INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Gaolin Wen,Lingling Xue,Mengdi Qiu,Junlan Qiu,Xinhua Zhu,Haozhen Ren
Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.
研究领域:
肿瘤学
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药学
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生物材料
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DOI
高影响因子
Colloid and Interface Science Communications
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2023
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IF 4.5
Peng Wang,Jiwen Geng,Chunyu Tan,Qiang Wei
Adhesive interface stiffness is capable of modulating cellular behavior and gene expression, yet the underlying mechanobiological mechanisms remain unclear. In this study, we investigated the effects of interface stiffness on gene expression pathways by hydrogels with divergent stiffness. Our results reveal that adhesive interface stiffness affects cytoplasmic mechanotranduction as well as nuclear mechanics, and ultimately regulating the subcellular localization of HDAC3. Further investigation unfolds that HDAC3 directly affects global acetylation levels within nucleus. And HDAC3-induced acetylation changes are regulated by myosin contraction, thereby portraying downstream gene expression. Additionally, our study indicates that the interface stiffness-mediated regulation of HDAC3 nuclear-cytoplasmic redistribution is dependent on CRM1, and inhibition of CRM1 impedes the nuclear export of HDAC3. In summary, our work provides an overview of how the subcellular localization of HDAC3 can be manipulated through the regulation of cell adhesion interface stiffness, thereby altering upstream RNA polymerase II activity and gene expression.
研究领域:
细胞生物学
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力学生物学
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分子生物学
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高影响因子
Science Advances
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2025
·Vol. 11
·期 9
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IF 12.5
Kai Tang,Yufan Zheng,Guanshuo Hu,Ying Xin,Keming Li,Cunyu Zhang,Xi Chen,Bai Zhang,Xueyi Li,Bing Hu,Qiong Jia,Yong-ping Zheng,Mo Yang,Youhua Tan
Tumor cells with organ-specific metastasis traits arise in primary lesions with substantial variations of local niche mechanics owing to intratumoral heterogeneity. However, the roles of mechanically heterogeneous primary tumor microenvironment in metastatic organotropism remain an enigma. This study reports that persistent priming in soft but not stiff niches that mimic primary tumor mechanical heterogeneity induces transcriptional reprogramming reminiscent of neuron and promotes the acquisition of brain metastatic potential. Soft-primed cells generate brain metastases in vivo through enhanced transendothelial migration across blood-brain barrier and brain colonization, which is further supported by the findings that tumor cells residing in local soft niches of primary xenografts exhibit brain metastatic tropism. Mechanistically, soft niches suppress cytoskeleton-nucleus–mediated mechanotransduction, which promotes histone deacetylase 3 activity. Inhibiting histone deacetylase 3 abolishes niche softness-induced brain metastatic ability. Collectively, this study uncovers a previously unappreciated role of local niche softness within primary tumors in brain metastasis, highlighting the significance of primary tumor mechanical heterogeneity in metastatic organotropism.
研究领域:
肿瘤学
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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
FASEB JOURNAL
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2025
·Vol. 39
·期 16
·e70906
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IF 4.2
Lina Wei,Lei Wang,Yang Yu,Xiaozhou Sun,Liang Liu,Jing Han,Yongji Wang,Yinan Guo
Pediatric bacterial pneumonia continues to pose a significant global health burden, often resulting in serious complications. Recent studies have emphasized the pivotal role of the gut-lung axis in the progression of respiratory diseases, wherein disruptions in gut microbiota can aggravate pulmonary inflammation. This research investigates the underlying mechanisms by which Ma-Xing-Shi-Gan Decoction (MXSG), a classical formula in traditional Chinese medicine, influences the gut-lung axis in the context of childhood bacterial pneumonia. Clinical data indicated pronounced alterations in intestinal microbial composition and a marked decline in short-chain fatty acid (SCFA) levels among affected pediatric patients—changes that coincided with dysfunctional gut-lung signaling. In a murine model of bacterial pneumonia, MXSG administration restored microbial diversity, elevated SCFA production, and attenuated inflammatory responses by suppressing the HDAC3/NF-κB signaling cascade. Key bioactive constituents of MXSG—namely, quercetin, osajin, nobiletin, and solasodine—were identified as critical regulators, modulating lipid metabolism and promoting SCFA biosynthesis. These results highlight the therapeutic promise of MXSG in reestablishing gut-lung homeostasis and shed light on its mechanistic potential in the treatment of pediatric bacterial pneumonia. Graphical This schematic illustrates how MXSG restores gut microbiota diversity and SCFA levels, suppresses HDAC3/NF-κB signaling, and alleviates lung inflammation in pediatric bacterial pneumonia. Integrated multi-omics and mouse model experiments reveal that MXSG modulates the gut-lung axis and provides a novel mechanism for its clinical efficacy.
