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Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications., Competing Interests: Declaration of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication., (Copyright © 2025. Published by Elsevier Inc.)

Ischaemia-reperfusion (IR) damage is an inevitable adverse effect of liver surgery. Recent research has found that IR damage is involved in severe mitochondrial dysfunction. Mitochondrial biosynthesis and dynamics control mitochondrial mass, distribution, and function. Sirtuin 3 (SIRT3) is widely known for preserving health and functionality of mitochondria. DEX has been proven to alleviate liver damage through antioxidant and anti-apoptotic pathways. But it's unclear how DEX protects mitochondria at this time. In this research, the mechanism behind the protective benefits of DEX was examined using the rat liver IR model and the rat liver cells (BRL-3 A) hypoxia reoxygenation (HR) model. We discovered that DEX treatment restored mitochondrial membrane potential, promoted ATP production, prevented oxidative stress, and decreased apoptosis in BRL-3 A cells. Furthermore, HR damage increased mitochondrial fission while decreasing mitochondrial fusion and biogenesis in BRL-3 A cells, which DEX partially corrected. The benefits of DEX on mitochondrial protection were reversed after addition of SR-18,292. Additionally, DEX showed the ability to enhance SIRT3 expression, and after cells were transfected with SIRT3 siRNA, DEX's effects on mitochondria were partially prevented. Similarly, in the rat model, DEX alleviating liver histopathological injury and oxidative stress. DEX inhibited IR-induced mitochondrial damage through improving ETC complex I- IV activities and ATP content, reducing apoptosis, controlling mitochondrial quality, and upregulating the expression of SIRT3. Additionally, our research shows that DEX's ability to protect the liver against IR damage is mediated by the modulation of mitochondrial quality control. Overall, the modification of SIRT3 activity could be responsible for this outcome., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics statement: The animal study was reviewed and approved by Ethics Committee of Hebei Agricultural University, China., (© 2025. The Author(s).)

Ethnopharmacological Relevance: Yanghe Decoction(YHD) is a traditional Chinese medicine compound known for its efficacy in treating osteoarthritis (OA)., Aim of the Study: We aimed to explore the underlying mechanisms of YHD in relation to OA., Materials and Methods: UHPLC-MS technology was used to identify the material basis of YHD. In vivo, OA rat model was induced by the modified Hulth method and then treated with YHD at three different doses (0.625, 1.3 and 2.6 g/kg/d). In vitro,YHD-Contained serum was prepared and administrated into rat chondrocytes, followed by simulation of Lipopolysaccharide(LPS). The protective mechanism was determined by observation of morphology, Flow cytometry and Protein level detection., Results: In vivo, YHD reduced chondrocyte apoptosis and joint inflammation while promoting mitophagy. It also elevated the protein levels of p-AMPK, SIRT3, PINK1, Parkin, and LC3II/I. In vitro, YHD-Contained Serum reduced chondrocyte apoptosis, decreased mitochondrial ROS, enhanced mitochondrial membrane potential, and upregulated the protein expressions of p-AMPK, SIRT3, PINK1, Parkin, and LC3II/I., Conclusion: Through this study, we demonstrated YHD protect chondrocytes against apoptosis, and its underlying mechanisms may involve the regulation of AMPK-SIRT3 positive feedback loop and activation of PINK1/Parkin mediated mitophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Triple-negative breast cancer (TNBC) represents a highly malignant subtype of breast cancer with limited therapeutic options. In this study, we designed and synthesized a series of 1,4-DHP derivatives by structure-based strategy, 43 was documented to be a potent SIRT3 activator and exhibited profound anti-proliferative activity in BT-549 and MDA-MB-231 cells with low toxicity over normal cells. Additionally, 43 displayed the ability of direct binding to SIRT3 with a K d value of 51.51 μM in BLI assay, and the potential bonding mode was elucidated through molecular docking. 43 could inhibit the proliferation, migration, and glycolysis, induced mitochondrial membrane potential decreased and apoptosis in BT-549 and MDA-MB-231 cells. Collectively, these results demonstrate that 43 is a potent SIRT3 activator with the potential to anti-TNBC through signaling pathways regulated by SIRT3., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: High-fat diet (HFD) currently is reported that in connection with cognitive impairment. Tirzepatide is a novel dual receptor agonist for glycemic control. But whether Tirzepatide exerts a protective effect in HFD-related cognitive impairment remains to be explore., Methods: During the study, the cognitive dysfunction mice model induced by HFD were established. The expressions synapse-associated protein and other target proteins were detected. The oxidative stress parameters, levels of inflammatory cytokine were also detected., Results: Our findings proved that Tirzepatide administration attenuates high fat diet-related cognitive impairment. Tirzepatide administration suppresses microglia activation, alleviates oxidative stress as well as suppressed the expression of NLRP3 in HFD mice by up-regulating SIRT3 expression. In conclusion, Tirzepatide attenuates HFD-induced cognitive impairment through reducing oxidative stress and neuroinflammation via SIRT3-NLRP3 signaling., Conclusion: This study suggest that Tirzepatide has neuroprotective effects in HFD-related cognitive dysfunction mice model, which provides a promising treatment of HFD-related cognitive impairment., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests. Ethical approval: All experiments were approved by the Ethics Committee of Huaian First People’s Hospital (license number: YX-Z-2023-009-01)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sustained activation of the SIRT3-NLRP3 inflammasome has been associated with worse outcomes after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Following tMCAO, significantly elevated levels of NLRP3, ASC, cleaved caspase 1, IL-1β, and IL-18 were observed in the ischemic subventricular zone. Moreover, tMCAO increased NLRP3 expression while decreasing SIRT3 levels, suggesting a connection between these two processes. Furthermore, we discovered that inflammation induced by the NLRP3 inflammasome impaired post-stroke hippocampal and subventricular neurogenesis, while nestin (a marker for NSPCs) and Sox2 (a marker for stem cell pluripotency) were downregulated after tMCAO. However, systemic administration of MCC950 reduced inflammatory signaling and effectively restored neurogenesis. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke., Competing Interests: Declaration of Competing Interest AABR is inventor of intellectual property (WO2016131098, WO2017140778, WO2018215818), granted in multiple jurisdictions, which discloses NLRP3 inhibitors for treatment of inflammatory diseases. These patents are licensed to Inflazome Ltd., which sold to Roche in 2020, and the compounds disclosed are progressing through clinical trials., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Diabetes-associated periodontitis (DP) is recognized as an inflammatory disease that can lead to teeth loss. Uncontrolled chronic low-grade inflammation-induced senescence impairs the stemness of human periodontal stem cells (hPDLSCs). Sirtuin 3 (SIRT3), an NAD + -dependent deacetylase, is pivotal in various biological processes and is closely linked to aging and aging-related diseases. This study aims to explore the mechanism of SIRT3-related senescence and osteogenic differentiation of hPDLSCs under DP and explored the novelty therapeutic targets. Our study revealed that SIRT3 expression was markedly inhibited in periodontal ligament stem cells (PDLSCs) stimulated by high glucose and lipopolysaccharide. Both in vitro and in vivo, reduced SIRT3 expression accelerated cell senescence and impaired osteogenic differentiation of hPDLSCs. We demonstrated that SIRT3 binds to and deacetylates leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), thereby modulating senescence. Additionally, we found that LRPPRC regulates senescence by modulating oxidative phosphorylation and oxidative stress. The activation of SIRT3 by honokiol significantly delayed senescence and promoted alveolar bone regeneration in mice after DP. Our findings indicate that the activation of SIRT3 negatively regulates hPDLSCs senescence by deacetylating LRPPRC, suggesting SIRT3 as a promising therapeutic target for DP., Competing Interests: Competing interests The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Silent mating-type information regulation 2 homology 3 (SIRT3) is a member of the sirtuins family expressed in mitochondria performs deacetylation of metabolic enzymes and promotes longevity. 7-hydroxy-3-(4'-methoxyphenyl) coumarin (C12) is a small molecule first ever known for its direct activation of SIRT3. SIRT3 performs its function by balancing the redox system by activating manganese superoxide dismutase (MnSOD) and 8-Oxoguanine glycosylase (OGG1). For the first time, we reported that activation of SIRT3 by C12 attenuated bleomycin (BLM)-)-induced acute lung injury and pulmonary fibrosis. C12 prevented the oxidative stress and injury caused by BLM in alveolar epithelial cells (BEAS-2B) in in vitro and inhibited the fibrosis in transforming growth factor-beta (TGF-β) induced fibrosis in fibroblasts (MRC-5). Additionally, activation of SIRT3 by C12 in vivo mice model alleviated BLM-induced inflammation, collagen accumulation, cellular infiltration, and restoration of alveolar architecture by inhibiting TGF-β, smooth muscle actin (α-SMA), collagen-1A, collagen-3A, and mesenchymal markers. The protective effect of C12 was through activation of MnSOD and OGG1 in both in vitro and in vivo models suggesting C12 can be a potent SIRT3 activator and helps to treat fibrotic-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sirtuin-3 (SIRT3) in mitochondria has nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase activity. As such, SIRT3 is crucial in cardiovascular and neurodegenerative diseases. Advanced proteomics and transcriptomics studies have revealed that SIRT3 expression becomes altered when the heart or brain is affected by external stimuli or disease, such as diabetic cardiomyopathy, atherosclerosis, myocardial infarction, Alzheimer's disease, Huntington's disease, and Parkinson's disease. More specifically, SIRT3 participates in the development of these disorders through its deacetylase activity and in combination with downstream signaling pathways. The paper reviews SIRT3's expression changes, roles, and mechanisms associated with the development of cardiovascular and neurodegenerative diseases. Additionally, strategies targeting SIRT3 to treat or regulate cardiovascular and neurodegenerative disease development are discussed., Competing Interests: Declaration of Competing Interest The authors declare no competing interests, (Copyright © 2025. Published by Elsevier B.V.)

