 could reverse the effects of fisetin on cell viability, cell apoptosis, and also oxidative stress of HR hepatocytes, suggesting that Nrf2 signaling was necessary in fisetin-mediated regulations of liver IRI., Conclusion: Fisetin alleviates liver damage, cell apoptosis, and oxidative stress induced by liver IRI, at least through Nrf2/HO-1 signaling pathway, suggesting that fisetin could be considered as a targeted drug for liver IRI treatment., (Copyright © 2021 IMSS. Published by Elsevier Inc. All rights reserved.)

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus. High glucose has resulted in oxidative stress and following renal fibrosis as the crucial nodes of this disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating transcription of many antioxidant genes and suppressing synthesis of extracellular matrix. To discover Nrf2 activators targeting DN, we have evaluated polypodiside using cell-based assays. The results showed polypodiside inhibited the high glucose-induced self-limited proliferation of glomerular meangial cells. Activation of Nrf2 and enhanced transcription to antioxidant response elements were observed in the presence of polypodiside. Oxidative stress and accumulation of extracellular matrix induced by high glucose in glomerular meangial cells have been ameliorated by polypodiside. Further investigations revealed the effects of polypodiside on glomerular meangial cells were associated with activation of Nrf2. Co-immunoprecipitation of Nrf2 disclosed polypodiside disrupted the Kelch-like ECH-associated protein-1 (Keap1)-Nrf2 interaction. Molecular docking elucidated polypodiside could enter the Nrf2 binding cavity of Keap1 via interacting with the residues encompassing that cavity. These findings indicate polypodiside is a Keap1-dependent Nrf2 activator affording the catabatic effects against oxidative stress and accumulation of extracellular matrix in glomerular meangial cells under high glucose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The aim of this study was to explore the impact of prenatal Al and Mg on placental oxidative stress and inflammatory mRNA expression. A total of 2519 pregnant women from the China Ma'anshan birth cohort participated in this study. Al and Mg levels were measured by inductively coupled plasma mass spectrometry (ICP-MS). Placental stress and inflammatory mRNA expression were assessed by RT-PCR. The median Al levels in the first and second trimesters of pregnancy and in cord blood were higher than the corresponding median Mg levels. Predictors of lower Al and Mg levels included Han ethnicity and high education according to a mixed linear model. Multiple linear regression analysis revealed that Al and Al/Mg levels had a positive association with inflammatory mRNA expression and placental oxidative stress in the second trimester of pregnancy. A negative association existed between Al and Al/Mg levels and inflammatory mRNA expression and placenta oxidative stress in the cord blood, with the exception of IL-1β expression. In conclusion, prenatal Al and Mg status was associated with placental oxidative stress and inflammatory mRNA expression. More preclinical studies are needed to confirm the relevant mechanism.

Obesity has been recognized as a major risk factor for chronic kidney disease, but the underlying mechanism remains elusive. Here, we investigated the mechanism whereby long-term high-fat diet (HFD) feeding induces renal injury in mice. The C57BL/6 mice fed HFD for 16 weeks developed obesity, diabetes, and kidney dysfunction manifested by albuminuria and blood accumulation of BUN and creatinine. The HFD-fed kidney showed marked glomerular and tubular injuries, including prominent defects in the glomerular filtration barrier and increased tubular cell apoptosis. Mechanistically, HFD feeding markedly increased triglyceride and cholesterol contents in the kidney and activated lipogenic pathways for cholesterol and triglyceride synthesis. HFD feeding also increased oxidative stress and induced mitochondrial fission in tubular cells, thereby activating the pro-apoptotic pathway. In HK-2 and mesangial cell cultures, high glucose, fatty acid, and TNF-α combination was able to activate the lipogenic pathways, increase oxidative stress, promote mitochondrial fission, and activate the pro-apoptotic pathway, all of which could be attenuated by an inhibitor that depleted reactive oxygen species. Taken together, these observations suggest that long-term HFD feeding causes kidney injury at least in part as a result of tissue lipid accumulation, increased oxidative stress, and mitochondrial dysfunction, which promote excess programmed cell death.

Bakuchiol (BAK), a monoterpene phenol reported to have exerted a variety of pharmacological effects, has been related to multiple diseases, including myocardial ischemia reperfusion injury, pressure overload-induced cardiac hypertrophy, diabetes, liver fibrosis, and cancer. However, the effects of BAK on hyperglycemia-caused diabetic cardiomyopathy and its underlying mechanisms remain unclear. In this study, streptozotocin-induced mouse model and high-glucose-treated cell model were conducted to investigate the protective roles of BAK on diabetic cardiomyopathy, in either the presence or absence of SIRT1-specific inhibitor EX527, SIRT1 siRNA, or Nrf2 siRNA. Our data demonstrated for the first time that BAK could significantly abate diabetic cardiomyopathy by alleviating the cardiac dysfunction, ameliorating the myocardial fibrosis, mitigating the cardiac hypertrophy, and reducing the cardiomyocyte apoptosis. Furthermore, BAK achieved its antifibrotic and antihypertrophic actions by inhibiting the TGF- β 1/Smad3 pathway, as well as decreasing the expressions of fibrosis- and hypertrophy-related markers. Intriguingly, these above effects of BAK were largely attributed to the remarkable activation of SIRT1/Nrf2 signaling, which eventually strengthened cardiac antioxidative capacity by elevating the antioxidant production and reducing the reactive oxygen species generation. However, all the beneficial results were markedly abolished with the administration of EX527, SIRT1 siRNA, or Nrf2 siRNA. In summary, these novel findings indicate that BAK exhibits its therapeutic properties against hyperglycemia-caused diabetic cardiomyopathy by attenuating myocardial oxidative damage via activating the SIRT1/Nrf2 signaling., Competing Interests: The authors declare that they have no conflicts of interest in the studies described., (Copyright © 2020 Wenshuai Ma et al.)

