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Cisplatin is a widely used chemotherapeutic drug in the treatment of various solid tumors. However, the cisplatin-induced acute kidney injury remains a disturbing complication, which still lacks effective prevention. Cisplatin-induced oxidative damage and mitochondrial dysfunction are anticipated to be crucial in the occurrence of kidney injury. Astragalus polysaccharide (APS) has been reported to possess multiple biological activities including anti-inflammatory, antioxidant, and mitochondria protection. In this study, we investigated the potentially protective effect of APS against cisplatin-induced kidney injury both in vivo and in vitro. We found that APS pretreatment attenuated the cisplatin-induced renal dysfunction and histopathological damage in mice; in addition, it also protected the viability of HK-2 cells upon cisplatin exposure. APS attenuated the cisplatin-induced oxidative damage by reducing reactive oxygen species (ROS) generation and recovering the activities of total superoxide dismutase and glutathione peroxidase in mice kidney. In addition, electron microscope analysis indicated that cisplatin induced extensive mitochondrial vacuolization in mice kidney. However, APS administration reversed these mitochondrial morphology changes. In HK-2 cells, APS reduced the cisplatin-induced mitochondrial and intracellular ROS generation. Furthermore, APS protected the normal morphology of mitochondria, blocked the cisplatin-induced mitochondrial permeability transition pore opening, and reduced the cytochrome c leakage. Subsequently, APS reduced the cisplatin-induced apoptosis in mice renal and HK-2 cells. In conclusion, our data suggested that APS pretreatment might prevent cisplatin-induced kidney injury through attenuating oxidative damage, protecting mitochondria, and ameliorating mitochondrial-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive intracellular lipid accumulation, oxidative stress, and inflammation. Cinnamyl alcohol (CA), one of the cinnamon extracts, has been shown to exhibit anti-oxidative and anti-inflammatory activities. We proposed that CA was beneficial to NAFLD. Serum cytokines and components of the lipid metabolism were determined in children with NAFLD against age-matched comparisons. A NAFLD mouse model was established by high fat and high carbohydrate (HFHC) diet in male C57BL/6 mouse pups, followed by administration of CA. The effects of CA on lipid metabolism, oxidative stress, and inflammation in hepatic tissues were assessed. Abnormal lipid metabolism and inflammatory responses were observed in the children with NAFLD as compared with the controls. CA reduced the weight of obese mice without affecting food intake as well as alleviating liver injury caused by HFHC feeding. CA was found to mitigate dyslipidemia and reduce hepatic steatosis in HFHC-fed mice by down-regulating genes related to lipogenesis, including peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor-1c (SREBP-1c), and acetyl-CoA carboxylase 1 (ACC1). Additionally, CA treatment reversed HFHC-induced oxidative stress and inflammation, evidenced by the decreased liver reactive oxygen species (ROS), hepatic inflammatory cytokine levels, and F4/80-positive macrophage infiltration in HFHC diet mice. CA reduced the protein levels of pyrin domain-containing protein 3 (NLRP3), adapter protein apoptosis-associated speck-like protein (ASC), and caspase-1 in the liver tissues significantly. CA alleviates HFHC-induced NAFLD in mice, which is associated with the amelioration in lipid metabolism, oxidative stress, and inflammation. [ABSTRACT FROM AUTHOR]

Cataract is the leading cause of blindness with an estimated 16 million people affected worldwide. d -galactose ( d -gal) is a reducing sugar that widely distributed in foodstuffs, and studies show that d -gal could promote cataract formation by damaging nature lens epithelial cells (LECs). However, the underlying mechanism is unclear. In our present study, d -gal resulted in premature senescence of LECs, which was confirmed by determining the β-galactosidase activity, cell proliferative potential and cell cycle distribution, though apoptosis of LECs was not observed. We also verified that d -gal induced the impairment of autophagy flux by measuring the expression of LC3II and P62. Meanwhile, we found that d -gal induced mitochondrial dysfunctions of LECs through increasing reactive oxygen species (ROS), reducing ATP synthesis and mitochondrial potential (MMP), enhancing the concentration of cytoplasm Ca 2+ and permeability transition pore (mPTP) opening. Metformin, as a potential anti-aging agent, suppressed the senescence of LECs by restoring autophagy flux and mitochondria functions. Nevertheless, the antioxidant N-acetylcysteine (NAC) scavenged ROS significantly but was not efficient in preventing LECs from premature senescence. Our data suggests that restoring autophagy activity and improving mitochondrial functions may be a potential strategy for the prevention of LECs senescence-related cataract. [ABSTRACT FROM AUTHOR]

