JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Deng Yu,Tao Yongjian,Qing Yali,Wang Jianwei,Jie Chuanhong
Ethnopharmacological relevance Diabetic retinopathy (DR) is a severe microvascular complication of diabetes that is closely associated with hyperglycemia-induced mitochondrial dysfunction. Lishui Xiaozhong granules (LSXZ) are an empirical traditional Chinese medicine used to treat DR. However, its precise molecular targets and underlying mechanisms remain unclear. Aim of the study This study investigated whether LSXZ protects retinal cells under hyperglycemic conditions by regulating PINK1/Parkin-mediated mitophagy. Materials and methods Human Müller cells were exposed to high glucose (HG; 50 mM) to establish an in vitro model and treated with LSXZ-containing serum and the mitophagy inhibitor cyclosporin A (CsA). Genetic knockdown via siRNA was performed to validate the necessity of the PINK1/Parkin pathway. A zebrafish DR model was induced using an HG, high-fat diet, and treated with different LSXZ concentrations. Cell viability, mitophagy, apoptosis, ferroptosis, mitochondrial function, and ultrastructural changes were assessed using CCK-8 assays, western blotting, qPCR, immunofluorescence, and transmission electron microscopy. Retinal histopathology, vascular diameter, inflammatory cell activation, oxidative stress, and gene expression profiles in zebrafish were assessed using hematoxylin–eosin staining, fluorescence microscopy, and transcriptomic sequencing. Results LSXZ treatment reversed pathological changes by restoring PINK1/Parkin signaling, elevating LC3-II/LC3-I ratio, enhancing mitochondrial function, and suppressing apoptosis and ferroptosis—effects partially attenuated by CsA. Mitophagosomes increased after LSXZ treatment. Crucially, specific knockdown of PINK1 or Parkin significantly abolished LSXZ-induced cytoprotection, reversing the regulation of apoptotic/ferroptotic markers and mitochondrial recovery, thereby confirming the pivotal necessity of this pathway. In zebrafish, LSXZ alleviated hyperglycemia-induced retinal inner nuclear layer thinning, vascular dilation, excessive macrophage/astrocyte activation, and oxidative stress. These protective effects were mediated through upregulation of the TOMM40/TOMM20–PINK1/Parkin–MFN2 axis.
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高影响因子
MOLECULAR NEUROBIOLOGY
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2026
·Vol. 63
·期 1
·454
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IF 5.5
Yu Jia-Xin,Zhang Wen-Xuan,Li Pu-Yu,Yang Yi-Liang,Huang Han-Chang
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized primarily by deterioration in memory, cognition, and learning ability. Its etiology is complex and influenced by multiple factors, including genetics and environment. With advancing research into mitochondrial function and mechanisms, impaired mitophagy has been proposed as a significant mechanism contributing to AD. The ApoE ε4 allele, a high-risk genetic factor for AD, may play a key role in disease pathogenesis by inducing mitophagy dysfunction and apoptosis. From the perspective of APOE gene polymorphisms, this study investigates abnormal changes in mitochondrial function and autophagy in humanized APOE4 mice primary astrocytes under oxidative stress, as well as the regulatory effect of curcumin (Cur) on mitophagy and oxidative stress-induced apoptosis, thereby exploring its potential to ameliorate AD through targeting mitophagy. Mitochondrial function analysis revealed that APOE4 expression reduced the antioxidant capacity and respiratory function of primary astrocytes, leading to mitochondrial membrane damage, intracellular reactive oxygen species (ROS) accumulation, and decreased ATP production. Curcumin effectively protected mitochondrial integrity, reduced the number of damaged mitochondria, improved overall mitochondrial function, and helped maintain mitochondrial homeostasis involving in PINK1/Parkin pathway. Regarding autophagy and apoptosis, curcumin was shown to restore autophagic flux, mitigate autophagy disruption caused by oxidative stress, and reverse early-stage apoptosis. Graphical
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MOLECULAR NEUROBIOLOGY