Compound K (CK), an active ingredient in ginseng, has anti-cancer, anti-inflammatory, and antioxidant properties. However, its effects on thermogenesis and mitochondrial dynamics in white adipose tissue (WAT) adipocytes are not well understood. This study explores CK's impact on thermogenesis and mitochondrial metabolism in cold-exposed mice and mouse stromal vascular fraction (SVF) cells. CK increased the expression of UCP1 and other brown/beige adipocyte markers (Cd137, Cytb, Letm1, Pgc1α, Prdm16, Tbp1, Tbx1, Uqcrc1) and mitochondrial biogenesis/dynamics factors (Cidea, Cox8b, Cycs, Dio2, Drp1, Fis1, Fgf21, Nrf1, Sirt3, Tfam) in 3T3-L1/iWAT SVF cells. CK enhanced mitochondrial respiration, reduced mitochondrial ROS levels, and restored MMP in iWAT SVF cells, leading to the differentiation of WAT into beige adipocytes, and that was also observed in cold-exposed subcutaneous tissue. CK administration to cold-exposed mice reduced fat droplet size and increased the number of mitochondria. Additionally, CK stimulated non-shivering thermogenesis, indicated by the upregulation of thermogenic and mitochondrial division proteins. The browning effect of CK was nullified by SIRT3 knockdown, suggesting that CK induces beige remodeling of WAT by regulating mitochondrial dynamics and SIRT3 expression. These findings suggest CK's potential as a therapeutic agent for obesity and metabolic disorders that promotes the transformation of WAT into a metabolically active beige phenotype., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: The effect of hyperuricemia (HUA) on testicular spermatogenesis cannot be ignored. The classical Chinese medicine compound Shenling Baizhu San (SLBZS) can reduce uric acid and improve testicular spermatogenesis, while researchers have not well explored the related pathology and pharmacodynamic mechanism have., Aims of Study: To investigate whether the dysfunction of testicular spermatogenesis caused by HUA and the therapeutic effect of SLBZS are related to testicular cell ferroptosis., Materials and Methods: C57BL/6 mice and C57BL/6 background Sirt3 -/- mice were induced by oxazinate potassium (OXO), and HUA spermatogenic dysfunction mice model were constructed and treated with SLBZS. Sperm quality detection and testicular histopathology served for evaluating the protective mechanism of SLBZS against testicular spermatogenesis in HUA mice. Biochemical detection, transmission electron microscopy, immunohistochemistry and immunofluorescence were used to evaluate ferroptosis level of testicular cells. Western blot analysis assisted in verifying the expression of the corresponding pathway proteins., Results: The testes of mice with HUA spermatogenic dysfunction were subjected to OXO-induced oxidative stress and ferroptosis, and the Sirt3/Nrf2 pathway-related protein expressions were changed. SLBZS improved the testes of mice with HUA spermatogenic dysfunction in terms of their spermatogenic function, oxidative stress and ferroptosis, and promoted Sirt3/Nrf2 antioxidant pathway-related proteins to be expressed. The analysis of Sirt3 -/- mice was modeled and dosed, and it was found that SLBZS could not improve the spermatogenic function, oxidative stress and ferroptosis of Sirt3-deficient model mice' testes., Conclusions: OXO-induced spermatogenic dysfunction in HUA is associated with ferroptosis of testicular cells. SLBZS can be used for treating spermatogenic dysfunction in HUA possibly by activating Sirt3/Nrf2 signaling pathway, which inhibits ferroptosis due to oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Interleukin (IL)-9-producing CD4 + T cells (T H 9) are essential for mediating antitumor immunity, but the mechanisms of T H 9 cell differentiation remain unclear. Here, we found that the mechanical force receptor Piezo1 is critical for regulating T H 9 cell differentiation. Piezo1 deficiency in CD4 + T cells intrinsically inhibited T H 9 cell differentiation, whereas ectopic Piezo1 expression promoted this process. Notably, Piezo1 deficiency inhibited T H 9 cell differentiation and contributed to tumor development. Mechanistically, Piezo1 deficiency inhibits T H 9 cell differentiation mainly through the SIRT3-succinate dehydrogenase A (SDHA)-oxidative phosphorylation (OXPHOS) pathway. SIRT3 deficiency or blockade of SDHA-OXPHOS signaling activity reversed the T H 9 cell differentiation induced by Piezo1 deficiency. Moreover, HIF1α signaling is responsible for the T H 9 cell differentiation induced by Piezo1 deficiency. Thus, our findings identify a redox metabolism signaling mechanism regulated by the mechanical force receptor Piezo1 that limits the mitochondrial SIRT3-SDHA-dependent OXPHOS pathway and triggers HIF1α-IL-9 to reprogram T H 9 cell differentiation, with implications for future immunotherapy approaches., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite a deep understanding of Parkinson's disease (PD) and levodopa-induced dyskinesia (LID) pathogenesis, current therapies are insufficient to effectively manage the progressive nature of PD or halt LID. Growing hypotheses suggested the NOD-like receptor 3 (NLRP3) inflammasome and orphan nuclear receptor-related 1 (Nurr1)/glycogen synthase kinase-3β (GSK-3β) and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α)/sirtuin 3 (SIRT3) pathways as potential avenues for halting neuroinflammation and oxidative stress in PD., Aims: This study investigated for the first time the neuroprotective effect of canagliflozin against PD and LID in rotenone-intoxicated rats, emphasizing the crosstalk among the NLRP3/caspase-1 cascade, PGC-1α/SIRT3 pathway, mammalian target of rapamycin (mTOR)/beclin-1, and Nurr1/β-catenin/GSK-3β pathways as possible treatment strategies in PD and LID. Also, correlating NLRP3 expression with all evaluated parameters., Main Methods: The PD rat model was induced via eleven rotenone (1.5 mg/kg) subcutaneous injections day after day. Canagliflozin (20 mg/kg) and/or L-dopa/carbidopa (100/25 mg/kg) were orally administered daily from the beginning until the end of the experiment., Key Findings: Canagliflozin significantly improved neurobehavioral and histological assessments, whereas dyskinesia scores declined. The improvement was confirmed through tyrosine hydroxylase and β-catenin upregulation in contrast to NLRP3 and caspase-1 in substantia nigra pars compacta, as revealed immunohistochemically. In addition, canagliflozin induced a prominent elevation in dopamine, Nurr1, PGC-1α, SIRT3, and beclin-1, whereas mTOR and GSK-3β expressions were downregulated., Significance: Our results revealed the aspiring canagliflozin neuroprotective properties against PD and LID in rotenone-lesioned rats via the assumed anti-inflammatory activity and implication of NLRP3/caspase-1, Nurr1/GSK-3β/β-catenin, PGC-1α/SIRT3, and beclin-1/mTOR pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH., Competing Interests: Competing interests: The authors declare no competing interests. Ethics: This study was approved by the Ethics Committee of Guangzhou University of Chinese Medicine, Guangzhou, China (Ethics No. 20230526001) and was performed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national). Informed consent was obtained from the SIONFH patients in the study., (© 2025. The Author(s).)