Sestrins (Sesns) have been identified as a family of highly conserved stress-inducible proteins that are strongly up-regulated by various stresses, including DNA damage, oxidative stress, and hypoxia. The Sesns play protective roles in most physiological and pathological conditions mainly through the regulation of oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and metabolic homeostasis. In this review, we discussed the possible regulators of Sesns expression, such as p53, forkhead box O, nuclear factor erythroid 2 like 2 (Nrf2), NH (2)-terminal kinase (JNK)/c-Jun pathway and hypoxia-inducible factor-1a (Hif-1a), and the downstream pathways regulated by the Sesns including AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, mitogen-activated protein kinases (MAPKs) signaling, Nrf2 signaling, NADPH oxidase signaling and transforming growth factor ß (TGF-ß) signaling in heart diseases, lung diseases, gastrointestinal tract diseases, liver and metabolism diseases, neurological diseases, kidney diseases and immunological diseases. This review aims to provide a comprehensive understanding the protective effects of Sesns. [ABSTRACT FROM AUTHOR]

Nephrotoxicity remains a serious adverse effect of cisplatin chemotherapy, limiting its clinical usage. Numerous studies show that oxidative stress and inflammation are closely associated with cisplatin-induced renal damage. Astragaloside IV (AS-IV) has been found to possess antioxidant and anti-inflammation functions. Therefore, we investigated the potential curative effects of AS-IV against cisplatin-induced renal injury and the possible cellular mechanism for activity, bothin vitroandin vivo. We found that pretreatment of HK-2 cells with AS-IV could mitigate cisplatin-induced cell damage caused by oxygen-free radicals and the inflammatory response, as evidenced by reduced formation of reactive oxygen species (ROS) and inflammatory cytokines. AS-IV improved cisplatin-induced renal dysfunction and histopathological injury in mice. Additionally, AS-IV enhanced the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). It also inhibited cisplatin-induced overproduction of kidney injury molecule-1 (KIM-1), malondialdehyde (MDA), tumour necrosis factor-α (TNF − α), and interleukin-1β (IL-1β) in kidney tissues. We found that the protective effects of AS-IV occurred via activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins and inhibition of nuclear factor-κappaB (NF-κB) activation. Further, small interfering RNA (siRNA) knockdown of Nrf2 abrogated the protective effects of AS-IV against cisplatin-induced oxidative stress and blocked the inhibitory effects of AS-IV on cisplatin-induced NF-κB activation and inflammatory cytokine production. In conclusion, our data suggested that AS-IV attenuated cisplatin-mediated renal injury, and these protective effects might be due to inhibition of both oxidative damage and inflammatory response via activation of Nrf2 system and suppression of NF-κB activation. [ABSTRACT FROM PUBLISHER]

