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The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level globally, which is recognized to form non-alcoholic steatohepatitis (NASH) by the "two-hit" model, including oxidative stress and inflammation. AMP-activated protein kinase (AMPK) has long been regarded as a key regulator of energy metabolism, which is recognized as a critical target for NAFLD treatment. Here we introduce a natural product, demethyleneberberine (DMB), which potentially ameliorated NAFLD by activating AMPK pathways. Our study showed that the intraperitoneal injection of DMB (20 or 40 mg/kg body weight) decreased hepatic lipid accumulation in methionine and choline deficient (MCD) high-fat diet feeding mice and db/db mice. The further investigation demonstrated that DMB activated AMPK by increasing its phosphorylation in vitro and in vivo. Accompanied with AMPK activation, the expression of lipogenic genes were significantly reduced while genes responsible for the fatty acid β-oxidation were restored in DMB-treated NAFLD mice. In addition, the remarkable oxidative damage and inflammation induced by NAFLD were both attenuated by DMB treatment, which is reflected by decreased lipid oxidative product, malonaldehyde (MDA) and inflammatory factors, tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). Based on all above, DMB could serve as a novel AMPK activator for treating NAFLD and preventing the pathologic progression from NAFLD to NASH by inhibiting the oxidative stress and inflammation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Excessive alcohol consumption induces oxidative stress and lipid accumulation in the liver. Mitochondria have long been recognized as the key target for alcoholic liver disease (ALD). Recently, the artificial mitochondria-targeted antioxidant MitoQ has been used to treat ALD effectively in mice. Here, we introduce the natural mitochondria-targeted antioxidant demethyleneberberine (DMB), which has been found in Chinese herb Cortex Phellodendri chinensis. The protective effect of DMB on ALD was evaluated with HepG2 cells and acutely/chronically ethanol-fed mice, mimicking two common patterns of drinking in human. The results showed that DMB, which is composed of a potential antioxidant structure, could penetrate the membrane of mitochondria and accumulate in mitochondria either in vitro or in vivo. Consequently, the acute drinking-caused oxidative stress and mitochondrial dysfunction were significantly ameliorated by DMB. Moreover, we also found that DMB suppressed CYP2E1, hypoxia inducible factor α, and inducible nitric oxide synthase, which contributed to oxidative stress and restored sirtuin 1/AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ coactivator-1α pathway-associated fatty acid oxidation in chronic ethanol-fed mice, which in turn ameliorated lipid peroxidation and macrosteatosis in the liver. Taking these findings together, DMB could serve as a novel and potential therapy for ALD in human beings., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Alcohol consumption is customary in many cultures and it is a common human behavior worldwide. Binge ethanol and chronic alcohol consumption, two usual drinking patterns of human beings, produce a state of oxidative stress in liver and disturb the liver function. However, a safe and effective therapy for alcoholic liver disease in humans is still elusive. This study identified the natural product berberine as a potential agent for treating or preventing ethanol-induced liver injury. We demonstrated that berberine attenuated oxidative stress resulted from binge drinking in liver by reducing hepatic lipid peroxidation, glutathione exhaust and mitochondrial oxidative damage. Furthermore, berberine also prevented the oxidative stress and macrosteatosis in response to chronic ethanol exposure in mice. Either the total cytochrome P450 2E1 or the mitochondria-located cytochrome P450 2E1, which is implicated in ethanol-mediated oxidative stress, was suppressed by berberine. On the other hand, berberine significantly blunted the lipid accumulation in liver due to chronic alcohol consumption, at least partially, through restoring peroxisome proliferator-activated receptor α/peroxisome proliferator-activated receptor-gamma Co-activator-1α and hepatocyte nuclear factor 4α/microsomal triglyceride transfer protein pathways. These findings suggested that berberine could serve as a potential agent for preventing or treating human alcoholic liver disease.

