Search

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 sp3 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 sp3 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). [ABSTRACT FROM AUTHOR]

Inhibition of SIRT3 triggered differentiation of multiple myeloma (MM) cells. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound S27. A total of 49 compounds divided into two series were designed and synthesized. In the enzyme inhibitory assay, several molecules (A7, A13, B15, and B26) exhibited potent SIRT3 inhibitory activity and selectivity. Significantly, representative compounds, especially A7, promoted differentiation of MM cells from cancer phenotype to normal cells, accompanied by increased expression of antigen CD49e, human immunoglobulin light chain λ‐IgLG and κ‐IgLG. Additionally, molecule A7 reversed growth factor IL‐6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inhibition of SIRT3 exhibited potency in triggering leukemic cell differentiation. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound P6. A total of 33 compounds were designed and synthesized. In the enzyme inhibitory assay, several molecules S18, S26, S27 and T5 showed potent SIRT3 inhibitory activity with IC50 value of 0.53, 1.86, 5.06, and 2.88 μM, respectively. Moreover, the tested compounds exhibited SIRT3 inhibitory selectivity over SIRT1 and SIRT2. Compounds S27 and T5 were potent in inhibition the growth of MM1.S and RPMI‐8226 cells in the in vitro antiproliferative test. Significantly, representative compounds, especially S27 and T5, promoted differentiation of tested MM cells in the cellular morphological evaluation, accompanied by increasing the expression of differentiation antigen CD49e and human immunoglobulin light chain lambda and kappa. Additionally, molecule S18 without antiproliferative potency itself, showed significant inhibitory activity against growth factor IL‐6 induced RPMI‐8226 cell proliferation. Collectively, potent SIRT3 selective inhibitors with MM cell differentiation potency were developed for further discovery of anticancer drugs. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia‐induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear. Objective: To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia‐induced neuroinflammation and DNP and to explore potential therapeutic interventions. Method and Results: Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA‐sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia‐induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high‐glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy‐lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia‐induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia‐induced Sirt3 downregulation. Conclusion: Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP. [ABSTRACT FROM AUTHOR]

Aims: Postoperative delirium (POD) is a common neurological complication in elderly patients after anesthesia/surgery. The main purpose of this study is to explore the effect of circRNA‐targeted miRNA regulating SIRT3 on mitochondrial function through ceRNA mechanism under the surgical model of tibial fracture and to further explore the potential mechanism of postoperative delirium mediated by circRNA, so as to provide new ideas for clinical diagnosis and prevention of POD. Methods: The surgical model of tibial fracture under sevoflurane anesthesia caused acute delirium‐like behavior in elderly mice. We observed that the decrease of SIRT3 and mitochondrial dysfunction was related to POD, and miRNA and circRNA (circRNA_34414) related to SIRT3 were further studied. Through luciferase and RAP, we observed that circRNA_34414, as a miRNA sponge, was involved in the regulation of SIRT3 expression. Results: Postoperative delirium in elderly mice showed decreased expression of hippocampal circRNA_34414, increased expression of miR‐6960‐5p, decreased expression of SIRT3, and impaired mitochondrial membrane potential. Overexpression of circRNA_34414, or knockdown of miR‐6960‐5p, or overexpression of SIRT3 in hippocampal CA1 glutamatergic neurons significantly upregulated hippocampal SIRT3 expression, increased mitochondrial membrane potential levels, and significantly ameliorated postoperative delirium in aged mice; CircRNA_34414 ameliorates postoperative delirium in mice, possibly by targeting miR‐6960‐5p to upregulate SIRT3. Conclusions: CircRNA_34414 is involved in the improvement of postoperative delirium induced by anesthesia/surgery by upregulating SIRT3 via sponging miR‐6960‐5p. [ABSTRACT FROM AUTHOR]

Background: This work elucidated the effect of honokiol (HKL) on hippocampal neuronal mitochondrial function in Alzheimer's disease (AD). Methods: APP/PS1 mice were used as AD mice models and exposed to HKL and 3‐TYP. Morris water maze experiment was performed to appraise cognitive performance of mice. Hippocampal Aβ+ plaque deposition and neuronal survival was evaluated by immunohistochemistry and Nissl staining. Hippocampal neurons were dissociated from C57BL/6 mouse embryos. Hippocampal neuronal AD model was constructed by Aβ oligomers induction and treated with HKL, CsA and 3‐TYP. Neuronal viability and apoptosis were detected by cell counting kit‐8 assay and TUNEL staining. mRFP–eGFP–LC3 assay, MitoSOX Red, dichlorodihydrofluorescein diacetate, and JC‐1 staining were performed to monitor neuronal autophagosomes, mitochondrial reactive oxygen species (ROS), neuronal ROS, and mitochondrial membrane potential. Autophagy‐related proteins were detected by Western blot. Results: In AD mice, HKL improved cognitive function, relieved hippocampal Aβ1–42 plaque deposition, promoted hippocampal neuron survival, and activated hippocampal SIRT3 expression and mitochondrial autophagy. These effects of HKL on AD mice were abolished by 3‐TYP treatment. In hippocampal neuronal AD model, HKL increased neuronal activity, attenuated neuronal apoptosis and Aβ aggregation, activated SIRT3 and mitochondrial autophagy, reduced mitochondrial and neuronal ROS, and elevated mitochondrial membrane potential. CsA treatment and 3‐TYP treatment abrogated the protection of HKL on hippocampal neuronal AD model. The promotion of mitochondrial autophagy by HKL in hippocampal neuronal AD model was counteracted by 3‐TYP. Conclusions: HKL activates SIRT3‐mediated mitochondrial autophagy to mitigate hippocampal neuronal damage in AD. HKL may be effective in treating AD. [ABSTRACT FROM AUTHOR]

Aims: Astrocytic senescence is inextricably linked to aging and neurodegenerative disorders, including Parkinson's disease (PD). P7C3 is a small, neuroprotective aminopropyl carbazole compound that exhibits anti‐inflammatory properties. However, the effects of P7C3 on astrocytic senescence in PD remain to be elucidated. Methods: An in vitro, long culture‐induced, replicative senescence cell model and a 1‐methyl‐4‐phenylpyridinium (MPP+)/rotenone‐induced premature senescence cell model were used to investigate the effects of P7C3 on astrocytic senescence. An in vivo, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse PD model was used to study the role of P7C3 in astrocytic senescence. Immunoblotting, real‐time quantitative RT‐PCR (qPCR), immunofluorescence, subcellular fractionation assays, and immunohistochemistry were utilized to confirm the effects of P7C3 on astrocytic senescence and elucidate its underlying mechanisms. Results: This study determined that P7C3 suppressed the senescence‐associated secretory phenotype (SASP) in both cell models, as demonstrated by the reduction in the critical senescence marker p16 and proinflammatory factors (IL‐6, IL‐1β, CXCL10, and MMP9) and increased laminB1 levels, implying that P7C3 inhibited replicative astrocytic senescence and MPP+/rotenone‐induced premature astrocytic senescence, Most importantly, we demonstrated that P7C3 prevented the death of dopamine (DA) neurons and reduced the behavioral deficits in the MPTP‐induced mouse model of PD, which is accompanied by a decrease in senescent astrocytes in the substantia nigra compacta (SNc). Mechanistically, P7C3 promoted Nrf2/Sirt3‐mediated mitophagy and reduced mitochondrial reactive oxygen species (mitoROS) generation, which contributed to the suppression of astrocytic senescence. Furthermore, Sirt3 deficiency obviously abolished the inhibitory effects of P7C3 on astrocytic senescence. Conclusion: This study revealed that P7C3 inhibited astrocytic senescence via increased Nrf2/Sirt3‐mediated mitophagy and suppression of mitoROS, which further protected against DA neuronal loss. These observations provide a prospective theoretical basis for P7C3 in the treatment of age‐associated neurodegenerative diseases, such as PD. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a typical and lethal digestive system malignancy. In this study, we investigated the effect of sirtuin 3 (SIRT3) expression, a fidelity mitochondrial protein, on the proliferation of CRC cells and the mechanisms involved. Using the University of Alabama at Birmingham Cancer Data Analysis Portal database and the Clinical Proteomic Tumour Analysis Consortium database, we discovered that low expression of SIRT3 in CRC was a negative factor for survival prognosis (P <.05). Meanwhile, SIRT3 expression was correlated with distant metastasis and tumour, node, metastasis stage of CRC patients (P <.05). Subsequently, we observed that CRC cells with stable SIRT3 expression exhibited a significant decrease in proliferative capacities both in vitro and in vivo, compared to their counterparts (P <.05). Further investigation using western blot, immunoprecipitation and TOPflash/FOPflash assay showed the mechanism of growth retardation of these cells was highly associated with the degradation of β‐catenin in cytosol, and the localization of β‐catenin/α‐catenin complex in the nucleus. In conclusion, our findings suggest that the inhibition of CRC cell proliferation by SIRT3 is closely associated with the inactivation of the Wnt/β‐catenin signalling pathway. [ABSTRACT FROM AUTHOR]

Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti‐inflammatory properties, but its role in treating sepsis‐induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis‐induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)‐induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC‐1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor‐erythroid 2‐related factor (Nrf2)/sirtuin‐3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS‐induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS‐induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO‐1, and vascular endothelial‐Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway. [ABSTRACT FROM AUTHOR]

The pathogenesis of age‐related hearing loss (ARHL) remains unclear. OPA1 is the sole fusion protein currently known to be situated in the inner mitochondrial membrane, which is pivotal for maintaining normal mitochondrial function. While it has already been demonstrated that mutations in OPA1 may lead to hereditary deafness, its involvement in the occurrence and development of ARHL has not been previously explored. In our study, we constructed D‐gal‐induced senescent HEI‐OC1 cells and the cochlea of C57BL/6J mice with a mutated SUMOylation site of SIRT3 using CRISPR/Cas9 technology. We found enhanced L‐OPA1 processing mediated by activated OMA1, and increased OPA1 acetylation resulting from reductions in SIRT3 levels in senescent HEI‐OC1 cells. Consequently, the fusion function of OPA1 was inhibited, leading to mitochondrial fission and pyroptosis in hair cells, ultimately exacerbating the aging process of hair cells. Our results suggest that the dysregulation of mitochondrial dynamics in cochlear hair cells in aged mice can be ameliorated by activating the SIRT3/OPA1 signaling. This has the potential to alleviate the senescence of cochlear hair cells and reduce hearing loss in mice. Our study highlights the significant roles played by the quantities of long and short chains and the acetylation activity of OPA1 in the occurrence and development of ARHL. This finding offers new perspectives and potential targets for the prevention and treatment of ARHL. [ABSTRACT FROM AUTHOR]

Introduction: Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated. Methods: In this study, we used high‐fat diet/low‐dose streptozotocin‐induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole‐cell patch‐clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real‐time PCR, western blot, and immunofluorescence were performed to investigate the mechanism. Results: We found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD+‐dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV‐SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a‐PINK1‐Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected. Conclusion: These results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a‐PINK1‐Parkin‐mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN. [ABSTRACT FROM AUTHOR]

There was a link between exposure to PM2.5 and male infertility. Melatonin has beneficial effects on the male reproductive processes. How PM2.5 caused spermatogenesis disturbance and whether melatonin could prevent PM2.5‐induced reproductive toxicity have remained unclear. The results showed that PM2.5 could inhibit the Nrf2‐mediated antioxidant pathway and distinctly increase the cell apoptosis in testes. Moreover, PM2.5 also perturbed the process of meiosis by modulating meiosis‐associated proteins such as γ‐H2AX and Stra8. Mechanistically, PM2.5 inhibited G9a‐dependent H3K9 methylation and SIRT3‐mediated p53 deacetylation, which consistent with decreased sperm count and motility rate in ApoE−/− mice. Further investigation revealed melatonin effectively alleviated PM2.5‐induced meiosis inhibition by preserving H3K9 methylation. Melatonin also alleviated PM2.5‐induced apoptosis by regulating SIRT3‐mediated p53 deacetylation. Overall, our study revealed PM2.5 resulted in spermatogenesis disorder by perturbing meiosis via G9a‐dependent H3K9 di‐methylation and causing cell apoptosis via SIRT3/p53 deacetylation pathway and provided promising insights into the protective role of melatonin in air pollution associated with male infertility. [ABSTRACT FROM AUTHOR]

Hesperetin (HST) is a flavonoid compound naturally occurring in citrus fruits and is widespread in various traditional medicinal herbs such as grapefruit peel, orange peel, and tangerine peel. These plant materials are commonly used in traditional Chinese medicine to prepare herbal remedies. The study aimed to investigate the potential molecular mechanisms through which HST reduces ferroptosis in human umbilical vein endothelial cells (HUVECs) and promotes angiogenesis and wound healing. We employed network pharmacology to predict the downstream targets affected by HST. The expression of markers related to ferroptosis was assessed through Western blot (WB) and polymerase chain reaction. Intracellular levels of ferroptosis‐related metabolism were examined using glutathione/oxidized glutathione (GSH/GSSG) and malondialdehyde (MDA) assay kits. Mitochondrial status and iron levels within the cells were investigated through staining with Mitosox, FerroOrange, and JC1 staining. Potential downstream direct targets of HST were identified using molecular docking. Additionally, wound healing and neovascularization within the wound site were analyzed using various methods including HE staining, Masson's staining, immunohistochemistry, and Doppler hemodynamics assessment. HST effectively inhibits the elevated levels of intracellular ferroptosis stimulated by ERASTIN. Furthermore, we observed that HST achieves this inhibition of ferroptosis by activating SIRT3. In a diabetic rat wound model, HST significantly promotes wound healing, reducing levels of tissue ferroptosis, consistent with our in vitro findings. This study demonstrates that HST can inhibit the progression of ferroptosis and protect the physiological function of HUVECs by activating SIRT3. HST holds promise as a natural compound for promoting diabetic wound healing. [ABSTRACT FROM AUTHOR]

Background: Psoriasis, a common chronic inflammatory skin condition, impacts around 2%–3% of the global population. Theacrine is recognized for its potential anti‐inflammatory and antioxidant properties. However, the role of theacrine in psoriasis remains unclear. Purposes: To investigate the effects of theacrine on psoriasis and explore the underlying signaling pathways. Methods: For imiquimod (IMQ)‐induced Psoriasis‐like mice, the psoriatic inflammation was monitored using Psoriasis Area and Severity Index (PASI). The skin damage was observed using Hematoxylin and Eosin staining. The KI67 and CD4 in skin tissues were assessed using Immunohistochemistry analysis. Western blots were performed to evaluate the expression of Keratin 1 (KRT1), KRT6, LC3, P62, Beclin1, T‐bet, GATA3, RAR‐related orphan receptor (ROR)‐γt, Sirtuin‐3 (SIRT3), Forkhead Box O3a (FOXO3a) and Parkin. Additionally, LC3B expression was analyzed using an immunofluorescent assay, while flow cytometry was performed to analyze the percentage of Th17, Th1, and Th2 positive cells in skin‐draining lymph node. Results: Theacrine improved skin condition by reducing hyperkeratosis and acanthosis, lowering PASI scores, and decreasing KI67‐positive cells. Theacrine also modulated keratin expression, elevating KRT1 while reducing KRT6 levels. Theacrine enhanced autophagy indicated by an increased LC3‐II/LC3‐I ratio and Beclin1, while reduced P62 levels. Additionally, Theacrine reduced CD4‐positive cells and suppressed Th17 and Th1 cell activation. Theacrine activated the FOXO3a/Parkin pathway by upregulating SIRT3 expression, and down‐regulation of SIRT3 counteracted theacrine's effects in psoriasis‐like mice. Conclusion: Theacrine inhibits skin damage, promotes autophagy, and mediates inflammation in IMQ‐induced psoriasis mice via upregulating SIRT3 to activate FOXO3a/Parkin pathway, positioning theacrine as a candidate for psoriasis treatment. [ABSTRACT FROM AUTHOR]