20 (R)-Dammarane-3β, 12β, 20, 25-tetrol (25-OH-PPD), a ginsenoside, was derived from Panax ginseng (C. A. Meyer) and inhibited growth of several cancer cell lines. To improve the anti-cancer activity, we introduced the pyrazine ring to 25-OH-PPD and obtained the compound 20(R)-[2,3-β]-Pyrazine-dammarane-12β,20,25-triol (2-Pyrazine-PPD). we evaluated the anti-cancer activity of 2-Pyrazine-PPD and investigated the main anti-cancer mechanisms of 2-Pyrazine-PPD in gastric cancer cells. We found that 2-Pyrazine-PPD remarkably suppressed the proliferation of gastric cancer cells in a concentration-dependent, and showed little toxicity to the normal cell (human gastric epithelial cell line-GES-1). Further study indicated that 2-Pyrazine-PPD induced apoptosis by mitochondria pathway in BGC-803 cancer cells, and activated unfolded protein response and the protein kinase RNA-activated (PKR)-like ER kinase (PERK)/Eukaryotic translation initiation factor-2α (eIF-2α)/Activating transcription factor 4 (ATF4) axis, the expression level of the protein C/EBP homologous protein (CHOP), the marker of endoplasmic reticulum stress, and the apoptosis inducing by 2-Pyrazine-PPD can partly be inhibited by siRNA-mediated knockdown of CHOP. Moreover, the production of reactive oxygen species was remarkably up-regulated in BGC-803 cancer cells treated with 2-Pyrazine-PPD. N-acetylcysteine (NAC, a reactive oxygen species scavenger) can attenuate 2-Pyrazine-PPD-induced apoptosis and endoplasmic reticulum stress. Taken together, we suggested that 2-Pyrazine-PPD exhibited remarkable anti-cancer activity by reactive oxygen species-mediate cell apoptosis and endoplasmic reticulum stress in gastric cancer cells. Our results uncovered the mechanism of 2-Pyrazine-PPD as a promising anti-tumor candidate for gastric cancer therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Collagen is a promising biomaterial used in the beauty and biomedical industries. In this study, the physicochemical characterization, antioxidant activities, and protective effects against H 2 O 2 -induced injury of collagen isolated from Acaudina molpadioides were investigated. The amino acid composition analysis showed that the collagen was rich in glycine (Gly), alanine (Ala), and glutamic acid (Glu), but poor in tyrosine (Tyr) and phenylalanine (Phe). Zeta potential analysis revealed that the isoelectric point (pI) of collagen from Acaudina molpadioides was about 4.25. It possessed moderate scavenging activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals in a dose-dependent manner. In addition, the collagen was able to effectively improve cell viability and morphology, inhibit the production of Malondialdehyde (MDA), and increase the activities of Superoxide Dismutase (SOD) and Glutathione Peroxidase (GSH-Px) in cultured RAW264.7 cells, resulting in a protective effect against H 2 O 2 -induced injury. Overall, the results showed that collagen extracted from A. molpadioides has promising prospects in the beauty and cosmetics industries.

Progressive memory loss and cognitive impairment are the main clinical manifestations of Alzheimer's disease (AD). Currently, there is no effective drug available for the treatment of AD. Previous studies have demonstrated that the cognitive impairment of AD is associated with oxidative stress and the inhibition of AKT and ERK phosphorylation. Grape seed proanthocyanidin extract (GSPE) has been shown to have strong antioxidant effect and can protect the nervous system from oxidative stress damage. This study aimed to investigate the protective effect of GSPE on the cognitive and synaptic impairments of AD using a sporadic AD rat model induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) (ICV-STZ). Rats were treated with GSPE (50, 100, or 200 mg/kg every day) by intragastrical (ig.) administration for continuous 7 weeks, and ICV-STZ (3 mg/kg) was performed on the first day and third day of week 5. Learning and memory abilities were assessed by the Morris water maze (MWM) test at week 8. After behavioral test, hippocampal long-term potentiation (LTP) was recorded, and the levels of malondialdehyde (MDA), superoxide dismutases (SOD), glutathione (GSH) and the protein expression of AKT and ERK were measured in the hippocampus and cerebral cortex of rats. Our study revealed that ICV-STZ significantly impaired the working learning ability and hippocampal LTP of rats, significantly increased the levels of MDA, and decreased the activity of SOD and GSH in the hippocampus and cerebral cortex. In contrast, GSPE treatment prevented the impairment of cognitive function and hippocampal LTP induced by ICV-STZ, decreased the level of MDA, and increased the level of SOD and GSH. Furthermore, Western blot results showed that GSPE treatment could prevent the loss of AKT and ERK activities in the hippocampus and cerebral cortex induced by ICV-STZ. Our findings demonstrate that GSPE treatment could ameliorate the impairment of cognitive ability and hippocampal synaptic plasticity in a rat model of sporadic AD by inhibiting oxidative stress and preserving AKT and ERK activities. Therefore, GSPE may be an effective agent for the treatment of cognitive deficits associated with sporadic AD.