Background and Purpose: Non-alcoholic hepatic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver and non-alcoholic steatohepatitis (NASH) represents its advanced stage. R17 derived from bouchardatine, shows benefits in the metabolic syndrome, but has not been tested in the liver. The present study examined the pharmacological effects of R17 in a model of NAFLD/NASH and its mode of action.Experimental Approach: The effects of R17 were examined in mice fed a high-fat (HF) diet to induce the pathological characteristics of NAFLD/NASH and in cultures of HuH7 cells. We used histological and immunohistochemical techniques along with western blotting and siRNA. Generation of ROS and apoptosis were measured.Key Results: Administration of R17 (20 mg·kg-1 , i.p. every other day) for 5 weeks reversed HF-induced hepatic triglyceride content, inflammation (inflammatory cytokines and macrophage numbers), injury (hepatocyte ballooning and apoptosis, plasma levels of alanine aminotransferase and aspartate aminotransferase), and fibrogenesis (collagen deposition and mRNA expression of fibrosis markers). In cultured cells, R17 reduced cell steatosis from both lipogenesis and fatty acid influx. The attenuated inflammation and cell injury were associated with inhibition of both endoplasmic reticulum (ER) stress and oxidative stress. Notably, R17 activated the liver kinase B1-AMP-activated protein kinase (AMPK) pathway by inhibiting activity of ATP synthase, rather than direct stimulation of AMPK.Conclusion and Implications: R17 has therapeutic potential for NAFLD/NASH. Its mode of action involves the elimination of ER and oxidative stresses, possibly via activating the LKB1-AMPK axis by inhibiting the activity of ATP synthase. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that bone morphogenetic proteins (BMPs) play important roles in cardiovascular diseases, including atherosclerosis, artery calcification, myocardial remodeling, pulmonary arterial hypertension, and diabetic cardiomyopathy. Kielin/chordin-like protein (KCP) is a secreted protein that regulates the expression and function of BMPs. However, the role of KCP in cardiac aging remains unknown. In this study, we aimed to investigate the role of KCP in cardiac aging and its possible mechanisms. Echocardiogram showed that heart function was impaired in aged mice (24 months). In addition, analysis of heart structure showed that KCP knockout (KO) aggravated cardiac remodeling in aged mice. Moreover, KCP KO increased p-smad2/3 and TGF-β expression, while decreased BMP-2 expression in aged mice. Furthermore, KCP KO increased the expression of cardiac senescence-related proteins in aged mice. KCP KO aggravated the imbalance of oxidants and antioxidants and increased the expression of proinflammatory cytokines and cardiomyocyte apoptosis in aged mice. Our study demonstrated that KCP KO aggravated cardiac aging in mice by increasing the levels of oxidative stress, inflammation, and cardiomyocyte apoptosis. Key message: KCP KO aggravated aging-related cardiac dysfunction and remodeling in male mice. KCP KO aggravated cardiac aging by increasing the levels of oxidative stress, inflammation, and cardiomyocyte apoptosis. [ABSTRACT FROM AUTHOR]

