CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Tingbiao Wu,Deyao Li,Qiuyu Chen,Dezhi Kong,Hongxuan Zhu,Hefeng Zhou,Qingwen Zhang,Guozhen Cui
Ginkgolide B (GB), a compound derived from Ginkgo biloba , exhibits significant cardioprotective properties, although its precise molecular target has yet to be identified. In this study, we synthesized a biotin-labeled GB probe (GB-biotin) to identify the molecular targets of GB. Our experiments demonstrated that treatment with GB or GB-biotin reduced mitochondrial injury, restored mitochondrial membrane potential, and decreased cell apoptosis in a concentration-dependent manner. Additionally, GB increased mitochondrial oxygen consumption rate, indicating improved mitochondrial bioenergetics. Proteomic analysis revealed that the voltage-dependent anion channel 1 (VDAC1) is a key protein that interacts with GB-biotin. This finding was further confirmed through cellular thermal shift assay (CETSA) and molecular docking, which revealed hydrogen bond formation between GB and VDAC1. Furthermore, overexpression of VDAC1 diminished the protective effects of GB, highlighting the crucial role of VDAC1 in GB-mediated cardioprotection. These findings identify VDAC1 as a therapeutic target for GB in vitro , providing valuable insights into the cardioprotective mechanisms of GB and the development of novel cardioprotective strategies.
研究领域:
药理学
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分子生物学
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心血管科学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Wei Yang,Yu Li,Ruzhen Feng,Peiyao Liang,Kefan Tian,Lingli Hu,Kejing Wang,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Xiaofeng Yao
Perfluorooctane sulfonate (PFOS), a listed persistent organic pollutant, poses risks to human health and is closely linked to chronic metabolic diseases. Although the role of mitochondrial fission in these diseases has garnered attention, whether and how PFOS induces mitochondrial fission remains obscure. Here, we found that PFOS induced mitochondrial fission, as demonstrated by the fragmentation of mitochondria and the upregulation of dynamin-related protein 1 (DRP1), phospho-DRP1 and mitochondrial fission protein 1 (FIS1) in human hepatocytes MIHA and mice liver. Blocking the calcium transfer from lysosomes to mitochondria that was executed by transient receptor potential mucolipin 1 (TRPML1) of lysosomes and voltage-dependent anion channel 1 (VDAC1) of mitochondria, did not affect PFOS-induced mitochondrial fission. In contrast, knockdown of TRPML1 or VDAC1 reversed this process. Knockdown of mitochondrial calcium uniporter (MCU), rather than inhibiting its activity, effectively alleviated PFOS-induced mitochondrial fission. Additionally, PFOS increased MCU oligomers without affecting MCU monomer. Inhibiting autophagy reversed the MCU oligomerization. Further investigation unveiled the interactions of MCU with VDAC1, TRPML1, mitochondrial Fo complex subunit F2 (ATP5J2) and DRP1 in PFOS-exposed mice liver and MIHA cells. We also discovered that knockdown of ATP5J2 alleviated PFOS-induced mitochondrial fission. Ulteriorly, PFOS upregulated ATP5J2 that underwent oligomerization. Knockdown of MCU reversed the increase in ATP5J2. Our study uncovers the presence and molecular basics of lysosomes-regulated mitochondrial fission under PFOS exposure, explains the regulatory pathways on MCU and ATP5J2 oligomerization and their pivotal roles in mitochondrial fission, highlighting the involvement of mitochondrial fission in PFOS-related health risks.