Repression of the electron transport in mitochondria can result in an increase of reactive oxygen species (ROS) in plant cells. This study was to clarify inhibition of the mitochondrial respiratory components (Complex I and Complex III) as stimuli to induce oxidative damage in Oryza sativa L. under exogenous SCN - exposure with special emphasis on lipid peroxidation, protein modification, and DNA damage at the biochemical and molecular levels. Our results showed that enzymatic activity and gene expression of cytochrome c reductase (Complex III) in roots and shoots of rice seedlings were significantly repressed by SCN - exposure, where significant inhibition of NADH dehydrogenase (Complex I) was only detected in shoots, suggesting that Complex III was the main target attacked by SCN - ligand in rice roots, and both components were arrested in shoots. ROS analysis in tissues indicated that SCN - exposure caused significant accumulation of H 2 O 2 and O 2 -• , increased malondialdehyde (MDA) and carbonyl content in rice materials in a dose-dependent manner. Similarly, a remarkable elevation of electrolyte leakage was observed in rice tissue samples. The comet assay indicated a positive correlation between DNA damage and external SCN - exposure. In conclusion, oxidative burst generated from the inhibitions of the electron transport in mitochondria in rice seedlings under SCN - exposure can cause lipid peroxidation, protein modification and DNA damage, eventually decreasing fresh weight of rice seedlings., Competing Interests: Declaration of competing interest Xiao-Zhang Yu has received the grants from the National Natural Science Foundation of China. The other authors, Yu-Juan Lin, Yan-Hong Li and Li Yang, declare that they have no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Atherosclerosis is an inflammatory disease of the arterial wall, which involves endothelial cells and immune cells. Endothelial dysfunction has been considered an important step in the initiation of the disease. TIPE1 is a newly identified protein of the TIPE family, and plays a vital role in inflammation and tumorigenesis. However, its role in atherogenesis remains unclear. In this study, we demonstrated that TIPE1 promoted atherogenesis by inducing endothelial dysfunction. When human umbilical vein endothelial cells (HUVECs) were exposed to oxidative stress, the level of TIPE1 was significantly up-regulated, and the ROS generation markedly increased in TIPE1 over-expressing HUVECs. As a result, the growth of HUVECs was inhibited, and the apoptosis was enhanced. However, the cell contact ability between HUVECs and THP-1 cells were augmented due to the up-regulation of adhesion molecules such as E-selectin and ICAM-1 induced by TIPE1 overexpression. Importantly, ApoE - / - mice injected with TIPE1 recombinant lentivirus developed significantly severe atherosclerosis accompanied by hyperglycemia, hypercholesterolemia and increased white blood count. These findings indicated that excessive ROS induced by the overexpression of TIPE1 in endothelial cells accelerated the process of atherogenesis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cerebral ischemic stroke is a severe disease afflicting people worldwide. Phytochemicals play a pivotal role in the discovery of novel therapeutic approaches for the prevention of ischemic stroke. In our continual search for bioactive natural products for the treatment of ischemic stroke, we have evaluated the protective effects of theaflavic acid (TFA) from black tea using PC12 cells injured by oxygen and glucose deprivation/restoration (OGD/R), and investigated the possible mechanisms. The results showed that TFA can protect PC12 cells against OGD/R through increasing cell viability and decreasing intracellular lactate dehydrogenase (LDH) release. Further investigations found that TFA could inhibit the overproduction of intracellular reactive oxygen species (ROS), reduce malondialdehyde content, and elevate superoxide dismutase activity, which implied that TFA suppresses oxidative stress in PC12 cells induced by OGD/R. In addition, overload of intracellular calcium and collapse of the mitochondrial membrane potential were improved in the presence of TFA, and the activity of caspase-3 was significantly reduced by TFA. Western blot analysis showed that the expression of Bcl-2 was up-regulated while Bax was down-regulated. Therefore, it can be concluded that TFA can inhibit mitochondria-dependent apoptosis of PC12 cells induced by OGD/R. In addition, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway was explored to elucidate the mechanism by which TFA inhibits ROS-mediated apoptosis in PC12 cells. The results revealed that TFA promoted the translocation of Nrf2 into nuclei, enhanced the transcriptional activity of ARE, and up-regulated expression of downstream HO-1, which indicates that the Nrf2/ARE signaling pathway is involved in the protection by TFA of PC12 cells injured by OGD/R.

Depression is a common disease that afflicts one in 6 people. Numerous hypotheses have been raised in the past decades, but the exact mechanism for depression onset remains obscure. Recently, the neuroinflammatory response and oxidative stress are being attracted more and more attention due to their roles in depression pathogenesis. The inhibition of neuroinflammatory response and oxidative stress is now considered a potential strategy for depression prevention and/or therapy. Sodium butyrate (SB) is a sodium form of the endogenous butyrate. It can inhibit proinflammatory responses and oxidative stress in different models of disease. In the present study, we investigated the effect of SB on lipopolysaccharide (LPS)-induced depression-like behaviors, neuroinflammatory response, and oxido-nitrosative stress in the hippocampus and prefrontal cortex in C57BL6/J mice. Our results showed that 10 days of SB pretreatment at the dose of 300 but not 100 mg/kg markedly ameliorated LPS (0.83 mg/kg)-induced depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test. Further analysis showed that 10 days of SB pretreatment not only prevented LPS-induced increases in proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, in the hippocampus and prefrontal cortex but also prevented LPS-induced enhancement of oxido-nitrosative stress. Taken together, these results demonstrate that SB is such an agent that could be used to prevent depression onset and/or progression, and inhibition of neuroinflammatory response and oxido-nitrosative stress may be a potential mechanism for its antidepressant actions., (© 2020 S. Karger AG, Basel.)

Ischemic cerebral stroke is a severe cause of human death and disability. Natural products play an important role in the discovery of novel therapy for cerebral ischemia. Herein, we investigate the neuroprotective effects of sikokianin A identifiedfrom Wikstroemia indica using PC12 cell exposed to OGD/R. The results revealed sikokianin A can improve the poor viability and release of intracellular LDH in PC12 cells induced by OGD/R. Further studies have demonstrated the increased ROS and MDA together with reduced SOD activity were attenuated by sikokianin A. Meanwhile, decreased mitochondrial membrane potential, activated Caspase-3, down-regulated Bcl-2 and up-regulated Bax were reversed. These results indicate the protective effects of sikokianin A are associated with inhibiting oxidative stress and apoptosis resulting from OGD/R. Additionally, sikokianin A can activate Nrf2 and downstream HO-1 in PC12 cells treated by OGD/R, which implied Nrf2/HO-1 signaling pathway was involved in the protective effects of sikokianin A.

