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Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2-null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2-knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron's plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a major cause of drug‐induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP‐induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5‐ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Aims: Preterm birth (PTB), recognized as delivery before 37 weeks of gestation, is a multifactorial syndrome characterizing as the main cause of neonatal mortality. Reactive oxygen species (ROS) have been identified as proinflammatory factors to cause placental inflammation, thereby resulting in several pregnancy outcomes. To date, limited knowledge regarding the underlying mechanisms of ROS-induced PTB has been reported. In this study, we aimed to investigate the role of oxidative stress in PTB and the protective effects of mitochondria-targeted antioxidant MitoTEMPO (MT) on preterm labor and offspring mice. Results: In this study, we found that preterm placentas had abnormal mitochondrial function, oxidative stress, and inflammatory response. In the lipopolysaccharide (LPS)-induced PTB mouse model, MT inhibited PTB by ameliorating maternal oxidative stress and inflammation, especially in placentas, thus improving placental function to maintain pregnancy. Antenatal administration of MT prevented LPS-induced fetal brain damage in acute phase and improved long-term neurodevelopmental impairments. Furthermore, our in vitro investigations validated that MT retarded the ROS accumulation and inflammatory response in LPS-stimulated trophoblast cells by promoting Kelch-like ECH-associated protein 1 (Keap1) degradation and subsequently activating nuclear factor erythroid 2-related factor 2 (Nrf2). By inhibiting Nrf2 activation, we discovered that the anti-inflammation and protective characteristics of MT were Nrf2/ARE pathway dependent. Innovation and Conclusion: MT inhibited PTB and fetal brain injury by inhibiting maternal inflammation and improving placental function through Keap1/Nrf2/antioxidant response element signaling pathway. Our findings provide a novel therapeutic strategy for PTB. Antioxid. Redox Signal. 41, 597–615. [ABSTRACT FROM AUTHOR]

Naringenin, a potent antioxidant with anti-apoptotic effects, holds potential in counteracting rotenone-induced neurotoxicity, a model for Parkinson's disease, by reducing oxidative stress and supporting mitochondrial function. Rotenone disrupts ATP production in SH-SY5Y cells through mitochondrial complex-I inhibition, leading to increased reactive oxygen species (ROS) and cellular damage. However, the therapeutic use of naringenin is limited by its poor solubility, low bioavailability, and stability concerns. Nano crystallization of naringenin (NCs), significantly improved its solubility, dissolution rates, and stability for targeted drug delivery. The developed NAR-NC and HSA-NAR-NC formulations exhibit particle sizes of 95.23 nm and 147.89 nm, with zeta potentials of -20.6 mV and -28.5 mV, respectively. These nanocrystals also maintain high drug content and show stability over time, confirming their pharmaceutical viability. In studies using the SH-SY5Y cell line, these modified nanocrystals effectively preserved mitochondrial membrane potential, sustained ATP production, and regulated ROS levels, counteracting the neurotoxic effects of rotenone. Naringenin nanocrystals offer a promising solution for improving the stability and bioavailability of naringenin, with potential therapeutic applications in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

UNC-51-like kinase 1( ULK1) is an important factor involved in regulating the initiation of autophagy. ULK1 regulates inflammatory cytokines through autophagy and mitochondrial oxidative stress, and is involved in the pathological processes of various diseases. ULK1 and its complexes are regulated by rapamycin( mTOR) and AMP-activated protein kinase( AMPK) to initiate autophagy, thereby exerting differential effects on a variety of inflammatory diseases. In inflammatory diseases, mitochondrial oxidative stress can induce ULK1 into the nucleus to accelerate apoptosis. Therefore, ULK1 plays different important roles in inflammatory diseases. For example, ULK1 initiates airway epithelial mitochondrial autophagy in asthma, participates in mitochondrial oxidative stress in acute liver failure, affects related inflammatory factors in atherosclerosis, and modulates beneficial effects of autophagy in diabetes. This article reviews the biological function of ULK1, its impact on inflammatory diseases and the research progress of targeted drugs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and tau phosphorylation-induced neurofibrillary tangles. This review comprehensively summarizes AD pathogenesis and related factors, drawing on a wealth of authoritative reports and research findings. Specifically, we delve into the intricate mechanisms underlying AD pathology, including Aβ deposition, tau protein phosphorylation, cholinergic dysfunction, neuroinflammation, mitochondrial oxidative stress, ferroptosis, imbalance in the gut microbiota, and microRNA dysregulation. We also explored the effects of these factors on the brain, including synaptic damage and cognitive impairment. Moreover, our review highlights the associations between the pathogenesis of AD and inflammatory cytokines in the peripheral blood and cerebrospinal fluid, dysbiosis of the gut microbiota, and changes in microRNA expression. Overall, we provided a systematic and illustrative overview of the pathogenesis and therapeutic drugs for AD, offering help in the prevention and treatment of this condition.

Abstract Acetaminophen (APAP) overdose is a major cause of drug‐induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP‐induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5‐ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention.

Photothermal therapy (PTT) may lead to healthy tissue damage, tumor metastasis, and recurrence, which makes mild photothermal therapy (mild PTT) stand out. However, overcoming heat resistance, insufficient therapeutic effect, and poor photothermal conversion efficiency has become new challenge. Herein, we report a dynamic supramolecular nanocarrier formed from amide-sericin and aldehyde-polyhydroxy glucan (denoted as SDA), the loose cavity of which can be filled by using the pharmaceutical combination of lonidamine (LND) and NIR-II photothermal agent of IR-1061, producing SDLI with a tighter inner hole, smaller and uniform particle size and excellent stability due to multiple pulling forces. Moreover, the intricate internal network structure prevents the hydrophobic IR-1061 from forming aggregates in the small cavity, and the photothermal conversion efficiency (PCE) can reach 48.9%. At the acidic tumor microenvironment of pH 6.5, the controlled release of LND can solve the problem of heat resistance of NIR-II mild PTT and significantly improve the therapeutic effect of NIR-II mild PTT. Meanwhile, SDLI also shows a reasonable tumor inhibition rate, so the synergistic strategy of inhibiting tumor energy metabolism and NIR-II mild PTT to magnify mitochondrial oxidative stress, continuous cell stress state-induced immunogenic cell death to promote the induction of tumor apoptosis is proposed to achieve more effective cancer treatment. [ABSTRACT FROM AUTHOR]

Aims: Mitochondrial dysfunction is the primary mechanism of liver ischemia/reperfusion (I/R) injury. The lysine desuccinylase sirtuin 5 (SIRT5) is a global regulator of the mitochondrial succinylome and has pivotal roles in mitochondrial metabolism and function; however, its hepatoprotective capacity in liver I/R remains unclear. In this study, we established liver I/R model in SIRT5-silenced and SIRT5-overexpressed mice to examine the role and precise mechanisms of SIRT5 in liver I/R injury. Results: Succinylation was strongly enriched in liver mitochondria during I/R, and inhibiting mitochondrial succinylation significantly attenuated liver I/R injury. Importantly, the levels of the desuccinylase SIRT5 were notably decreased in liver transplant patients, as well as in mice subjected to I/R and in AML12 cells exposed to hypoxia/reoxygenation. Furthermore, SIRT5 significantly ameliorated liver I/R-induced oxidative injury, apoptosis, and inflammation by regulating mitochondrial oxidative stress and function. Intriguingly, the hepatoprotective effect of SIRT5 was mediated by PRDX3. Mechanistically, SIRT5 specifically desuccinylated PRDX3 at the K84 site, which enabled PRDX3 to alleviate mitochondrial oxidative stress during liver I/R. Innovation: This study denoted the new effect and mechanism of SIRT5 in regulating mitochondrial oxidative stress through lysine desuccinylation, thus preventing liver I/R injury. Conclusions: Our findings demonstrate for the first time that SIRT5 is a key mediator of liver I/R that regulates mitochondrial oxidative stress through the desuccinylation of PRDX3, which provides a novel strategy to prevent liver I/R injury. Antioxid. Redox Signal. 40, 616–631. [ABSTRACT FROM AUTHOR]

Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through its copper chelating derivatives and induction of oxidative stress in mitochondria. Since chronic/persistent borreliosis is characterized by increased amounts of pro-inflammatory macrophages, this study investigated opsonin-independent phagocytosis, migration, and surface marker expression of in vivo activated and in vitro cultured human monocyte-derived phagocytes (macrophages and dendritic cells) with and without DSF treatment. Phagocytosis of non-opsonized Dynabeads® M-450 and migration of macrophages and dendritic cells were monitored using live cell analyzer Juli™ Br for 24 h, imaging every 3.5 min. To simultaneously monitor phagocyte function, results were analyzed by a newly developed software based on the differential phase contrast images of cells before and after ingestion of Dynabeads. DSF decreased the phagocytic capacities exhibited by in vitro enriched and long-lived phagocytes. Although no chemotactic gradient was applied to the test system, vigorous spontaneous migration was observed. We therefore set up an algorithm to monitor and quantify both phagocytosis and migration simultaneously. DSF not only reduced phagocytosis in a majority of these long-lived phagocytes but also impaired their migration. Despite these selective effects by DSF, we found that DSF reduced the expression densities of surface antigens CD45 and CD14 in all of our long-lived phagocytes. In cells with a high metabolic activity and high mitochondrial contents, DSF led to cell death corresponding to mitochondrial oxidative stress, whereas metabolically inactive phagocytes survived our DSF treatment protocol. In conclusion, DSF affects the viability of metabolically active phagocytes by inducing mitochondrial stress and secondly attenuates phagocytosis and migration in some long-lived phagocytes. [ABSTRACT FROM AUTHOR]

Aims: Studies demonstrated that oxidized fish oil (OFO) promoted oxidative stress and induced mitochondrial dysfunction and lipotoxicity, which attenuated beneficial effects of fish oil supplements in the treatment of nonalcoholic fatty liver disease (NAFLD). The current study was performed on yellow catfish, a good model to study NAFLD, and its hepatocytes to explore whether selenium (Se) could alleviate OFO-induced lipotoxicity via the inhibition of oxidative stress and determine its potential mechanism. Results: The analysis of triglycerides content, oxidative stress parameters, and histological and transmission electronic microscopy observation showed that high dietary Se supplementation alleviated OFO-induced lipotoxicity, oxidative stress, and mitochondrial injury and dysfunction. RNA-sequencing and immunoblotting analysis indicated that high dietary Se reduced OFO-induced decline of peroxisome-proliferator-activated receptor alpha (Pparα) and ubiquitin-specific protease 4 (Usp4) protein expression. High Se supplementation also alleviated OFO-induced reduction of thioredoxin reductase 2 (txnrd2) messenger RNA (mRNA) expression level and activity. The txnrd2 knockdown experiments revealed that txnrd2 mediated Se- and oxidized eicosapentaenoic acid (oxEPA)-induced changes of mitochondrial reactive oxygen species (mtROS) and further altered Usp4 mediated-deubiquitination and stabilization of Pparα, which, in turn, modulated mitochondrial fatty acid β-oxidation and metabolism. Mechanistically, Usp4 deubiquitinated Pparα and ubiquitin-proteasome-mediated Pparα degradation contributed to oxidative stress-induced mitochondrial dysfunction. Innovation: These findings uncovered a previously unknown mechanism by which Se and OFO interacted to affect lipid metabolism via the Txnrd2-mtROS-Usp4-Pparα pathway, which provides the new target for NAFLD prevention and treatment. Conclusion: Se ameliorated OFO-induced lipotoxicity via the inhibition of mitochondrial oxidative stress, remodeling of Usp4-mediated deubiquitination, and stabilization of Pparα. Antioxid. Redox Signal. 40, 433–452. [ABSTRACT FROM AUTHOR]

Reducing mitochondrial oxidative stress has become an important strategy to prevent neuronal death in ischemic stroke. Previous studies have shown that 20(R)‐ginsenoside Rg3 can significantly improve behavioral abnormalities, reduce infarct size, and decrease the number of apoptotic neurons in cerebral ischemia/reperfusion injury rats. However, it remains unclear whether 20(R)‐ginsenoside Rg3 can inhibit mitochondrial oxidative stress in ischemic stroke and the potential molecular mechanism. In this study, we found that 20(R)‐ginsenoside Rg3 notably inhibited mitochondrial oxidative stress in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and maintained the stability of mitochondrial structure and function. Treatment with 20(R)‐ginsenoside Rg3 also decreased the levels of mitochondrial fission proteins (Drp1 and Fis1) and increased the levels of fusion proteins (Opa1, Mfn1, and Mfn2) in MCAO/R rats. Furthermore, we found that 20(R)‐ginsenoside Rg3 promoted nuclear aggregation of nuclear factor erythroid2‐related factor 2 (Nrf2) but did not affect Kelch‐like ECH‐associated protein‐1 (Keap1), resulting in the downstream expression of antioxidants. In in vitro oxygen‐glucose deprivation/reperfusion stroke models, the results of PC12 cells treated with 20(R)‐ginsenoside Rg3 were consistent with animal experiments. After transfection with Nrf2 short interfering RNA (siRNA), the protective effect of 20(R)‐ginsenoside Rg3 on PC12 cells was reversed. In conclusion, the inhibition of mitochondrial oxidative stress plays a vital position in the anti‐cerebral ischemia‐reperfusion injury of 20(R)‐ginsenoside Rg3, and its neuroprotective mechanism is related to the activation of the nuclear factor erythroid2‐related factor 2/heme oxygenase 1 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Targeting mitochondrial oxidative stress can be a promising strategy for the prevention of hepatocellular carcinoma (HCC). In the current study, we investigated the modulatory effect of mitochondria-targeted antioxidant, mitoQ against N-nitrosodiethylamine (NDEA)-induced hepatic damage in mouse. Methods: BALB/c mice were administered NDEA (10 mg/kg b. w., single dose, intraperitoneally) and the hepatoprotective effect of mitoQ was studied by administering mitoQ (0.125 mg/kg b. w., orally once a week) to the animals. The administration of mitoQ started two weeks prior the NDEA administration. The animals were sacrificed 24 h following NDEA administration after which the blood samples and hepatic tissues were collected. Serum was used for the estimation of liver injury markers and hepatic tissues were analyzed for histopathological changes, antioxidant defense status, mitochondrial functional status, level of mitochondrial reactive oxygen species (mtROS) and mitochondrial lipid peroxidation (mtLPO). Results: MitoQ treatment to the NDEA-challenged group normalized liver injury markers, level of mtROS and mtLPO. MitoQ treatment also improved the status of mitochondrial antioxidant defense system, mitochondrial complex enzymes. Conclusion: Our findings indicate that mito-Q significantly protected against NDEA-induced hepatic damage by modulating mitochondrial function and redox status which may be one of the causes of its purported chemopreventive effect.

Ischemic heart disease invariably leads to devastating damage to human health. Nicotinamide ribose (NR), as one of the precursors of NAD+ synthesis, has been discovered to exert a protective role in various neurological and cardiovascular disorders. Our findings demonstrated that pretreatment with 200 mg/kg NR for 3 h significantly reduced myocardial infarct area, decreased levels of CK-MB and LDH in serum, and improved cardiac function in the rats during myocardial ischemia-reperfusion (I/R) injury. Meanwhile, 0.5 mM NR also effectively increased the viability and decreased the LDH release of H9c2 cells during OGD/R. We had provided evidence that NR pretreatment could decrease mitochondrial reactive oxygen species (mtROS) production and MDA content, and enhance SOD activity, thereby mitigating mitochondrial damage and inhibiting apoptosis during myocardial I/R injury. Further investigations revealed that NR increased NAD+ content and upregulated SIRT3 protein expression in myocardium. Through using of SIRT3 small interfering RNA and the SIRT3 deacetylase activity inhibitor 3-TYP, we had confirmed that the cardioprotective effect of NR on cardiomyocytes was largely dependent on the inhibition of mitochondrial oxidative stress via SIRT3-SOD2 axis. Overall, our study suggested that exogenous supplementation with NR mitigated mitochondrial damage and inhibited apoptosis during myocardial I/R injury by reducing mitochondrial oxidative stress via SIRT3-SOD2-mtROS pathway.