研究领域:
细胞生物学
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毒理学
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代谢疾病研究
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2023
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IF 3.7
Jinpeng Lv,Ximei Zhang,Xiaohong An,Yan Cao,Duo Meng,Kun Zou,Rongyin Gao,Ruzhi Zhang
The voltage-dependent anion channel 1 (VDAC1) forms an oligomeric structure on the mitochondrial outer membrane , which plays critical roles in many physiological processes . Research studies have demonstrated that the knockout of VDAC1 increases pigment content and up-regulates the expression of melanogenic genes. Due to its involvement in various physiological processes, the depletion of VDAC1 has significant detrimental effects on cellular functions and the inhibition of VDAC1 oligomerization has recently emerged as a promising strategy for the treatment of several diseases. In this study, we found that VDAC1 oligomerization inhibitors, VBIT-12 and NSC-15364, promote melanogenesis , dendrite formation and melanosome transport in human epidermal melanocytes (HEMCs). Mechanistically, treatment of HEMCs with an oligomerization inhibitor increased the level of cytoplasmic calcium ions , which activated calcium-calmodulin dependent protein kinase (CaMK) and led to the phosphorylation of CREB and the nuclear translocation of CREB-regulated transcription coactivators (CRTCs). Subsequently, CRTCs, p-CREB and CREB-binding protein (CBP) in the nucleus cooperatively recruit the transcription machinery to initiate the transcription of MITF thus promoting pigmentation . Importantly, our study also demonstrates that VDAC1 oligomerization inhibitors increase pigmentation in zebrafish and in human skin explants , highlighting their potential as a therapeutic strategy for skin pigmentation disorders.
研究领域:
细胞生物学
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分子生物学
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皮肤生理学
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药理学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Yu Ma,Wei Yang,Peiyao Liang,Ruzhen Feng,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Qiujuan Li,Guang Yang,Xiaofeng Yao
As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.
研究领域:
毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
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IF 7.9
Gai Gao,Jie Zhao,Jing Ding,Shuyan Liu,Yanyan Shen,Changxin Liu,Huifen Ma,Yu Fu,Jiangyan Xu,Yiran Sun,Xiaowei Zhang,Zhenqiang Zhang,Zhishen Xie
Background The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma , has been reported to ameliorate NASH and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. Purpose To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. Study Design HepG2, HL7702 cells, and C57BL/6J were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro . Methods Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro . Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to VDAC1. Results ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum to Golgi apparatus. Further investigations indicated that the activation of AMPK by ALB was independent on traditional CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. Conclusion Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.
研究领域:
药理学
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分子生物学
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生物化学
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细胞生物学
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代谢
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PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Shuhan Wang,Yaqi Yang,Jiahong Lin,Weishan Zhang,Cuizhu Yang,Runheng Zhang,Chang Zhou,Li Zhang,Xin Wang,Jing Liu,Xiaobao Jin,Yuxin Ma
Alzheimer's disease (AD) as a common neurodegenerative disease, which characterized by amyloid Aβ deposition and neurofibrillary tangles. Astragalin (AST), a natural flavonoid, has anti-inflammatory, antioxidant, anti-cancer, and other pharmacological effects. Astrocytes can phagocytize and degrade Aβ in their vicinity. In this study, we used the AD mice model established by injecting the mixture of Aβ1-42 and Aβ25-35 into the CA1 region of the hippocampus, and C8D1A cells injured by Aβ1-42 to explore the neuroprotective effects of AST. Our findings showed that AST enhances learning and cognitive ability of AD mice, reduces Aβ deposition and neurofibrillary tangles in the brain, and improves the structural morphology of hippocampal nerve cells. Furthermore, AST promoted autophagy and suppressed apoptosis of astrocytes in the AD model. Additionally, AST inhibited the expression of proteins associated with the Fas/Fasl-VDAC1 signaling pathway, while autophagy inhibitor chloroquine (CQ) or apoptosis agonist phenoxodiol reversed above change. Interestingly, consistent with the action of pathway Fas inhibitor KR-33493, AST could activate autophagy of Aβ1-42 injured C8D1A cells while inhibit their apoptosis. In conclusion, AST activated autophagy and inhibited apoptosis of hippocampal astrocytes in AD mice, ameliorating animal cognitive deficits by down-regulating Fas/Fasl-VDAC1 signaling pathway. Thus, this study provided a new perspective and experimental foundation for developing AD treatment drugs.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2017