Carbon monoxide (CO) presents anti-inflammatory and antioxidant activities as a new gaseous neuromessenger produced by heme oxygenase-1 (HO-1) in the body. High salt-induced hypertension is relevant to the levels of pro-inflammatory cytokines (PICs) and oxidative stress in the hypothalamic paraventricular nucleus (PVN). We explored whether CO in PVN can attenuate high salt-induced hypertension by regulating PICs or oxidative stress. Male Dahl Salt-Sensitive rats were fed high-salt (8% NaCl) or normal-salt (0.3% NaCl) diet for 4 weeks. CORM-2, ZnPP IX, or vehicle was microinjected into bilateral PVN for 6 weeks. High-salt diet increased the levels of MAP, plasma norepinephrine (NE), reactive oxygen species (ROS), and the expressions of COX2, IL-1β, IL-6, NOX2, and NOX4 significantly in PVN (p < 0.05), but decreased the expressions of HO-1 and Cu/Zn-SOD in PVN (p < 0.05). Salt increased sympathetic activity as measured by circulating norepinephrine, and increased the ratio of basal RSNA to max RSNA, in part by decreasing max RSNA. PVN microinjection of CORM-2 decreased the levels of MAP, NE, RSNA, ROS and the expressions of COX2, IL-1β, IL-6, NOX2, NOX4 significantly in PVN of hypertensive rat (p < 0.05), but increased the expressions of HO-1 and Cu/Zn-SOD significantly (p < 0.05), which were all opposite to the effects of ZnPP IX microinjected in PVN (p < 0.05). We concluded that exogenous or endogenous CO attenuates high salt-induced hypertension by regulating PICs and oxidative stress in PVN.

Diets high in animal fats are associated with increased risks of inflammatory bowel disease, but the mechanism remains unclear. In this study, we investigated the effect of high-fat diet (HFD) on the development of experimental colitis in mice. Relative to mice fed low-fat diet (LFD), HFD feeding for 4 wk increased the levels of triglyceride, cholesterol, and free fatty acids in the plasma as well as within the colonic mucosa. In an experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), mice on 4-wk HFD exhibited more severe colonic inflammation and developed more severe colitis compared with the LFD counterparts. HFD feeding resulted in higher production of mucosal pro-inflammatory cytokines, greater activation of the myosin light chain kinase (MLCK) tight junction regulatory pathway, and greater increases in mucosal barrier permeability in mice following TNBS induction. HFD feeding also induced gp91, an NADPH oxidase subunit, and promoted reactive oxygen species (ROS) production in both colonic epithelial cells and lamina propria cells. In HCT116 cell culture, palmitic acid or palmitic acid and TNF-α combination markedly increased ROS production and induced the MLCK pathway, and these effects were markedly diminished in the presence of a ROS scavenger. Taken together, these data suggest that HFD promotes colitis by aggravating mucosal oxidative stress, which rapidly drives mucosal inflammation and increases intestinal mucosal barrier permeability. NEW & NOTEWORTHY This study demonstrates high-fat diet feeding promotes colitis in a 2,4,6-trinitrobenzenesulfonic acid-induced experimental colitis model in mice. The underlying mechanism is that high-fat diet induces oxidative stress in the colonic mucosa, which increases colonic epithelial barrier permeability and drives colonic mucosal inflammation. These observations provide molecular evidence that diets high in saturated fats are detrimental to patients with inflammatory bowel diseases.

Muscle redox disturbances and oxidative stress have emerged as a common pathogenetic mechanism and potential therapeutic intervention in some muscle diseases. Parthenolide (PTL), a sesquiterpene lactone found in large amounts in the leaves of feverfew, possesses anti-inflammatory, anti-migraine, and anticancer properties. Although PTL was reported to alleviate cancer cachexia and improve skeletal muscle characteristics in a cancer cachexia model, its actions on oxidative stress-induced damage in C2C12 myoblasts have not been reported and the regulatory mechanisms have not yet been defined. In our study, PTL attenuated H 2 O 2 -induced growth inhibition and morphological changes. Furthermore, PTL exhibited scavenging activity against reactive oxygen species and protected C2C12 cells from apoptosis in response to H 2 O 2 . Meanwhile, PTL suppressed collapse of the mitochondrial membrane potential, thereby contributing to normalizing H 2 O 2 -induced autophagy flux and mitophagy, correlating with inhibiting degradation of mitochondrial marker protein TIM23, the increase in LC3-II expression and the reduction of mitochondria DNA. Besides its protective effect on mitochondria, PTL also prevented H 2 O 2 -induced lysosomes damage in C2C12 cells. In addition, the phosphorylation of p53, cathepsin B, and Bax/Bcl-2 protein levels, and the translocation of Bax from the cytosol to mitochondria induced by H 2 O 2 in C2C12 cells was significantly reduced by PTL. In conclusion, PTL modulates oxidative stress-induced mitophagy and protects C2C12 myoblasts against apoptosis, suggesting a potential protective effect against oxidative stress-associated skeletal muscle diseases., (© 2019 Wiley Periodicals, Inc.)