Manganese (Mn) is an essential element for maintaining normal metabolism in vertebrates. Mn dioxide nanoparticles (MnO 2 NPs), a novel Mn source, have shown great potentials in biological and biomedical applications due to their distinct physical and chemical properties. However, little is known about potential adverse effects on animal or cellular metabolism. Here, we investigated whether and how dietary MnO 2 NPs affect hepatic lipid metabolism in vertebrates. We found that, excessive MnO 2 NPs intake increased hepatic and mitochondrial Mn content, promoted hepatic lipotoxic disease and lipogenesis, and inhibited hepatic lipolysis and fatty acid β-oxidation. Moreover, excessive MnO 2 NPs intake induced hepatic mitochondrial oxidative stress, damaged mitochondrial function, disrupted mitochondrial dynamics and activated mitophagy. Importantly, we uncovered that mtROS-activated phosphorylation of heat shock factor 1 (Hsf1) at Ser326 residue mediated MnO 2 NPs-induced hepatic lipotoxic disease and mitophagy. Mechanistically, MnO 2 NPs-induced lipotoxicity and mitophagy were via mtROS-induced phosphorylation and nucleus translocation of Hsf1 and its DNA binding capacity to plin2 / dgat1 and bnip3 promoters, respectively. Overall, our findings uncover novel mechanisms by which mtROS-mediated mitochondrial dysfunction and phosphorylation of Hsf1S326 contribute to MnO 2 NPs-induced hepatic lipotoxicity and mitophagy, which provide new insights into the effects of metal oxides nanoparticles on hepatotoxicity in vertebrates. [Display omitted] • MnO 2 NPs increased Mn and lipid contents, promoted lipogenesis, and inhibited lipolysis and fatty acid β-oxidation. • MnO 2 NPs induced mitochondrial oxidative stress, damaged mitochondrial structure and function, and activated mitophagy. • mtROS-activated phosphorylation of Hsf1Ser326 residue mediated MnO 2 NPs-induced hepatic lipotoxicity and mitophagy. • MnO 2 NPs-induced lipotoxicity and mitophagy were via mtROS-induced Hsf1 phosphorylation and bnip3 activation. • Hsf1 mediated MnO 2 NPs-induced lipotoxicity through transcriptional activation of plin2 and dgat1. [ABSTRACT FROM AUTHOR]

Diets with an elevated content of fat, sucrose, or fructose are recognized models of diet-induced metabolic alterations, since they induce metabolic derangements, oxidative stress, and chronic low-grade inflammation associated with local and systemic accumulation of advanced glycation end-products (AGEs). This study used four-week-old C57BL/6 male mice, randomly assigned to three experimental dietary regimens: standard diet (SD), high-fat high-sucrose diet (HFHS), or high fructose diet (HFr), administered for 12 weeks. Plasma, heart, and tibialis anterior (TA) skeletal muscle were assayed for markers of metabolic conditions, inflammation, presence of AGEs, and mitochondrial involvement. The HFHS diet induced a tissue-specific differential response featuring (1) a remarkable adaptation of the heart to HFHS-induced heavy oxidative stress, demonstrated by an increased presence of AGEs and reduced mitochondrial biogenesis, and efficaciously counteracted by a conspicuous increase in mitochondrial fission and PRXIII expression; (2) the absence of TA adaptation to HFHS, revealed by a heavy reduction in mitochondrial biogenesis, not counteracted by an increase in fission and PRXIII expression. HFr-induced mild oxidative stress elicited tissue-specific responses, featuring (1) a decrease in mitochondrial biogenesis in the heart, likely counteracted by a tendency for increased fission and (2) a mild reduction in mitochondrial biogenesis in TA, likely counteracted by a tendency for increased fusion, showing the adaptability of both tissues to the diet. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1), an extremely toxic mycotoxin that extensively contaminates feed and food worldwide, poses a major hazard to poultry and human health. Curcumin, a polyphenol derived from turmeric, has attracted great attention due to its wonderful antioxidant properties. Nevertheless, effects of curcumin on the kidneys of ducks exposed to AFB1 remain unclear. Additionally, the underlying mechanism between AFB1 and ferroptosis (based on excessive lipid peroxidation) has not been sufficiently elucidated. This study aimed to investigate the protective effects and potential mechanisms of curcumin against AFB1-induced nephrotoxicity in ducklings. The results indicated that curcumin alleviated AFB1-induced growth retardation and renal distorted structure in ducklings. Concurrently, curcumin inhibited AFB1-induced mitochondrial-mediated oxidative stress by reducing the expression levels of oxidative damage markers malondialdehyde (MDA) and 8-hydroxy-2 deoxyguanosine (8-OHdG) and improved the expression of mitochondria-related antioxidant enzymes and the Nrf2 pathway. Notably, curcumin attenuated iron accumulation in the kidney, inhibited ferritinophagy via the NCOA4 pathway, and balanced iron homeostasis, thereby alleviating AFB1-induced ferroptosis in the kidney. Collectively, our results suggest that curcumin alleviates AFB1-induced nephrotoxicity in ducks by inhibiting mitochondrial-mediated oxidative stress, ferritinophagy, and ferroptosis and provide new evidence for the mechanism of AFB1-induced nephrotoxicity in ducklings treated with curcumin. [ABSTRACT FROM AUTHOR]

Objective To investigate the inhibitory effect of metformin on the proliferation and migration of esophageal squamous cell carcinoma, and the regulatory mechanism of the growth ⁃arrest ⁃specific 6 (Gas6) and its ligand Axl. Methods The EC109 and TE ⁃1 cells of esophageal squamous cell carcinoma were treated with different concentrations of metformin. The cell proliferation was measured by the CCK⁃8 assay or the plate clone formation. The migration ability was detected by wound healing and transwell migration assays. Apoptosis was detected by TUNEL assay and the mitochondrial oxidative stress state was detected by Mito⁃SOX. The revealed mitochondrial membrane potential (MMP) was measured by JC⁃1 staining. The expression of Gas6 was detected by immunofluorescence and by the changes of the Gas6/Axl pathway and apoptosis⁃related proteins were analyzed using Western blot. In addition, after treatment with Axl inhibitor (bemcentinib, R428), the effect of metformin on the proliferation, migration of EC109 cells, and subcutaneous tumor formation in nude mice were observed. Results Metformin significantly decreased the cell viability of EC109 and TE⁃1 cells compared to the control group ( PEC109<0.001; PTE⁃1<0.001), while the effect was not significant on the activity of Het⁃1A cells (P=0.380). Metformin inhibited the colony formation (P=0.002) and migration (P<0.001) of EC109 cells, and increased the apoptosis rate (P=0.002), inducing a dose ⁃dependent increase in mitochondrial reactive oxygen species (P<0.001) and decreasing MMP levels (P<0.001). Furthermore, Metformin reduced Gas6 fluorescence intensity in EC109 cells, blocked Gas6 expression in EC109 and TE⁃1 cells, down⁃regulated the levels of p⁃Axl, Axl and Bcl2 in EC109 cells, and increased the activities of Bax, cytochrome C and Caspase3 in EC109 cells. In addition, compared with metformin alone, metformin combined with R428 demonstrated superior efficacy in inhibiting tumor growth, migration and subcutaneous tumor formation in nude mice. Conclusions Metformin can regulate mitochondrial homeostasis, activate an oxidative stress⁃induced apoptotic response, and exert anti⁃proliferative and anti⁃migrative effects on EC109 cells, which may be associated with the down⁃regulation of Gas6/Axl signaling pathway. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca2+ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca2+ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF. [ABSTRACT FROM AUTHOR]

Periodontitis is an inflammatory and destructive disease of tooth‐supporting tissue and has become the leading cause of adult tooth loss. The most central pathological features of periodontitis are tissue damage and inflammatory reaction. As the energy metabolism center of eukaryotic cells, mitochondrion plays a notable role in various processes, such as cell function and inflammatory response. When the intracellular homeostasis of mitochondrion is disrupted, it can lead to mitochondrial dysfunction and inability to generate adequate energy to maintain basic cellular biochemical reactions. Recent studies have revealed that mitochondrial dysfunction is closely related to the initiation and development of periodontitis. The excessive production of mitochondrial reactive oxygen species, imbalance of mitochondrial biogenesis and dynamics, mitophagy and mitochondrial DNA damage can all affect the development and progression of periodontitis. Thus, targeted mitochondrial therapy is potentially promising in periodontitis treatment. In this review, we summarize the above mitochondrial mechanism in the pathogenesis of periodontitis and discuss some potential approaches that can exert therapeutic effects on periodontitis by modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in periodontitis might provide new research directions for pathological intervention or treatment of periodontitis. [ABSTRACT FROM AUTHOR]

Mitochondrial oxidative stress has been implicated in various forms of brain injury, both traumatic and non-traumatic. Due to its oxidative demand, the brain is intimately dependent on its mitochondrial functioning. However, there remains appreciable heterogeneity in the development of these injuries regarding ROS and their effect on the sequelae. These include traumatic insults such as TBIs and intracranial hemorrhaging secondary to this. In a different vein, such injuries may be attributed to other etiologies such as infection, neoplasm, or spontaneous hemorrhage (strokes, aneurysms). Clinically, the manner of treatment may also be adjusted in relation to each injury and its unique progression in the context of ROS. In the current review, then, the authors highlight the role of mitochondrial ROS in various forms of brain injury, emphasizing both the collective and unique elements of each form. Lastly, these narratives are met with the current therapeutic landscape and the role of emerging therapies in treating reactive oxygen species in brain injuries.