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10 μM within 48 h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: Animal experimental protocols and procedures were performed under the approval of the animal care committee at Mudanjiang Medical University (Ethical approval code: IACUC-20230618-056). Informed consent: Participants provided their verbal informed consent for animal blood sampling as well as for the related survey questions. Collection of blood samples was carried out adhering to the regulations and guidelines on animal welfare. Consent to participate: Not applicable., (© 2025. The Author(s) under exclusive licence to Japan Human Cell Society.)

Over-accumulation of reactive oxygen species (ROS) causes hepatocyte dysfunction and apoptosis that might lead to the progression of liver damage. Sirtuin-3 (SIRT3), the main NAD+-dependent deacetylase located in mitochondria, has a critical role in regulation of mitochondrial function and ROS production as well as in the mitochondrial antioxidant mechanism. This study explores the roles of astragaloside IV (AST-IV) and formononetin (FMR) in connection with SIRT3 for potential antioxidative effects. It was shown that the condition of combined pre- and post-treatment with AST-IV or FMR at all concentrations statistically increased and rescued cell proliferation. ROS levels were not affected by pre-or post-treatment individually with AST-IV or pre-treatment with FMR; however, post-treatment with FMR resulted in significant increases in ROS in all groups. Significant decreases in ROS levels were seen when pre- and post-treatment with AST-IV were combined at 5 and 10 μM, or FMR at 5 and 20 μM. In the condition of combined pre- and post-treatment with 10 μM AST-IV, there was a significant increase in SOD activity, and the transcriptional levels of Sod2, Cat, and GPX1 in all treatment groups, which is indicative of reactive oxygen species detoxification. Furthermore, AST-IV and FMR activated PGC-1α and AMPK as well as SIRT3 expression in AML12 hepatocytes exposed to t -BHP-induced oxidative stress, especially at high concentrations of FMR. This study presents a novel mechanism whereby AST-IV and FMR yield an antioxidant effect through induction of SIRT3 protein expression and activation of an antioxidant mechanism as well as mitochondrial biogenesis and mitochondrial content and potential. The findings suggest these agents can be used as SIRT3 modulators in treating oxidative-injury hepatocytes.

Nanoplastics (NPs) are an emerging class of pollutants. They can act as a"Trojan horse" to change the bioavailability and toxicity of heavy metals in the environment. However, research on the combined toxicity of heavy metals and NPs is scarce, especially during the critical developmental period of adolescence. In this study, polystyrene nanoplastics (PS-NPs) and/or cadmium (Cd) were exposed to 4-week-old female rats for 28 days, with the aim of exploring the potential effects of combined exposure to PS-NPs and Cd on the ovaries of adolescence rats. Results showed that co-exposure to PS-NPs and Cd exacerbated ovarian toxicity in rats, primarily through increased atretic follicle numbers and endocrine disruption. Further studies revealed that PS-NPs and Cd synergistically repressed the SIRT3-SOD2/Gpx4 pathway, inducing mitochondrial oxidative stress and ferroptosis, resulting in damage to ovarian structure and function. However, the addition of the mitochondrion-targeted antioxidant SS-31 and the ferroptosis inhibitor Fer-1 reversed the harm to the ovaries from co-exposure to PS-NPs and Cd, the aberrant expression of genes related to the SIRT3-SOD2/Gpx4 pathway was also improved. Our results suggested that co-exposure to PS-NPs and Cd may trigger ferroptosis by inhibiting the SIRT3-SOD2/Gpx4 pathway, leading to mitochondrial redox imbalance, which provided novel insights into reproductive toxicity due to the interaction of PS-NPs and Cd during adolescence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxidative stress in endothelial cells is pivotal in diabetic retinopathy (DR), with mitochondrial homeostasis being crucial to mitigate this stress. This study explored the roles of mitochondrial sirtuins (SIRTs) in high glucose (HG)-induced oxidative stress, related endothelial impairment, and mitochondrial homeostasis damage in rat retinal microvascular endothelial cells (RMECs). RMECs were cultured under HG or equivalent osmotic conditions. Cell viability was assessed using the Cell Counting Kit-8 assay, whereas cell death and survival were determined via calcein-AM/propidium iodide double staining. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein fluorescence. Expression of mitochondrial SIRTs3-5 and key mitochondrial homeostasis molecules was quantified by the quantitative real-time polymerase chain reaction and confirmed by western blotting. Mitochondrial morphology was evaluated using electron microscopy and the MitoTracker fluorescent probe. A SIRT3-overexpressing RMEC line was constructed to assess the role of SIRT3 in oxidative stress and mitochondrial dynamics. After 48 h of HG exposure, cell viability was significantly reduced, with a concomitant increase in cell death and ROS levels, alongside a marked decrease in SIRT3 expression and molecules associated with mitochondrial dynamics. SIRT3 overexpression reversed these effects, particularly increasing the mitochondrial fusion-related molecule, optic atrophy 1 (OPA1). However, the OPA1 inhibitor, MYLS22, blocked the protective effect of SIRT3, leading to more dead cells, a higher ROS level, and intensified mitochondrial fragmentation. These results suggest that SIRT3 is involved in HG-induced imbalanced mitochondrial dynamics of endothelial cells in DR, potentially through the OPA1 pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The incidence of obesity-related glomerulopathy (ORG) is rising worldwide with very limited treatment methods. Paralleled with the gut–kidney axis theory, the beneficial effects of butyrate, one of the short-chain fatty acids (SCFA) produced by gut microbiota, on metabolism and certain kidney diseases have gained growing attention. However, the effects of butyrate on ORG and its underlying mechanism are largely unexplored. In this study, a mice model of ORG was established with a high-fat diet feeding for 16 weeks, and sodium butyrate treatment was initiated at the 8th week. Podocyte injury, oxidative stress and mitochondria function were evaluated in mice kidney and validated in vitro in palmitic acid-treated-mouse podocyte cell lines. Further, the molecular mechanisms of butyrate on podocytes were explored. Compared with controls, sodium butyrate treatment alleviated kidney injuries and renal oxidative stress in high-fat diet-fed mice. In mouse podocyte cell lines, butyrate ameliorated palmitic acid-induced podocyte damage and helped maintain the structure and function of the mitochondria. Moreover, the effects of butyrate on podocytes were mediated via the GPR43-Sirt3 signal pathway, as evidenced by the diminished effects of butyrate with the intervention of GPR43 or Sirt3 inhibitors. In summary, we conclude that butyrate has therapeutic potential for the treatment of ORG. It attenuates high-fat diet-induced ORG and podocyte injuries through the activation of the GPR43-Sirt3 signalling pathway.

