EXPERIMENTAL CELL RESEARCH
·
2026
·
IF 3.5
Ruman Chen,Jiqing He,Na An,Mingzhi Xu,Liheng Wang,Yafei Bai
Background Vascular calcification (VC) is a severe cardiovascular complication of chronic kidney disease (CKD), driven by vascular smooth muscle cell (VSMC) osteogenic trans-differentiation and exacerbated by oxidative stress and cellular dysfunction. Despite its clinical relevance, the molecular mechanisms underlying CKD-associated VC remain incompletely understood. This study investigates the role of Sirtuin 1 (SIRT1) in modulating VC through ferroptosis inhibition and mitophagy activation and examines whether microRNA-181c-5p (miR-181c-5p) contributes to SIRT1 dysregulation in this context. Methods A CKD-associated VC model was induced in rats by 5/6 nephrectomy followed by high calcium/phosphate and calcitriol loading, and an in vitro calcification model was established in primary rat VSMCs. SIRT1 was manipulated using AAV9-mediated overexpression in vivo and plasmid overexpression or inhibition in vitro . Upstream regulation of SIRT1 by miR-181c-5p was predicted bioinformatically and validated by RNA pull-down and dual-luciferase assays. Ferroptosis was assessed by redox and Fe 2+ indices, and mitophagy by Pink1/Parkin, LC3-II and p62 expression. Rescue experiments employed erastin, Mdivi-1 and Parkin knockdown. Results SIRT1 expression was markedly reduced in calcified aortic tissues and VSMCs. SIRT1 overexpression suppressed VC by reducing calcium deposition, downregulating osteogenic markers, and increasing fetuin-A levels. SIRT1 also suppressed ferroptosis by restoring the GSH/GPX4/SLC7A11 axis and limiting ROS and lipid peroxidation, whereas erastin abolished these effects. Mechanistically, miR-181c-5p was found to directly target SIRT1 and promote VSMC calcification by repressing SIRT1. Moreover, SIRT1 promoted mitophagy via the Pink1/Parkin pathway activation. Furthermore, inhibition of mitophagy reversed the anti-ferroptotic effects of SIRT1, confirming their functional interplay. Conclusions SIRT1, negatively regulated by miR-181c-5p, mitigates CKD-associated VC by suppressing ferroptosis and activating Pink1/Parkin-dependent mitophagy in VSMCs, highlighting a potential therapeutic axis for vascular protection in CKD. Clinical trial registration number Not applicable.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCELL
·
2026
·Vol. 50
·期 6
·
IF 1.8
Junming Yan,Boran Xiong,Yingjie Zhu
Objective: Neural stem cells (NSCs) are essential for replenishing nerve cells, providing neuroprotection, and repairing damaged brain function, while mitophagy is critical for maintaining NSCs’ homeostasis. The study investigated whether pyruvate kinase M2 (PKM2) regulates NSCs’ proliferation and differentiation by modulating mitophagy. Method: This study established a model of excessive autophagy in neural stem cell mitochondria induced by cobalt chloride (CoCl 2 ) and used plasmid transfection technology to knock down PKM2 expression, examining its effects on NSCs proliferation and differentiation. Additionally, potential mechanisms were explored by overexpressing phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and adding the mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Result: Treatment with CoCl 2 significantly inhibited the proliferation of NSCs and their differentiation into neurons, induced excessive mitophagy, and activated the PKM2/PINK1/Parkin pathway. Knockdown of PKM2 markedly enhanced cell viability, promoted NSCs’ proliferation, and neuronal differentiation. Mechanistically, PKM2 knockdown not only decreased the protein levels of PINK1, Parkin, p-Parkin, Beclin1, and LC3 II/I but also increased p62 expression, thereby mitigating excessive mitophagy. Overexpression of PINK1 attenuated the inhibitory effect of PKM2 knockdown on CoCl 2 -induced mitophagy in NSCs. Moreover, PKM2 knockdown significantly reversed the detrimental effects of CCCP on mitochondrial function, cell survival, and neuronal differentiation, further confirming that PKM2 promotes NSC proliferation and neuronal differentiation by inhibiting mitophagy. Conclusion: Knocking down PKM2 could inhibit PINK1/Parkin-mediated excessive mitophagy, thereby promoting NSCs proliferation and neuronal differentiation.