Abstract Background Persistent inflammatory response in the brain can lead to tissue damage and neurodegeneration. In Alzheimer's disease (AD), there is an aberrant activation of inflammasomes, molecular platforms that drive inflammation through caspase-1-mediated proteolytic cleavage of proinflammatory cytokines and gasdermin D (GSDMD), the executor of pyroptosis. However, the mechanisms underlying the sustained activation of inflammasomes in AD are largely unknown. We have previously shown that high brain cholesterol levels promote amyloid-β (Aβ) accumulation and oxidative stress. Here, we investigate whether these cholesterol-mediated changes may regulate the inflammasome pathway. Methods SIM-A9 microglia and SH-SY5Y neuroblastoma cells were cholesterol-enriched using a water-soluble cholesterol complex. After exposure to lipopolysaccharide (LPS) plus muramyl dipeptide or Aβ, activation of the inflammasome pathway was analyzed by immunofluorescence, ELISA and immunoblotting analysis. Fluorescently-labeled Aβ was employed to monitor changes in microglia phagocytosis. Conditioned medium was used to study how microglia-neuron interrelationship modulates the inflammasome-mediated response. Results In activated microglia, cholesterol enrichment promoted the release of encapsulated IL-1β accompanied by a switch to a more neuroprotective phenotype, with increased phagocytic capacity and release of neurotrophic factors. In contrast, in SH-SY5Y cells, high cholesterol levels stimulated inflammasome assembly triggered by both bacterial toxins and Aβ peptides, resulting in GSDMD-mediated pyroptosis. Glutathione (GSH) ethyl ester treatment, which recovered the cholesterol-mediated depletion of mitochondrial GSH levels, significantly reduced the Aβ-induced oxidative stress in the neuronal cells, resulting in lower inflammasome activation and cell death. Furthermore, using conditioned media, we showed that neuronal pyroptosis affects the function of the cholesterol-enriched microglia, lowering its phagocytic activity and, therefore, the ability to degrade extracellular Aβ. Conclusions Changes in intracellular cholesterol levels differentially regulate the inflammasome-mediated immune response in microglia and neuronal cells. Given the microglia-neuron cross-talk in the brain, cholesterol modulation should be considered a potential therapeutic target for AD treatment, which may help to block the aberrant and chronic inflammation observed during the disease progression.

Diabetic nephropathy (DN) is one of the serious complications of diabetes mellitus, primarily arising from type 2 diabetes (T2DM), and can progress to chronic kidney disease (CKD) and end stage renal disease (ESRD). The pathogenesis of DN involves various factors such as hemodynamic changes, oxidative stress, inflammatory response, and lipid metabolism disorders. Increasing attention is being given to DN caused by oxidative stress in the mitochondrial pathway, prompting researchers to explore drugs that can regulate these target pathways. Chinese herbal medicine, known for its accessibility, rich historical usage, and remarkable efficacy, has shown promise in ameliorating renal injury caused by DN by modulating oxidative stress in the mitochondrial pathway. This review aims to provide a reference for the prevention and treatment of DN. Firstly, we outline the mechanisms by which mitochondrial dysfunction impairs DN, focusing on outlining the damage to mitochondria by oxidative stress. Subsequently, we describe the process by which formulas, herbs and monomeric compounds protect the kidney by ameliorating oxidative stress in the mitochondrial pathway. Finally, the rich variety of Chinese herbal medicine, combined with modern extraction techniques, has great potential, and as we gradually understand the pathogenesis of DN and research techniques are constantly updated, there will be more and more promising therapeutic targets and herbal drug candidates. This paper aims to provide a reference for the prevention and treatment of DN.

Background: Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity. Methods: Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress. Results: 5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO. Conclusion: Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute kidney injury (SA-AKI) results in significant morbidity and mortality, and ferroptosis may play a role in its pathogenesis. Our aim was to examine the effect of exogenous H2S (GYY4137) on ferroptosis and AKI in in vivo and in vitro models of sepsis and explore the possible mechanism involved. Sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice, which were randomly divided into the sham, CLP, and CLP + GYY4137 group. The indicators of SA-AKI were most prominent at 24 h after CLP, and analysis of the protein expression of ferroptosis indicators showed that ferroptosis was also exacerbated at 24 h after CLP. Moreover, the level of the endogenous H2S synthase CSE (Cystathionine-γ-lyase) and endogenous H2S significantly decreased after CLP. Treatment with GYY4137 reversed or attenuated all these changes. In the in vitro experiments, LPS was used to simulate SA-AKI in mouse renal glomerular endothelial cells (MRGECs). Measurement of ferroptosis-related markers and products of mitochondrial oxidative stress showed that GYY4137 could attenuate ferroptosis and regulate mitochondrial oxidative stress. These findings imply that GYY4137 alleviates SA-AKI by inhibiting ferroptosis triggered by excessive mitochondrial oxidative stress. Thus, GYY4137 may be an effective drug for the clinical treatment of SA-AKI. [ABSTRACT FROM AUTHOR]

The injury of vascular endothelial cell function is the beginning of the pathological process of atherosclerosis. Mitochondrial oxidative stress is closely related to vascular endothelial cell function, which causes the dysfunction of vascular endothelial cell by inducing mitophagy, reducing nitric oxide production, inflammation, cellular metabolic imbalance and apoptosis. Meanwhile, vascular endothelial cell could also maintain their homeostasis by regulating mitochondrial oxidative stress. The molecular signaling pathways of the vascular endothelial cell injury caused by mitochondrial oxidative stress in the pathological process of atherosclerosis were outlined in this review, which provided reference for further research on the molecular mechanism between mitochondrial oxidative stress and endothelial damage. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction, causing increased reactive oxygen species (ROS) production, is a molecular feature of heart failure (HF). A defective antioxidant response and mitophagic flux were reported in circulating leucocytes of patients with chronic HF and reduced ejection fraction (HFrEF). Atrial natriuretic peptide (ANP) exerts many cardiac beneficial effects, including the ability to protect cardiomyocytes by promoting autophagy. We tested the impact of ANP on autophagy/mitophagy, altered mitochondrial structure and function and increased oxidative stress in HFrEF patients by both ex vivo and in vivo approaches. The ex vivo study included thirteen HFrEF patients whose peripheral blood mononuclear cells (PBMCs) were isolated and treated with αANP (10–11 M) for 4 h. The in vivo study included six HFrEF patients who received sacubitril/valsartan for two months. PBMCs were characterized before and after treatment. Both approaches analyzed mitochondrial structure and functionality. We found that levels of αANP increased upon sacubitril/valsartan, whereas levels of NT-proBNP decreased. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment with sacubitril/valsartan caused: (i) improvement of mitochondrial membrane potential; (ii) stimulation of the autophagic process; (iii) significant reduction of mitochondrial mass—index of mitophagy stimulation—and upregulation of mitophagy-related genes; (iv) reduction of mitochondrial damage with increased inner mitochondrial membrane (IMM)/outer mitochondrial membrane (OMM) index and reduced ROS generation. Herein we demonstrate that αANP stimulates both autophagy and mitophagy responses, counteracts mitochondrial dysfunction, and damages ultimately reducing mitochondrial oxidative stress generation in PBMCs from chronic HF patients. These properties were confirmed upon sacubitril/valsartan administration, a pivotal drug in HFrEF treatment. [ABSTRACT FROM AUTHOR]