研究领域:
中医药学
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微生物学
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免疫学
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药理学
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分子生物学
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儿科学
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呼吸疾病
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PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2026
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IF 3.5
Fang Tong,Xue Gao,Yuhong Shang
Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer research. Ubiquitin-specific peptidase 18 (USP18), a member of the deubiquitinating enzyme family, has been recognized as an oncoprotein in various cancers; however, its functional role and underlying mechanisms in EC remain largely unexplored. In this study, we found that USP18 was markedly upregulated in EC patients (n=15, stage I; n=4, stage II and n=1, stage III), and elevated USP18 expression correlated with unfavorable prognosis. Functional assays demonstrated that knockdown of USP18 significantly inhibited EC cell proliferation. Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ , thereby enhancing erastin-induced ferroptosis. In contrast, USP18 overexpression produced opposing effects. These in vitro findings were further validated in vivo, where USP18 knockdown suppressed tumor growth and promoted ferroptosis. Mechanistic investigations revealed that USP18 interacted with and deubiquitinated histone deacetylase 3 (HDAC3), thus leading to its stabilization. Subsequent rescue experiments confirmed that the tumor-promoting effects of USP18 were abrogated upon HDAC3 knockdown. Taken together, our results identify the USP18/HDAC3 axis as a key regulator of EC cell proliferation and ferroptosis suppression, underscoring the potential of USP18 as a therapeutic target in EC.
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AMERICAN JOURNAL OF CHINESE MEDICINE
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2024
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IF 4.8
Xiaowei Zhang,Jiajun Wang,Shixie Xiang,Liang Zhao,Mingzhen Lv,Yafei Duan,Gai Gao,Pan Wang,Jenny Jie Chen,Jiangyan Xu,Zhishen Xie,Zhenqiang Zhang
Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease (ESRD), causing an urgent need for preventive strategies for DKD. Astragaloside I (ASI), a bioactive saponin extracted from Astragalus membranaceus (Fisch.) Bunge has been demonstrated to possess a variety of biological activities. This study investigates the therapeutic potential of ASI in DKD and the underlying molecular mechanism using db/db mice in vivo and high glucose (HG)-induced SV40-MES-13 cells in vitro . The results indicated that ASI significantly ameliorated renal dysfunction and mitigated the pathological alterations in the renal tissues of db/db mice. Moreover, ASI was found to reduce the levels of renal fibrosis makers and suppress the activation of TGF- β 1/Smad2/3 pathway in both db/db mice and HG-induced SV40-MES-13 cells. Furthermore, ASI downregulated HDAC3 expression, upregulated Klotho expression, and enhanced Klotho release. ASI is directly bound to HDAC3, and the beneficial effects of ASI on Klotho/TGF- β 1/Smad2/3-mediciated renal fibrosis in DKD were reversed by the HDAC3 agonist ITSA-1. In conclusion, ASI attenuates renal fibrosis in DKD, and may act through concurrently inhibiting HDAC3 and TGF- β 1, thereby regulating HDAC3-mediciated Klotho/TGF- β 1/Smad2/3 pathway.
研究领域:
药理学
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肾病学
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分子生物学
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糖尿病
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2021
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IF 4.219
Dingchao Xia,Dazhi Chen,Tingchen Cai,Lujian Zhu,Yanhan Lin,Sijie Yu,Kailu Zhu,Xiaodong Wang,Lanman Xu,Yongping Chen
A chronic liver disease named autoimmune hepatitis (AIH) will carry elevated levels of inflammatory cytokines, but there is currently no effective treatment to cure it. Histone deacetylase 3 (HDAC3) takes an important position in regulating the expression of inflammatory genes. Nimbolide (NIB) is a limonoid extracted from the neem tree (Azadirachta indica) that has been found to be effective against many diseases, including cancer, scleroderma, and acute respiratory distress syndrome. Here, we investigated the protective effect of nimbolide on AIH liver. Mice and AML12 cells were employed to establish AIH model with liver antigen S100 and cell injury model of LPS, and then treated with different concentrations of nimbolide. After the successful establishment of the animal model and cell model, inflammatory cytokines of IL-1β, IL-6 and TNF-α as well as cellular signaling related to inflammation such as STAT3, IκB-α and NF-κB were examined. We observed for the first time about nimbolide can effectively inhibit inflammation in AIH mice's liver and AML12 cells by inhibiting HDAC3 expression. HDAC3 knocked down by siRNA in cells can also effectively alleviate the inflammation in AML12 cells, further confirming that HDAC3 plays an important role in the inflammation of liver cells. These results suggest nimbolide could be a potential new treatment for autoimmune hepatitis, and HDAC3 may become a new target for autoimmune hepatitis.