Trehalose has neuroprotective effects in neurodegenerative diseases. This study aimed to explore the impact of trehalose on traumatic brain injury (TBI) by investigating its role in neuroprotection. The TBI mice model was established utilizing the cortical impact technique followed by trehalose treatment. Traumatic neuronal injury induced by scratch followed by trehalose treatment was performed to mimic TBI in vitro. Memory function was assessed using the Water maze test. Brain damage was evaluated through various methods including brain water content analysis, Nissl staining, Evans blue exudation, and TUNEL staining. Biochemical and morphological changes related to ferroptosis post-TBI were also examined. The results showed that trehalose was found to enhance spatial memory, reduce brain injury, and inhibit ferroptosis in TBI mice, similar to ferroptosis inhibitors. The influence of trehalose on TBI was reversed by the SIRT3 inhibitor. Trehalose upregulated SIRT3 to increase SOD activity in TBI, which could also be counteracted by the SIRT3 inhibitor. Combining trehalose with a ferroptosis inhibitor had a more significant effect on reducing brain injury and inhibiting ferroptosis. Furthermore, in TBI mice treated with trehalose and SIRT3 inhibitors, the effect of trehalose was reversed by SIRT3 inhibitors, but the addition of ferroptosis inhibitors reversed the effect of SIRT3 inhibitors, as shown by decreased ferroptosis and neuronal apoptosis in damaged brain tissue. In summary, this study provides initial evidence that trehalose plays a crucial role in neuroprotection post-TBI through the SIRT3/SOD2 pathway-mediated ferroptosis., Competing Interests: Declarations. Ethics Approval and Consent to Participate: All experimental procedures were approved by the Medical Ethics Committee of Wuxi No 2 People’s Hospital (No. 2023-Y-203). Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The adverse impact of disturbmitochondrialbiogenesis onearly brain injury (EBI) following subarachnoid haemorrhage (SAH) has been broadly recognized and is closely associated with oxidative stress and neuronal apoptosis. Previous studies have indicated the therapeutic potential of Ropinirole, a dopamine D2 agonist, in Ischemic Stroke. However, there is a lack of evidence regarding the ability of Ropinirole to enhance mitochondrial biogenesis and quality control after subarachnoid haemorrhage. The objective of this study is to investigate the effects of Ropinirole specific doses (10 & 20 mg/kg b. wt.) on mitochondria dysfunction in endovascular perforation SAH model in male Wistar rat. An endovascular perforation model was established using male Wistar rats that had sustained SAH injury. After the SAH injury, SAH grading on blood clot, Nissl staining, and neurobehavioral assessment were used to determine the severity. ROS and MMP, which are indicators of oxidative stress, were examined using flow cytometry. The findings demonstrated that the use of Ropinirole improved neurobehavioral outcomes, decreased brain edema, and reduced oxidative stress and mitochondrial based apoptosis. Further research showed that, Ropinirole therapy inhibit Drp1-mediated fission by accelerating the activity of fusion protein Mfn2/OPA1 along with regulating the translocation of PGC1-α and SIRT3 through restricting cytochrome C inside mitochondria to maintain mitochondrial metabolism. Ropinirole exerted neuroprotective effects by improving mitochondrial activity in a PGC1-α/SIRT3-dependent way via regulating Drp1 mediated fission. The effective treatment for SAH-induced EBI may involve increasing biogenesis and inhibiting excessive mitochondrial fission with Ropinirole., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Calorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR., Methods: Mice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications., Results: In the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number., Conclusion: This study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. While chemotherapy remains the standard treatment approach, natural products have emerged as a promising alternative. Among these, apigenin, a natural flavonoid, has garnered significant attention due to its pro-oxidant and antioxidant properties in various types of cancer. This study aimed to assess the potential impact of apigenin in CRC treatment by targeting mitochondrial SIRT3, HMGB1, and beclin 1-mediated autophagy in a mouse model of CRC. We administered 20 mg/kg of dimethyl hydrazine (DMH) intraperitoneally once weekly for 20 weeks to induce CRC in C57BL/6 mice. After 6 weeks of initiating the study, apigenin was intragastrically co-administered by oral gavage at 25 and 50 mg/kg until the end of week 20. The results revealed significant weight loss, shortening of the colon, and diarrhea in DMH-induced CRC, which are considered the marks of CRC. In addition, histopathological examination revealed dysplastic changes in the DMH-treated group, while no dysplasia was found in the apigenin-treated CRC groups. Importantly, the administration of apigenin to DMH-treated animals has led to a significant reduction of SIRT3 and MnSOD expression levels with a significant increase in LC3-II at either dose and a significant dose-dependent increase in the levels of MDA, c-JNK, HMGB1, and beclin 1 compared to the DMH-treated group. In conclusion, apigenin may have a promising role in suppressing DMH-induced CRC. It elicits a pro-oxidant activity by suppressing the gene expression of SIRT3 and subsequently, its target MnSOD, resulting in increased reactive oxygen species (ROS) and lipid peroxidation. The released ROS, in turn, activates JNK-mediated autophagy by enhancing HMGB1, beclin 1, and LC3-II protein levels., (© 2024 Wiley Periodicals LLC.)