Purpose: The mitochondria-targeted antioxidants (MTAs) are known to offer protection against mitochondrial oxidative stress. The recent evidences support their role in mitigating oxidative stress-induced diseases, including cancer. Therefore, this study investigated cardioprotective potential of mito-TEMPO against 5-FU-induced cardiotoxicity. Methods: Mito-TEMPO was administered to male BALB/C mice (intraperitoneally, 0.1 mg/kg b.w. for 7 days) followed by intraperitoneal administration of 5- FU (12 mg/kg b.w. for 4 days). During this period, mito-TEMPO treatment was also continued. The cardioprotective potential of mito-TEMPO was assessed by evaluating cardiac injury markers, extent of non-viable myocardium and histopathological alterations. Mitochondrial functional status and mitochondrial oxidative stress were assessed in cardiac tissue. 8-OHdG expression and apoptotic cell death were assessed using immunohistochemical techniques. Results: The level of cardiac injury markers CK-MB and AST were significantly (P ≤ 0.05) decreased in mito-TEMPO pre-protected group which was further reflected in histopathology as decrease in the percentage of non-viable myocardial tissue, disorganization, and loss of myofibrils. Mito-TEMPO ameliorated mtROS, mtLPO and conserved mitochondrial membrane potential. Further, it had significantly (P ≤ 0.05) improved the activity of mitochondrial complexes and mitochondrial enzymes. A significant (P ≤ 0.05) increase in the level of mtGSH, activity of mitochondrial glutathione reductase, glutathione peroxidase, and mitochondrial superoxide dismutase was observed. A decreased expression of 8-OHdG and reduced apoptotic cell death were observed in mito-TEMPO pre-protected group. Conclusion: Mito-TEMPO effectively mitigated 5-FU-induced cardiotoxicity by modulating mitochondrial oxidative stress, hence may serve as a protective agent/adjuvant in 5-FU-based combinatorial chemotherapy. [ABSTRACT FROM AUTHOR]

Mitochondria are one of the organelles undergoing rapid alteration during the senescence process. Senescent cells show an increase in mitochondrial size, which is attributed to the accumulation of defective mitochondria, which causes mitochondrial oxidative stress. Defective mitochondria are also targets of mitochondrial oxidative stress, and the vicious cycle between defective mitochondria and mitochondrial oxidative stress contributes to the onset and development of aging and age-related diseases. Based on the findings, strategies to reduce mitochondrial oxidative stress have been suggested for the effective treatment of aging and age-related diseases. In this article, we discuss mitochondrial alterations and the consequent increase in mitochondrial oxidative stress. Then, the causal role of mitochondrial oxidative stress on aging is investigated by examining how aging and age-related diseases are exacerbated by induced stress. Furthermore, we assess the importance of targeting mitochondrial oxidative stress for the regulation of aging and suggest different therapeutic strategies to reduce mitochondrial oxidative stress. Therefore, this review will not only shed light on a new perspective on the role of mitochondrial oxidative stress in aging but also provide effective therapeutic strategies for the treatment of aging and age-related diseases through the regulation of mitochondrial oxidative stress. [ABSTRACT FROM AUTHOR]

Severe burns are often complicated with hyperglycemia caused by mitochondrial oxidative stress-related pancreatic islet dysfunction. Silent information regulator of transcription 3 (Sirt3) can regulate mitochondrial oxidative stress. However, the role and mechanism of Sirt3 on islet function after severe burns remain unclear. Therefore, this study aimed to investigate whether Sirt3 played a role in both mitochondrial oxidative stress in islets and mediating islet function post severe burns. A mouse model of 30% total body surface area full-thickness burn and an in vitro MIN6 cell hypoxia model were established. Sirt3 KO mice were used to demonstrate further the role of Sirt3 in maintaining redox homeostasis and regulating islet function. Fasting blood glucose and glucose-stimulated insulin secretion (GSIS) were detected to assess the islet function. The levels of mitochondrial ROS and deacetylation, and the activities of Mn-SOD and IDH2 were measured to evaluate oxidative stress. The mitochondrial membrane potential (MMP)was detected and the apoptosis rate measured. In vitro MIN6 cells, the hypoxia treatment significantly reduced Sirt3 expression, resulting in increased deacetylation of Mn-SOD and IDH2, which further led to a higher level of mitochondrial ROS. In addition, hypoxia reduced MMP and increased apoptosis rate, which impaired GSIS eventually. Knockdown of Sirt3 caused similar alterations. The hypoxia-induced high level of mitochondrial ROS and apoptosis and impaired GSIS could be reversed by overexpression of Sirt3. Similarly, after severe burns, the expression of Sirt3 in islets decreased significantly with a high level of deacetylation of Mn-SOD, IDH2, mitochondrial ROS and apoptosis, and islet dysfunction. Oxidative stress and apoptosis also occurred in islets of Sirt3 KO mice, accompanied by islet dysfunction. Sirt3 and downstream signalling are critical in modulating the islet function post severe burns by regulating mitochondrial oxidative stress and apoptosis. [Display omitted] • Severe burns led to the decreased expression of Sirt3 and the dysfunction of mitochondria of pancreatic islets of mice. • The acetylation levels of Mn-SOD and IDH2 increased in pancreatic islets post severe burns due to the decreased expression of Sirt3, resulting in the mitochondrial oxidative stress and mitochondrial apoptosis. • Overexpression of Sirt3 could reverse the mitochondrial oxidative stress and apoptosis. • Sirt3 are critical in modulating the islet function post severe burns by regulating mitochondrial oxidative stress and apoptosis. [ABSTRACT FROM AUTHOR]

Background: Persistent inflammatory response in the brain can lead to tissue damage and neurodegeneration. In Alzheimer's disease (AD), there is an aberrant activation of inflammasomes, molecular platforms that drive inflammation through caspase-1-mediated proteolytic cleavage of proinflammatory cytokines and gasdermin D (GSDMD), the executor of pyroptosis. However, the mechanisms underlying the sustained activation of inflammasomes in AD are largely unknown. We have previously shown that high brain cholesterol levels promote amyloid-β (Aβ) accumulation and oxidative stress. Here, we investigate whether these cholesterol-mediated changes may regulate the inflammasome pathway. Methods: SIM-A9 microglia and SH-SY5Y neuroblastoma cells were cholesterol-enriched using a water-soluble cholesterol complex. After exposure to lipopolysaccharide (LPS) plus muramyl dipeptide or Aβ, activation of the inflammasome pathway was analyzed by immunofluorescence, ELISA and immunoblotting analysis. Fluorescently-labeled Aβ was employed to monitor changes in microglia phagocytosis. Conditioned medium was used to study how microglia-neuron interrelationship modulates the inflammasome-mediated response. Results: In activated microglia, cholesterol enrichment promoted the release of encapsulated IL-1β accompanied by a switch to a more neuroprotective phenotype, with increased phagocytic capacity and release of neurotrophic factors. In contrast, in SH-SY5Y cells, high cholesterol levels stimulated inflammasome assembly triggered by both bacterial toxins and Aβ peptides, resulting in GSDMD-mediated pyroptosis. Glutathione (GSH) ethyl ester treatment, which recovered the cholesterol-mediated depletion of mitochondrial GSH levels, significantly reduced the Aβ-induced oxidative stress in the neuronal cells, resulting in lower inflammasome activation and cell death. Furthermore, using conditioned media, we showed that neuronal pyroptosis affects the function of the cholesterol-enriched microglia, lowering its phagocytic activity and, therefore, the ability to degrade extracellular Aβ. Conclusions: Changes in intracellular cholesterol levels differentially regulate the inflammasome-mediated immune response in microglia and neuronal cells. Given the microglia-neuron cross-talk in the brain, cholesterol modulation should be considered a potential therapeutic target for AD treatment, which may help to block the aberrant and chronic inflammation observed during the disease progression. [ABSTRACT FROM AUTHOR]

Cytokine‐induced inflammation and mitochondrial oxidative stress are key drivers of liver tissue injury. Here, we describe experiments modeling hepatic inflammatory conditions in which plasma leakage leads to large amounts of albumin to reach the interstitium and parenchymal surfaces to explore whether this protein plays a role in preserving hepatocyte mitochondria against the damaging actions of the cytotoxic cytokine tumor necrosis factor alpha (TNFα). Hepatocytes and precision‐cut liver slices were cultured in the absence or presence of albumin in the cell media and then exposed to mitochondrial injury with the cytokine TNFα. The homeostatic role of albumin was also investigated in a mouse model of TNFα‐mediated liver injury induced by lipopolysaccharide and D‐galactosamine (LPS/D‐gal). Mitochondrial ultrastructure, oxygen consumption, ATP and reactive oxygen species (ROS) generation, fatty acid β‐oxidation (FAO), and metabolic fluxes were assessed by transmission electron microscopy (TEM), high‐resolution respirometry, luminescence‐fluorimetric‐colorimetric assays and NADH/FADH2 production from various substrates, respectively. TEM analysis revealed that in the absence of albumin, hepatocytes were more susceptible to the damaging actions of TNFα and showed more round‐shaped mitochondria with less intact cristae than hepatocytes cultured with albumin. In the presence of albumin in the cell media, hepatocytes also showed reduced mitochondrial ROS generation and FAO. The mitochondria protective actions of albumin against TNFα damage were associated with the restoration of a breakpoint between isocitrate and α‐ketoglutarate in the tricarboxylic acid cycle and the upregulation of the antioxidant activating transcription factor 3 (ATF3). The involvement of ATF3 and its downstream targets was confirmed in vivo in mice with LPS/D‐gal‐induced liver injury, which showed increased hepatic glutathione levels, indicating a reduction in oxidative stress after albumin administration. These findings reveal that the albumin molecule is required for the effective protection of liver cells from mitochondrial oxidative stress induced by TNFα. These findings emphasize the importance of maintaining the albumin levels in the interstitial fluid within the normal range to protect the tissues against inflammatory injury in patients with recurrent hypoalbuminemia. [ABSTRACT FROM AUTHOR]