Purpose: The nonsteroidal antiinflammatory drug sulindac is a promising chemopreventive agent against colon cancer. Here, we address whether sulindac enhances the anticancer effects of the proteasome inhibitor bortezomib (PS-341) in colon cancer cells., Experimental Design: The synergistic effects of sulindac with bortezomib were evaluated by cell death, colony formation assay, DNA fragmentation, and tumor progression of DLD-1 xenografts. Reactive oxygen species (ROS) generation was detected using carboxy-H2DCFDA or dihydroethidium. Oxidative stress was evaluated by heme oxygenase-1 induction and stress-activated mitogen-activated protein kinases p38 and c-Jun-NH2-kinase phosphorylation. Oxidative DNA damage was evaluated by histone H2AX phosphorylation and accumulation of 8-hydroxy-2'-deoxyguanosine., Results: Sulindac and its metabolites enhanced the anticancer effects of bortezomib in DLD-1 and BM314 colon cancer cells. Sulindac induced ROS generation and enhanced bortezomib-mediated oxidative stress and subsequent DNA damage. Their combined effects were highly sensitive to free radical scavengers L-N-acetylcysteine and alpha-tocopherol, but were much less sensitive to a p38 inhibitor SB203580., Conclusion: Sulindac synergistically augments the anticancer effects of bortezomib primarily through cooperative ROS generation and oxidative DNA damage, thereby representing a novel combination therapy against colon cancer.

Objective. The use of enalapril in combination with bisoprolol in patients with acute myocardial infarction (AMI) was studied for its effect on cardiac function and inflammatory parameters. Methods. Sixty-two cases of AMI patients admitted to our clinic from November 2019 to November 2021 were selected for the study and grouped according to the random number table method, those enrolled were given conventional treatment such as oxygenation, absolute bed rest, and sedation, and administered low molecular heparin, aspirin, atorvastatin calcium tablets, clopidogrel, and nitrates. The control group (31 cases) was treated with enalapril maleate folic acid tablets, and the treatment group (31 cases) was treated with bisoprolol fumarate tablets on top of the control group, and the efficacy, adverse effects, cardiac function, inflammatory indexes, and oxidative stress indexes of the two arms were contrasted. Results. The incidence of adverse reactions in the therapy cohort was 12.90% higher than that in the controlled arm, but the discrepancy was not medically relevant (P < 0.05). The SOD level was larger than the concentration in the corresponding drug therapy group, and the MDA level was lower than the concentration in the respective test cases (P < 0.05); the incidence of 12.90% adverse reactions in the treatment period was lower than that of 16.13% in the specific drug therapy group, but the variance was not scientifically evident (P > 0.05). Conclusion. Enalapril application combined with bisoprolol in AMI patients is beneficial to boost the efficacy, promote the improvement of cardiac function, reduce the inflammatory response, and improve the oxidative stress with fewer adverse effects, which can ensure the therapeutic security. [ABSTRACT FROM AUTHOR]

Background: As a ubiquitous environmental pollutant, methylmercury (MeHg) induces toxic effects in the nervous system, one of its main targets. However, the exact mechanisms of its neurotoxicity have not been fully elucidated. Hypoxia-inducible factor-1[alpha] (HIF-1[alpha]), a transcription factor, plays a crucial role in adaptive and cytoprotective responses in cells and is involved in cell survival, proliferation, apoptosis, inflammation, angiogenesis, glucose metabolism, erythropoiesis, and other physiological activities. Objectives: The aim of this study was to explore the role of HIF-1[alpha] in response to acute MeHg exposure in rat brain and primary cultured astrocytes to improve understanding of the mechanisms of MeHg-induced neurotoxicity and the development of effective neuroprotective strategies. Methods: Primary rat astrocytes were treated with MeHg (0-10 [micro]M) for 0.5 h. Cell proliferation and cytotoxicity were assessed with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) release assay, respectively. Reactive oxygen species (ROS) levels were analyzed to assess the level of oxidative stress using 2',7'-dichlorofluorescin diacetate (DCFH-DA) fluorescence. HIF-1[alpha], and its downstream proteins, glucose transporter 1 (GLUT-1), erythropoietin (EPO), and vascular endothelial growth factor A (VEGF-A) were analyzed by means of Western blotting. Real-time PCR was used to detect the expression of HIF-1[alpha] mRNA. Pretreatment with protein synthesis inhibitor (CHX), proteasome inhibitor (MG132), or proline hydroxylase inhibitor (DHB) were applied to explore the possible mechanisms of HIF-1[alpha] inhibition by MeHg. To investigate the role of HIF-1[alpha] in MeHg-induced neurotoxicity, cobalt chloride (Co[Cl.sub.2]), 2-methoxyestradiol (2-MeOE2), small interfering RNA (siRNA) transfection and adenovirus overexpression were used. Pretreatment with N-acetyl-L- cysteine (NAC) and vitamin E (Trolox) were used to investigate the putative role of oxidative stress in MeHg-induced alterations in HIF-1[alpha] levels. The expression of HIF-1[alpha] and related downstream proteins was detected in adult rat brain exposed to MeHg (0-10 mg/kg) for 0.5 h in vivo. Results: MeHg caused lower cell proliferation and higher cytotoxicity in primary rat astrocytes in a time- and concentration-dependent manner. In comparison with the control cells, exposure to 10 [micro]M MeHg for 0.5 h significantly inhibited the expression of astrocytic HIF-1[alpha], and the downstream genes GLUT-1, EPO, and VEGF-A (p < 0.05), in the absence of a significant decrease in HIF-1[alpha] mRNA levels. When protein synthesis was inhibited by CHX, MeHg promoted the degradation rate of HIF-1[alpha]. MG132 and DHB significantly blocked the MeHg-induced decrease in HIF-1[alpha] expression (p < 0.05). Overexpression of HIF-1[alpha] significantly attenuated the decline in MeHg-induced cell proliferation, whereas the inhibition of HIF-1[alpha] significantly increased the decline in cell proliferation (p < 0.05). NAC and Trolox, two established antioxidants, reversed the MeHg-induced decline in HIF-1[alpha] protein levels and the decrease in cell proliferation (p < 0.05). MeHg suppressed the expression of HIF- 1[alpha] and related downstream target proteins in adult rat brain. Discussion: MeHg induced a significant reduction in HIF-1[alpha] protein by activating proline hydroxylase (PHD) and the ubiquitin proteasome system (UPS) in primary rat astrocytes. Additionally, ROS scavenging by antioxidants played a neuroprotective role via increasing HIF-1[alpha] expression in response to MeHg toxicity. Moreover, we established that up-regulation of HIF-1[alpha] might serve to mitigate the acute toxicity of MeHg in astrocytes, affording a novel therapeutic target for future exploration. https://doi.org/10.1289/EHP5139, Introduction Methylmercury (MeHg) is a global environmental contaminant targeting the central nervous system (CNS) (Farina and Aschner 2017; Santos et al. 2016). Consumption of MeHg-containing fish products (Canuel et al. [...]

Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress. [ABSTRACT FROM AUTHOR]

This study aimed to explore the effect exerted by oxidative stress on apoptosis‐inducing factors (AIF)‐mediated apoptosis and bovine muscle tenderness during postmortem aging. We investigated the reactive oxygen species (ROS) content, mitochondrial membrane permeability, AIF expression level, nucleus apoptosis, shear force, myofibril fragmentation index, pH, and energy level. According to the results, a rise in ROS content was accompanied by the rise in mitochondrial membrane permeability from 6 to 72 hr. In the meantime, the AIF expression in mitochondria was downregulated significantly within 72 hr. However, samples treated with N‐acetylcysteine had significantly lower ROS content (6 to 72 hr) and mitochondrial membrane permeability (12 to 72 hr) than the control group. Moreover, during postmortem aging, the variations in AIF levels in mitochondria were closely associated with meat tenderization and nucleus apoptosis. These findings demonstrated that oxidative stress induced by ROS significantly promoted AIF release from mitochondria by enhancing the mitochondrial membrane permeability, and the released AIF mediated nucleus apoptosis that further enhanced bovine muscle tenderness. Besides, results suggest that in the early stage, the environmental factors (ATP content and pH) significantly decreased (0 to 72 hr), whereas ROS‐induced oxidative stress had no significant effect on environmental factors. These observations further suggested that during postmortem aging, the decrease of pH and ATP consumption are required by AIF release. We conclude that ROS‐induced oxidative stress and internal environment are vital for meat tenderization through the regulation of AIF‐mediated apoptosis pathway. Practical Application: ROS‐induced oxidative stress contributes to bovine muscle tenderization by promoting cell apoptosis. It is likely to lay a theoretical foundation for developing innovative tenderization techniques by altering the internal oxidation environment of postmortem muscles. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing Akt2 knockout (KO) and Nrf2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury. Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation. The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic. [Display omitted] • AKT2 deficiency alleviates DOX-induced cardiac injury. • AKT2 inhibits NRF2 nucleus translocation in cardiomyocytes upon DOX stimulation. • Inhibition of AKT2 facilitates SOD2 secretion from macrophages. [ABSTRACT FROM AUTHOR]