This study investigates the therapeutic potential of electroacupuncture (EA) on obesity, focusing on its influence on autophagy and energy metabolism, utilizing a high‐fat diet (HFD)‐induced mouse model. Treatment with EA significantly reduces body weight, fat deposition, and lipid accumulation in HFD‐fed mice. Additionally, EA effectively ameliorates metabolic imbalances, reducing blood glucose levels and plasma markers of liver function. At the molecular level, EA enhances the expression of thermogenesis‐associated genes in brown adipose tissue and decreases p53 expression, suggesting a decrease in apoptosis. Autophagy in white adipose tissue is inhibited by EA, as demonstrated by the suppression of key autophagy‐related proteins. Further experiments highlight the critical role of Sirtuin 3 (Sirt3) in EA's anti‐obesity effects. Sirt3 supplementation combined with EA results in reduced body weight, fat deposition, and lipid accumulation, along with modulations in key metabolic indicators. Moreover, EA's modulatory effect on uncoupling protein 1 (Ucp1), Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (Pgc‐1α), and p53 is found to be Sirt3 dependent. In conclusion, EA exerts beneficial effects against obesity through Sirt3‐dependent modulation of autophagy and energy metabolism, indicating a potential therapeutic approach for obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]

Treatments for organ‐confined prostate cancer include external beam radiation therapy, radical prostatectomy, radiotherapy/brachytherapy, cryoablation and high‐intensity focused ultrasound. None of these are cancer‐specific and are commonly accompanied by side effects, including urinary incontinence and erectile dysfunction. Moreover, subsequent surgical treatments following biochemical recurrence after these interventions are either limited or affected by the scarring present in the surrounding tissue. Carnosine (β‐alanyl‐L‐histidine) is a histidine‐containing naturally occurring dipeptide which has been shown to have an anti‐tumorigenic role without any detrimental effect on healthy cells; however, its effect on prostate cancer cells has never been investigated. In this study, we investigated the effect of carnosine on cell proliferation and metabolism in both a primary cultured androgen‐resistant human prostate cancer cell line, PC346Flu1 and murine TRAMP‐C1 cells. Our results show that carnosine has a significant dose‐dependent inhibitory effect in vitro on the proliferation of both human (PC346Flu1) and murine (TRAMP‐C1) prostate cancer cells, which was confirmed in 3D‐models of the same cells. Carnosine was also shown to decrease adenosine triphosphate content and reactive species which might have been caused in part by the increase in SIRT3 also shown after carnosine treatment. These encouraging results support the need for further human in vivo work to determine the potential use of carnosine, either alone or, most likely, as an adjunct therapy to surgical or other conventional treatments. [ABSTRACT FROM AUTHOR]

Brain damage in children due to seizures is irreversible and has been a major public health concern. The herbal monomer Xyloketal B (Xyl‐B) can be used as a neuroprotective drug because of its antioxidant, antiapoptotic, and anti‐inflammatory effects but with few adverse effects. In this article, we constructed a rat developmental convulsion model and a primary hippocampal neuronal cell convulsion model, through which we studied hippocampal neuronal morphology and neuronal apoptosis using H&E staining and TUNEL staining, respectively. Moreover, we measured TNF‐α, IL‐6, and IL‐1β inflammatory factor levels using ELISA, MDA, and SOD kits. The expression of SIRT3 in hippocampal tissues was determined by qPCR and Western blotting. The expression of autophagy‐related proteins such as LC3, p62, and Beclin‐1 was evaluated by Western blotting or immunohistochemistry. The role of SIRT3 and autophagic activity with Xyl‐B in convulsive seizure‐induced brain injury was investigated by knocking down SIRT3 expression levels. Our results showed that Xyl‐B plays a neuroprotective role in convulsive seizure‐induced brain injury by increasing SIRT3 expression and activating the autophagy pathway. The regulatory role of SIRT3 in the autophagy pathway with Xyl‐B treatment was explored by knocking down SIRT3 expression and inhibiting autophagy. Our results revealed that SIRT3 enhances the protective effect of Xyl‐B against postconvulsive brain injury by regulating AMPK/mTOR signaling‐mediated autophagy. [ABSTRACT FROM AUTHOR]

Cigarette smoking can cause damage of airway epithelial cells and contribute to chronic obstructive pulmonary disease (COPD). Honokiol is originally isolated from Magnolia obovata with multiple biological activities. Here, we investigated the protective effects of honokiol on cigarette smoke extract (CSE)‐induced injury of BEAS‐2B cells. BEAS‐2B cells were treated with 300 mg/L CSE to construct an in vitro cell injury model, and cells were further treated with 2, 5 and 10 μM honokiol, then cell viability and LDH leakage were analysed by CCK‐8 and LDH assay kits, respectively. Apoptosis was detected by flow cytometry analysis. ELISA was used to measure the levels of tumour necrosis factor (TNF)‐ɑ, IL‐1β, IL‐6, IL‐8 and MCP‐1. The results showed that honokiol (0.5–20 μM) showed non‐toxic effects on BEAS‐2B cells. Treatment with honokiol (2, 5 and 10 μM) reduced CSE (300 mg/L)‐induced decrease in cell viability and apoptosis in BEAS‐2B cells. Honokiol also decreased CSE‐induced inflammation through inhibiting expression and secretion of inflammatory cytokines, such as TNF‐ɑ, IL‐1β, IL‐6, IL‐8 and MCP‐1. Moreover, honokiol repressed CSE‐induced reactive oxygen species (ROS) production, decrease of ATP content and mitochondrial biogenesis, as well as mitochondrial membrane potential. Mechanistically, honokiol promoted the expression of SIRT3 and its downstream target genes, which are critical regulators of mitochondrial function and oxidative stress. Silencing of SIRT3 reversed the protective effects of honokiol on CSE‐induced damage and mitochondrial dysfunction in BEAS‐2B cells. These results indicated that honokiol attenuated CSE‐induced damage of airway epithelial cells through regulating SIRT3/SOD2 signalling pathway. [ABSTRACT FROM AUTHOR]

Introduction: Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as motor, sensory, and autonomic dysfunction below the level of damage. Our previous studies confirmed the ability of zinc to protect mitochondria, protect neurons and promote spinal cord recovery. However, the role of zinc in Parthanatos is unknown. Aim: We investigated the effects of zinc in Parthanatos from oxidative stress and mitophagy. We elucidated the role of SIRT3 in providing new ideas for treating spinal cord injury. The Results: Zinc protected SCI mice by regulating Parthanatos. On the one hand, zinc eliminated ROS directly through SIRT3 deacetylation targeting SOD2 to alleviate Parthanatos. On the other hand, zinc eliminated ROS indirectly through SIRT3‐mediated promotion of mitophagy to alleviate Parthanatos. Conclusion: Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3‐mediated anti‐oxidative stress and mitophagy. [ABSTRACT FROM AUTHOR]

Age‐related sensors Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) play an essential role in the protective response upon myocardial ischemia and/or reperfusion (I/R). However, the subcellular localization and co‐regulatory network between cardiac SIRT1 and SIRT3 remain unknown, especially their effects on age‐related metabolic regulation during acute ischemia and I/R. Here, we found that defects of cardiac SIRT1 or SIRT3 with aging result in an exacerbated cardiac physiological structural and functional deterioration after acute ischemic stress and failed recovery through reperfusion operation. In aged hearts, SIRT1 translocated into mitochondria and recruited more mitochondria SIRT3 to enhance their interaction during acute ischemia, acting as adaptive protection for the aging hearts from further mitochondria dysfunction. Subsequently, SIRT3‐targeted proteomics revealed that SIRT1 plays a crucial role in maintaining mitochondrial integrity through SIRT3‐mediated substrate metabolism during acute ischemic and I/R stress. Although the loss of SIRT1/SIRT3 led to a compromised PGC‐1α/PPARα‐mediated transcriptional control of fatty acid oxidation in response to acute ischemia and I/R, their crosstalk in mitochondria plays a more important role in the aging heart during acute ischemia. However, the increased mitochondria SIRT1‐SIRT3 interaction promoted adaptive protection to aging‐related fatty acid metabolic disorder via deacetylation of long‐chain acyl CoA dehydrogenase (LCAD) during ischemic insults. Therefore, the dynamic network of SIRT1/SIRT3 acts as a mediator that regulates adaptive metabolic response to improve the tolerance of aged hearts to ischemic insults, which will facilitate investigation into the role of SIRT1/SIRT3 in age‐related ischemic heart disease. [ABSTRACT FROM AUTHOR]