• Nrf2 was elevated in the serum of patients with RA. • Nrf2 levels were positively correlated with disease activity and pro-inflammatory factor levels. • Nrf2 levels were higher in RA patients with wrist joint involvement and interstitial lung disease. • Serum Nrf2 protein is expected to be a novel indicator for monitoring disease activity and prognosis in patients with RA. This study aimed to detect the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2) in the serum of patients with rheumatoid arthritis (RA) to clarify the correlation between Nrf2 levels and medical parameters, such as disease activity, pro-inflammatory factor, clinical characteristics, as well as changes after treatment. Serum samples were collected from 100 patients with RA and 42 normal controls (NCs). Serum levels of Nrf2 protein, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17A, and malondialdehyde (MDA) were analyzed. The receiver operating characteristic (ROC) curve was adopted to assess the potential of Nrf2 to predict different levels of disease activity in patients with RA. The relationship between clinical variables and parameters were evaluated. For the first time, it was reported that Nrf2 levels were significantly elevated in the serum of patients with RA compared to those of NCs, as were the MDA levels. The levels of Nrf2 were positively correlated with the disease activity and pro-inflammatory factor levels. The significant cut-off points for Nrf2 to determine RA disease activity were 0.69 ng/mL, 0.69 ng/mL and 1.18 ng/mL. Levels of Nrf2 were higher in RA patients with wrist joint involvement and interstitial lung disease. Moreover, Nrf2 levels decreased after treatment. Serum Nrf2 protein level is potentially a novel indicator to monitor disease activity and prognosis in patients with RA. [ABSTRACT FROM AUTHOR]

Neuroinflammation and oxidative stress have been implicated in the pathogenesis of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are associated with neuronal death in AD. Astrocytes are linked to neuroinflammation during AD. Astrocytes are important contributors to AD progression. Although the role of thioredoxin-interacting protein (TXNIP) has been identified in inflammation and oxidative stress, the mechanism by which TXNIP regulates inflammation and oxidative stress in astrocytes during AD remains unclear. In the present study, we found that TXNIP gene levels were elevated in cerebral cortex of patients with AD. The protein levels of TXNIP were elevated in GFAP-positive astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. Our results showed that TXNIP increased expression of genes related to pro-inflammatory reactive astrocytes and pro-inflammatory cytokines and chemokines in human astrocytes. Moreover, TXNIP increased production of pro-inflammatory cytokines and chemokines in human astrocytes. TXNIP induced activation of NK-kB signaling and over-production of mitochondrial reactive oxygen species (mtROS) in human astrocytes. TXNIP also induced mitochondrial oxidative stress by reduction of mitochondrial respiration and ATP production in human astrocytes. Furthermore, elevated TXNIP levels are correlated with caspase-3 activation of GFAP-positive astrocytes in patients with AD and mouse AD. TXNIP induced mitochondria-dependent apoptosis via caspase-9 and caspase-3 activation in human astrocytes. These results suggest that TXNIP contributes to induction of pro-inflammatory phenotype and caspase-3 activation in astrocytes during AD.

Elevation of blood triglycerides, primarily triglyceride-rich lipoproteins (TGRL), is an independent risk factor for cardiovascular disease and vascular dementia (VaD). Accumulating evidence indicates that both atherosclerosis and VaD are linked to vascular inflammation. However, the role of TGRL in vascular inflammation, which increases risk for VaD, remains largely unknown and its underlying mechanisms are still unclear. We strived to determine the effects of postprandial TGRL exposure on brain microvascular endothelial cells, the potential risk factor of vascular inflammation, resulting in VaD. We showed in Aung et al., J Lipid Res., 2016 that postprandial TGRL lipolysis products (TL) activate mitochondrial reactive oxygen species (ROS) and increase the expression of the stress-responsive protein, activating transcription factor 3 (ATF3), which injures human brain microvascular endothelial cells (HBMECs) in vitro. In this study, we deployed high-throughput sequencing (HTS)-based RNA sequencing methods and mito stress and glycolytic rate assays with an Agilent Seahorse XF analyzer and profiled the differential expression of transcripts, constructed signaling pathways, and measured mitochondrial respiration, ATP production, proton leak, and glycolysis of HBMECs treated with TL. Conclusions: TL potentiate ROS by mitochondria which activate mitochondrial oxidative stress, decrease ATP production, increase mitochondrial proton leak and glycolysis rate, and mitochondria DNA damage. Additionally, CPT1A1 siRNA knockdown suppresses oxidative stress and prevents mitochondrial dysfunction and vascular inflammation in TL treated HBMECs. TL activates ATF3-MAPKinase, TNF, and NRF2 signaling pathways. Furthermore, the NRF2 signaling pathway which is upstream of the ATF3-MAPKinase signaling pathway, is also regulated by the mitochondrial oxidative stress. We are the first to report differential inflammatory characteristics of transcript variants 4 (ATF3-T4) and 5 (ATF3-T5) of the stress responsive gene ATF3 in HBMECs induced by postprandial TL. Specifically, our data indicates that ATF3-T4 predominantly regulates the TL-induced brain microvascular inflammation and TNF signaling. Both siRNAs of ATF3-T4 and ATF3-T5 suppress cells apoptosis and lipotoxic brain microvascular endothelial cells. These novel signaling pathways triggered by oxidative stress-responsive transcript variants, ATF3-T4 and ATF3-T5, in the brain microvascular inflammation induced by TGRL lipolysis products may contribute to pathophysiological processes of vascular dementia.

IntroductionUveitis and related intraocular inflammations are a major cause of blindness due to retinal damage caused by degeneration and loss of the photoreceptor cells. In mouse experimental autoimmune uveitis (EAU) previously we have shown mitochondrial oxidative stress with marked upregulation of αA crystallin in the inner segments of the photoreceptors. Furthermore, αA crystallin treatment prevented photoreceptor mitochondrial oxidative stress by suppressing innate and adaptive immunity in EAU.MethodsSince these immune processes are modulated by microRNAs, in this study we investigated (a) modulation of microRNAs during development of EAU by αA crystallin administration and (b) microRNA therapeutic intervention.ResultsFew microRNAs were significantly upregulated in EAU mice with intravenous injection of αA crystallin and among these, computational bioinformatic analysis revealed that the upregulated microRNA 146a targets the innate and adaptive immune responses. In EAU, intravenous as well as intravitreal administration of this microRNA prevented inflammatory cell infiltration in uvea and retina and preserved photoreceptor cells.DiscussionThis protective function suggests that microRNA146a can be a novel therapeutic agent in preventing retinal damage in uveitis.