Postoperative cognitive dysfunction (POCD) is a common complication in patients who undergo anesthesia in different types of surgeries. Emerging evidence implicates elevated beta-amyloid (Aβ) in the pathogenesis of POCD. Meanwhile, Dexmedetomidine (DEX) has recently shown promise in reducing POCD incidence. This study aimed to elucidate the role of Aβ in inducing endothelial permeability in cerebral microvascular endothelial cells and the underlying mechanisms and testing the effects of DEX. We demonstrated that Aβ 1-42 , the prevalent Aβ form related to POCD, is cytotoxic to HBMECs, increasing transendothelial permeability and inducing mitochondrial dysfunction, as evidenced by elevated mitochondrial reactive oxygen species (ROS) and decreased ATP production and mitochondrial membrane potential. Furthermore, Aβ 1-42 was shown to inhibit Sirt3, exacerbating mitochondrial dysfunction. Conversely, DEX was found to prevent Aβ 1-42 -induced mitochondrial dysfunction and permeability increases and preserved tight junction proteins in HBMECs.These findings suggest that DEX, as a Sirt3 activator, may offer a pharmacological strategy to mitigate Aβ 1-42 -related cerebral microvascular endothelial cell dysfunction and preserve cognitive function post-surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mitochondrial ROS (mtROS) accumulation and NLRP3 inflammasome activation are critical in the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). However, their upstream regulatory mechanisms and interaction remain inadequately understood., Purpose: The study aims to investigate the therapeutic effect of Salvianolic acid B (Sal B) on MIRI and elucidate its potential molecular mechanism, mainly focusing on the role of SIRT3., Methods: SIRT3 was knocked down (SIRT3 KD ) and overexpressed (SIRT3 OE ) using small interfering RNA and plasmid, respectively. The role of SIRT3 in the cardioprotective effect of Sal B was explored using MIRI rat models and H9c2 cell hypoxia/reoxygenation (H/R) models. SIRT3, NLRP3 inflammasome proteins, and MnSOD expression were analyzed by Western blot and immunofluorescence staining. MtROS levels were assessed with mitochondrial superoxide indicators (MitoSOX™ Red). ELISA was utilized to measure the levels of LDH, CK-MB, cTnT, and markers of inflammation and oxidative stress. The interaction between SIRT3 and Sal B was studied through biolayer interferometry, cellular thermal shift assay and molecular docking., Results: Our findings revealed significantly decreased SIRT3 level, enhanced MnSOD acetylation, and activated NLRP3 inflammasome in myocardium after MIRI and H9c2 cardiomyocytes exposed to H/R conditions. SIRT3 KD promoted MnSOD acetylation and NLRP3 expression, aggravating mtROS accumulation and inflammation. Conversely, SIRT3 OE significantly inhibited MnSOD acetylation and NLRP3 inflammasome activation. In vitro studies confirmed the crosstalk between mtROS and NLRP3, demonstrating that mtROS scavenger inhibited NLRP3 inflammasome activation induced by H/R and SIRT3 KD , and the NLRP3 inhibitor suppressed MnSOD acetylation in H/R and SIRT3 KD cardiomyocytes. Interestingly, Sal B was found to bind and upregulate SIRT3, reduce the expression of Acy-MnSOD, NLRP3, ASC, Caspase-1, and GSDMD, inhibit oxidative stress and inflammatory response, decrease myocardial infarct size and ST-segment elevation, and restore myocardial morphology. However, the protective effect of Sal B against MIRI was nullified by a specific SIRT3 inhibitor., Conclusion: This study unveils that the SIRT3-mediated interplay between mtROS and the NLRP3 inflammasome is pivotal in the pathogenesis of MIRI. Furthermore, it highlights Sal B as a novel therapeutic agent that alleviates MIRI by targeting SIRT3, offering new insights into MIRI treatment., Competing Interests: Declaration of competing interest There are no conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. we would like to declare on behalf of our co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Diabetic nephropathy (DN) is one of the most common complications of diabetes. Our previous study showed that CD38 knockout (CD38KO) mice had protective effects on many diseases. However, the roles and mechanisms of CD38 in DN remain unknown. Here, DN mice were generated by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection in male CD38KO and CD38flox mice. Mesangial cells (SV40 MES 13 cells) were used to mimic the injury of DN with palPagination Donemitic acid (PA) treatment in vitro. Our results showed that CD38 expression was significantly increased in kidney of diabetic CD38flox mice and SV40 MES 13 cells treated with PA. CD38KO mice were significantly resistant to diabetes-induced renal injury. Moreover, CD38 deficiency markedly decreased HFD/STZ-induced lipid accumulation, fibrosis, and oxidative stress in kidney tissue. In contrast, overexpression of CD38 aggravated PA-induced lipid accumulation and oxidative stress. CD38 deficiency increased expression of SIRT3, while overexpression of CD38 decreased its expression. More importantly, 3-TYP, an inhibitor of SIRT3, significantly enhanced PA-induced lipid accumulation and oxidative stress in CD38 overexpressing cell lines. In conclusion, our results demonstrated that CD38 deficiency prevented DN by inhibiting lipid accumulation and oxidative stress through activation of the SIRT3 pathway., Competing Interests: The authors confirm that there are no conflicts of interest.

Aims: Diabetic heart damage can lead to cardiomyocyte death, which endangers human health. Baicalin (BAI) is a bioactive compound that plays an important role in cardiovascular diseases. Sentrin/SUMO-specific protease 1 ( SENP1 ) regulates the de-small ubiquitin-like modifier (deSUMOylation) process of Sirtuin 3 ( SIRT3 ) and plays a crucial role in regulating mitochondrial mass and preventing cell injury. Our hypothesis is that BAI regulates the deSUMOylation level of SIRT3 through SENP1 to enhance mitochondrial quality control and prevent cell death, ultimately improving diabetic cardiomyopathy (DCM). Results: The protein expression of SENP1 decreased in cardiomyocytes induced by high glucose and in db/db mice. The cardioprotective effects of BAI were eliminated by silencing endogenous SENP1 , whereas overexpression of SENP1 showed similar cardioprotective effects to those of BAI. Furthermore, co-immunoprecipitation experiments showed that BAI's cardioprotective effect was due to the inhibition of the SUMOylation modification level of SIRT3 by SENP1 . Inhibition of SENP1 expression resulted in an increase in SUMOylation of SIRT3 . This led to increased acetylation of mitochondrial protein, accumulation of reactive oxygen species, impaired autophagy, impaired mitochondrial oxidative phosphorylation, and increased cell death. None of these changes could be reversed by BAI. Conclusion: BAI improves DCM by promoting SIRT3 deSUMOylation through SENP1 , restoring mitochondrial stability, and preventing the cell death of cardiomyocytes. Innovation: This study proposes for the first time that SIRT3 SUMOylation modification is involved in the development of DCM and provides in vivo and in vitro data support that BAI inhibits cardiomyocyte ferroptosis and apoptosis in DCM through SENP1 . Antioxid. Redox Signal. 42, 53-76.

Acute lung injury (ALI) is a major cause of death in bacterial sepsis due to endothelial inflammation and endothelial permeability defects. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of sepsis-induced ALI. Sirtuin 3 (SIRT3) is a histone protein deacetylase involved in preservation of mitochondrial function, which has been demonstrated in our previous study. Here, we investigated the effects of SIRT3 deficiency on impaired mitophagy to promote lung endothelial cells (ECs) pyroptosis during sepsis-induced ALI. We found that 3-TYP aggravated sepsis-induced ALI with increased lung ECs pyroptosis and enhanced NLRP3 activation. Mitochondrial reactive oxygen species (mtROS) and extracellular mitochondrial DNA (mtDNA) released from damaged mitochondria could be exacerbated in SIRT3 deficiency, which further elicit NLRP3 inflammasome activation in lung ECs during sepsis-induced ALI. Furthermore, Knockdown of SIRT3 contributed to impaired mitophagy via downregulating Parkin, which resulted in mitochondrial dysfunction. Moreover, pharmacological inhibition NLRP3 or restoration of SIRT3 attenuates sepsis-induced ALI and sepsis severity in vivo. Taken together, our results demonstrated SIRT3 deficiency facilitated mtROS production and cytosolic release of mtDNA by impaired Parkin-dependent mitophagy, promoting to lung ECs pyroptosis through the NLRP3 inflammasome activation, which providing potential therapeutic targets for sepsis-induced ALI.