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2026
·Vol. 63
·期 1
·432
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IF 5.5
Lin Jinyu,You Bowen,Yang Xin,Li Xue,Sun Wenjuan,Xu Zhongyu,Zhang Yi,Tong Xuhui,Dong Shuying
Cerebral ischemia/reperfusion injury (CIRI) refers to the secondary brain injury that occurs when blood supply is restored to ischemic cerebral tissue, and represents one of the primary causes of adult disability and mortality. Current evidence indicates that aesculin exhibits antioxidative and anti-inflammatory activities; however, its therapeutic effects on CIRI remain to be elucidated. The objective of this study was to investigate the potential role of Esculin (ESCU) in protecting against CIRI and to elucidate its underlying mechanisms. Adult male mice were used to establish the middle cerebral artery occlusion/reperfusion (MCAO/R) model. The mice were administered varying doses of ESCU or a reference positive control drug. To evaluate the neuroprotective effects of ESCU, neurological deficit scores were assessed, and cerebral blood flow was measured. 2,3,5-triphenyltetrazolium chloride staining, H&E staining, and Nissl staining were used to determine neuronal damage. NLRP3-related markers and mitophagy-related markers were determined to investigate the mechanism of action of ESCU. ESCU afforded robust neuroprotection in mice, ameliorating functional deficits, reducing infarct size, and preserving neuronal structure. It potently alleviated oxidative stress and restored mitochondrial function (reduced ROS, improved cristae morphology, and increased mitochondrial membrane potential). Mechanistically, ESCU activated mitophagy (upregulating LC3Ⅱ, PINK1, and Parkin; downregulating p62) and inhibited the NLRP3 inflammasome (downregulating NLRP3, GSDMD-N, cleaved caspase-1, IL-1β, and IL-18). Notably, the mitophagy inhibitor Mdivi-1 abolished ESCU’s inhibition of the NLRP3 pathway, establishing a causal relationship. Thus, ESCU mitigates cerebral ischemia-reperfusion injury by coordinately enhancing mitophagy and suppressing NLRP3 inflammasome activation. Our study demonstrates that ESCU attenuates CIRI mechanistically by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. These findings not only elucidate a novel pathway underlying ESCU’s neuroprotection but also position it as a promising therapeutic candidate for CIRI, warranting further investigation into its precise targets and clinical potential.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Lanxin Li,Yang Zhang,Zhengqian Chen,Can Xu,Zhongqiu Xu,Haitao Pei,Wei Wang,Ruyong Yao,Cui Hao
Parkinson's disease (PD) is a common age-related neurodegenerative disorder, which may be largely due to the mitochondrial dysfunction and impaired mitophagy. Thus, it is of great importance to seek novel therapeutic strategies for PD targeting mitochondrial function and mitophagy. Cytarabine is a marine-derived antimetabolite used in the treatment of acute leukemia, which is also used in the study of the nervous system. In this study, we found that cytarabine pretreatment significantly inhibited the apoptosis and necrosis in the ROT-induced SH-SY5Y cell PD model and reduced the oxidative stress, as evidenced by the reduced MDA levels and the increased levels of SOD, GSH, and total antioxidant capacity. Cytarabine can also enhance mitochondrial vitality, improve mitochondrial respiratory function, and preserve mitochondrial morphology. Cytarabine also enhanced the expression of the mitophagy-related proteins PINK1, Parkin, VDAC1, and DJ-1, and its actions can be reversed by treatment with AMPK inhibitor - Compound C (CC), suggesting that AMPK activation may be involved in cytarabine-enhanced mitophagy. Furthermore, cytarabine can also ameliorate the motor symptoms in the MPTP-induced PD-like mice model, and attenuate the neuropathy in the substantia nigra (SN) of PD mice, while Compound C antagonized cytarabine's beneficial effects. In summary, marine-derived compound cytarabine could resist neurological damage both in vitro and in vivo by activating AMPK to increase PINK1/Parkin-induced mitophagy, serving as a promising disease modulator for treating neurodegenerative disease.