Background and Purpose: Astrocytic nuclear factor erythroid‐derived 2‐related factor 2 (Nrf2) is a potential therapeutic target of ischaemic preconditioning (IPC). Icariside II (ICS II) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify if exposure to ICS II mimicks IPC neuroprotection and if Nrf2 from astrocytes contributes to ICS II preconditioning against ischaemic stroke. Experimental Approach: Mice with transient middle cerebral artery occlusion (MCAO)‐induced focal cerebral ischaemia and primary astrocytes challenged with oxygen–glucose deprivation (OGD) were used to explore the neuroprotective effect of ICS II preconditioning. Additionally, Nrf2‐deficient mice were pretreated with ICS II to determine whether ICS II exerts its neuroprotection by activating Nrf2. Key Results: ICS II pretreatment mitigated cerebral injury in the mouse model of ischaemic stroke along with improving long‐term recovery. Furthermore, proteomics screening identified Nrf2 as a crucial gene evoked by ICS II treatment and required for the anti‐oxidative effect and anti‐inflammatory effect of ICS II. Also, ICS II directly bound to Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS II pretreatment exerted cytoprotective effects on astrocyte cultures following lethal OGD exposure, by promoting Nrf2 nuclear translocation and activating the OXPHOS/NF‐κB/ferroptosis axis, while neuroprotection was decreased in Nrf2‐deficient mice and Nrf2 siRNA blocked effects of ICS II. Conclusion and Implications: ICS II preconditioning provides robust neuroprotection against ischaemic stroke via the astrocytic Nrf2‐mediated OXPHOS/NF‐κB/ferroptosis axis. Thus, ICS II could be a promising Nrf2 activator to treat ischaemic stroke. [ABSTRACT FROM AUTHOR]

BACKGROUND: Romina strawberry cultivar is rich in bioactive compounds. Healthy properties of Romina have been only partially investigated. There are almost no information concerning aging and age-related diseases like Alzheimer's Disease (AD). OBJECTIVE: To evaluate about the effects of a methanolic extract of the strawberry Romina cultivar on aging, redox biology, and tau protein-related aspects of AD in Caenorhabditis elegans. METHODS: Caenorhabditis elegans strains were treated with 100, 500 or 1000μg/mL of a methanolic extract of the Romina cultivar and evaluated for toxicity, lifespan, tau protein expression and redox biology markers. RESULTS: No toxicity was found. Tau expression was lower in nematodes treated with 500 and 1000μg/mL. All treatments induced higher lifespan than control. Lipofuscin expression was higher in old nematodes and the treatments led to a lower expression in young and old animals. Redox biology markers were improved by strawberry treatment in young and old animals, but the best results were found for different dosages depending on age. CONCLUSIONS: Romina cultivar presented promising effects concerning tau-related AD and longevity. Romina might be considered from the point of view of a proper regulation of redox biology, but considering that treatment conditions should be adjusted by age. [ABSTRACT FROM AUTHOR]

Abstract Background Cigarette smoking (CS) is a strong risk factor for idiopathic pulmonary fibrosis (IPF). It can activate lung fibroblasts (LF) by inducing redox imbalance. We previously showed that clearing mitochondrial reactive oxygen species (mtROS) protects against CS-induced pulmonary fibrosis. However, the precise mechanisms of mtROS in LF need further investigation. Here we focused on mtROS to elucidate how it was regulated by CS in LF and how it contributed to LF activation. Methods We treated cells with 1% cigarette smoking extract (CSE) and examined mtROS level by MitoSOX™ indicator. And the effect of CSE on expression of SIRT1, SOD2, mitochondrial NOX4 (mtNOX4), fatty acid oxidation (FAO)-related protein PPARα and CPT1a and LF activation marker Collagen I and α-SMA were detected. Nile Red staining was performed to show cellular lipid content. Then, lipid droplets, autophagosome and lysosome were marked by Bodipy 493/503, LC3 and LAMP1, respectively. And lipophagy was evaluated by the colocalization of lipid droplets with LC3 and LAMP1. The role of autophagy on lipid metabolism and LF activation were explored. Additionally, the effect of mitochondria-targeted ROS scavenger mitoquinone and SIRT1 activator SRT1720 on mitochondrial oxidative stress, autophagy flux, lipid metabolism and LF activation were investigated in vitro and in vivo. Results We found that CS promoted mtROS production by increasing mtNOX4 and decreasing SOD2. Next, we proved mtROS inhibited the expression of PPARα and CPT1a. It also reduced lipophagy and upregulated cellular lipid content, suggesting lipid metabolism was disturbed by CS. In addition, we showed both insufficient FAO and lipophagy resulted from blocked autophagy flux caused by mtROS. Moreover, we uncovered decreased SIRT1 was responsible for mitochondrial redox imbalance. Furthermore, we proved that both SRT1720 and mitoquinone counteracted the effect of CS on NOX4, SOD2, PPARα and CPT1a in vivo. Conclusions We demonstrated that CS decreased SIRT1 to activate LF through dysregulating lipid metabolism, which was due to increased mtROS and impaired autophagy flux. These events may serve as therapeutic targets for IPF patients.

The role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is multifaceted, paradoxically promoting both cell survival and cell death across multiple organs. However, its impact on lung homeostasis remains elusive. Here, we investigate the function of DNA-PKcs in mouse lungs, aiming to elucidate its role for lung abnormalities associated with DNA-PKcs deficiency. Histological assessment and immunohistochemistry were used to reveal the pathological changes of the lungs in DNA-PKcs-deficient mice. Transcriptomic analysis identified differentially expressed genes and pathways in DNA-PKcs-deficient lungs. Furthermore, mitochondrial dysfunction induced by DNA-PKcs deficiency was investigated by qPCR and immunoblotting. Mouse primary lung fibroblasts were used to evaluate the potential therapeutic effect of inhibiting mitochondrial fission with Mdivi-1. In DNA-PKcs-deficient mouse lungs, we observed pathological changes including alveolar septal thickening, capillary congestion and hemorrhage, along with lung cell proliferation. Transcriptome analysis revealed an upregulation of the reactive oxygen species (ROS) biosynthesis process and the apoptotic signaling pathway caused by DNA-PKcs deficiency. Further investigations demonstrated that DNA-PKcs deficiency led to mitochondrial dysfunction and increased oxidative stress, along with increased cell apoptosis in the mouse lungs. Notably, we detected enhanced phosphorylation of the mitochondrial fission protein DRP1 in DNA-PKcs-deficient mouse lungs. Intriguingly, inhibiting mitochondrial fission using Mdivi-1 suppressed cell death in primary mouse lung fibroblasts with siRNA-mediated DNA-PKcs knockdown. Our study provides insights into the crucial role of DNA-PKcs in sustaining lung homeostasis via the maintenance of mitochondrial functionality and provides a therapeutic strategy targeting mitochondrial fission against DNA-PKcs deficiency-associated lung diseases. [ABSTRACT FROM AUTHOR]

• RDN improved cardiac function, sympathetic nerve activity and myocardial hypertrophy and fibrosis. • RDN ameliorated mitochondrial oxidative stress and expressions of mitochondria-related BACH1 and PACS2. • Silencing of BACH1 or PACS2 repressed NE-triggered cardiomyocyte hypertrophy, fibrosis, mitochondrial dysregulation, and oxidative stress. • RDN inactivated TGF-β1/SMADs/SP1 pathway to inhibit SP1-mediated PACS-2 or BACH1 transcription. Renal denervation (RDN) has been proved to relieve cardiac hypertrophy; however, its detailed mechanisms remain obscure. This study investigated the detailed protective mechanisms of RDN against cardiac hypertrophy during hypertensive heart failure (HF). Male 5-month-old spontaneously hypertension (SHR) rats were used in a HF rat model, and male Wistar–Kyoto (WKY) rats of the same age were used as the baseline control. Myocardial hypertrophy and fibrosis were evaluated by hematoxylin-eosin (HE) staining and Masson staining. The expression of target molecule was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, immunohistochemical and immunofluorescence, respectively. Cardiomyocyte hypertrophy was induced by norepinephrine (NE) in H9c2 cells in vitro and evaluated by brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC), and α-myosin heavy chain (α-MHC) levels. Oxidative stress was determined by malondialdehyde (MDA) level, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzyme activities. Mitochondrial function was measured by mitochondrial membrane potential, adenosine triphosphate (ATP) production, mitochondrial DNA (mtDNA) number, and mitochondrial complex I-IV activities. Molecular mechanism was assessed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RDN decreased sympathetic nerve activity, attenuated myocardial hypertrophy and fibrosis, and improved cardiac function in the rat model of HF. In addition, RDN ameliorated mitochondrial oxidative stress in myocardial tissues as evidenced by reducing MDA and mitochondrial reactive oxygen species (ROS) levels, and enhancing SOD and GSH-Px activities. Moreover, phosphofurin acid cluster sorting protein 2 (PACS-2) and broad-complex, tramtrak and bric à brac (BTB) domain and cap'n'collar (CNC) homolog 1 (BACH1) were down-regulated by RDN. In NE-stimulated H9c2 cells, PACS-2 and BACH1 levels were markedly elevated, and knockdown of them could suppress NE-induced oxidative stress, cardiomyocyte hypertrophy, fibrosis, as well as mitochondrial dysfunction. Transforming growth factor beta1(TGFβ1)/SMADs signaling pathway was inactivated by RDN in the HF rats, which sequentially inhibited specificity protein 1 (SP1)-mediated transcription of PACS2 and BACH1. Collectively, these data demonstrated that RDN improved cardiac hypertrophy and sympathetic nerve activity of HF rats via repressing BACH1 and PACS-2-mediated mitochondrial oxidative stress by inactivating TGF-β1/SMADs/SP1 pathway, which shed lights on the cardioprotective mechanism of RDN in HF. [ABSTRACT FROM AUTHOR]