✓ 已验证
DOI
高影响因子
JOURNAL OF POULTRY SCIENCE
·
2026
·
IF 2.1
Min Huo,Mengxuan Sun,Wanying Qu,Shuo Yang
Oxidative stress is a major constraint on broiler health and productivity.Mitochondrial dysfunction and gut–liver axis disruption play pivotal roles in thisprocess. The present study investigated whether dietary quercetagetin (QG) alleviateddiquat (DQ)-induced oxidative stress in broiler chickens through modulation ofPINK1/Parkin-mediated mitophagy and gut–liver axis homeostasis. A total of 144 1-day-oldWOD168 broilers were randomly assigned to four treatments with six replicate cages ofsix birds per cage: control group (non-challenged, basal diet), DQ group (DQ-challenged,basal diet), D_QG group (DQ-challenged, basal diet with 20 mg/kg QG), and QG group(non-challenged, basal diet with 20 mg/kg QG). On day 35, the DQ and D_QG groups wereintraperitoneally administered DQ (20 mg/kg body weight). Dietary QG significantlyincreased body weight and attenuated the loss in average daily gain induced by DQ, whilereducing serum aspartate aminotransferase levels. DQ challenge impaired gut barrierfunction, as indicated by decreased villus height, villus height/crypt depth ratio, andmRNA expression of Claudin-1 and ZO-1 ( P < 0.05), exacerbated hepatic lesions, and significantly altered cecalmicrobial diversity. QG supplementation significantly attenuated the drop in glutathioneperoxidase activity and downregulated PINK1 and LC3-II in hepatic mitochondria. It also significantly increased complex I activity,mitochondrial DNA copy number, and adenosine triphosphate content, while decreasingDQ-induced reactive oxygen species. Collectively, these results indicate that dietary QGalleviates DQ-induced oxidative stress by preserving mitochondrial function, potentiallymodulating PINK1/Parkin-related mitophagy, enhancing intestinal barrier integrity, andmodulating cecal microbial composition.
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2026
·
IF 4.7
Xinmiao Piao,Jinfang Song,Jingjing Piao,Yuhan Shang,Yang Jin,Ranji Cui,Bingjin Li
A growing focus in nutritional psychiatry is examining dietary interventions as a therapeutic strategy for depression. Chlorogenic acid (CGA), a naturally occurring polyphenol, has demonstrated promising anti-inflammatory and neuroprotective effects. This study aimed to elucidate the underlying molecular targets and mechanisms responsible for CGA's antidepressant-like actions. The potential targets and pathways of CGA related to FoxO3a were initially predicted using network pharmacology and molecular docking. In vitro, the protective effects of CGA were investigated in H 2 O 2 -stimulated HT-22 cells by assessing cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential, and the expression of mitophagy-related proteins. In vivo, a depression model was established in male mice via intraperitoneal injection of lipopolysaccharide (LPS). The antidepressant efficacy of CGA was evaluated through a behavioral test battery. Microglial activation was detected via immunofluorescence. Furthermore, mitochondrial ultrastructure was examined by transmission electron microscopy (TEM), and the expression of mitophagy-related proteins was additionally validated by Western blotting. Finally, the direct interaction between SIRT1 and FoxO3a was examined by co-immunoprecipitation. In vitro, CGA pretreatment improved HT-22 cells viability under H 2 O 2 -induced oxidative stress, reduced ROS levels, and restored mitochondrial membrane potential. In vivo, CGA reduced neuroinflammation by lowering the levels of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), inhibited microglial activation, and alleviated depressive-like behaviors in LPS-treated mice. Additionally, CGA activated the sirtuin 1 (SIRT1) / forkhead box O3a (FoxO3a) / PTEN-induced kinase 1 (PINK1) / Parkin signaling pathway, promoting hippocampal mitophagy. The antidepressant-like effects of CGA were suppressed upon SIRT1 antagonism with EX527. This study suggests that CGA may serve as a potential therapeutic agent for depression.