Acute pneumonia induced by Pseudomonas aeruginosa is characterized by massive infiltration of inflammatory cell and the production of reactive oxygen species (ROS), which lead to severe and transient pulmonary inflammation and acute lung injury. However, P.aeruginosa infection is resistant to multiple antibiotics and causes high mortality in clinic, the search for alternative prophylactic and therapeutic strategies is imperative. This study was aimed to investigate the anti-inflammatory and antioxidant effects of DMB, a novel derivative of berberine, and explore the role of AIM2 inflammasome in P. aeruginosa -induced acute pneumonia. Acute pneumonia mice were established by tracheal injection of P. aeruginosa suspension. Pathological changes of lung tissue were observed by its appearance and H&E staining. The lung coefficient ratio was measured to evaluate pulmonary edema. Inflammatory factors were detected by qRT-PCR, western blotting and immunohistochemistry. ROS and other indicators of oxidative damage were analyzed by flow cytometry and specific kit. Proteins related to AIM2 inflammasome were detected by western blotting. Compared with the P. aeruginosa -induced group, DMB ameliorated pulmonary edema, hyperemia, and pathological damage based on its appearance and H&E staining in DMB groups. First, DMB attenuated the inflammatory response induced by P.aeruginosa. Compared with the P. aeruginosa -induced group, the lung coefficient ratio was decreased by 31.5%, the MPO activity of lung tissue was decreased by 44.0%, the mRNA expression levels of TNF-α, IL-1β and IL-6 were decreased by 64.8%, 51.2% and 64.0% respectively, and those protein expression levels were decreased by 40.1%, 42.8% and 47.8% respectively, and the number of white blood cells, neutrophils and monocytes were decreased by 53.5%, 29.4% and 13.7% in high dose (200 mg/kg) DMB group. Second, DMB alleviates oxidative stress in the lung tissue during P. aeruginosa -induced acute pneumonia. Compared with the P. aeruginosa -induced group, the level of GSH was increased by 42.5% and MDA was decreased by 49.5% in high dose DMB group. Moreover, the western blotting results showed that DMB markedly suppressed the expression of AIM2, ASC, Cleaved caspase1 and decreased the secretion of IL-1β. Additionally, these results were also confirmed by in vitro experiments using MH-S and BEAS-2B cell lines. Taken together, these results indicated that DMB ameliorates P. aeruginosa -induced acute pneumonia through anti-inflammatory, antioxidant effects, and inhibition of AIM2 inflammasome activation. [ABSTRACT FROM AUTHOR]

• This study investigated the responses of purple lettuce grown under part-time high light. • Short-term high light irradiation promoted biomass production, but the effect on secondary metabolites accumulation was not significant. • 4 h high light irradiation (500 μmol·m−2·s−1) in the middle of 16 h light period induced higher secondary metabolites content but caused stress on lettuce. • The responses of lettuce to high light irradiation are more sensitive in the early growth stage. In this study, effects of high light irradiation (HLI, 500 μmol m−2·s-1) duration in the middle of light period (16 h, 150 μmol m−2·s-1) provided by red (R) and blue (B) LEDs (4R:1B) on the growth, nutritional quality, and oxidative stress of hydroponic purple leaf lettuce grown in an environmentally controlled plant factory were examined on the 10th and 20th day after treatment. Set up five treatments with 0 h (CK), 0.5 h (HL0.5), 1 h (HL1), 2 h (HL2), and 4 h (HL4) HLI, respectively. We found that the shoot fresh weight of lettuce increased first and then decreased with the prolongation of HLI duration, whether in the early or late growth stage. On the 10th day after treatment, the root fresh weight and specific leaf weight of lettuce increased linearly with the prolongation of HLI duration, while the shoot/root ratio decreased linearly. On the 20th day after treatment, the lettuce of HL1 had the highest shoot fresh weight, leaf area, and shoot dry weight, followed by HL2. Besides, HL4 promoted the accumulation of soluble sugar, anthocyanin, flavonoid, and total phenolic simultaneously decreased the maximum quantum efficiency compared with others on the 10th day after treatment. On the 20th day after treatment, HL0.5 and HL4 stimulated the accumulation anthocyanin, flavonoid, total phenolic, and ascorbic acid compared with other treatments. The results showed that short-term HLI promotes biomass production and secondary metabolite accumulation, but HL4 caused photo-oxidative damage to lettuce. Therefore, lettuce growth and qualities can be purposely adjusted by adopting different duration of HLI provided by red and blue light in the plant factory, also these responses depended on lettuce growth stage closely. [ABSTRACT FROM AUTHOR]