Accumulating evidence indicates that cellular senescence is closely associated with osteoarthritis. However, there is limited research on the mechanisms underlying fibroblast-like synoviocyte senescence and its impact on osteoarthritis progression. Here, we elucidate a positive correlation between fibroblast-like synoviocyte senescence and osteoarthritis progression and reveal that GATD3A deficiency induces fibroblast-like synoviocyte senescence. Mechanistically, GATD3A deficiency enhances the binding of Sirt3 to MDH2, leading to deacetylation and decreased activity of MDH2. Reduced MDH2 activity impairs tricarboxylic acid cycle flux, resulting in mitochondrial dysfunction and fibroblast-like synoviocyte senescence. Intra-articular injection of recombinant adeno-associated virus carrying GATD3A significantly alleviates the osteoarthritis phenotype in male mice. This study increases our current understanding of GATD3A function. In particular, we reveal a novel mechanism of fibroblast-like synoviocyte senescence, suggesting that targeting GATD3A is a potential therapeutic approach for osteoarthritis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Synovial inflammation, Cartilage erosion, and subchondral osteosclerosis, which are collectively referred to as the triad of pathogenesis, contribute to osteoarthritis (OA) progression. Specifically, the M1 macrophage in the synovium worsens the development of the illness and is a significant factor in the deterioration and functioning of cartilage., Objective: To investigate whether Ruscogenin attenuates progressive degeneration of articular cartilage in rats with anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) by modulating macrophage reprogramming and to explore its specific mechanism of action., Methods: In vitro, SW1353 cells and RAW264.7 cells were applied to elucidate the mechanisms by which Ruscogenin protects articular cartilage. Specifically, the expression levels of molecules related to cartilage ECM synthesis and degradation enzymes and macrophages were analysed. In vivo, a rat osteoarthritis model was established using ACLT. The protective effect of Ruscogenin on articular cartilage was observed., Results: Ruscogenin significantly reversed LPS-induced macrophage inflammatory response and promoted cartilage regeneration-related factors. In addition, Ruscogenin had a significant protective effect on the knee joint of ACLT rats, effectively preventing cartilage degeneration. These positive therapeutic effects were achieved on the one hand by Ruscogenin regulating macrophage reprogramming by targeting Sirt3, and on the other hand Ruscogenin could attenuate the ROS level of chondrocytes thereby inhibiting chondrocyte ferroptosis., Conclusions: Ruscogenin exerts chondroprotective effects by regulating macrophage reprogramming and inhibiting chondrocyte ferroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Existing evidence indicates that exercise training can enhance neural function by regulating mitochondrial quality control (MQC), which can be impaired by cerebral ischemia, and that sirtuin-3 (SIRT3), a protein localized in mitochondria, is crucial in maintaining mitochondrial functions. However, the relationship among exercise training, SIRT3, and MQC after cerebral ischemia remains obscure. This study attempted to elucidate the relationship among exercise training, SIRT3 and MQC after cerebral ischemia in rats. Male adult SD rats received tMCAO after the transfection of adeno-associated virus encoding either sirtuin-3 (AAV-SIRT3) or SIRT3 knockdown (AAV-sh-SIRT3) into the ipsilateral striata and cortex. Subsequently, the animals were randomly selected for exercise training. The index changes were measured by transmission electron microscopy, Western blot analysis, nuclear magnetic resonance imaging, TUNEL staining, and immunofluorescence staining, etc. The results revealed that after cerebral ischemia, exercise training increased SIRT3 expression, significantly improved neural function, alleviated infarct volume and neuronal apoptosis, maintained the mitochondrial structural integrity, and re-established MQC. The latter promoted mitochondrial biogenesis, balanced mitochondrial fission/fusion, and enhanced mitophagy. These favorable benefits were reversed after SIRT3 interference. In addition, a cellular OGD/R model showed that the increased SIRT3 expression alleviates neuronal apoptosis and re-establishes mitochondrial quality control by activating the β-catenin pathway. These findings suggest that exercise training may optimize mitochondrial quality control by increasing the expression of SIRT3, thereby improving neural functions after cerebral ischemia, which illuminates the mechanism underlying the exercise training-conferred neural benefits and indicates SIRT3 as a therapeutic strategy for brain ischemia., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Ethical Approval: The protocols adhered to the National Institute of Health guidelines (NIH Publications NO. 80–23, revised 1996). Approval for this experiment was obtained from the Institutional Animal Care and Use Committee (IACUC) of Fujian Medical University, Fujian, China [Approval No. 20220603]., (© 2024. The Author(s).)

Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella 's metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella . Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella -induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella . Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella- induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis., Competing Interests: DH, RR, AC, SG, DC No competing interests declared, (© 2024, Hajra et al.)

Staphylococcus aureus persists within mammary epithelial cells for an extended duration, exploiting the host metabolic resources to facilitate replication. This study revealed a mechanism by which intracellular S aureus reprograms host metabolism, with PFKFB3 playing a crucial role in this process. Mechanistically, S aureus induced mitochondrial damage, leading to increased levels of mitochondrial reactive oxygen species and dysfunction in the electron transport chain. Moreover, S aureus shifted the balance of mitochondrial dynamics from fusion to fission, subsequently activating PINK1-PRKN-dependent mitophagy, causing loss of sirtuin 3 to stabilize hypoxic inducible factor 1α, and shifting the host metabolism toward enhanced glycolysis. The inhibition of PFKFB3 reversed the mitochondrial damage and degradation of sirtuin 3 induced by S aureus. Overall, our findings elucidate the mechanism by which S aureus reprograms host metabolism, thereby offering insights into the treatment of S aureus infection., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Growth differentiation factor 11 (GDF11) is considered to be a potential molecular target for treating pulpitis. However, whether GDF11 regulates osteogenic/odontogenic differentiation of dental pulp stem cells (DPSCs) to mediate pulpitis process remains unclear., Methods: Lipopolysaccharide (LPS) was used to induce inflammation conditions in DPSCs. The levels of GDF11, sirtuin 3 (SIRT3), forkhead box O-3 (FOXO3), osteogenic/odontogenic differentiation-related markers were measured by quantitative real-time PCR (qRT-PCR) and western blot (WB). Immunofluorescence staining was used to measure mitophagy. Mitophagy-related proteins were analyzed by WB, and the levels of inflammation factors were examined using qRT-PCR, ELISA and immunohistochemistry. Alkaline phosphatase activity and alizarin red S intensity were evaluated to assess osteogenic differentiation. Acute pulp (AP) injury rat model was constructed to study the role of oe-GDF11 in vivo., Results: GDF11 was downregulated in LPS-induced DPSCs, and LPS suppressed osteogenic/odontogenic differentiation and mitophagy. GDF11 overexpression promoted osteogenic/odontogenic differentiation in DPSCs through the activation of mitophagy. Furthermore, GDF11 upregulated SIRT3 to enhance FOXO3 expression by inhibiting its acetylation. GDF11 ameliorated LPS-induced inflammation and promoted osteogenic/odontogenic differentiation in DPSCs via enhancing SIRT3/FOXO3-mediated mitophagy. Besides, GDF11 overexpression suppressed inflammation and promoted dentin repair in AP rat models., Conclusion: GDF11 promoted SIRT3/FOXO3-mediated mitophagy to accelerate osteogenic/odontogenic differentiation in DPSCs, providing a novel target for pulpitis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acylcarnitine (ACar) is a novel fuel source for activating thermogenesis in brown adipose tissue (BAT). However, whether ACar metabolism underlies BAT thermogenesis decline with aging remain unclear. Here, the L-carnitine-treated young and aging mice were used to investigate the effects of activation of ACar metabolism on BAT thermogenesis during aging. We showed that long term L-carnitine feeding, which results in an elevation in circulating ACar levels, failed to improve cold sensitivity of aging mice, which still displayed impaired thermogenesis and ACar metabolism in interscapular BAT (iBAT). The RNA-sequencing was used to identify the key regulator for the response of aging mice to LCar induced activation of ACar metabolism in BAT, and we identified Sirt3 as a key regulator for the response of aging mice to L-carnitine induced activation of ACar metabolism in iBAT. Then the adipose-specific Sirt3 knockout (Sirt3 AKO) mice were used to investigate the role of Sirt3 in ACar metabolism and thermogenesis of BAT and explore the underlying mechanism, and the results showed that Sirt3 AKO mice displayed defective ACar metabolism and thermogenesis in iBAT. Mechanically, Sirt3 regulated ACar metabolism via HIF1α-PPARα signaling pathway to promote iBAT thermogenesis, and knockdown or inhibition of HIF1α ameliorated impaired ACar metabolism and thermogenesis of iBAT in the absence of Sirt3. Collectively, we propose that Sirt3 regulated ACar metabolism is critical in maintaining thermogenesis in BAT of aging mice, which can promote the development of anti-aging intervention strategy., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aims: Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on sirtuin (SIRT)3-induced optic atrophy protein 1 (OPA1) deacetylation. Results: The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3-(1H-1, 2, 3-triazol-4-yl) pyridine (3TYP)-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI. Innovation: Our study revealed, for the first time, the regulation of mitochondrial dynamics and AM polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease. Conclusions: Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury. Antioxid. Redox Signal. 41, 1014-1030.