Background Sestrins (Sesns) family, which including three members Sesn1, Sesn2 and Sesn3, is known as stress-inducible proteins and participate in multiple diseases via regulating oxidative stress, inflammatory response and cell apoptosis. The present study aimed to investigate the plasma levels and the clinical significance of Sesns in patients with coronary artery disease (CAD). Methods In the case-control study, 119 CAD patients, including stable angina pectoris (SAP, n = 44), unstable angina pectoris (UAP, n = 41) and acute myocardial infarction (AMI, n = 29) were included. Patients with chest pain syndrome but excluded CAD (n = 35) were enrolled as control. Plasma levels of Sesn1, Sesn2, Sesn3, superoxide dismutase (SOD) and malondialdehyde (MDA) in all patients were measured and analyzed. Results Compared with control group, plasma levels of Sesn1, Sesn2 and Sesn3 were significantly increased in patients with SAP, UAP and AMI. In addition, a significant lower SOD levels and higher MDA levels were observed in CAD patients, Sesn1/2/3 levels were negatively correlated with SOD levels and positively correlated with MDA levels. Gensini Score were positively correlated with Sesn1/2/3 levels and MDA levels, whereas negatively correlated with SOD levels. Furthermore, as the main risk factors for CAD, the elderly and obesity increased plasma Sesn2 levels, diabetes increased both plasma Sesn2 and Sesn3 levels. Conclusions Our study was the first to report that the plasma Sesns levels were increased in CAD patients and positively related to the severity of coronary heart disease. Although the exact mechanisms of Sesns in CAD are still unknown, alleviated oxidative stress may be the possible reasons. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) in sepsis is a vital and dangerous organ failure caused by an infection-induced dysregulation of the host reaction. Malvidin possesses significant anti-inflammatory and antioxidant bioactivities. This study explored the critical roles of malvidin in sepsis AKI and the crosstalk among mitochondrial function, nucleotide-binding oligomerization-like receptor 3 (NLRP3) inflammasome and nuclear factor erythroid 2 (Nrf2) signaling pathway. First, C57BL/6 mice were administered lipopolysaccharide intraperitoneally for 6 h to create an AKI model of sepsis. Hematoxylin-eosin staining and serum biomarker assays showed that malvidin protected from AKI in sepsis. Real-time fluorescence quantitative polymerase chain reaction analysis revealed that malvidin was able to inhibit inflammatory cytokines and mediators. Western blot assays indicated that malvidin suppressed NLRP3 inflammasome activation and enhanced antioxidant properties. Additionally, human renal tubular epithelial cells were stimulated by lipopolysaccharide/adenosine triphosphate to establish an NLRP3 inflammasome activation model in vitro , and in line with findings in vivo , malvidin significantly inhibited NLRP3 inflammasome activation. Furthermore, our data indicate that malvidin restored mitochondrial quality and function, reduced reactive oxygen species production, increased mitochondrial membrane potential, enhanced mitochondrial DNA copy number, and promoted peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) nuclear translocation. Moreover, inhibitor blockade assays indicated that both PGC-1α and Nrf2 affected the inhibition of the NLRP3 inflammasome by malvidin. Finally, immunoprecipitation assays showed that malvidin promoted PGC-1α and Nrf2 interactions. Overall, malvidin alleviated lipopolysaccharide-induced sepsis AKI, improved mitochondrial function and mitochondrial biogenesis, and inhibited the NLRP3 inflammasome through the PGC-1α/Nrf2 signaling pathway, suggesting that malvidin might translate into clinical applications for sepsis AKI therapy. • Mv inhibited NLRP3 inflammasome and oxidative stress both in vitro and in vivo. • Mv reduced mitochondrial dysfunction and promoted mitochondrial biogenesis. • Mv's inhibitory impact on NLRP3 inflammasome activation was regulated by the PGC-1/Nrf2 signaling pathway. • Mv can facilitate the interaction between PGC-1α and Nrf2. [ABSTRACT FROM AUTHOR]

Abstract Retinal pigment epithelium (RPE) dysfunction is thought to increase the risk of the development and progression of diabetic retinopathy (DR), the leading cause of blindness. However, the molecular mechanism behind high glucose-induced RPE cell damage is still blurred. We reported that ARPE-19 exposed to 25 mM glucose for 48 h did not induce apoptosis, but senescence validated by SA-β-Gal staining, p21 expression and cell cycle distribution. High glucose also increased oxidant species that exerted a pivotal role in senescence, which could be relieved by the treatment with antioxidant N-acetylcysteine (NAC). The accumulation of lipid droplets and the increase of lipid oxidation were also observed in ARPE-19 treated with high glucose. And the supplementation of free fatty acids (FFAs) indicated that lipid metabolism was associated with the generation of hydrogen peroxide (H 2 O 2) and subsequent senescence in ARPE-19. PI3K/Akt/mTOR signaling pathway was shown to be responsible for the accumulation of intracellular lipids by regulating fatty acid synthesis, which in turn controlled senescence. Furthermore, high glucose induced autophagy in ARPE-19 with the treatment of glucose for 48 h, and autophagy inhibitor hydroxychloroquine (HCQ) or bafilomycin further aggravated the senescence, accompanying by an increase in oxidant species. Whereas, prolonged high glucose exposure inhibited autophagy and increased apoptotic cells. Experiments above provide evidence that lipid metabolism plays an important role in oxidative stressed senescence of RPE. Graphical abstract fx1 Highlights • Early high glucose exposure induces RPE cell senescence rather than apoptosis. • Fatty acid synthesis induced by high glucose through PI3K/AKT/mTOR pathway leads to lipid accumulation. • Lipid oxidation contributes to high glucose-induced RPE senescence by accumulating oxidant species. • Early high glucose treatment induces protective autophagy, while prolonged high glucose exposure inhibits autophagy. [ABSTRACT FROM AUTHOR]

