Sonodynamic Therapy-Driven Immunotherapy: Constructing AIE Organic Sonosensitizers Using an Advanced Receptor-Regulated Strategy.

Benefit from the deeper penetration of mechanical wave, ultrasound (US)-based sonodynamic therapy (SDT) executes gratifying efficacy in treating deep-seated tumors. Nevertheless, the complicated mechanism of SDT undeniably hinders the exploration of ingenious sonosensitizers. Herein, a receptor engineering strategy of aggregation-induced emission (AIE) sonosensitizers (TPA-Tpy) with acceptor (A)-donor (D)-A' structure is proposed, which inspects the effect of increased cationizations on US sensitivity. Under US stimulation, enhanced cationization in TPA-Tpy improves intramolecular charge transfer (ICT) and accelerates charge separation, which possesses a non-negligible promotion in type I reactive oxygen species (ROS) production. Moreover, abundant ROS-mediated mitochondrial oxidative stress triggers satisfactory immunogenic cell death (ICD), which further promotes the combination of SDT and ICD. Subsequently, subacid pH-activated nanoparticles (TPA-Tpy NPs) are constructed with charge-converting layer (2,3-dimethylmaleic anhydride-poly (allylamine hydrochloride)-polyethylene glycol (DMMA-PAH-PEG)) and TPA-Tpy, achieving the controllable release of sonosensitizers. In vivo, TPA-Tpy-mediated SDT effectively initiates the surface-exposed of calreticulin (ecto-CRT), dendritic cells (DCs) maturation, and CD8+ T cell infiltration rate through enhanced ROS production, achieving suppression and ablation of primary and metastatic tumors. This study provides new opinions in regulating acceptors with eminent US sensitization, and brings a novel ICD sono-inducer based on SDT to realize superior antitumor effect.

Nicotinamide riboside attenuates myocardial ischemia-reperfusion injury via regulating SIRT3/SOD2 signaling pathway.

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.

Exosomes from SHED-MSC regulate polarization and stress oxidative indexes in THP-1 derived M1 macrophages.

OBJECTIVE: The inhibition of M1 macrophages may be interesting for targeted therapy with mesenchymal stem cell-derived Exosomes (MSC-EXOs). This study aimed to investigate the stem cells of human exfoliated deciduous teeth-derived EXOs (SHED-MSC-EXOs) effect on regulating the pro- and anti-oxidant indexes and inhibiting M1 macrophage polarization. Besides, an in-silico analysis of SHED-MSC-EXO miRNAs as the highest frequency of small RNAs in the exosomes was performed to discover the possible mechanism. METHODS: The flow cytometry analysis of CD80 and CD86 as M1-specific markers confirmed the polarization of macrophages derived from THP-1 cells. After exosome isolation, characterization, and internalization, THP-1-derived M1 macrophages were treated with SHED-MSC-EXOs. M1-specific markers and pro- and anti-oxidant indexes were evaluated. For in-silico analysis of SHED-MSC-EXOs miRNAs, initial miRNA array data of SHED-EXOs is collected from GEO, and the interaction of the miRNAs in M1 macrophage polarization (M1P), mitochondrial oxidative stress (MOS) and LPS-induced oxidative stress (LOS) were analyzed by miRWalk 3.0 server. Outcomes were filtered by 75th percentile signal intensity, score cut-off ≥0.95, minimum free energy (MEF)≤ -20 kcal/mol, and seed = 1. RESULTS: It shows a decrease in the expression of CD80 and CD81, a reduction in pro-oxidant indicators, and an increase in the anti-oxidant indexes (P < 0.05). Computational analysis showed that eight microRNAs of SHED-MSC-EXO miRNAs can bind to and interfere with the expression of candidate genes in the M1P, MOS, and LOS pathways simultaneously. CONCLUSION: SHED-MSCs-EXOs can be utilized to treat conditions related to M1 macrophage-induced diseases (M1IDs) due to their unique physical properties and ability to penetrate target cells easily.

Targeting Mitochondrial Oxidative Stress to Protect Against Preterm Birth and Fetal Brain Injury via Nrf2 Induction.

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.

Cucurbitacin B induces ferroptosis in oral leukoplakia via the SLC7A11/mitochondrial oxidative stress pathway.