Damaged mitochondria, a key factor in liver fibrosis, can be removed by the mitophagy pathway to maintain homeostasis of the intracellular environment to alleviate the development of fibrosis. PINK1 (PTEN‐induced kinase 1) and NIPSNAP1 (nonneuronal SNAP25‐like protein 1), which cooperatively regulate mitophagy, have been predicted to include the sites of lysine acetylation related to SIRT3 (mitochondrial deacetylase sirtuin 3). Our study aimed to discuss whether SIRT3 deacetylates PINK1 and NIPSNAP1 to regulate mitophagy in liver fibrosis. Carbon tetrachloride (CCl4)‐induced liver fibrosis as an in vivo model and LX‐2 cells as activated cells were used to simulate liver fibrosis. SIRT3 expression was significantly decreased in mice in response to CCl4, and SIRT3 knockout in vivo significantly deepened the severity of liver fibrosis, as indicated by increased α‐SMA and Col1a1 levels both in vivo and in vitro. SIRT3 overexpression decreased α‐SMA and Col1a1 levels. Furthermore, SIRT3 significantly regulated mitophagy in liver fibrosis, as demonstrated by LC3‐Ⅱ/Ⅰ and p62 expression and colocalization between TOM20 and LAMP1. Importantly, PINK1 and NIPSNAP1 expression was also decreased in liver fibrosis, and PINK1 and NIPSNAP1 overexpression significantly improved mitophagy and attenuated ECM production. Furthermore, after simultaneously interfering with PINK1 or NIPSNAP1 and overexpressing SIRT3, the effect of SIRT3 on improving mitophagy and alleviating liver fibrosis was disrupted. Mechanistically, we show that SIRT3, as a mitochondrial deacetylase, specifically regulates the acetylation of PINK1 and NIPSNAP1 to mediate the mitophagy pathway in liver fibrosis. SIRT3‐mediated PINK1 and NIPSNAP1 deacetylation is a novel molecular mechanism in liver fibrosis. [ABSTRACT FROM AUTHOR]

Random skin flap grafting is the most common skin grafting technique in reconstructive surgery. Despite progress in techniques, the incidence of distal flap necrosis still exceeds 3%, which limits its use in clinical practice. Current methods for treating distal flap necrosis are still lacking. Pinocembrin (Pino) can inhibit reactive oxygen species (ROS) and cell death in a variety of diseases, such as cardiovascular diseases, but the role of Pino in random flaps has not been explored. Therefore, we explore how Pino can enhance flap survival and its specific upstream mechanisms via macroscopic examination, Doppler, immunohistochemistry, and western blot. The results suggested that Pino can enhance the viability of random flaps by inhibiting ROS, pyroptosis and apoptosis. The above effects were reversed by co‐administration of Pino with adeno‐associated virus‐silencing information regulator 2 homolog 3 (SIRT3) shRNA, proving the beneficial effect of Pino on the flaps relied on SIRT3. In addition, we also found that Pino up‐regulates SIRT3 expression by activating the AMP‐activated protein kinase (AMPK) pathway. This study proved that Pino can improve random flap viability by eliminating ROS, and ROS‐induced cell death through the activation of SIRT3, which are triggered by the AMPK/PGC‐1α signaling pathway. [ABSTRACT FROM AUTHOR]

Radiation resistance is the leading cause of radiotherapy failure in patients with cancer. Enhanced DNA damage repair is the main reason for cancer cells to develop resistance to radiation. Autophagy has been widely reported to be linked to increased genome stability and radiation resistance. Mitochondria are highly involved in the cell response to radiotherapy. However, the autophagy subtype mitophagy has not been studied in terms of genome stability. We have previously demonstrated that mitochondrial dysfunction is the cause of radiation resistance in tumour cells. In the present study, we found that SIRT3 was highly expressed in colorectal cancer cells with mitochondrial dysfunction, leading to PINK1/Parkin‐mediated mitophagy. Excessive activation of mitophagy enhanced DNA damage repair, therefore promoting the resistance of tumour cells to radiation. Mechanistically, mitophagy resulted in decreased RING1b expression, which led to a reduction in the ubiquitination of histone H2A at K119, thereby enhancing the repair of DNA damage caused by radiation. Additionally, high expression of SIRT3 was related to a poor tumour regression grade in rectal cancer patients treated with neoadjuvant radiotherapy. These findings suggest that restoring mitochondrial function could be an effective method for increasing the radiosensitivity of patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD+‐dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to be an HCC tumor suppressor. Here we report that SIRT3 can delactylate non‐histone proteins and suppress HCC development. Using SILAC‐based quantitative proteomics, we identify cyclin E2 (CCNE2) as one of the lactylated substrates of SIRT3 in HCC cells. Furthermore, our crystallographic study elucidates the mechanism of CCNE2 K348la delactylation by SIRT3. Our results further suggest that lactylated CCNE2 promotes HCC cell growth, while SIRT3 activation by Honokiol induces HCC cell apoptosis and prevents HCC outgrowth in vivo by regulating Kla levels of CCNE2. Together, our results establish a physiological function of SIRT3 as a delactylase that is important for suppressing HCC, and our structural data could be useful for the future design of activators. Synopsis: Delactylation of cyclin E2 (CCNE2) by SIRT3 suppresses hepatocellular carcinoma (HCC) development.SIRT3 is negatively correlated with lysine lactylation levels in HCC tissues.SIRT3‐mediated delactylation of CCNE2 suppresses HCC cell growth.Honokiol induces SIRT3 delactylation activity to prevent HCC growth in vivo. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication of diabetes that severely affects the quality of life of diabetic patients. Long noncoding RNAs (lncRNAs) play important roles in the pathogenesis of DCM. However, the role of the lncRNA homeobox transcript antisense RNA (HOTAIR) in the progression of DCM remains unclear. The present study aimed to investigate the role of HOTAIR in high glucose (HG)‐induced pyroptosis in cardiomyocytes. The expression of the lncRNA HOTAIR, FUS, and SIRT3 in H9C2 cardiomyocytes was detected by RT–qPCR. Western blotting was used to evaluate the expression of FUS and SIRT3 as well as that of pyroptosis‐ and inflammation‐related proteins. RT–qPCR and ELISA were used to determine the expression and secretion of IL‐1β and IL‐18. RNA pulldown and RIP experiments were used to validate the binding relationship among HOTAIR, FUS, and SIRT3. Flow cytometry was performed to detect pyroptosis. HG induced pyroptosis and elevated the expression of proteins associated with pyroptosis and inflammation (NLRP3, GSDMD‐N, cleaved caspase‐1, IL‐1β, and IL‐18) in cardiomyocytes. HOTAIR and SIRT3 levels were decreased in HG‐exposed H9C2 cells. Additionally, overexpression of HOTAIR inhibited the HG‐induced pyroptosis and inflammatory response in cardiomyocytes. HOTAIR upregulated SIRT3 expression in H9C2 cells by targeting FUS. Moreover, SIRT3 upregulation suppressed HG‐mediated pyroptosis of cardiomyocytes. Notably, SIRT3 depletion reversed the inhibitory effect of HOTAIR on HG‐triggered pyroptosis in cardiomyocytes. Our research indicates that HOTAIR alleviates pyroptosis in diabetic cardiomyocytes through the FUS/SIRT3 axis, providing a potential marker for the diagnosis and treatment of DCM. [ABSTRACT FROM AUTHOR]

Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression of osteoarthritis (OA); however, the underlying mechanisms are unknown. This study aims to investigate the role of mitochondrial deacetylation reaction and investigate the mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation with the severity of OA in both human arthritic cartilage and mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype in post‐traumatic OA mice, as evidenced by cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1 polarization. Mechanistically, SIRT3 prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis at the post‐translational level. The activation of SIRT3 by honokiol restores cartilage metabolic equilibrium and protects mice from the development of post‐traumatic OA. Collectively, the loss of mitochondrial SIRT3 is essential for the development of OA, whereas SIRT3‐mediated proteins deacetylation of COX4I2 rescues OA‐impaired mitochondrial respiratory chain functions to improve the OA phenotype. Herein, the induction of SIRT3 provides a novel therapeutic candidate for OA treatment. [ABSTRACT FROM AUTHOR]