The aging process is a complex phenomenon characterised by a gradual decline in physiological functions and an increased susceptibility to age-related diseases. An important factor in aging is mitochondrial dysfunction, which leads to an accumulation of cellular damage over time. Mitochondrial Sirtuin 3 (Sirt3), an important regulator of energy metabolism, plays a central role in maintaining mitochondrial function. Loss of Sirt3 can lead to reduced energy levels and an impaired ability to repair cellular damage, a hallmark of the aging process. In this study we investigated the impact of Sirt3 loss on mitochondrial function, metabolic responses and cellular aging processes in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage, which is commonly associated with cellular dysfunction and senescence. We found that Sirt3 contributes to the sex-specific metabolic response to etoposide treatment. While male MEF exhibited minimal damage suggesting potential prior adaptation to stress due to Sirt3 loss, female MEF lacking Sirt3 experienced higher vulnerability to genotoxic stress, implying a pivotal role of Sirt3 in their resistance to such challenges. These findings offer potential insights into therapeutic strategies targeting Sirt3- and sex-specific signalling pathways in diseases associated with DNA damage that play a critical role in the aging process., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cardiac hypertrophy is a prevalent early pathological manifestation in various cardiovascular diseases, lacking effective interventions to impede its progression. Although oxymatrine (OMT) has shown potential benefits for cardiac function, its therapeutic efficacy and mechanism in cardiac hypertrophy remain incompletely understood. Notably, mitochondrial damage and dysregulated autophagy are pivotal pathogenic mechanisms in cardiac hypertrophy., Purpose: We investigate the pharmacological characteristics and mechanism of OMT in mitochondrial function and autophagy in cardiac hypertrophy., Study Design and Methods: A murine model of cardiac hypertrophy was induced by aldosterone in combination with high-salt drinking water, while primary cardiomyocyte hypertrophy was induced by aldosterone in vitro. Cardiac hypertrophy was assessed using echocardiography and histopathological staining. Autophagosomes and mitochondrial morphology were visualized by transmission electron microscopy. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and adenosine triphosphate (ATP) were quantified using commercial kits. The binding affinity of OMT with Nrf2 was assessed through molecular docking. Furthermore, adenovirus, agonists, and inhibitors were employed to modulate Nrf2, followed by quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, co-immunoprecipitation, chromatin immunoprecipitation, immunohistochemistry, and cellular thermal shift assay., Results: OMT effectively attenuated aldosterone-induced cardiac hypertrophy both in vivo and in vitro. OMT promoted the activation of Nrf2, leading to elevated SIRT3 expression and enhanced autophagolysosome fusion, thereby modulating mitophagy and improving mitochondrial function. Moreover, the cardioprotective effects of OMT were abolished upon silencing or inhibition of Nrf2. OMT binds to Nrf2, facilitating its dissociation and nuclear translocation., Conclusion: OMT activates Nrf2, consequently enhancing SIRT3 transcription, restoring autophagic flux, and preserving mitochondrial integrity, thereby mitigating aldosterone-induced cardiac hypertrophy. In summary, our study is the first to discover and confirm that OMT can stabilize Nrf2, promoting its activation and subsequently up-regulating SIRT3, which in turn facilitates mitochondrial autophagy. Additionally, PARKIN appears to play a key role in SIRT3-mediated regulation of mitophagy, warranting further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2025. Published by Elsevier GmbH.)

N7-methylguanosine (m 7 G) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the m 7 G methyltransferase complex. METTL1-catalyzed m 7 G as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that m 7 G modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of m 7 G modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and m 7 G levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated m 7 G modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/m 7 G/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Intervertebral disc degeneration (IVDD) is a common cause of low back pain. Procyanidin C1 (PCC1) has been demonstrated to exert a protective effect on nucleus pulposus (NP) cells, and therefore, plays a critical role in the prevention and therapy of IVDD. Clarifying the pathophysiological characteristics and molecular mechanisms of IVDD may be helpful in establishing novel preventive and therapeutic strategies. This study aimed to investigate the probable mechanisms underlying the protection against acidic pH stress induced human NP cell injury. In vitro, acidic pH stress induced degeneration, mitochondrial dynamics imbalance, mitophagy, and mitochondria-mediated apoptosis in NP cells, all of which were ameliorated by PCC1. Autophagy inhibition partially eliminated the protective effects of PCC1 on mitochondrial homeostasis in NP cells. Moreover, PCC1 activated the sirtuin 3 (SIRT3)/forkhead box O3 (FOXO3) signaling pathway, a pivotal signaling pathway involved in the regulation of mitochondrial homeostasis in NP cells. In vivo, PCC1 ameliorated IVDD in a rat model and preserved the extracellular matrix of NP cells. Consequently, the protective effects of PCC1 on NP cells may inhibit IVDD progression via regulation of the SIRT3/FOXO3 signaling pathway. Therefore, regulation of the SIRT3/FOXO3 signaling pathway may be a novel preventive and therapeutic strategy for IVDD., Competing Interests: Declarations. Conflict of interest: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2024. The Author(s).)