Diets with an elevated content of fat, sucrose, or fructose are recognized models of diet-induced metabolic alterations, since they induce metabolic derangements, oxidative stress, and chronic low-grade inflammation associated with local and systemic accumulation of advanced glycation end-products (AGEs). This study used four-week-old C57BL/6 male mice, randomly assigned to three experimental dietary regimens: standard diet (SD), high-fat high-sucrose diet (HFHS), or high fructose diet (HFr), administered for 12 weeks. Plasma, heart, and tibialis anterior (TA) skeletal muscle were assayed for markers of metabolic conditions, inflammation, presence of AGEs, and mitochondrial involvement. The HFHS diet induced a tissue-specific differential response featuring (1) a remarkable adaptation of the heart to HFHS-induced heavy oxidative stress, demonstrated by an increased presence of AGEs and reduced mitochondrial biogenesis, and efficaciously counteracted by a conspicuous increase in mitochondrial fission and PRXIII expression; (2) the absence of TA adaptation to HFHS, revealed by a heavy reduction in mitochondrial biogenesis, not counteracted by an increase in fission and PRXIII expression. HFr-induced mild oxidative stress elicited tissue-specific responses, featuring (1) a decrease in mitochondrial biogenesis in the heart, likely counteracted by a tendency for increased fission and (2) a mild reduction in mitochondrial biogenesis in TA, likely counteracted by a tendency for increased fusion, showing the adaptability of both tissues to the diet.

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.

The potential coexistence of Alzheimer's disease (AD) and atrial fibrillation (AF) is increasingly common as aging-related diseases. However, little is known about mechanisms responsible for atrial remodeling in AD pathogenesis. α7 nicotinic acetylcholine receptors (α7nAChR) has been shown to have profound effects on mitochondrial oxidative stress in both organ diseases. Here, we investigate the role of α7nAChR in mediating the effects of amyloid-β (Aβ) in cultured mouse atrial cardiomyocytes (HL-1 cells) and AD model mice (APP/PS1). In vitro, apoptosis, oxidative stress and mitochondrial dysfunction induced by Aβ long-term (72h) in HL-1 cells were prevented by α-Bungarotoxin(α-BTX), an antagonist of α7nAChR. This cardioprotective effect was due to reinstating Ca2+ mishandling by decreasing the activation of CaMKII and MAPK signaling pathway, especially the oxidation of CaMKII (oxi-CaMKII). In vivo studies demonstrated that targeting knockdown of α7nAChR in cardiomyocytes could ameliorate AF progression in late-stage (12 months) APP/PS1 mice. Moreover, α7nAChR deficiency in cardiomyocytes attenuated APP/PS1-mutant induced atrial remodeling characterized by reducing fibrosis, atrial dilation, conduction dysfunction, and inflammatory mediator activities via suppressing oxi-CaMKII/MAPK/AP-1. Taken together, our findings suggest that diminished α7nAChR could rescue Aβ-induced atrial remodeling through oxi-CaMKII/MAPK/AP-1-mediated mitochondrial oxidative stress in atrial cells and AD mice.

Mitochondrial oxidative stress（Mito-OS）is a kind of imbalance between reactive oxygen species production and antioxidant system in mitochondria. And oxidative stress induced by reactive oxygen species（ROS）is considered as important factors for aging and disease. At present，the evaluation methods of oxidative stress in cells or animal models are mainly based on cell morphology，animal phenotype or production of characteristic metabolites，et al. It is unable to monitor dynamic changes in real time. This study established a mitochondrial oxidative stress fluorescent protein monitoring system，named Mito-OS-Timer，which can monitor the dynamic changes of mitochondrial oxidative stress in real time. Based on the mechanism that dsRed1-E5 red/green fluorescence conversion rate was positively correlated with oxygen concentration change，dsRed1-E5 gene was fused with ATP5PB fragment of ATP synthase subunit located in mitochondrial inner membrane. Then，we established a recombinant plasmid pMito-OS-Timer and stably expressed cell line HEK293T. After being treated with 0-300 μmol/L H2O2 and 0-5 μmol/L rotenone，the results showed that there was a significantly positive correlation between the rate of red-green fluorescence transformation and the degree of mitochondrial oxidative stress. In addition，Mito-OS-Timer was used to detect the enhancement of oxidative stress induced by folliculin（FLCN）gene silencing by pLVX-shFLCN. This system provides a new visualization method for studying mitochondrial oxidative stress. [ABSTRACT FROM AUTHOR]

Vascular calcification (VC) is a common pathophysiological process of chronic kidney disease (CKD). Sirtuin 3 (Sirt3), a major NAD+-dependent protein deacetylase predominantly in mitochondria, is involved in the pathogenesis of VC. We previously reported that intermedin (IMD) could protect against VC. In this study, we investigated whether IMD attenuates VC by Sirt3-mediated inhibition of mitochondrial oxidative stress. A rat VC with CKD model was induced by the 5/6 nephrectomy plus vitamin D3. Vascular smooth muscle cell (VSMC) calcification was induced by CaCl2 and β-glycerophosphate. IMD1-53 treatment attenuated VC in vitro and in vivo, rescued the depressed mitochondrial membrane potential (MMP) level and decreased mitochondrial ROS levels in calcified VSMCs. IMD1-53 treatment recovered the reduced protein level of Sirt3 in calcified rat aortas and VSMCs. Inhibition of VSMC calcification by IMD1-53 disappeared when the cells were Sirt3 absent or pretreated with the Sirt3 inhibitor 3-TYP. Furthermore, 3-TYP pretreatment blocked IMD1-53-mediated restoration of the MMP level and inhibition of mitochondrial oxidative stress in calcified VSMCs. The attenuation of VSMC calcification by IMD1-53 through upregulation of Sirt3 might be achieved through activation of the IMD receptor and post-receptor signaling pathway AMPK, as indicated by pretreatment with an IMD receptor antagonist or AMPK inhibitor blocking the inhibition of VSMC calcification and upregulation of Sirt3 by IMD1-53. AMPK inhibitor treatment reversed the effects of IMD1-53 on restoring the MMP level and inhibiting mitochondrial oxidative stress in calcified VSMCs. In conclusion, IMD attenuates VC by improving mitochondrial function and inhibiting mitochondrial oxidative stress through upregulating Sirt3. [ABSTRACT FROM AUTHOR]

Background Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown. Methods and results In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, intervention experiments were achieved by CCl4 combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl4 exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-β as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl4-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP. Conclusion In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease. [ABSTRACT FROM AUTHOR]

Background: As the most common subtype of colorectal cancer, colorectal adenocarcinoma (COAD) still needs better prognostic stratification methods and new intervention targets. The mitochondrial stress response, linked to mitochondrial homeostasis and cancer metabolism, warrants further investigation., Methods: We identified mitochondrial oxidative stress-related genes (MOS) associated with COAD prognosis through the TCGA and GEO databases. Molecular subtype characteristics were identified based on MOS gene signatures, and an MOS scoring system was established to comprehensively evaluate its clinical value. Additionally, the effect of one of the screened genes, NDRG1, was investigated through a series of in vitro experiments, including Western blot, qRT-PCR, CCK8 assay, clone formation, and Transwell assay, to explore its impact on COAD proliferation and migration ability., Results: Our analysis revealed that MOS gene signatures effectively distinguished molecular subtypes of COAD, and the MOS scoring system was found to be independent in predicting prognosis. Evaluation of microenvironment infiltration characteristics, mutation characteristics, immunotherapy response, and drug sensitivity analysis further suggested the potential clinical utility of this study. in vitro experimental results showed that NDRG1 significantly affected the proliferation and migration of COAD cells, partially verifying the reliability of our bioinformatics analysis., Conclusion: This study provides a novel perspective on the role of mitochondrial oxidative stress in COAD, proposing innovative prognostic evaluation methods and potential therapeutic targets, thus offering new directions for the clinical treatment of COAD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)