BACKGROUND: Oral leukoplakia (OLK), characterized by abnormal epithelial hyperplasia, is the most common precancerous oral mucosa lesion and is closely related to oxidative stress. Cucurbitacin B (CuB), a tetracyclic triterpenoid molecule derived from plants, has shown promising anti-proliferative and antioxidant effects in preclinical studies. However, whether CuB can play an antiproliferative role in OLK by regulating oxidative stress remains elusive. PURPOSE: To investigate the role of CuB in inhibiting the malignant progression of oral leukoplakia and to further explore its underlying mechanisms of action. METHODS: In vitro, the effect of CuB on the proliferation, migration, apoptosis, and cell cycle of OLK cells DOK was detected. The core genes and key pathways of OLK and CuB were analyzed in the transcriptome database, by using immunofluorescence, qRT-PCR, and Western blot to evaluate the expression levels of the ferroptosis markers ROS, GSH, MDA, Fe2+, and marker genes SLC7A11, GPX4, and FTH1. Immunohistochemistry of human tissue was performed to investigate the expression of the SLC7A11. In vivo, the model of OLK was established in C57BL/6 mice and the biosafety of CuB treatment for OLK was further evaluated. RESULTS: CuB substantially suppressed the proliferation of DOK cells. Bioinformatics analysis showed that the core targets of OLK crossing with CuB include SLC7A11 and that the essential pathways involve ROS and ferroptosis. In vitro experiments indicated that CuB might promote ferroptosis by down-regulating the expression of SLC7A11. We observed a gradual increase in SLC7A11 expression levels during the progression from normal oral mucosa to oral leukoplakia with varying degrees of epithelial dysplasia. In vivo experiments demonstrated that CuB inhibited the malignant progression of OLK by promoting ferroptosis in OLK mice and exhibited a certain level of biosafety. CONCLUSION: This study demonstrated for the first time that CuB could effectively inhibit the malignant progression of OLK by inducing ferroptosis via activating the SLC7A11/ mitochondrial oxidative stress pathway. These findings indicate that CuB could serve as the lead compound for the future development of anti-oral leukoplakia drugs.

Disulfiram Inhibits Opsonin-Independent Phagocytosis and Migration of Human Long-Lived In Vitro Cultured Phagocytes from Multiple Inflammatory Diseases.

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.

Elesclomol-Copper Nanoparticles Overcome Multidrug Resistance in Cancer Cells.

Elesclomol (ES), a copper-binding ionophore, forms an ES-Cu complex with copper ions (Cu(II)). ES-Cu has been proven to induce mitochondrial oxidative stress and copper-dependent cell death (cuprotosis). However, ES-Cu is poorly water-soluble, and its delivery to various cancer cells is a challenge. Herein, we designed a d-α-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS-CA)-based micellar nanoparticle for delivering the ES-Cu complex to various cancer cell lines to demonstrate its efficacy as an anticancer agent. The ES-Cu nanoparticles exerted high encapsulation efficiency and excellent serum stability. The anticancer efficacy of ES-Cu nanoparticles was evaluated in various drug-sensitive cell lines (DU145, PC3, and A549) and drug-resistant cell lines (DU145TXR, PC3TXR, and A549TXR). The results showed that ES-Cu nanoparticles exerted potent anticancer activities in both drug-sensitive and drug-resistant cell lines. The Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and molecular docking results suggested that ES-Cu is not a substrate for P glycoprotein (P-gp), which is an efflux transporter potentially causing multidrug resistance (MDR) in cancer cells. ES-Cu nanoparticles could bypass P-gp without compromising their activity, indicating that they may overcome MDR in cancer cells and provide a novel therapeutic strategy. Additionally, the extracellular matrix of ES-Cu nanoparticles-pretreated drug-resistant cells could polarize Raw 264.7 macrophages into the M1 phenotype. Therefore, our TPGS/CS-CA-based ES-Cu nanoparticles provide an effective method of delivering the ES-Cu complex, a promising strategy to overcome MDR in cancer therapy with potential immune response stimulation.

20(R)-ginsenoside Rg3 attenuates cerebral ischemia-reperfusion injury by mitigating mitochondrial oxidative stress via the Nrf2/HO-1 signaling pathway.

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.

Sirtuin 5 Alleviates Liver Ischemia/Reperfusion Injury by Regulating Mitochondrial Succinylation and Oxidative Stress.

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.

Selenium Ameliorated Oxidized Fish Oil-Induced Lipotoxicity via the Inhibition of Mitochondrial Oxidative Stress, Remodeling of Usp4-Mediated Deubiquitination, and Stabilization of Pparα.

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 ß-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.

Inhibition of PTEN-induced kinase 1 autophosphorylation may assist in preventing epileptogenesis induced by pentylenetetrazol.