Telmisartan, an angiotensin II receptor blocker, has been widely used for hypertension. It has also been reported to improve insulin sensitivity in animal models of obesity and diabetic patients by targeting to the peroxisome proliferator-activated receptor (PPAR)-γ. High glucose/high lipid (HG/HL)-induced apoptosis of pancreatic β-cells impairs its function of insulin secretion and is generally believed to be the key factor in the development of diabetes. In this study, we investigated whether telmisartan exerted a protective effect against HG/HL-induced apoptosis and insulin secretion in vitro as well as in vivo; 10-μM telmisartan treatment significantly reduced HG (25 mM) or/and HL (0.4 mM palmitic acid) induced-cell apoptosis and greatly improved insulin secretion in INS-1 pancreatic β-cells, which is consistent in an obesity rat model induced by HG/HL diets. Furthermore, telmisartan treatment markedly reduced the protein level of GRP78, CHOP, and caspase 12, while increasing anti-apoptotic Bcl-2 protein expression. Moreover, telmisartan treatment significantly reduced intracellular ROS levels. Mechanistically, we demonstrated that PPARγ signaling pathway may be involved in the telmisartan protective effects, which were blocked by a PPARγ blocker, GW9662. In conclusion, the protective effect of telmisartan was mediated by an anti-ER stress-induced apoptotic and anti-oxidative pathway. SIGNIFICANCE OF THIS STUDY: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder worldwide pathologically characterized by hyperglycemia and insulin resistance. Long-term high glucose in the blood has been proposed to induce pancreatic β-cell loss and is generally believed to be the key factor in the development of diabetes. In the present study, we demonstrated that telmisartan, a common drug used for hypertension treatment, has a protective effect against high glucose/high lipid-induced cell apoptosis and greatly improves the insulin secretion function by inhibiting the oxidative stress and ER stress. Furthermore, this protective effect of telmisartan is mediated by the PPAR-γ signal pathway, which may provide a potential strategy against T2DM., (© 2019 John Wiley & Sons, Ltd.)

Maize is a sensitive crop to drought and heat stresses, particularly at the reproductive stages of development. The present study investigated the individual and interactive effects of drought (50% field capacity) and heat (38 °C/30 °C) stresses on morpho-physiological growth, yield, nutrient uptake and oxidative metabolism in two maize hybrids i.e., 'Xida 889' and 'Xida 319'. The stress treatments were applied at tasseling stage for 15 days. Drought, heat and drought + heat stress caused oxidative stress by the over-production of ROS (O 2- , H 2 O 2 , OH - ) and enhanced malondialdehyde contents, which led to reduced photosynthetic components, nutrients uptake and yield attributes. The concurrent occurrence of drought and heat was more severe for maize growth than the single stress. However, both stresses induced the metabolites accumulation and enzymatic and non-enzymatic antioxidants to prevent the oxidative damage. The performance of Xida 899 was more prominent than the Xida 319. The greater tolerance of Xida 889 to heat and drought stresses was attributed to strong antioxidant defense system, higher osmolyte accumulation, and maintenance of photosynthetic pigments and nutrient balance compared with Xida 319.

Purpose: To investigate the effects of icariside II on brain tissue oxidative stress and Nrf2/HO-1 expression in rats with cerebral ischemia-reperfusion injury (CIRI)., Methods: One hundred SD rats were randomly divided into sham-operated, model, and 5, 10 and 20 mg/kg icariside II groups, 20 rats in each group. The middle cerebral artery occlusion model (ischemia for 2 h followed by reperfusion for 24 h) was established in the later 4 groups. In later 3 groups, at reperfusion beginning, the rats were intragastrically administrated with 5, 10 and 20 mg/kg icariside II, respectively. After 24 h of reperfusion, the neurological severity score, cerebral water content and cerebral infarction volume, brain tissue oxidative stress indexes and Nrf2 and HO-1 protein expressions were determined., Results: Compared with model group, in 20 mg/kg icariside II group the neurological severity score, cerebral water content and cerebral infarction volume, brain tissue ROS content and MDA level were significantly decreased (P<0.05), and the brain tissue SOD, GSH-Px and catalase levels and Nrf2 and HO-1 protein levels were significantly increased (P<0.05)., Conclusion: Icariside II can alleviate the CIRI in rats through reducing brain tissue oxidative stress and improving Nrf2/HO-1 expression.

Angiotensin (Ang)-(1-7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1-7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1-7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1-7) in the PVN, through modulation of PICs and oxidative stress.

Ferroportin (FPN), the only known vertebrate iron exporter, transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues and cells in vivo. Most of the circulating iron is consumed by erythroid cells to synthesize hemoglobin. Here we found that erythroid cells not only consumed large amounts of iron, but also returned significant amounts of iron to the blood. Erythroblast-specific Fpn knockout ( Fpn KO) mice developed lower serum iron levels in conjunction with tissue iron overload and increased FPN expression in spleen and liver without changing hepcidin levels. Our results also showed that Fpn KO mice, which suffer from mild hemolytic anemia, were sensitive to phenylhydrazine-induced oxidative stress but were able to tolerate iron deficiency upon exposure to a low-iron diet and phlebotomy, supporting that the anemia of Fpn KO mice resulted from erythrocytic iron overload and resulting oxidative injury rather than a red blood cell (RBC) production defect. Moreover, we found that the mean corpuscular volume (MCV) values of gain-of-function FPN mutation patients were positively associated with serum transferrin saturations, whereas MCVs of loss-of-function FPN mutation patients were not, supporting that erythroblasts donate iron to blood through FPN in response to serum iron levels. Our results indicate that FPN of erythroid cells plays an unexpectedly essential role in maintaining systemic iron homeostasis and protecting RBCs from oxidative stress, providing insight into the pathophysiology of FPN diseases., (© 2018 by The American Society of Hematology.)