[Display omitted] Several interleukins (ILs) have been demonstrated to participate in cardiac injury. This study aimed to investigate whether IL-27p28 plays a regulatory role in doxorubicin (DOX)-induced cardiac injury by regulating inflammation and oxidative stress. Dox was used to establish a mouse cardiac injury model, and IL-27p28 was knocked out to observe its role in cardiac injury. In addition, monocytes were adoptively transferred to clarify whether monocyte-macrophages mediate the regulatory role of IL-27p28 in DOX-induced cardiac injury. IL-27p28 knockout significantly aggravated DOX-induced cardiac injury and cardiac dysfunction. IL-27p28 knockout also upregulated the phosphorylation levels of p65 and STAT1 and promoted M1 macrophage polarization in DOX-treated mice, which increased cardiac inflammation and oxidative stress. Moreover, IL-27p28-knockout mice that were adoptively transferred WT monocytes exhibited worse cardiac injury and cardiac dysfunction and higher cardiac inflammation and oxidative stress. IL-27p28 knockdown aggravates DOX-induced cardiac injury by worsening the M1 macrophage/M2 macrophage imbalance and its associated inflammatory response and oxidative stress. [ABSTRACT FROM AUTHOR]

Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic Oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation. [ABSTRACT FROM AUTHOR]

Maresin 1 (MaR1) is a pro-resolving lipid mediator that has been reported to have strong regulatory effects on oxidative stress and inflammation. This study aimed to determine the effect of MaR1 on lipopolysaccharide (LPS)-induced sepsis-related cardiac injury and explore its possible mechanisms. Mice were administered MaR1 or PBS and then treated with LPS or saline for 6 h. Then, cardiac function, cardiac injury markers, cardiac macrophage differentiation, oxidative stress and myocardial cell apoptosis in each group were measured. MaR1 treatment significantly decreased the serum levels of lactate dehydrogenase (LDH) and kinase isoenzyme (CK-MB) and improved cardiac function in LPS-induced mice. Treatment with MaR1 also inhibited LPS-induced M1 macrophage differentiation and reduced M1 macrophage-related cytokine secretion while promoting M2 macrophage differentiation and increasing M2 macrophage-related inflammatory mediator expression. In addition, MaR1 decreased serum malondialdehyde (MDA) levels and increased serum levels of superoxide dismutase (SOD) and glutathione (GSH), as well as cardiac expression of nuclear factor erythroid-2 related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1), in LPS-induced mice. Furthermore, fewer TUNEL-positive cells were observed in the LPS + MaR1 group than in the LPS group. Our experimental results show that MaR1 alleviates cardiac injury and protects against cardiac dysfunction and may be beneficial in reducing sepsis-induced cardiac injury. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX)-induced cardiotoxicity impairs the quality of life of cancer patients during or after DOX treatment, and it is imperative to explore a novel strategy to address this problem. Resolvin E1 (RvE1) is derived from eicosapentaenoic acid (EPA), which has been reported to exert beneficial effects on DOX-induced oxidative stress in cardiomyocytes. This study was designed to investigate whether RvE1 protects against DOX-induced cardiotoxicity, and the underlying mechanism was explored. DOX (20 mg/kg, one injection, i.p.) was used to induce DOX-induced cardiotoxicity in C57BL/6 mice. At 5 days after DOX administration, the effect of RvE1 was assessed by measuring cardiac function, oxidative stress, autophagy and apoptosis in cardiac tissue. We used an AKT inhibitor and rapamycin to investigate the underlying mechanisms. Our results showed that RvE1 inhibited the DOX-induced decrease in body weight and heart weight, the reduction in left ventricular ejection fraction and fractional shortening, and the increase in lactate dehydrogenase, creatine kinase myocardial bound and cardiomyocyte vacuolization. Compared to the control group, the DOX group exhibited increased oxidative stress, autophagy and apoptosis in cardiac tissue, which were alleviated by treatment with RvE1. The AKT/mTOR signaling pathways were responsible for RvE1-mediated regulation of DOX-induced oxidative stress, autophagy and myocardial apoptosis. In conclusion, RvE1 protected against DOX-induced cardiotoxicity via the regulation of AKT/mTOR signaling. [ABSTRACT FROM AUTHOR]