PTEN-induced kinase 1 (PINK1) autophosphorylation-triggered mitophagy is the main mitophagic pathway in the nervous system. Moreover, multiple studies have confirmed that mitophagy is closely related to the occurrence and development of epilepsy. Therefore, we speculated that the PINK1 autophosphorylation may be involved in epileptogenesis by mediating mitophagic pathway. This study aimed to explore the contribution of activated PINK1 to epileptogenesis induced by pentylenetetrazol (PTZ) in Sprague‒Dawley rats. During PTZ-induced epileptogenesis, the levels of phosphorylated PINK1 were increased, accompanied by elevated mitophagy, mitochondria oxidative stress and neuronal damage. After microRNA intervention targeting translocase outer mitochondrial membrane 7 (TOM7) or overlapping with the m-AAA protease 1 homolog (OMA1), the levels of PINK1 phosphorylation, mitophagy, mitochondrial oxidative stress, neuronal injury were observed in the rats with induced epileptogenesis. Furthermore, inhibiting of the expression of TOM7, a positive regulator of PINK1 autophosphorylation, reversed the increase in PINK1 phosphorylation and alleviated mitophagy, neuronal injury, thereby preventing epileptogenesis. In contrast, reducing the levels of OMA1, a negative regulator of PINK1 autophosphorylation, led to increased phosphorylation of PINK1, accompanied by aggravated neuronal injury and ultimately, epileptogenesis. This study confirmed the contribution of activated PINK1 to PTZ-induced epileptogenesis and suggested that the inhibition of PINK1 autophosphorylation may assist in preventing epileptogenesis.

MnO2 nanoparticles trigger hepatic lipotoxicity and mitophagy via mtROS-dependent Hsf1Ser326 phosphorylation.

Manganese (Mn) is an essential element for maintaining normal metabolism in vertebrates. Mn dioxide nanoparticles (MnO2 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 MnO2 NPs affect hepatic lipid metabolism in vertebrates. We found that, excessive MnO2 NPs intake increased hepatic and mitochondrial Mn content, promoted hepatic lipotoxic disease and lipogenesis, and inhibited hepatic lipolysis and fatty acid ß-oxidation. Moreover, excessive MnO2 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 MnO2 NPs-induced hepatic lipotoxic disease and mitophagy. Mechanistically, MnO2 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 MnO2 NPs-induced hepatic lipotoxicity and mitophagy, which provide new insights into the effects of metal oxides nanoparticles on hepatotoxicity in vertebrates.

Activation of sigma-1 receptor ameliorates sepsis-induced myocardial injury by mediating the Nrf2/HO1 signaling pathway to attenuate mitochondrial oxidative stress.

BACKGROUND: Sepsis is a condition that triggers the release of large amounts of reactive oxygen species and inflammatory factors in the body, leading to myocardial injury and cardiovascular dysfunction - an important contributor to the high mortality rate associated with sepsis. Although it has been demonstrated that the sigma-1 receptor (S1R) is essential for preventing oxidative stress, its effectiveness in treating sepsis is yet unknown. AIM: This study aimed to investigate the role and mechanisms of S1R activation in sepsis-induced myocardial injury. METHODS: A model of sepsis-induced myocardial injury was constructed by performing cecum ligation and puncture(CLP) surgery on rats. Flv or BD1047 were intraperitoneally injected into rats for one consecutive week before performing CLP, and then intraperitoneally injected into the rats again 1 h after the surgery.The effects of Flv and BD1047 were detected by HE staining, immunofluorescence staining, IHC staining, echocardiography measurements,TUNEL, oxidative stress detection, TEM, flow cytometry and western blot. We further validated the mechanism in vitro using neonatal rat cardiomyocites and H9C2 cells. RESULTS: S1R protein level was reduced in the hearts of septic rats, whereas administration of Flv, an S1R activator, ameliorated myocardial injury, mitochondrial oxidative stress, and pathological manifestations of sepsis. On the other hand, administration of the S1R inhibitor BD1047 exacerbated the mitochondrial oxidative stress, and apoptosis, as well as symptoms and pathological manifestations of sepsis. In addition, we found that up-regulation of S1R activated the Nrf2/HO1 signaling pathway and promoted nuclear translocation of Nrf2, which activated downstream proteins to generate antioxidant factors, such as HO1, in turn alleviating oxidative stress and countering myocardial damage. CONCLUSION: By scavenging ROS accumulation and reducing mitochondrial oxidative stress via the Nrf2/HO1 signaling pathway, activation of S1R improves cardiac function, mitigates death of cardiomyocytes, and attenuates sepsis-induced myocardial injury.

Different Effects of High-Fat/High-Sucrose and High-Fructose Diets on Advanced Glycation End-Product Accumulation and on Mitochondrial Involvement in Heart and Skeletal Muscle in Mice.

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.

NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.

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.

Curcumin alleviates AFB1-induced nephrotoxicity in ducks: regulating mitochondrial oxidative stress, ferritinophagy, and ferroptosis.

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.

mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.

Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments.

Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.

Advances in the pharmacological study of Chinese herbal medicine to alleviate diabetic nephropathy by improving mitochondrial oxidative stress.

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.

The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy.

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.