Excess intracellular reactive oxygen species (ROS) production is a significant causative factor of many diseases, exemplified by vascular diseases. Mitochondria are a major source of endogenous ROS, which simultaneously induce mitochondrial dysfunction. Nuclear factor-erythroid 2-related factor 2 (Nrf2) represents an important intracellular defense system that protects cells against oxidative insults caused by ROS. Therefore, molecules with the capacities of inducing Nrf2, and preventing mitochondrial dysfunction can inhibit cell apoptosis, and thus are potential drug candidates for the therapy of ROS-mediated vascular diseases. Homoeriodictyol (HE), previously isolated from Viscum articulatum Burm, has been found to be an Nrf2 inducer. In the present study, we investigated its protection on ROS-induced endothelial cell injury using a H 2 O 2 -induced human umbilical vein EA.hy926 cell oxidative insult model. Our results indicated that HE activated Nrf2 signaling pathway and protected cells against H 2 O 2 -induced cell damage. HE alleviated H 2 O 2 -induced loss of mitochondrial membrane potential (MMP), blocked the releases of cytochrome C and apoptosis inducing factor (AIF) from mitochondria, and thus inhibited mitochondria-mediated cell apoptosis. Furthermore, HE inhibited H 2 O 2 -induced changes of apoptosis-related proteins, such as Bcl-2, Bcl-xL, caspases -3, -9 and PARP. Further study demonstrated that the protection of HE against H 2 O 2 -induced endothelial cell damage was Nrf2-dependent. Collectively, our observations suggest that HE is capable of counteracting oxidative insults in endothelial cells, and has a potential to be a therapeutic agent against ROS-mediated vascular diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chlorogenic acid (CGA), an ester formed between caffeic acid and quinic acid, is one of the most abundant phenolic acids and is widespread in fruits, vegetables, cereals and tuber crops. Therefore, the present study was conducted to test the hypothesis that dietary supplementation with CGA could improve intestinal health and regulate intestinal selected microbiota in weaned piglets. A total of twenty-four piglets (21 d of age) were randomly assigned to one of four groups according to their initial BW and sex and fed a basal diet (control group) or a basal diet containing 250, 500 and 1000 mg kg-1 CGA, respectively. The whole trial lasted for 28 d. Dietary CGA supplementation increased (P < 0.05) the duodenal villous height and villous height : crypt depth ratio, but decreased (P < 0.05) the F/G ratio and duodenal crypt depth when compared with the control group. Meanwhile, an increase (P < 0.05) in the jejunal villous height and in the ileal villous height : crypt depth ratio were also observed in CGA-fed piglets. Supplementation with CGA significantly increased (P < 0.05) the activity of serum GSH-Px and the activities of duodenal GSH-Px and CAT, upregulated (P < 0.05) the expression of OCLN in the duodenum and jejunum, and decreased (P < 0.05) the ileal MDA content when compared to the control group. In addition, an increase (P < 0.05) in the population of Lactobacillus and a decrease (P < 0.05) in the population of Escherichia coli were observed in the colon of pigs fed CGA diets. Furthermore, pigs fed CGA diets had higher (P < 0.05) propionic and butyric acid concentrations in the colon. Altogether, our results provide evidence that dietary CGA is beneficial for preserving intestinal morphological integrity and selectively regulating intestinal microbiota, which can provide a means to improve gut health and growth performance post-weaning.

Cytochrome c (CYTc) is one of the redox-active molecules responsible for electron transport in plant mitochondria. It is important in the interaction of metal ions with mitochondrial proteome, it is also essential for insights into electron transport during oxidative stress. This study focused on the clarification of interactions of CYTc with metal accumulation and associated modulation of CYTc with reactive oxygen species (ROS) generation in rice seedlings exposed to chromium either hexavalent Cr(VI) or trivalent Cr(III). The result indicates that exposures to both Cr species resulted in significant accumulation of Cr in rice tissues. ROS-dependent growth inhibition of rice seedlings was also evident from both Cr treatments. Changes of CYTc content in roots and shoots maintained almost the same pattern after both Cr exposures. However, dynamically transcriptional levels of rice CYTc genes conducted by real-time quantitative RT-PCR were inconsistent in rice tissues. The results presented here demonstrate that oxidative stresses induced by ROS accumulation do not equally and/or detrimentally influence the perturbations of CYTc content and expression patterns of CYTc genes in rice tissues after Cr exposure, suggesting that the decrease of CYTc levels in roots did not originate ROS accumulation, it may be due to metal-binding properties, while enhancement of CYTc content in shoots was probably a signal of severe growth inhibition owing to ROS accumulation.