Vitiligo is a skin depigmentation disorder. GATA3 expression is downregulated in vitiligo patients, and its role and regulatory mechanism in vitiligo are unclear. GATA3 and HMGB1 levels were detected by qRT‐PCR in peripheral blood cells of vitiligo patients and healthy controls, as well as H2O2‐treated PIG1 cells. Their expression correlation was assessed by Pearson analysis. qRT‐PCR, MTT assay, Ki67 immunostaining, flow cytometry, ELISA and Western blot were applied to determine GATA3 expression, cell survival, cell proliferation, cell apoptosis, melanin contents, and melanin‐related protein expressions. The cellular distributions of HMGB1 and its deacetylation levels were detected by Western blot. The binding of GATA3 to SIRT3 promoter and effects on SIRT3 expression and HMGB1 deacetylation was determined by dual‐luciferase assay, ChIP assay, and Western blot. GATA3 was decreased, and HMGB1 was increased in vitiligo. Pearson correlation assay showed that they were negatively correlated. H2O2 significantly inhibited cell survival, proliferation, melanin secretion, and melanin‐related protein expressions but remarkably increased cell apoptosis. GATA3 overexpression could distinctly reverse the effects of H2O2 through decreasing HMGB1 expression and retained HMGB1 in nuclear due to the decreased HMGB1 acetylation. GATA3 bound to the SIRT3 and subsequently decreased H2O2‐induced HMGB1 acetylation. Overexpressing HMGB1 or knockdown of SIRT3 could reverse the effects of GATA3 overexpression. GATA3 inhibited H2O2‐induced injury in PIG1 cells and enhanced melanin secretion by SIRT3‐regulated HMGB1 deacetylation, which might provide new evidence to treat vitiligo. [ABSTRACT FROM AUTHOR]

Background: Skin photoaging is the damage caused by excessive exposure to ultraviolet (UV) irradiation. We investigated the effect of adenosine triphosphate (ATP) supplementation on UVB‐induced photoaging in HaCaT cells and its potential molecular mechanism. Materials and methods: The toxicity of ATP on HaCaT cells was examined by the MTT assay. The effects of ATP supplementation on the viability and apoptosis of HaCaT cells were determined by crystal‐violet staining and flow cytometry, respectively. Cellular and mitochondrial ROS were stained using fluorescent dyes. Expression of Bax, B‐cell lymphoma (Bcl)‐2, sirtuin (SIRT)3, and superoxide dismutase (SOD)2 was measured via western blotting. Results: ATP (1, 2 mM) exerted no toxic effect on the normal growth of HaCaT cells. UVB irradiation caused the apoptosis of HaCaT cells, and ATP supplementation inhibited the apoptosis induced by UVB significantly, as verified by expression of Bax and Bcl‐2. UVB exposure resulted in accumulation of cellular and mitochondrial reactive oxygen species (ROS), but ATP supplementation suppressed these increases. Expression of SIRT3 and SOD2 was decreased upon exposure to UVB irradiation but, under ATP supplementation, expression of SIRT3 and SOD2 was reversed, which was consistent with the reduction in ROS level observed in ATP‐treated HaCaT cells after exposure to UVB irradiation. Conclusions: ATP supplementation can suppress UVB irradiation‐induced photoaging in HaCaT cells via upregulation of expression of SIRT3 and SOD2. [ABSTRACT FROM AUTHOR]

Background and Purpose: Gut microbiota dysbiosis induced by acute pancreatitis (AP) exacerbates pancreatic injury and systemic inflammatory responses. The alleviation of gut microbiota dysbiosis through faecal microbiota transplantation (FMT) is considered a potential strategy to reduce tissue damage and inflammation in many clinical disorders. Here, we aim to investigate the effect of gut microbiota and microbiota‐derived metabolites on AP and further clarify the mechanisms associated with pancreatic damage and inflammation. Experimental Approach: AP rat and mouse models were established by administration of caerulein or sodium taurocholate in vivo. Pancreatic acinar cells were exposed to caerulein and lipopolysaccharide in vitro to simulate AP. Key Results: Normobiotic FMT alleviated AP‐induced gut microbiota dysbiosis and ameliorated the severity of AP, including mitochondrial dysfunction, oxidative damage and inflammation. Normobiotic FMT induced higher levels of NAD+ (nicotinamide adenine dinucleotide)‐associated metabolites, particularly nicotinamide mononucleotide (NMN). NMN administration mitigated AP‐mediated mitochondrial dysfunction, oxidative damage and inflammation by increasing pancreatic NAD+ levels. Similarly, overexpression of the NAD+‐dependent mitochondrial deacetylase sirtuin 3 (SIRT3) alleviated the severity of AP. Furthermore, SIRT3 deacetylated peroxiredoxin 5 (PRDX5) and enhanced PRDX5 protein expression, thereby promoting its antioxidant and anti‐inflammatory activities in AP. Importantly, normobiotic FMT‐mediated NMN metabolism induced SIRT3–PRDX5 pathway activation during AP. Conclusion and Implications: Gut microbiota‐derived NMN alleviates the severity of AP by activating the SIRT3–PRDX5 pathway. Normobiotic FMT could be served as a potential strategy for AP treatment. [ABSTRACT FROM AUTHOR]

Objective: This research aimed to explore the effect of periodontitis on renal tissues injury in rats and the role of Sirtuin3 (Sirt3) and its regulation of autophagy in this progression. Material and Methods: Thirty Wistar rats were assigned into three groups: control, periodontitis (P), and periodontitis with gavage administration of Sirt3 activator resveratrol (P + RSV). To induce periodontitis, the wire ligature was placed around the cervical region of the rat maxillary first molar. After 8 weeks, micro-computed tomography (Micro-CT) and hematoxylin and eosin (HE) were used to evaluate the alveolar bone resorption and periodontal inflammation. Serum and urine biochemical indicators were measured to assess renal function. The pathological changes of the kidney were observed via HE and periodic acid Schiff (PAS) staining. Autophagosome was viewed by transmission electron microscopy (TEM). Real-time PCR and western blot were used to test expressions of Sirt3 and autophagy indicators in renal and periodontal tissues, including mammalian target of rapamycin (mTOR), phosphor-mTOR (p-mTOR), BECN1 (Beclin-1), and microtubule-associated protein 1 light chain 3 (LC3). Results: Alveolar bone destruction, resorption, and periodontal inflammation were observed in the P group (compared with the control group), and the above indexes were significantly improved after RSV intervention; the obvious changes in renal tissue structure in the P group were partially recovered after RSV intervention, while renal functional status was not affected (among the three groups); in addition, the levels of Sirt3 and autophagy in kidney and periodontal tissues of P group were inhibited, manifested as a decrease in the number of autophagosomes (renal tissue) and expressions of autophagy marker Beclin-1 and LC3 conversion rate and an increase in the expression of p-mTOR. After Sirt3 activation (RSV), the above indicators were significantly improved. Conclusion: Periodontitis causes renal structural damage in rats, which may be connected to the effect of Sirt3-induced autophagy. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is a common neurological complication of diabetes mellitus without efficient interventions. Both lysine demethylase 5B (KDM5B) and sirtuin‐3 (SIRT3) have been found to regulate islet function and glucose homeostasis. KDM5B was predicted to bind to the SIRT3 promoter by bioinformatics. Here, we investigated whether KDM5B affected DPN development via modulating SIRT3. Methods: The db/db mice and high glucose‐stimulated Schwann cells (RSC96) were used as in vivo and in vitro models of DPN, respectively. Glucose level, glucose and insulin tolerance of mice were measured. Neurological function was evaluated by motor nerve conduction velocity (MNCV), tactile allodynia assay and thermal sensitivity assay. Adenosine triphosphate level, oxygen consumption rate, extracellular acidification rate, β‐oxidation rate, acetyl‐CoA level, acetylation levels and activities of long‐chain acyl CoA dehydrogenase (LCAD) and pyruvate dehydrogenase (PDH) were detected. Methyl thiazolyl tetrazolium assay was adopted to determine cell viability. Reactive oxygen species (ROS) production was detected by MitoSox staining. Western blotting for measuring target protein levels. Molecular mechanisms were investigated by co‐immunoprecipitine (Co‐IP), chromatin immunoprecipitation (ChIP) and luciferase reporter assay. Results: KDM5B was up‐regulated, while SIRT3 was down‐regulated in DPN models. SIRT3 overexpression or AMPK activation ameliorated mitochondrial metabolism dysfunction and ROS overproduction during DPN. KDM5B overexpression triggered mitochondrial metabolism disorder and oxidative stress via directly transcriptional inhibiting SIRT3 expression by demethylating H3K4me3 or indirectly repressing AMPK pathway‐regulated SIRT3 expression. Conclusion: KDM5B contributes to DPN via regulating SIRT3‐mediated mitochondrial glucose and lipid metabolism. KDM5B inhibition may be an effective intervention for DPN. [ABSTRACT FROM AUTHOR]