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IF 3.778
Xiayun Yang,Shusheng Tang,Chongshan Dai,Daowen Li,Shen Zhang,Sijun Deng,Yan Zhou,Xilong Xiao
Quinocetone (QCT) has been used as an animal feed additive in China since 2003. However, investigations indicate that QCT has potential toxicity due to the fact that it shows cytotoxicity, genotoxicity , hepatotoxicity, nephrotoxicity and immunotoxicity in vitro and animal models. Although QCT-induced mitochondrial apoptosis has been established, the molecular mechanism remains unclear. This study was aimed to investigate the role of voltage-dependent anion channel 1 (VDAC1) oligomerization and Wnt/β-catenin pathway in QCT-induced mitochondrial apoptosis. The results showed VDAC inhibitor 4, 4-diisothiocyano stilbene-2, 2-disulfonic acid (DIDS) partly compromised QCT-induced cell viability decrease (from 34.1% to 68.5%) and mitochondrial apoptosis accompanied by abating VDAC1 oligomerization, cytochrome c (Cyt c ) release and the expression levels of cleaved caspase-9, -3 and poly (ADP-ribose) polymerase (PARP). Meanwhile, overexpression VDAC1 exacerbated QCT-induced VDAC1 oligomerization and Cyt c release. In addition, lithium chloride (LiCl), an activator of Wnt/β-catenin pathway, markedly attenuated QCT-induced mitochondrial apoptosis by partly restoring the expression levels of Wnt1 and β-catenin. Finally, reactive oxygen species (ROS) scavenger N -acetyl- l -cysteine (NAC) obviously blocked QCT-induced VDAC1 oligomerization and the inhibition of Wnt1/β-catenin pathway. Taken together, our results reveal that QCT induces mitochondrial apoptosis by ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/β-catenin pathway.
研究领域:
毒理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 7
·期 30
·4706-4716
·
IF 5.047
Dan Liu,Angelina Angelova,Jianwen Liu,Vasil M. Garamus,Borislav Angelov,Xinlei Zhang,Yawen Li,Guillaume Feger,Na Li,Aihua Zou
Mitochondria-targeting peptides represent an emergent tool for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)–hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial α-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Of significance, Pal-pHK-pKV treatment of non-cancerous NCM460 cells resulted in substantially lower cytotoxicity. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy.
研究领域:
生物技术
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癌症生物学
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分子生物学
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纳米技术
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药学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
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IF 4.2
Congna Zi,Xian Ma,Maodong Zheng,Ying Zhu
Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca 2+ )-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro . We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca 2+ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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病理生理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Jinpeng Lv,Huansha Zhang,Wenhao Yu,Peiwen Jiang,Chuanwei Yin,Wenhui Xu,Yan Cao,Rongyin Gao
Vitiligo is a chronic depigmentary disorder initiated by oxidative stress, which activates inflammatory signaling and innate immunity, ultimately leading to melanocyte destruction. Although melanocyte defects have been widely studied, dermal fibroblasts-the predominant stromal regulators of cutaneous immunity-remain insufficiently characterized in vitiligo pathogenesis. Here, we demonstrate that subtoxic oxidative stress in normal human dermal fibroblasts (NHDFs) induces a VDAC1-dependent, non-apoptotic release of mitochondrial DNA (mtDNA), thereby linking redox imbalance to immune activation. Low-dose hydrogen peroxide preserved mitochondrial morphology while promoting VDAC1 oligomerization, forming pores that enabled selective mtDNA efflux from structurally intact mitochondria. The released mtDNA activated the cGAS-STING pathway and the NLRP3 inflammasome, driving the expression of IL-1β, IL-6, ICAM-1, and Occludin-a pattern consistent with a senescence-associated secretory phenotype. Pharmacological interventions using ethidium bromide, RU.521, VBIT-4, and exogenous mtDNA established mtDNA release as an upstream event in fibroblast innate immune activation. Notably, inhibiting VDAC1 oligomerization with VBIT-4 effectively prevented mtDNA leakage, attenuated fibroblast senescence and inflammatory signaling, and restored epidermal repigmentation in a vitiligo mouse model. These findings identify dermal fibroblasts as active sensors and amplifiers of oxidative stress via the VDAC1-mtDNA-cGAS-STING axis and highlight VDAC1 oligomerization as a promising therapeutic target.