研究领域:
免疫学
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药理学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Wang Hao,Li Xianjia,Chang Mengjun,Yu Shuangjie,Li Ye,Zhang Lingling,Du Yunyun,Ji jin,Yu Zexin,Fu Youjuan,Guan Suzhen
Triclosan (TCS), a broad-spectrum antimicrobial agent widely used in personal care products and medical disinfectants due to its potent antibacterial properties, is an emerging environmental endocrine-disrupting chemical. While its potential neurodevelopmental toxicity to offspring has raised significant concern, the precise epigenetic mechanisms involved remain unclear. Methyl CpG binding protein-2 (MeCP2), a crucial epigenetic regulator in brain development, recognizes DNA methylation marks and recruits co-factors such as Histone Deacetylase 3 (HDAC3) to form transcriptional repressor complexes that precisely control the expression of neuron-related genes. Dysfunction of MeCP2 is implicated in numerous neuropsychiatric disorders. This study employed a murine model of long-term, low-dose TCS exposure during gestation and lactation to investigate its neurotoxicity and epigenetic mechanisms in female offspring. The results demonstrate that gestational and lactational TCS exposure induced anxiety-like behavior and cognitive memory impairments in female offspring, accompanied by neuronal disorganization in the prefrontal cortex (PFC), increased pyknotic neurons, and ultrastructural damage to synapses. Specifically, TCS exposure downregulated the methylation level of the MeCP2 promoter region in the PFC of female offspring, increased the expression of MeCP2 and HDAC3, and enhanced their interaction, consequently repressing the protein expression of PSD95, SYN, BDNF, DCX, and PCNA. Notably, an exposure dose of 8 mg/kg TCS emerged as a critical threshold for these epigenetic alterations. In summary, TCS exposure during pregnancy and lactation may mediate neurodevelopmental impairment in female offspring by downregulating MeCP2 promoter methylation, subsequently enhancing MeCP2 recruitment of HDAC3 and their interaction. These findings provide novel experimental evidence elucidating the epigenetic mechanisms underlying TCS-induced neurodevelopmental toxicity.
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Journal of Advanced Research
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2025
·
IF 13
Yajing Li,Runping Liu,Jianan Li,Feng Gao,Zhi Ma,Kaihong Xie,Fanghong Li,Bing Xu,Qi Zheng,Yajie Cai,Jiaorong Qu,Xiaoyong Xue,Kexin Jia,Xiaojiaoyang Li
Introduction Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. Objective: This study aims to unveil the underlying mechanisms of the protective effects of senkyunolide A (SenA) on cholangiocyte overproliferation in cholestatic liver diseases. Methods : Through comprehensive characterization using RNA sequencing, CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we explored the effects and mechanisms of SenA in vivo in bile duct ligation mice and in vitro in primary cholangiocytes. Results : We demonstrated that SenA effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19, Let-7a and Lin28a. Mechanically, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Conclusion : We highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.