Hypoxia has been reported to be an important factor leading to male infertility, and it has been reported that hypoxia can induce the apoptosis of mouse spermatogenic cells. Sirtuin 3 (SIRT3) has been reported to promote the degradation of hypoxia‐inducible factor 1α (HIF‐1α), and thus, we hypothesized that SIRT3 may influence hypoxia‐induced apoptosis of spermatogonia. In this study, we overexpressed or inhibited SIRT3 in mouse type B spermatogonia GC‐2 cells and then subjected the cells to hypoxia or normoxia, before examining hypoxia‐responsive gene expression and cell viability. We report that SIRT3 stabilizes hypoxia‐inducible factor 1α (HIF‐1α) and activates its downstream target gene expression in GC‐2 cells. We also show that the SIRT3 inhibitor 3‐TYP suppresses HIF‐1α target gene expression and alleviates hypoxia‐induced apoptosis of GC‐2 cells. Our study reveals the critical role and underlying mechanisms of SIRT3 in hypoxia‐induced apoptosis of mouse type B spermatogonia GC‐2 cells. [ABSTRACT FROM AUTHOR]

Resveratrol (Resv) has antitumorigenic and antimetastatic activities; however, the molecular mechanisms underlying the inhibitory effects of Resv on the invasion and metastasis of breast cancer cells are still a subject of debate. In our study, we demonstrated that Resv inhibited tumor cell proliferation and tumor growth. It also suppressed invasion and pulmonary metastasis of breast cancer by reversing the transforming growth factor beta 1 (TGF-β1)-mediated EMT process. Meanwhile, the anticarcinogenic effects of Resv were abolished by the autophagy blocker 3-methyladenine (3-MA) or Beclin 1 small interfering RNA. Moreover, Resv upregulated autophagy-related genes and protein levels and induced the formation of autophagosomes in 4T1 breast cancer cells and xenograft mice, suggesting that autophagy was involved in the anticarcinogenic activities of Resv in both models. In addition, Resv-induced autophagy by increasing the expression of SIRT3 and phosphorylated AMPK. SIRT3 knockdown reduced AMPK phosphorylation and autophagy-related proteins levels, and suppressed the anticancer effects of Resv, demonstrating that the inhibitory effects of Resv on tumor progression were mediated via the SIRT3/AMPK/autophagy pathway. Taken together, our study provided novel insight into the anticancer effects of Resv and revealed that targeting the SIRT3/AMPK/autophagy pathway can serve as a new therapeutic target against breast cancer. [ABSTRACT FROM AUTHOR]

Sepsis is a life‐threatening condition, and treatment for sepsis in clinic is often not available, partially due to insufficient understanding of the pathogenesis of sepsis. Extensive study to elucidate the pathogenesis is required to improve the clinical management and outcome of sepsis. In this study, we investigated the pathogenesis of sepsis using peripheral blood mononuclear cells (PBMCs) from septic patients and studied the underlying mechanism of miR‐16‐5p on aerobic glycolysis in lipopolysaccharide (LPS)‐treated THP1 and Raw264.7 cells. The levels of RNA and protein were determined by real‐time quantitative PCR and immunoblotting assay, respectively. The production of high mobility group box 1 (HMGB1) was measured by enzyme‐linked immunosorbent assay. The levels of succinate and lactate were determined using colorimetric kits. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured by extracellular flux analyzer. The results showed that the expression of miR‐16‐5p was elevated, while sirtuin 3 (SIRT3) was decreased in PBMCs from septic patients and LPS‐treated cells, along with accumulation of acetylated succinate dehydrogenase complex, subunit A. Concomitantly, an increase in HMGB1, succinate, lactate, as well as ECAR and a decrease in OCR were observed. Knockdown of miR‐16‐5p upregulated SIRT3 expression, facilitated SDHA deacetylation, and attenuated sepsis‐related aerobic glycolysis. Further study identified that SIRT3 is targeted by miR‐16‐5p, and overexpression of SIRT3 rescued LPS‐induced responses via deacetylation of SDHA. Our findings revealed a novel miR‐16‐5p‐regulated SIRT3‐SDHA axis in sepsis and provided novel insights for sepsis treatment. [ABSTRACT FROM AUTHOR]

This study was designed to explore the effects of exosomal miR‐421 secreted by cancer‐associated fibroblasts (CAFs) on pancreatic cancer (PC) progression and the mechanisms involved. CAFs and exosomes (exos) were isolated and identified. PC cells were treated with CAF‐derived exos (CAF‐exos). Western blotting and quantitative polymerase chain reaction (qPCR) were used to measure miR‐421, sirtuin‐3 (SIRT3), and hypoxia duciblefactors‐1 alpha (HIF‐1α) levels. Cell counting kit‐8 (CCK‐8), wound‐healing, and transwell migration assays were used to measure proliferation, migration, and invasion abilities of the cells. Dual‐luciferase assay and RNA immunoprecipitation (RIP) experiment analyzed the relationship between miR‐421 and SIRT3. Chromatin immunoprecipitation (f)‐verified H3K9Ac enrichment in the HIF‐1α promoter region. In vivo tumorigenesis experiments were performed to further explore the effects of exosomal miR‐421 from CAFs on PC. CAFs and exos were successfully isolated. CAF‐exo‐treated PC cells highly expressed miR‐421 and had increased cell proliferation, migration, and invasion abilities. Knocking down miR‐421 increased the expression of SIRT3. SIRT3 is a target of miR‐421, and inhibiting the expression of SIRT3 reversed the negative effects of miR‐421 knockdown on PC cell. Knocking down miR‐421 in CAF‐exo inhibited the expression of HIF‐1α in PC cells. Moreover, SIRT3‐mediated HIF‐1α expression by regulating H3K9Ac. HIF‐1α overexpression reversed the inhibiting effects of SIRT3 overexpression on PC progression and counteracted the inhibiting effects of miR‐421 knockdown on glycolysis. Moreover, in vivo tumorigenesis experiments showed that knocking down miR‐421 attenuated CAF‐exo induced tumor growth. Exosomal miR‐421 from CAFs promoted PC progression by regulating the SIRT3/H3K9Ac/HIF‐1α axis. This study provided insights into the molecular mechanism of PC. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia (TH) may attenuate myocardial ischaemia–reperfusion injury, thereby improving outcomes in acute myocardial infarction. However, the specific mechanism by which TH alleviates MIRI has not been elucidated so far. In this study, 120 healthy male Sprague‐Dawley rats were randomly divided into five groups. Haemodynamic parameters, myocardial infarction area, histological changes and the levels of cardiac enzymes, caspase‐1 and inflammatory cytokines were determined. In addition, the extent of myocardial fibrosis, the degree of cardiomyocyte apoptosis and the expression levels of SIRT3, GSDMD‐N, fibrosis‐related proteins and inflammation‐related proteins were estimated.TH reduced myocardial infarct area and cardiac enzyme levels, improved cardiomyopathic damage and haemodynamic indexes, and attenuated myocardial fibrosis, the protein expression levels of collagen I and III, myocardial apoptosis, the levels of inflammatory cytokines and inflammation‐related proteins. Notably, the immunofluorescence and protein expression levels of SIRT3 were upregulated in the 34H+DMSO group compared to the I/R group, but this protective effect was abolished by the SIRT3 inhibitor 3‐TYP. After administration of Mcc950, the reversal effects of 3‐TYP were significantly abolished, and TH could protect against MIRI in a rat isolated heart model by inhibiting inflammation and fibrosis. The SIRT3/NLRP3 signalling pathway is one of the most important signalling pathways in this regard. [ABSTRACT FROM AUTHOR]