✓ 已验证
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2025
·
IF 8.9
Xin-Meng Zhou,Ying Yang,Dao-Jiang Yu,Teng Xie,Xi-Lu Sun,Ying-Xuan Han,Hai-Ying Tian,Qing-Qing Liao,Yu-Jie Zhao,Yih-Cherng Liou,Wei Huang,Yong Xu,Xi Kuang,Xiao-Dong Sun,Yuan-Yuan Zhang
Diabetic foot ulcer (DFU) is an increasing global burden due to the rising prevalence of diabetes, and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment. In this study, naringenin (NAR) was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type mice by reducing oxidative stress, as assessed through histological assay. NAR also alleviated the inhibition of proliferation, inflammation, cell senescence, and apoptosis in HaCaT cells induced by high glucose (HG). Mechanistically, the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin. NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation, thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control (MQC). Moreover, the wound healing-promoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout DFU mice. Inhibition of NAR binding to estrogen receptors (ERs) using tamoxifen abolished the protective effects of NAR in HG-induced HaCaT cells. The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element (ERE), thereby upregulating Parkin transcription. Additionally, the cellular thermal shift assay revealed that NAR specifically bound to estrogen receptor alpha (ERα). In conclusion, NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERα, highlighting its potential as a promising therapeutic candidate.
研究领域:
药理学
·
分子生物学
·
内分泌学
·
糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Jia-Yi Dou,Mei-Jie Zhou,Mei-Yan Xuan,Jia Guo,Sai-Hu Liu,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Background Astilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated. Purpose This study explored the effect of ATB against the hepatic fibrosis and its regulation of hepatic microenvironment by regulating hepatic stellate cells-macrophage crosstalk. Method Thioacetamide (TAA) was intraperitoneal injected to establish hepatic fibrosis mice, and treated with ATB or curcumin by gavage, respectively. Hepatic stellate cells (HSCs) were stimulated with TGF-β or conditioned medium (CM) from LPS-induced THP-1, then cultured with ATB, PXR agonist or antagonist. Results In TAA-induced mice, ATB improved histopathological changes, serum transaminases increase; alleviated extracellular matrix (ECM) deposition, epithelial-mesenchymal transformation (EMT), inflammatory infiltration, PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy and activated pregnane X receptor (PXR) expression. In vitro , ATB significantly reduced ECM, inflammatory cytokines release, mitophagy, EMT, and activated PXR expression. ATB could increase PXR and decrease PINK1/Parkin, functioning as a PXR agonist. PXR deficiency in LX-2 could degrade the regulation of ATB on ECM, inflammation, EMT, and mitophagy. CM from LPS-induced THP-1 activated LX-2 and resulted in PXR decreasing, while ATB could regulate the crosstalk between HSCs and macrophages. Deficiency of PXR, whether in LX-2 or in macrophages, all weakened the inhibitory effect of ATB on α-SMA, EMT, inflammatory cytokines, and PINK1/Parkin signaling. Conclusion ATB ameliorated hepatic fibrosis by inhibiting HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signaling. Especially, ATB targeted the hepatic microenvironment between hepatic stellate cells and macrophages, which might be a promising strategy for the treatment of hepatic fibrosis.
研究领域:
药理学
·
肝病学
·
细胞生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 40
·期 1
·e70320
·
IF 1.7
Ying Ma,Yu Yao,Yue Pu,Hong Chen,Juan Zhang
Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra and the pathological accumulation of α-synuclein (α-Syn). Rotenone, a mitochondrial complex I inhibitor, reliably reproduces these hallmark features and is therefore widely used to establish experimental PD models. Shiliuwei Kangchanzhijing capsules (SLW-KCZJ capsules), a traditional Chinese medicine (TCM) formulation comprising 16 herbal components, were specifically developed for PD management. This study systematically evaluated the neuroprotective effects and underlying mechanisms of SLW-KCZJ in a rotenone-induced PD mouse model. SLW-KCZJ treatment significantly improved movement distance and balance–coordination, attenuated neuronal loss in the substantia nigra, and markedly suppressed neuroinflammatory responses. At the molecular level, the capsules increased tyrosine hydroxylase expression by approximately 200% and elevated Parkin and protein phosphatase 2A levels by approximately 60% and 80%, respectively. In contrast, they robustly inhibited polo-like kinase 2 expression and reduced α-Syn levels by approximately 60% and 40%. The intervention also increased striatal dopamine (DA) and homovanillic acid levels while lowering neurofilament light chain and oligomeric α-Syn. In summary, this study provides the first evidence that SLW-KCZJ capsules exert neuroprotective effects by modulating the Parkin/PP2A/α-Syn signaling pathway, offering a promising TCM-based therapeutic strategy for PD.