研究领域:
医学
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分子生物学
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药理学
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PubMed
高影响因子
Biology Direct
·
2024
·Vol. 19
·期 1
·1-16
·
IF 5.7
Xie Qingpeng,Hu Bin,Li Haosong
Background Clear cell renal cell carcinoma (RCC) is the most common kidney tumor. The analysis from medical database showed that Scm-like with four MBT domains protein 2 (SFMBT2) was decreased in advanced clear cell RCC cases, and its downregulation was associated with the poor prognosis. This study aims to investigate the role of SFMBT2 in clear cell RCC. Methods The expression of SFMBT2 in clear cell RCC specimens were determined by immunohistochemistry staining and western blot. The overexpression and knockdown of SFMBT2 was realized by infection of lentivirus loaded with SFMBT2 coding sequence or silencing fragment in 786-O and 769-P cells, and its effects on proliferation and metastasis were assessed by MTT, colony formation, flow cytometry, wound healing, transwell assay, xenograft and metastasis experiments in nude mice. The interaction of SFMBT2 with histone deacetylase 3 (HDAC3) and seven in absentia homolog 1 (SIAH1) was confirmed by co-immunoprecipitation. Results In our study, SFMBT2 exhibited lower expression in clear cell RCC specimens with advanced stages than those with early stages. Overexpression of SFMBT2 inhibited the growth and metastasis of clear cell RCC cells, 786-O and 769-P, in vitro and in vivo, and its silencing displayed opposites effects. HDAC3 led to deacetylation of SFMBT2, and the HDAC3 inhibitor-induced acetylation prevented SFMBT2 from SIAH1-mediated ubiquitination modification and proteasome degradation. K687 in SFMBT2 protein molecule may be the key site for acetylation and ubiquitination. Conclusions SFMBT2 exerted an anti-tumor role in clear cell RCC cells, and HDAC3-mediated deacetylation promoted SIAH1-controlled ubiquitination of SFMBT2. SFMBT2 may be considered as a novel clinical diagnostic marker and/or therapeutic target of clear cell RCC, and crosstalk between its post-translational modifications may provide novel insights for agent development.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2023
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IF 5.6
Ze Wang,Li Zhao,Bo Zhang,Jiahe Feng,Yule Wang,Bin Zhang,Haixiao Jin,Lijian Ding,Ning Wang,Shan He
Pan-histone deacetylase (HDAC) inhibitors often have some toxic side effects. In this study, three series of novel polysubstituted N-alkyl acridone analogous were designed and synthesised as HDAC isoform-selective inhibitors. Among them, 11b and 11c exhibited selective inhibition of HDAC1, HDAC3, and HDAC10, with IC50 values ranging from 87 nM to 418 nM. However, these compounds showed no inhibitory effect against HDAC6 and HDAC8. Moreover, 11b and 11c displayed potent antiproliferative activity against leukaemia HL-60 cells and colon cancer HCT-116 cells, with IC50 values ranging from 0.56 μM to 4.21 μM. Molecular docking and energy scoring functions further analysed the differences in the binding modes of 11c with HDAC1/6. In vitro anticancer studies revealed that the hit compounds 11b and 11c effectively induced histone H3 acetylation, S-phase cell cycle arrest, and apoptosis in HL-60 cells in a concentration-dependent manner.
研究领域:
药理学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 14
·e72138
·
IF 4.3
Yong Sun,Huayue Wu,Yutong Zhou,Pengsheng Yin,Long Wu,Haiyang Li,Shi Zuo,Zhe Yang,Kun Cao
Liver fibrosis remains a major global health challenge, driving interest in bioactive metabolites from natural sources as potential therapies. Sodium butyrate (NaB), a gut microbiota–derived short‐chain fatty acid with notable anti‐fibrotic activity, shows promise, although its mechanisms remain unclear. This study aims to explore the molecular mechanisms through which NaB attenuates liver fibrosis. This study integrates bioinformatics and network pharmacology to predict the molecular targets through which NaB exerts its anti‐fibrotic effects. Candidate targets were validated through molecular docking, histopathology, CETSA, and SPR. The inferred mechanisms were further validated in vitro (LX‐2 cells) and in vivo (CCl 4 ‐induced mice) using Western blot, IF Co‐IP, RT‐qPCR, ELISA, and histopathological staining. HDAC3 was identified as a key driver of liver fibrosis. As a natural HDAC3 inhibitor, NaB markedly attenuated CCl 4 ‐induced hepatic injury and fibrosis, accompanied by reduced expression of HDAC3, c‐Myc, glycolytic enzymes (HK2, PFKFB3, and PKM2), and fibrotic markers (α‐SMA and type I collagen) in fibrotic liver tissues and LX‐2 cells. Mechanistically, NaB exerts its anti‐fibrotic effects by inhibiting HDAC3 expression and deacetylase activity, promoting c‐Myc acetylation and downregulating its expression, thereby suppressing glycolytic metabolic reprogramming in hepatic stellate cells. These findings indicate that NaB attenuates liver fibrosis by inhibiting HDAC3/c‐Myc–mediated metabolic reprogramming, revealing a gut‐derived anti‐fibrotic mechanism and potential therapeutic targets. This study explores the molecular mechanisms by which NaB ameliorates liver fibrosis from the perspectives of the gut–liver axis and metabolic reprogramming. In vivo and in vitro experiments demonstrate that gut‐derived NaB may alleviate liver injury and fibrosis by inhibiting hepatic stellate cell activation and aerobic glycolysis through the HDAC3/c‐Myc signaling axis.
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高影响因子
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