Accumulation of lipid substances decreased the activity of osteoblasts. Trehalose is a typical stress metabolite to form a protective membrane on cell surface which has been demonstrated to regulate lipid metabolism. This activity of Trehalose indicates the potential effect of osteoporosis treatment. Our study aimed to determine the therapeutic effect of Trehalose in high fat‐induced osteoporosis. We used palmitic acid (PA) to mimic the state of high fat and observed the apoptosis ratio of osteoblasts increased. After adding Trehalose, the apoptosis ratio decreased obviously. Autophagy is a regulatory means involved in the process of apoptosis. We detected the autophagy protein and found that the expression of Beclin‐1, Atg5, and LC3 II increased, and p62 decreased after Trehalose treatment. When adding an autophagy inhibitor (3‐MA), the expression of Beclin‐1, Atg5, and LC3 II decreased, and p62 increased. These results indicated autophagy was an important factor involved in the preventive effect of Trehalose in PA‐induced apoptosis. SIRT3 is a mitochondrial gene that can inhibit apoptosis, which has been reported to promote autophagy. We used SIRT3‐siRNA to silence the expression of SIRT3 and found the effect of Trehalose was counteracted. The apoptosis ratio increased and the expression of Beclin‐1, Atg5, and LC3 II decreased, p62 increased. Additionally, we also fed the mice with a high‐fat diet (HFD) and intragastrical Trehalose. The results showed that Trehalose could inhibit the bone mass loss with HFD. Our study revealed the effect and mechanism of Trehalose in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Ultraviolet A (UVA) radiation is a major contributor to the pathogenesis of skin photoaging, and the aim of this study was to investigate the effect of Acacetin on skin photoaging in UVA‐irradiated mice and human dermal fibroblasts (HDF). Healthy dorsal depilated rats were irradiated with UVA 30 J/cm2 daily, every other day, for 1 month. Acacetin (40, 80 mg kg/day) was coated to the bare skin of the rats' backs 1 h before UVA irradiation. HDF were treated different concentrations of Acacetin (5, 10, 20 μg/ml) and then irradiated with UVA (20 J/cm2). Acacetin was found to be effective in ameliorating UVA‐induced oxidative stress and cell death. Acacetin also prevented the UVA‐induced decrease of SIRT3, reduced the activation of mitogen‐activated protein kinases (MAPKs, p‐38 and p‐JNK) and blocked the down‐regulated activation of oxidative stress in matrix metalloproteinases (MMPs). In addition, Acacetin increased the expressions of collagen‐promoting proteins (TGF‐β and Smad3). Finally, the SIRT3 inhibitor 3‐TYP blocked all protective effects of Acacetin, indicating that the protective effect of Acacetin against UVA photoaging is SIRT3‐dependent. Acacetin effectively mitigated photoaging by targeting the promotion of SIRT3, inhibiting the UVA‐induced increases in MMPs and pro‐inflammatory factors, and promoting TGF‐β and Smad3. [ABSTRACT FROM AUTHOR]

Background and Purpose: Mitochondrial damage and oxidative stress are crucial contributors to the tubular cell injury and death in acute kidney injury. Novel therapeutic strategies targeting mitochondria protection and halting the progression of acute kidney injury are urgently needed. Honokiol is a small‐molecule polyphenol that exhibits extraordinary cytoprotective effects, such as anti‐inflammatory and anti‐oxidative. Thus, we investigated whether honokiol could ameliorate cisplatin‐induced acute kidney injury via preventing mitochondrial dysfunction. Experimental Approach: Acute kidney injury was induced by cisplatin administration. Biochemical and histological analysis were used to determine kidney injury. The effect of honokiol on mitochondrial function and morphology were determined using immunohistochemistry, transmission electron microscopy, immunoblot and immunofluorescence. To investigate the mechanism by which honokiol alters mitochondrial dynamics, remodelling and resistance to apoptosis, we used transfection experiments, immunoblotting, immunoprecipitation and flow cytometry assay. Key Results: We demonstrated that the prominent mitochondrial fragmentation occurred in experimental models of cisplatin‐induced nephrotoxicity, which was coupled to radical oxygen species (ROS) overproduction, deterioration of mitochondrial function, release of apoptogenic factors and the consequent apoptosis. Honokiol treatment caused notable reno‐protection and attenuated of these cisplatin‐induced changes. Mechanistically, honokiol treatment recovered the expression of SIRT3 and improved AMPK activity in tubular cells exposure to cisplatin, which preserved the Drp1 phosphorylation at Ser637 and blocked its translocation in mitochondria, consequently preventing mitochondrial fragmentation and subsequent cell injury and death. Conclusion and Implications: Our results indicate that honokiol may protect against cisplatin‐induced acute kidney injury by preserving mitochondrial integrity and function by SIRT3/AMPK‐dependent mitochondrial dynamics remodelling. [ABSTRACT FROM AUTHOR]

Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti‐oxidative stress, anti‐inflammation and anti‐apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF‐κB‐mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin‐induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3‐mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin‐induced AKI by synergic anti‐oxidative stress and anti‐inflammation actions via SIRT3/OPA1‐mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI. [ABSTRACT FROM AUTHOR]

The mammalian sirtuin family consists of seven proteins, three of which (SIRT3, SIRT4, and SIRT5) localise specifically within mitochondria and preserve mitochondrial function and homeostasis. Mitochondrial sirtuins are involved in diverse functions such as deacetylation, ADP‐ribosylation, demalonylation and desuccinylation, thus affecting various aspects of cell fate. Intriguingly, mitochondrial sirtuins are able to manage these delicate processes with accuracy mediated by crosstalk between the nucleus and mitochondria. Previous studies have provided ample information about their substrates and targets, whereas less is known about their role in cancer and stem cells. Here, we review and discuss recent advances in our understanding of the structural and functional properties of mitochondrial sirtuins, including their targets in cancer and stem cells. These advances could help to improve the understanding of their interplay with signalling cascades and pathways, leading to new avenues for developing novel drugs for sirtuin‐related disease treatments. We also highlight the complex network of mitochondrial sirtuins in cancer and stem cells, which may be important in deciphering the molecular mechanism for their activation and inhibition. [ABSTRACT FROM AUTHOR]

Ergothioneine (Egt) is a dietary amino acid which acts as an antioxidant to protect against ageing-related diseases. We investigated the anti-cancer properties of Egt in colorectal cancer cells (CRC). Egt treatment exerted cytotoxicity in a dose-dependent manner, induced reactive oxygen species accumulation, loss of mitochondrial membrane potential and upregulation of the histone deacetylase SIRT3. Immunoblotting analysis indicated that the cell death occurred via necroptosis through activation of the RIP1/RIP3/MLKL pathway. An immunoprecipitation assay unveiled that the interaction between the terminal effector in necroptotic signalling MLKL and SIRT3 increased during the Egt treatment. SIRT3 gene silencing blocked the upregulation of MLKL and abolished the ability of Egt to induce necroptosis. The SIRT3–MLKL interaction may mediate the necroptotic effects of Egt in CRC, suggesting the potential of this dietary amino thione in the prevention of CRC. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a potent antitumor agent with a broad spectrum of activity; however, irreversible cardiotoxicity resulting from DOX treatment is a major issue that limits its therapeutic use. Sirtuins (SIRTs) play an essential role in several physiological and pathological processes including oxidative stress, apoptosis, and inflammation. It has been reported that SIRT1 and SIRT3 can act as a protective molecular against DOX‐induced myocardial injury through targeting numerous signaling pathways. Several natural compounds (NCs), such as resveratrol, sesamin, and berberine, with antioxidative, anti‐inflammation, and antiapoptotic effects were evaluated for their potential to suppress the cardiotoxicity induced by DOX via targeting SIRT1 and SIRT3. Numerous NCs exerted their therapeutic effects on DOX‐mediated cardiac damage via targeting different signaling pathways, including SIRT1/LKB1/AMPK, SIRT1/PGC‐1α, SIRT1/NLRP3, and SIRT3/FoxO. SIRT3 also ameliorates cardiotoxicity by enhancing mitochondrial fusion. [ABSTRACT FROM AUTHOR]