研究领域:
神经科学
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药理学
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细胞生物学
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神经退行性疾病
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高影响因子
BIOMACROMOLECULES
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2025
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IF 5.4
Yu Sun,Li Cui,Wanqiu Peng,Rong Chen,Xueneng Guan,Jiangyun Liu
Parkinson’s disease (PD) is difficult to treat clinically and lacks an effective treatment. The aim of this study was to synthesize and characterize butyrate-modified hyaluronic acid (HA-But), validate its therapeutic efficacy, and elucidate its mechanisms of action in PD. Behavioral tests, including the open field test, Y-maze, and elevated plus maze test, demonstrated that HA-But significantly alleviated motor dysfunction in PD mice. ELISA results indicated a marked reduction in pro-inflammatory cytokine levels following the HA-But treatment. In addition, immunohistochemistry, immunofluorescence, and Western blot analyses revealed that HA-But improved dopaminergic neuron survival and reduced α-synuclein aggregation. Furthermore, HA-But activated PINK1/Parkin-mediated mitophagy, modulated gut microbiota composition, and increased short-chain fatty acid (SCFA) levels, especially butyric acid. Combining HA-But with gastrodin further improved the PD symptoms in mice. These findings suggested the potential of HA-But as a novel approach for PD treatment.
研究领域:
神经科学
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药学
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分子生物学
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肠脑轴
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神经退行性疾病
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高影响因子
EXPERIMENTAL CELL RESEARCH
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2026
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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.
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高影响因子
BIOCELL
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2026
·Vol. 50
·期 6
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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.
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JOURNAL OF POULTRY SCIENCE
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2026
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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.
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高影响因子
CELLULAR SIGNALLING
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2026
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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.
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高影响因子
POULTRY SCIENCE
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2025
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IF 4.2
Yu Xia,Yidan Wang,Jiahui Xue,Jiahong Chu,Yanhe Zhang,Fuze She,Huijie Chen,Shu Li
Naringenin (Nar) is known to maintain mitochondrial homeostasis, antioxidation and anti-inflammation. Damaged mitochondria can promote excessive Reactive oxygen species (ROS) production, triggering pyroptosis and inflammation process in immune tissues. PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy contributes to removing damaged mitochondria. This study aims to investigate detailed mechanism of Nar against Lipopolysaccharide (LPS)-induced injury in broiler spleens and the role of mitophagy in this process. We used LPS as a stimulus and treated with Nar to establish relevant models in vivo and in vitro . Our findings demonstrated Nar increased the expression levels of Phospho-Adenosine 5 ’ -monophosphate (AMP)-activated protein kinase (p-AMPK)/AMPK, PINK1, Parkin and Microtubule-Associated Protein 1A/1B Light Chain 3 (LC3), and reduced the level of Sequestosome 1 (P62), leading to a reduction in levels of factors associated with mitochondrial fission, mtDNA release, pyroptosis, and inflammation. Conversely, Nar treatment enhanced the levels of factors related to mitochondrial fusion, energy metabolism, and anti-inflammatory response. Moreover, an increase was observed in ΔΨm, ATP content, and ATPase activity. Molecular docking analysis and cellular thermal shift assay (CETSA) supported the interaction between Nar and AMPK. In summary, Nar enhanced LPS-induced mitophagy and alleviated mitochondrial homeostasis imbalance and oxidative stress in broiler spleens through its interaction with AMPK, resulting in alleviating pyroptosis and inflammation.
研究领域:
兽医学
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免疫学
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分子生物学
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线粒体生物学
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药理学
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高影响因子
PHYTOMEDICINE
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2024
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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
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肝病学
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细胞生物学
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免疫学
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高影响因子
RENAL FAILURE
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2026
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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.
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