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高影响因子
Materials Today Bio
·
2026
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IF 11
Chu Z,Yang T,Zhang Y,Zhu Q,Wang D,Tang H,Zhang G,Jiang M,Zhou L,Xu L,Fan T,Zhang J,Ma A,Xu C,Wang J,Tang H.
Ulcerative colitis (UC) remains a clinical challenge due to limited efficacy and side effects of conventional therapies, highlighting the need for novel interventions. Here, we investigate the therapeutic potential of naturally derived self-assembled nanoparticles (XDNPs) from the traditional Chinese medicine formula Xiexin Decoction (XXD) and rationally designed carrier-free nanoparticles (RBNPs) composed of berberine (BBR) and rhein. Both formulations effectively mitigated DSS-induced colitis by normalizing gut dysbiosis, reducing the release of pro-inflammatory mediators and facilitating macrophage phenotypic switching. Mechanistically, activity-based protein profiling identified VDAC1 as a direct functional target of BBR. Binding to VDAC1 inhibits its oligomerization, preventing the cytosolic release of oxidized mitochondrial DNA and subsequent activation of the NLRP3 inflammasome in macrophages. Co-assembly with rhein further enhances cellular uptake and bioavailability, amplifying anti-inflammatory efficacy. Proteomic and molecular analyses confirmed broad modulation of immune and metabolic pathways, while in vivo safety assessments demonstrated excellent biocompatibility without detectable organ toxicity. Collectively, this work elucidates a VDAC1-mediated mechanistic axis underlying the potent therapeutic effects of BBR-containing nanoparticles and establishes a rational nanomedicine strategy inspired by traditional herbal formulations. These findings provide a promising platform for the development of targeted, biocompatible nanotherapeutics for UC and other inflammatory disorders.
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2026
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IF 12.2
Ge Yutong,Yu Tao,Yu Shaokun,Sun Ao,Zhang Shiyu,Zhang Meiling,Wang Qian,Liu Jia,Zhang Xuan,Zeng Lulin,Lu Kaihua
Tumor-associated macrophages (TAMs) enriched in tumor microenvironment (TME) promote immune evasion and poor prognosis. Mitochondrial dysfunction, especially branched-chain amino acid (BCAA) metabolic reprogramming, has been confirmed to be involved in regulating TAMs function. The mitochondria-related protein MTFR2 was significantly upregulated in LUAD and closely associated with reduced survival. We conducted flow cytometry, multiplex immunofluorescence, immunohistochemistry on LUAD tissues, combined with analysis of public single-cell sequencing datasets, to characterize the TME features under MTFR2 dysregulation. Transcriptomics, metabolomics, and proteomics analyses revealed BCAA metabolic reprogramming, which was driven by MTFR2 binding to Leu125 within the β8 strand of VDAC1 and promoting its oligomerization. This interaction triggered mtDNA release into the cytoplasm, activating the TLR9-NF-κB pathway to upregulate BCAT1. Elevated concentrations of BCAA metabolites such as α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) in the TME promoted M2 polarization and infiltration of TAMs by in vitro co-culture, 3D spheroid, and organoid models, and polarized M2 macrophages reciprocally promoted LUAD progression. Our findings establish a LUAD associated MTFR2-VDAC1-BCAT1 axis regulating the BCKAs-M2 axis in TAMs. Notably, targeting BCAT1 or depleting macrophages blocked this loop, offering a potential combination therapy for LUAD.
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DOI
PubMed
高影响因子
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