Background: Sirtuin 3 (SIRT3), a mitochondrial NAD+‐dependent deacetylase, has received much attention for its effect on metabolism and aging. However, the role of SIRT3 in periodontal disease remains unknown. Objective: This study aimed to investigate the functional role of SIRT3 in age‐related periodontal disease and underlying mechanisms. Methods: Sixteen mice were randomly assigned into four groups: the young wild type (WT), the aged WT, the young SIRT3‐knockout (KO), and the aged SIRT3‐KO. SIRT3 and cyclophilin D (CypD) expression and protein lysine acetylation levels in alveolar bones were detected by western blot. The bone architecture and the distance of CEJ‐ABC were assessed using micro‐CT and HE staining. The osteoclast number was observed through tartrate‐resistant acid phosphatase (TRAP) staining. Mitochondrial morphology in SIRT3 knockdown MC3T3‐E1 osteoblastic cells was analyzed by Immunofluorescence staining. In gingival tissues, the NAD+/NADH ratio was measured, and oxidative stress was detected by MitoSOX staining, HO‐1 staining, and MnSOD expression. Mitochondrial biogenesis was measured by PGC‐1α expression and oxygen consumption rate (OCR). Results: In parallel with the imbalanced NAD+/NADH ratio, the SIRT3 expression was significantly decreased in the alveolar bones of the aged mice, accompanied by a global elevation of protein acetylation levels. The aged SIRT3‐KO group showed the highest rate of bone resorption and the largest number of TRAP‐positive osteoclasts among the four groups. Moreover, the reactive oxygen species level was up‐regulated in the young and the aged SIRT3‐KO groups. SIRT3 deficiency promoted mitochondrial fission and increased the CypD expression. Furthermore, the lack of SIRT3 reduced the PGC‐1α expression in gingival tissues and exhibited a significant reduction in maximal OCR. Conclusion: Reduced SIRT3 abundance contributes to aged‐related periodontal disease via the exacerbation of oxidative stress and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Senescence of nucleus pulposus (NP) cells (NPC) is a major cause of intervertebral disc degeneration (IVDD), so delay NPC senescence may be beneficial for mitigating IVDD. We studied the effect and mechanism of silent information regulator 2 homolog 3 (SIRT3) on NPC senescence in vivo and in vitro. First, we observed SIRT3 expression in normal and degenerated NPC with immunohistochemical and immunofluorescence staining. Second, using SIRT3 lentivirus transfection, reactive oxygen species probe, senescence‐associated β‐galactosidase staining, polymerase chain reaction, and western blot to observe the oxidative stress, senescence, and degeneration degree among groups. Subsequently, pretreatment with adenosine monophosphate‐activated protein kinase (AMPK) agonists and inhibitors, observing oxidative stress, senescence, and degeneration degree among groups. Finally, the IVDD model was constructed and divided into Ctrl, Vehicle, LV‐shSIRT3, and LV‐SIRT3 groups. X‐ray and magnetic resonance imaging scans were performed on rat's tails after 1 week; hematoxylin and eosin and safranin‐O staining were used to evaluate the degree of IVDD; immunofluorescence staining was used to observe SIRT3 expression; immunohistochemical staining was used to observe oxidative stress, senescence, and degeneration degree of NP. We found that SIRT3 expression is reduced in degenerated NP tissues but increased in H2O2‐induced NPC. Moreover, SIRT3 upregulation decreased oxidative stress, delayed senescence, and degeneration of NPC. In addition, activation of the AMPK/PGC‐1α pathway can partially mitigate the NPC oxidative stress, senescence, and degeneration caused by SIRT3 knockdown. The study in vivo revealed that local SIRT3 overexpression can significantly reduce oxidative stress and ECM degradation of NPC, delay NPC senescence, thereby mitigating IVDD. In summary, SIRT3 mediated by the AMPK/PGC‐1α pathway mitigates IVDD by delaying oxidative stress‐induced NPC senescence. [ABSTRACT FROM AUTHOR]

To investigate the effects and the underlying mechanisms of salidroside on diabetic cardiomyopathy, diabetes was induced in mice by a long‐term high‐fat diet and a low‐dose injection of streptozocin. Measurements of cardiac function, biochemical analysis, and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. In this study, we found that diabetic mice exhibited decreased cardiac systolic function and impaired mitochondrial ultrastructure. Pre‐treatment with salidroside protected mice against myocardial dysfunction, reduced blood glucose, improved insulin resistance, and induced mitochondrial biogenesis. Neonatal rat cardiomyocytes were cultured to explore the mechanisms of salidroside in vitro. Salidroside alleviated decreased expression of peroxisome proliferator‐activated receptor‐γ coactivator 1‐alpha (PGC‐1α), mitochondrial transcription factor A (TFAM) via phosphorylation of 5′ AMP‐activated protein kinase (AMPK), which may be associated with mitochondrial biogenesis. Salidroside also increased sirtuin‐3 (SIRT3) expression in cardiomyocytes. Furthermore, salidroside promoted the translocation of SIRT3 from cytoplasm to mitochondria and increased the deacetylation of mitochondrial proteins such as manganese‐dependent superoxide dismutase (MnSOD). In Conclusion, salidroside not only improved diabetes, but also ameliorated diabetic cardiomyopathy, which was at least partly associated with the activation of mitochondrial SIRT3, AMPK/Akt, and PGC‐1α/TFAM and subsequent improving mitochondrial function. [ABSTRACT FROM AUTHOR]

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24–26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4–6 months) mice hearts impair cardiomyocyte contractility and shows aging‐like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age‐related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R. [ABSTRACT FROM AUTHOR]

Background: Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short‐term non‐ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury. Methods and Results: Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia‐reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R‐induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3‐dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral‐mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R‐induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning. Conclusions: The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self‐defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway‐dependent manner. [ABSTRACT FROM AUTHOR]

The neurotoxic level of ammonia in the brain during liver cirrhosis causes a nervous system disorder, hepatic encephalopathy (HE), by affecting mitochondrial functions. Sirtuin‐3 (SIRT3) is emerging as a master regulator of mitochondrial integrity, which is currently being focused as a pathogenic hotspot for HE. This article describes SIRT3 level versus mitochondrial dysfunction markers in the hippocampus of the control, the moderate‐grade hepatic encephalopathy (MoHE), developed in thioacetamide‐induced (100 mg/kg bw ip for 10 days) liver cirrhotic rats, and the MoHE rats treated with an SIRT3 activator, honokiol (HKL; 10 mg/kg bw ip), for 7 days from 8th day of the thioacetamide schedule. As compared with the control group rats, hippocampus mitochondria of MoHE rats showed a significant decline in SIRT3 expression and its activity with concordant enhancement of ROS and declined membrane permeability transition and organelle viability scores. This was consistent with the declined mitochondrial thiol level and thiol‐regenerating enzyme, isocitrate dehydrogenase 2. Also, significantly declined activities of electron transport chain complexes I, III, IV, and Q10, decreased NAD+/NADH and ATP/AMP ratios, and enhanced number of the shrunken mitochondria were recorded in the hippocampus of those MoHE rats. However, all these mitochondrial aberrations were observed to regain their normal profiles/levels, concordant to the enhanced SIRT3 expression and its activity due to treatment with HKL. The findings suggest a role of SIRT3 in mitochondrial structure–function derangements associated with MoHE pathogenesis and SIRT3 activation by HKL as a relevant strategy to protect mitochondrial integrity during ammonia neurotoxicity. Highlights: ‐Hippocampus mitochondria of MoHE rats showed a declined SIRT3 level.‐They also showed deranged mitochondrial integrity: mMPT, ROS, thiol, and MTT assay.‐Showed concordant bioenergetics deficits: ETC activity, ATP/AMP and NAD+/NADH ratio.‐SIRT3 activation by honokiol could normalize all these mitochondrial aberrations.‐SIRT3 modulation could be used to restore mitochondrial integrity during MoHE. [ABSTRACT FROM AUTHOR]