The past two decades have witnessed remarkable advances in oxidative stress research, particularly in the context of ischemic brain injury. Oxidative stress in ischemic tissues compromises the integrity of the genome, resulting in DNA lesions, cell death in neurons, glial cells, and vascular cells, and impairments in neurological recovery after stroke. As DNA is particularly vulnerable to oxidative attack, cells have evolved the ability to induce multiple DNA repair mechanisms, including base excision repair (BER), nucleotide excision repair (NER) and non-homogenous endpoint jointing (NHEJ). Defective DNA repair is tightly correlated with worse neurological outcomes after stroke, whereas upregulation of DNA repair enzymes, such as APE1, OGG1, and XRCC1, improves long-term functional recovery following stroke. Indeed, DNA damage and repair are now known to play critical roles in fundamental aspects of stroke recovery, such as neurogenesis, white matter recovery, and neurovascular unit remodeling. Several DNA repair enzymes are essential for comprehensive neural repair mechanisms after stroke, including Polβ and NEIL3 for neurogenesis, APE1 for white matter repair, Gadd45b for axonal regeneration, and DNA-PKs for neurovascular remodeling. This review discusses the emerging role of DNA damage and repair in functional recovery after stroke and highlights the contribution of DNA repair to regenerative elements after stroke. This article is part of the Special Issue entitled 'Cerebral Ischemia'., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Human lung tissue, directly exposed to the environmental oxidants and toxicants, is apt to be harmed to bring about acute or chronic oxidative insults. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents a central cellular defense mechanism, and is a target for developing agents against oxidative insult-induced human lung diseases. Our previous study found that the EtOH extract of Cinnamomum chartophyllum protected human bronchial epithelial cells against oxidative insults via Nrf2 activation. In this study, a systemic phytochemical investigation of the aerial parts of C. chartophyllum led to the isolation of thirty chemical constituents, which were further evaluated for their Nrf2 inducing potential using NAD(P)H: quinone reductase (QR) assay. Among these purified constituents, a sesquiterpenoid bearing α, β-unsaturated ketone group, 3S-(+)-9-oxonerolidol (NLD), and a diphenyl sharing phenolic groups, 3, 3', 4, 4'-tetrahydroxydiphenyl (THD) significantly activated Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO-1), and γ-glutamyl cysteine synthetase (γ-GCS), and enhanced the nuclear translocation and stabilization of Nrf2 in human lung epithelial cells. Importantly, NLD and THD had no toxicities under the Nrf2 inducing doses. THD also demonstrated a potential of interrupting Nrf2-Keap1 protein-protein interaction (PPI). Furthermore, NLD and THD protected human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. Taken together, we conclude that NLD and THD are two novel Nrf2 activators with potential application of preventing acute and chronic oxidative insults in human lung tissue., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Many studies have shown that hydrogen sulfide (H 2 S) is both detrimental and beneficial to animals and plants, whereas its effect on bacteria is not fully understood. Here, we report that H 2 S, released by sodium hydrosulfide (NaHS), significantly inhibits the growth of Escherichia coli in a dose-dependent manner. Further studies have shown that H 2 S treatment stimulates the production of reactive oxygen species (ROS) and decreases glutathione (GSH) levels in E. coli, resulting in lipid peroxidation and DNA damage. H 2 S also inhibits the antioxidative enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) and induces the response of the SoxRS and OxyR regulons in E. coli. Moreover, pretreatment with the antioxidant ascorbic acid (AsA) could effectively prevent H 2 S-induced toxicity in E. coli. Taken together, our results indicate that H 2 S exhibits an antibacterial effect on E. coli through oxidative damage and suggest a possible application for H 2 S in water and food processing.

Oxidative stress and inflammation undoubtedly contribute to the pathogenesis of many human diseases. The nuclear transcription factor erythroid 2-related factor (Nrf2) and the nuclear factor κ B (NF- κ B) play central roles in regulation of oxidative stress and inflammation and thus are targets for developing agents against oxidative stress- and inflammation-related diseases. Our previous study indicated that the EtOH extract of Litsea garrettii protected human bronchial epithelial cells against oxidative insult via the activation of Nrf2. In the present study, a systemic phytochemical investigation of L. garrettii led to the isolation of twenty-one chemical ingredients, which were further evaluated for their inhibitions on oxidative stress and inflammation using NAD(P)H:quinone reductase (QR) assay and nitric oxide (NO) production assay. Of these ingredients, 3-methoxy-5-pentyl-phenol (MPP, 5) was identified as an Nrf2 activator and an NF- κ B inhibitor. Further studies demonstrated the following: (i) MPP upregulated the protein levels of Nrf2, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase regulatory subunit (GCLM); enhanced the nuclear translocation and stabilization of Nrf2; and inhibited arsenic [As(III)]-induced oxidative insult in normal human lung epithelial Beas-2B cells. And (ii) MPP suppressed the nuclear translocation of NF- κ B p65 subunit; inhibited the lipopolysaccharide- (LPS-) stimulated increases of NF- κ B p65 subunit, COX-2, iNOS, TNF- α , and IL-1 β ; and blocked the LPS-induced biodegrade of I κ B- α in RAW 264.7 murine macrophages. Taken together, MPP displayed potential preventive effects against inflammation- and oxidative stress-related diseases.

The prevalence of type 2 diabetes mellitus has been increasing worldwide and more than two thirds of the patients may develop diabetic nephropathy (DN). However, the efficiency of existing approaches on DN progression is limited. 6-Shogaol (6-SG), a major dehydrated derivative of gingerols, possesses various biological properties. The present study was designed to evaluate the possible effects of 6-SG on DN in db/db mice and to investigate the mechanisms. We revealed that 6-SG reduced the levels of fasting blood glucose, serum insulin, C-peptide, glycosylated hemoglobin A1c, and systolic blood pressure. 6-SG decreased the levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR), ameliorated the pathological injuries of kidneys, reduced the surface area of Bowman's capsule, Bowman's space, glomerular tuft, and decreased the expression of collagen IV and fibronectin in kidneys of db/db mice. The high levels of systemic and renal triglyceride and cholesterol were decreased by 6-SG. Moreover, 6-SG exhibited anti-inflammatory effects, as reflected by reduction of tumor necrosis factor ɑ (TNFɑ), monocyte chemotactic protein-1 (MCP-1), and IL-6 levels in circulation and kidneys, and decrease of NF-κB expression. Furthermore, 6-SG also inhibited oxidative stress and restored the expression of NF-E2-related factor 2 (Nrf2) in kidneys of db/db mice. In conclusion, we have demonstrated that 6-SG exhibits anti-diabetic and renal protective effects against DN, in which effect the anti-inflammatory, hyperlipidemic, anti-oxidative activities may be involved. Overall, 6-SG could be a promising therapeutic treatment to ameliorate diabetes and the development of DN., (Copyright © 2017. Published by Elsevier Masson SAS.)

The present study aimed to investigate the effect of quercetin on cytotoxicity and cognitive degradation induced by amyloid β(Aβ)‑peptide in mice. Using the 1,1-diphenyl-2‑picrylhydrazyl (DPPH) method and a Y‑maze assay, the radical quenching ability and effect on working memory were determined, respectively, of quercetin treatment following 4 days of Aβ administration. The acute oral toxicity was assessed used to determine the concentration of quercetin at which 50% lethality of the neuronal cells was induced. For determination of the effect of quercetin on degradation of learning and memory loss induced by Aβ, a passive avoidance test was used. The results revealed that quercetin was involved in the inhibition of DPPH radical activity and was found to reduce radical activity by 76.5%. Quercetin significantly protected PC12 neuronal cells from death induced by Aβ treatment. Treatment of mice with daily doses of 100 mg/kg body weight quercetin for 30 days significantly improved the degradation of learning and memory loss induced by Aβ. The acute oral dose of quercetin in mice was determined to be 575 mg/kg body weight. Therefore, quercetin was found to be of therapeutic value for the treatment of neurological disorders, including AD, although further investigations are required.