研究领域:
神经科学
·
药理学
·
中医中药
·
神经退行性疾病
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RENAL FAILURE
·
2026
·
IF 3.8
Zhuangzhi Yang,Xiaowei Zhou,Chenhao Wu,Xia Lin
Objectives: Nicotiflorin has demonstrated efficacy in mitigating acute liver injury, and therefore, its potential in treating septic acute kidney injury (AKI) merits further investigation. This study evaluated whether nicotiflorin restores mitochondrial function and reduces oxidative stress in septic AKI via mediating the PTEN-induced putative protein kinase 1 (PINK1)/Parkin signaling pathway.Methods: Lipopolysaccharide (LPS) was applied to replicate septic AKI in C57BL/6 mice and NRK-52E cells, which were later treated with nicotiflorin. Renal function was assessed through biochemical markers, histopathology, and immunofluorescence. The impact of nicotiflorin on cell viability, apoptosis, and mitochondrial function was analyzed using cell counting kit 8 assay and flow cytometry. Mtphagy and Lyso staining was utilized to evaluate the effect of nicotiflorin on mitophagy in LPS-induced cells. Molecularly, Western blot was employed to quantify protein expressions of genes related to apoptosis, mitophagy and oxidative stress in vivo and in vitro.Results: Nicotiflorin treatment significantly improved renal dysfunction, kidney damage, reduced levels of apoptosis-related proteins, increased expressions of PINK1, Parkin, and LC3II/LC3I, and decreased expression of p62 in LPS-induced mice. In NRK-52E cells, nicotiflorin abrogated LPS-triggered reduction in cell viability, increase in apoptosis, elevation in ROS and mitochondrial mass, reduction in mitochondrial membrane potential, upregulation of apoptotic proteins, downregulated NF-E2-related factor-2 (Nrf2), PINK1, Parkin and LC3II/LC3I, and increased expressions of kelch-like ECH-associated protein 1 (KEAP1) and p62.Conclusions: Nicotiflorin attenuates mitochondrial dysfunction and oxidative stress in septic AKI via PINK1/Parkin signaling pathway, suggesting its potential as a therapeutic agent for septic AKI.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2026
·
IF 12.2
Zhou Daqian,Wang Liquan,Zhou Yang,Lv Jiale,Song Chao,Mei Yongliang,Liu Tao,Wu Taotao,Yu Fei,Liu Zongchao
Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particularly those targeting NPC senescence, remain underdeveloped. Research has shown that NPC senescence is closely associated with mitochondrial damage, leading to the accumulation of cytoplasmic reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). Mitochondrial autophagy, as a key mechanism of mitochondrial quality control, regulates ROS and mtDNA levels by eliminating dysfunctional and damaged mitochondria, thereby delaying cellular aging. Notably, mitophagy signaling associated with Sirtuin 6 (SIRT6) and PTEN-induced kinase 1 (PINK1)/Parkin has been implicated in this process. Traditional Chinese Medicine (TCM), with its holistic approach and unique theoretical system of syndrome differentiation and treatment, offers significant advantages in preventing and treating degenerative diseases such as IVDD. However, research into TCM formulations aimed at NPC senescence remains limited. In preliminary studies, we observed that Nodakenin, the primary active compound from the TCM formula Duhuo Jisheng decoction (DHJSD), exerts protective effects in a SIRT6-associated manner and appears to be associated with activation of PINK1/Parkin-related mitophagy signaling. In this study, we used single-cell analysis to construct human NPC senescence and rat IVDD models, assessing mitochondrial morphology, mitochondrial membrane potential, cell senescence, and autophagy-related gene expression. We further evaluated the effects of Nodakenin (Nod) on H 2 O 2 -induced NPC senescence and determined the optimal intervention concentration, followed by assessment of mitochondrial phenotypes and SIRT6- and PINK1/Parkin-associated markers. These findings provide new theoretical support for the clinical application of TCM in the treatment of IVDD.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2026