Background: Androgenetic alopecia (AGA) stands as the most prevalent form of hair loss, affecting the hair follicles (HFs). Aging emerges as a prominent contributor in this condition. In this study, our aim is to elucidate the expression patterns of candidate genes-SIRT3, SIRT7, NFATC1, and PDL-1-known to exhibit differential expression levels during HF aging, and to underscore the role of aging in AGA., Material and Methods: Mesenchymal stem cells (MSCs) were isolated from the vertex and occipital regions of six men affected by AGA. The aim was to assess the expression levels of SIRT3, SIRT7, NFATC1, and PDL-1 genes. RNA extraction was performed followed by cDNA synthesis, and gene expression levels were quantified using real-time PCR. To validate the experimental findings, two different RNA-seq datasets relevant to the study were analyzed using R software., Results: In the present study, experimental tests revealed that the expression levels of SIRT3 and SIRT7, known to decrease during HF aging, were diminished in AGA-affected samples as well. Conversely, the mean value of NFATC1 and PDL-1 expression level, which are known to increase during HF aging, were found to be elevated in AGA-affected samples. Moreover, bioinformatic analyses provide additional support for the role of SIRT3, SIRT7 and NFATC1in AGA pathogenesis., Conclusion: While SIRT3 and SIRT7 may play critical roles in AGA development, further research is needed to elucidate the significance of NFATC1 and PDL-1 in this context and to explore their potential as therapeutic targets for AGA treatment., Competing Interests: Declarations. Ethical approval and consent to participate: This research was approved by the Ethics Committee of Tarbiat Modares University (IR.MODARES.REC.1402.244), Tehran, Iran. All the participants have accepted and signed the informed consent during the standard genetic counselling sessions. Written informed consent was obtained from the patients for publication of this study. A copy of the written consent is available for review by the Editor of this journal. Consent for publication: All authors reviewed the results and approved the final version of the manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Serum testosterone (T) in males has been declining during the past decades. The previous reports found that 1-nitropyrene (1-NP) exposure suppressed testicular T synthesis. The purpose of the current study was to further explore whether premature senescence participates in 1-NP-triggered reduction of testicular T synthesis. Adult male mice were orally exposed to 1-NP (0, 100, and 500 μg/kg) daily for 14 days. Serum and testicular T contents were diminished in 1-NP-administered mice. Mitochondria-located steroidogenic synthases, including StAR, CYP11A1, and 3βHSD1, were downregulated in 1-NP-administered mouse testes and MLTC-1 cells. Mechanistically, 1-NP exposure increased acetylation modification of mitochondrial steroidogenic synthases by inhibiting the enzymatic activity of SIRT3, an NAD + -dependent deacetylase. Supplementing NAD  +  precursor and Sirt3 overexpression relieved 1-NP-triggered reduction of steroidogenic synthase levels in mouse testes and MLTC-1 cells. By contrast, Sirt3 silencing aggravated 1-NP-evoked acetylation and reduction of steroidogenic synthase levels in MLTC-1 cells. Further experiments demonstrated that 1-NP exposure caused mitochondrial malfunction and premature senescence in mouse testes and MLTC-1 cells. Supplementation with mitochondria-directed antioxidant mitoquinone (MitoQ) prevented 1-NP-evoked Leydig cell premature senescence and downregulation of testicular steroidogenic synthases. These results suggest that mitochondrial malfunction-initiated Leydig cell premature senescence may partially participate in 1-NP-evoked reduction of steroidogenic synthase levels in testes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study investigates the role of the deubiquitinating enzyme USP14 in alleviating doxorubicin (DOX)-induced cardiotoxicity (DIC), particularly concerning its mechanism of regulating pyroptosis through the stabilization of the mitochondrial protein SIRT3. Using in vivo and in vitro models, the research demonstrated that USP14 overexpression protects against DOX-induced cardiac damage by modulating pyroptosis. Silencing SIRT3 via siRNA revealed that SIRT3 is a key intermediary molecule in USP14-mediated regulation of pyroptosis. Notably, DOX exposure resulted in decreased USP14 expression, while its overexpression preserved mitochondrial function and reduced oxidative stress by stabilizing SIRT3. Immunoprecipitation confirmed that USP14 stabilizes SIRT3 through deubiquitination. These findings position USP14 as a promising therapeutic target for mitigating DOX-induced cardiotoxicity by stabilizing SIRT3 and maintaining mitochondrial integrity, suggesting potential novel strategies for cardio-protection in chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The accumulating evidence has made it clear that iron overload is a crucial mechanism in bone loss. Protocatechualdehyde (PCA) has also been used to prevent osteoporosis in recent years. Whether PCA can reverse the harmful effects of iron overload on bone mass in aged rats is still unknown. Therefore, this study aimed to assess the role of PCA in iron overload-induced bone loss in senile rats. In the aged rat model, we observed that iron overload affects bone metabolism and bone remodeling, manifested by bone loss and decreased bone mineral density. The administration of PCA effectively mitigated the detrimental effects caused by iron overload, and concomitant reduction in MDA serum levels and elevation of SOD were noted. In addition, PCA-treated rats were observed to have significantly increased bone mass and elevated expression of SIRT3，BMP2，SOD2 and reduced expression of TNF-α in bone tissue. We also observed that PCA was able to reduce oxidative stress and inflammation and restore the imbalance in bone metabolism. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclasts differentiation, PCA intervention could significantly recover the restriction of osteogenic differentiation and up-regulation of osteoclast differentiation treated by iron overload. Further, by detecting changes in ROS, SOD, MDA, expression of SIRT3 and mitochondrial membrane potentials, we confirm that the damage caused to cells by iron overload is associated with decreased SIRT3 activity, and that 3-TYP have similar effects on oxidative stress caused by FAC. In conclusion, PCA can resist iron overload-induced bone damage by improving SIRT3 activity, anti-inflammatory and anti-oxidative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The reintroduction of hemp production has resulted in increased consumption of cannabidiol (CBD) products, particularly CBD oil, yet their effects on intestinal health are not fully understood. Proper mitochondrial function and antioxidant defenses are vital for maintaining the intestinal epithelial barrier. AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC)1α are key mediators of mitochondrial metabolism., Methods & Results: Using Caco-2 cells, we found that CBD oil promoted AMPK phosphorylation, upregulated differentiation markers, and enhanced PGC1α/SIRT3 mitochondrial signaling. CBD oil reduced reactive oxygen species production and increased antioxidant enzymes. Moreover, CBD oil also increased levels of citrate, malate, and succinate-key metabolites of the tricarboxylic acid cycle-alongside upregulation of pyruvate dehydrogenase and isocitrate dehydrogenase 1. Similarly, pure CBD induced metabolic and antioxidant signaling., Conclusions: CBD enhances mitochondrial metabolic activity and antioxidant defense in Caco-2 cells, making it a promising candidate for treating intestinal dysfunction.

Osteoporosis is a major degenerative metabolic bone disease that threatens the life and health of postmenopausal women. Owing to limitations in detection methods and prevention strategy awareness, the purpose of osteoporosis treatment is more to delay further deterioration rather than to fundamentally correct bone mass. We aimed to clarify the pathogenesis of postmenopausal osteoporosis and optimize treatment plans. Our experiments were based on previous findings that oxidative stress mediates bone metabolism imbalance after oestrogen deficiency. Through energy metabolism-targeted metabolomics, we revealed that purine metabolism disorder is the main mechanism involved in inducing oxidative damage in bone tissue, which was verified via the use of machine-learning data from human databases. Xanthine and xanthine oxidase were used to treat osteoblasts to construct a purine metabolism disorder model. The activity and differentiation ability of osteoblasts decreased after X/XO treatment. Transcriptomic sequencing indicated that autophagic flux damage was involved in purine metabolism-induced oxidative stress in osteoblasts. Additionally, we performed serum metabolomics combined with network pharmacology to determine the pharmacological mechanism of metformin in the treatment of postmenopausal osteoporosis. HPRT1 was the potential target filtered from the hub genes, and FoxO1 signalling was the key pathway mediating the effect of metformin in osteoblasts. We also revealed that SIRT3-mediated deacetylation promoted the nuclear localization of FoxO1 to increase the expression of HPRT1. HPRT1 upregulation promoted purine anabolism and prevented the accumulation of ROS caused by purine catabolism to reverse oxidative damage in osteoblasts. We propose that purine metabolism disorder-induced oxidative stress is important for the pathogenesis of postmenopausal osteoporosis. The therapeutic mechanism of metformin should be confirmed through subsequent drug optimization and development studies to improve bone health in postmenopausal women., (© 2024. The Author(s).)

Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-β1 (TGF-β1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-β1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-β1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-β1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-β1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalyzed sp 3 C-H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C-H activation is also demonstrated by an unprecedented enantioselective sp 3 C-H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2 a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3)., (© 2024 Wiley-VCH GmbH.)

Several studies have observed renal cell ferroptosis during cisplatin-induced acute kidney injury (AKI). However, the mechanism is not completely clear. In this study, oxidized arachidonic acid (AA) metabolites are increased in cisplatin-treated HK-2 cells. Targeted metabolomics showed that the end product of pyrimidine biosynthesis is decreased and the initiating substrate of pyrimidine biosynthesis is increased in cisplatin-treated mouse kidneys. Mitochondrial DHODH, a key enzyme for pyrimidine synthesis, and its downstream product CoQH 2 , are downregulated. DHODH overexpression attenuated but DHODH silence exacerbated cisplatin-induced CoQH 2 depletion and lipid peroxidation. Mechanistically, renal DHODH acetylation is elevated in cisplatin-exposed mice. Mitochondrial SIRT3 is reduced in cisplatin-treated mouse kidneys and HK-2 cells. Both in vitro SIRT3 overexpression and in vivo NMN supplementation attenuated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis. By contrast, Sirt3 knockout aggravated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis, which can not be attenuated by NMN. Additional experiments showed that cisplatin caused mitochondrial dysfunction and SIRT3 SUMOylation. Pretreatment with mitochondria-target antioxidant MitoQ alleviated cisplatin-caused mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. MitoQ pretreatment protected against cisplatin-caused AKI and renal cell ferroptosis. Taken together, these results suggest that mitochondrial dysfunction-evoked DHODH acetylation partially contributes to renal cell ferroptosis during cisplatin-induced AKI., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)