Aim: To investigate the antioxidant and hepatoprotective effects of Cortex Dictamni aqueous extract (CDAE) in carbon tetrachloride (CCl 4 )-induced liver damage in rats., Methods: The in vitro antioxidant effect of CDAE was investigated using α,α-diphenyl-β-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), β-carotene bleaching, reducing power, and thiobarbituric acid reactive substance assays. A linoleic acid system, including ferric thiocyanate (FTC) and thiobarbituric acid (TBA) assays, was used to evaluate the inhibition of lipid peroxidation. The in vivo hepatoprotective and antioxidant effects of CDAE against CCl 4 -induced liver damage were evaluated in Sprague-Dawley rats. Silymarin was used as a positive control. Liver damage was assessed by determining hepatic histopathology and liver marker enzymes in serum. Enzyme and non-enzyme antioxidant levels and lipid peroxide content were measured in the liver. Cytochrome P450 2E1 (CYP2E1) protein expression was measured via immunohistochemical staining. Nuclear factor E2-related factor (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinine oxidoreductase 1 (NQO1), and γ-glutamylcysteine synthetase catalytic subunit (γ-GCSc) protein expression was measured by Western blot., Results: Our results showed that CDAE exhibited a strong antioxidant activity in vitro . CDAE scavenged DPPH and ABTS radicals in a dose-dependent manner. CDAE inhibited lipid peroxidation with a lipid peroxide inhibition rate of 40.6% ± 5.2%. In the FTC and TBA assays, CDAE significantly inhibited lipid peroxidation ( P < 0.01). In vivo histopathological studies indicated that CCl 4 -induced liver injury was alleviated following CDAE treatment in rats of both sexes. CDAE (160 and 320 mg/kg) significantly prevented CCl 4 -induced elevations of alkaline phosphatase, glutamate pyruvate transaminase, aspartate aminotransferase, and total bilirubin levels in rats of both sexes ( P < 0.05, 0.01, or 0.001). Moreover, CDAE restored the decreased activities of hepatic antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, as well as non-enzyme antioxidant glutathione, which were induced by CCl 4 treatment. CDAE significantly suppressed the up-regulation of CYP2E1 and promoted Nrf2, HO-1, NQO1, and γ-GCSc protein expression., Conclusion: CDAE exhibits good antioxidant performance in vitro , with marked radical-scavenging and anti-lipid peroxidation activities. CDAE is effective in preventing CCl 4 -induced hepatic damage in rats of both sexes. The hepatoprotective activity of CDAE may be attributable to its antioxidant activity, which may involve Keap1-Nrf2-mediated antioxidant regulation., Competing Interests: Conflict-of-interest statement: The authors declare no financial conflict of interest.

The rapid growth in silver nanoparticles (AgNPs) commercialization has increased environmental exposure, including aquatic ecosystem. It has been reported that the AgNPs have damaging effects on photosynthesis and induce oxidative stress, but the toxic mechanism of AgNPs is still a matter of debate. In the present study, on the model aquatic higher plant Spirodela polyrhiza, we found that AgNPs affect photosynthesis and significantly inhibit Photosystem II (PSII) maximum quantum yield (F v /F m ) and effective quantum yield (Φ PSII ). The changes of non-photochemical fluorescence quenching (NPQ), light-induced non-photochemical fluorescence quenching [Y(NPQ)] and non-light-induced non-photochemical fluorescence quenching [Y(NO)] showed that AgNPs inhibit the photo-protective capacity of PSII. AgNPs induce reactive oxygen species (ROS) that are mainly produced in the chloroplast. The activity of ribulose-1, 5-bisphosphate carboxylase-oxygenase (Rubisco) was also very sensitive to AgNPs. The internalized Ag, regardless of whether the exposure was Ag +  or AgNPs had the same capacity to generate ROS. Our results support the hypothesis that intra-cellular AgNP dissociate into high toxic Ag + . Rubisco inhibition leads to slowing down of CO 2 assimilation. Consequently, the solar energy consumption decreases and then the excess excitation energy promotes ROS generation in chloroplast.

The accumulation of β-amyloid (Aβ) peptide plaques is a major pathogenic event in Alzheimer's disease (AD). Aβ is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aβ generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aβ production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD. To investigate whether the therapeutic effect of EGCG is related to the PPARγ pathway, we analysed the alterations in the intracellular molecular expression of PPARγ after EGCG treatment in the N2a/APP695 cell line. In this study, we observed that EGCG attenuated Aβ generation in N2a/APP695 cells, such as the PPARγ agonist, pioglitazone, by suppressing the transcription and translation of BACE1 and that its effect was attenuated by the PPARγ inhibitor, GW9662. Intriguingly, EGCG significantly reinforced the activity of PPARγ by promoting its mRNA and protein expressions in N2a/APP695 cells. Moreover, EGCG also decreased the expression of pro-apoptotic proteins (Bax, caspase-3), reduced the activity of the anti-inflammatory agent NF-κB and inhibited the oxidative stress by decreasing the levels of ROS and MDA and increasing the expression of MnSOD. Co-administration of GW9662 also significantly decreased the EGCG-mediated neuroprotective effect evidenced by the increase in oxidative stress and inflammatory markers. The therapeutic efficacy of EGCG in AD may be derived from the up-regulation of PPARγ mRNA and protein expressions.

Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology., Competing Interests: The authors declare no competing financial interests.