·
IF 10.6
Sufang Wu,Xianglong Wu,Nuo Xu,Ze Li,Yang Dong,Chenxing Zhang,Qian Liu,Huang Chen,Lele Liu,Yanxin Hu,Gancen Zhang,Yunru Liu,Jin Xu,Aihua Gu
Silicon carbide nanoparticles (SiC-NPs), an emerging class of nanomaterials, have garnered extensive applications in industrial and biomedical fields. The escalating use of SiC-NPs engenders substantial concerns regarding the potential biosafety implications. Previous studies indicate the association between silicon carbide exposure and elevated incidence of pulmonary fibrosis. However, the underlying mechanisms remain insufficiently elucidated. In this study, we investigated the role of SiC-NPs in pulmonary fibrosis development, employing THP-1-derived macrophages (THP-M) for in vitro experimentation and C57BL/6 mice for in vivo analyses. Our study demonstrated that exposure to SiC-NPs led to the production of reactive oxygen species (ROS) and mitochondrial damage in macrophages. This sequence of events impaired mitophagy and subsequently triggered macrophage apoptosis, ultimately contributing to the pathogenesis of pulmonary fibrosis. Mechanistically, we elucidated that SiC-NPs promoted the ubiquitin-mediated degradation of Parkin, resulting in dysregulated mitophagy. Furthermore, we revealed that emodin treatment mitigated SiC-NPs-induced pulmonary fibrosis by restoring Parkin expression. Our study provides novel insights into the detrimental effects and underlying mechanisms of SiC-NPs in pulmonary fibrosis, as well as highlighting the therapeutic potential of emodin.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
·
2023
·
IF 3.3
Yuxuan Chen,Wei Cao,Bin Li,Xiaofei Qiao,Xiangdong Wang,Guang Yang,Siying Li
Objective: Sepsis is one of major reasons of cardiorenal syndrome type 5 (CRS-5), resulting in irreversible tissue damage and organ dysfunction. Macrophage has been demonstrated to play key role in the pathophysiology of sepsis, highlighting the need to identify therapeutic targets for modulating macrophage phenotype in sepsis.Methods and Results: In this study, a rapid-releasing hydrogen sulfide (H2S) donor NaSH, and a slow-releasing H2S compound S-propargyl-cysteine (SPRC) which is derived from garlic, have been studied for the immune-regulatory effects on macrophages. The NaSH and SPRC showed the potential to protect the heart and kidney from tissue injury induced by LPS. The immunohistochemistry of F4/80+ revealed that the infiltration of macrophages in the heart and kidney tissues of LPS-treated mice was reduced by NaSH and SPRC. In addition, in the LPS-triggered inflammatory cascade of RAW264.7 macrophage cells, NaSH and SPRC exhibited significantly inhibitory effects on the secretion of inflammatory cytokines, production of reactive oxygen species (ROS), and regulation of the macrophage phenotype from M1-like to M2-like. Moreover, autophagy, a crucial process involved in the elimination of impaired proteins and organelles during oxidative stress and immune response, was induced by NaSH and SPRC in the presence of LPS stimulation. Consequently, there was an increase in the number of mitochondria and an improvement in mitochondrial membrane potential. This process was mainly mediated by PINK1/Parkin pathway mediated mitophagy.Discussion: These results demonstrated that the immunoregulatory effects of H2S donors were through the PINK1/Parkin-mediated mitophagy pathway. Overall, our study provided a new therapeutic direction in LPS-induced cardiorenal injury.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 5.4
Jinni Meng,Ping Wei,Heping Yang,Lin Chen,Cheng Peng,Ou Dai,Qinmei Zhou,Liang Xiong
Ethnopharmacological relevance Ligusticum chuanxiong Hort. (Chuanxiong) is a traditional Chinese medicinal herb whose rhizome has been historically and clinically used to treat conditions such as headache, dizziness, and depression. These traditional application broadly correlate with modern diagnoses of cerebrovascular dysfunction, impaired cerebral blood flow, and neuroinflammation. As a characteristic phthalide dimer and major bioactive constituent of Chuanxiong, levistilide A (LA) has shown significant therapeutic potential. However, its specific antidepressant and anxiolytic properties require further clarification. Aim of the study This study aimed to assess the efficacy of LA against depression and anxiety, with the further goal of elucidating its underlying molecular mechanisms. Materials and methods A depression- and anxiety-like state was induced in C57BL/6 mice by LPS challenge after which they received therapeutic intervention with different doses of LA. The therapeutic efficacy was assessed by behavioral tests, histopathological analyses, and enzyme-linked immunosorbent assays (ELISA). Concurrently, we assessed microglial activation via immunofluorescence, along with mitochondrial status by measuring reactive oxygen species (ROS) levels with flow cytometry and examining ultrastructure with transmission electron microscopy (TEM). To investigate the cellular mechanisms, LPS-stimulated BV2 cells was established . In this model, autophagic flux was quantitatively measured using Bafilomycin A1 (Baf A1) inhibition assays combined with western blot analysis of LC3B-II. And mitophagy was evaluated by co-immunofluorescence LC3B with the mitochondrial marker Tomm40 in both BV2 cells and mouse hippocampal CA3. Building on this, computational approaches, along with experimental methodologies including immunofluorescence and western blotting, were utilized to elucidate the underlying molecular mechanisms. Furthermore, SIRT3-specific siRNA ( siRNA -SIRT3) was used for further validation. Results The LA treatment demonstrated a notable protective role against LPS-induced depression and anxiety through ameliorating behaviors accompanied by depression- and anxiety-like behaviors, attenuating neuronal damage, downregulating pro-inflammatory cytokine expression levels, and suppressing microglial overactivation. Mechanistically, LA alleviated oxidative stress and mitochondrial dysfunction by reducing ROS accumulation and mitigating mitochondrial damage. In the LPS-induced BV2 cells, LA treatment significantly enhanced autophagic flux, as evidenced by the further accumulation of LC3B-II upon Baf A1 inhibition, which confirmed the promotion of functional autophagy. Concurrently, the increased co-localization of Tomm40 with LC3B upon LA treatment provided direct evidence for mitophagy activation. Molecular docking combined with molecular dynamics simulation analyses revealed robust binding interactions between LA and SIRT3, as well as between SIRT3 and PINK1. Further investigation into the downstream pathway revealed that LA effectively activated the SIRT3/PINK1/Parkin pathway. This was supported by the western blot analyses. Specifically, LA treatment increased the SIRT3, PINK1, Parkin, and LC3B-II expression levels, while it decreased p62 levels. This result suggested mitophagy activation. An immunofluorescence analysis corroborated this result and revealed increased cytoplasmic colocalization of Tomm40 with LC3B following the LA treatment. Consistent with these findings, LA significantly suppressed neuroinflammation in LPS-stimulated BV2 microglial cells by inhibiting both NO production and the release of pro-inflammatory cytokines.. Importantly, LA recapitulated its favorable impacts on mitochondrial function and the SIRT3/PINK1/Parkin signaling cascade in this cellular model. The functional necessity of this pathway was demonstrated by the findings that SIRT3 knockdown with siRNA -SIRT3 in BV2 cells abolished regulatory impact of LA on PINK1/Parkin pathway proteins. Conclusions LA serves as a potential therapeutic agent for depression and anxiety through activating mitophagy mediated by the SIRT3/PINK1/Parkin pathway. The results of this study provide scientific evidence for the clinical application of LA in treating depression and anxiety.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）