Frontiers in Pharmacology
·
2025
·
IF 4.8
Ruibing Wu,Hengye Yuan,Yuehua Wang,Xianggang Gou,Wanhua Hou,Zhongzheng Zhou,Xinran Wang,Xiuling Deng,Changshan Wang,Haisheng Wang,Jia Yan
Background: Norcantharidin (NCTD), a bioactive compound derived from traditional Chinese medicine, has demonstrated promising anticancer activity against multiple malignancies, particularly hepatocellular carcinoma (HCC). However, its epigenetic regulatory mechanisms and associated transcriptional consequences remain poorly characterized.Methods: In this study, we integrated biochemical assays with a panel of cellular analyses assessing cell viability, proliferation, colony formation, and migratory capacity to investigate NCTD’s therapeutic potential in HCC progression. Potential molecular targets of NCTD were systematically identified through integrated network pharmacology approaches. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) was performed to quantify H3K27me3 enrichment level at the TOP2A locus in NCTD-treated HCC cells. Molecular docking simulations were employed to examine structural interactions between NCTD and EZH2 (enhancer of zeste homolog 2), while co-immunoprecipitation assays were further conducted to validate protein-protein interactions between EZH2 and protein phosphatase 1 (PP1).Results: We identified topoisomerase IIα (TOP2A) as a critical molecular target mediating NCTD’s anti-HCC effects. Functional characterization revealed that NCTD significantly attenuated HCC cell proliferation and induced G2/M phase cell cycle arrest through disruption of the TOP2A-p53 signaling axis. Mechanistic investigations demonstrated that NCTD epigenetically suppresses TOP2A transcription via PRC2 (Polycomb Repressive Complex 2)-mediated deposition of the repressive histone mark H3K27me3 at the TOP2A promoter. Structural biology analyses confirmed direct binding of NCTD to EZH2 protein, consequently impairing PP1-mediated dephosphorylation and enhancing PRC2 complex stability.Conclusion: Our findings establish that NCTD exerts anticancer effects in HCC through epigenetic silencing of TOP2A. This work not only elucidates a novel pharmacoepigenetic mechanism underlying NCTD’s antitumor activity but also provides translational rationale for developing PRC2-targeted therapeutic strategies in HCC management.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Brain Sciences
·
2023
·Vol. 13
·期 2
·334
·
IF 3.3
Shanshan Lin,Chengrui Wang,Zhiwen Li,Xiu Qiu
The pathological mechanisms of neural tube defects (NTDs) are not yet fully understood. Although the dysregulation of histone modification in NTDs is recognized, it remains to be fully elucidated on a genome-wide level. We profiled genome-wide H3K27me3 and H3K27ac occupancy by CUT&Tag in neural tissues from ICR mouse embryos with benzo[a]pyrene (BaP)-induced NTDs (250 mg kg−1) at E9.5. Furthermore, we performed RNA sequencing (RNA-seq) to investigate the regulation of histone modifications on gene expressions. Gene ontology and KEGG analysis were conducted to predict pathways involved in the development of NTDs. Our analysis of histone 3 lysine 27 modification in BaP-NTD neural tissues compared to BaP-nonNTD revealed 6045 differentially trimethylated regions and 3104 acetylated regions throughout the genome, respectively. The functional analysis identified a number of pathways uniquely enriched for BaP-NTD embryos, including known neurodevelopment related pathways such as anterior/posterior pattern specification, ephrin receptor signaling pathway, neuron migration and neuron differentiation. RNA-seq identified 423 differentially expressed genes (DEGs) between BaP-NTD and BaP-nonNTD group. The combination analysis of CUT&Tag and RNA-seq found that 55 DEGs were modified by H3K27me3 and 25 by H3K27ac in BaP-NTD, respectively. In the transcriptional regulatory network, transcriptional factors including Srsf1, Ume6, Zbtb7b, and Cad were predicated to be involved in gene expression regulation. In conclusion, our results provide an overview of histone modifications during neural tube closure and demonstrate a key role of genome-wide alterations in H3K27me3 and H3K27ac in NTDs corresponding with changes in transcription profiles.Keywords:neural tube defects;CUT&Tag;RNA-seq;epigenetics
研究领域:
表观遗传学
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神经科学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2026
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IF 7.3
Zhengyang Chen,Wenxiang Hong,Huanyue Yu,Han Yin,Zonghui Wei,Jiale Shen,Chenghao Pan,Yuchen Zhang,Yan Zhang,Zhujun Fang,Hong Zhu,Qinjie Weng,Bo Yang,Qiaojun He,Jiajia Wang,Lexian Tong
Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system (CNS) with a significant unmet need for new therapeutic options. Targeting embryonic ectoderm development (EED) is a potential novel therapeutic strategy for treating MS. Herein, based on optimization of potency and pharmacokinetic properties, we report a new class of trisubstituted pyridine derivatives as EED–H3K27me3 inhibitors for MS treatment. Notably, compounds 19 and 21 demonstrate potent EED binding affinity, significantly reduce H3K27me3 levels in dendritic cells (DCs), and effectively inhibit DC migration. Both compounds demonstrate appropriate pharmacokinetic (PK) properties, lymphoid tissue-targeting ability, and favorable in vivo safety profiles. Oral administrations of compounds 19 and 21 dose-dependently reduce spinal cord inflammation and alleviate disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results establish 19 and 21 as promising lead compounds for the development of EED inhibitors for MS therapy.
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DOI
高影响因子
DIGESTIVE DISEASES AND SCIENCES
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2022
·Vol. 68
·期 3
·778-790
·
IF 3.487
Gu Dan,Cao Ting,Yi Shijie,Liu Ya,Fan Chao
Background Ulcerative colitis (UC) features chronic, non-infectious inflammation of the colon. Insulin-like growth factor binding protein 5 (IGFBP5) has been indicated to be related to various inflammation-related diseases. However, its association with UC remains largely unclear. Aims Here, we investigate the role of IGFBP5 in colonic mucosal epithelial cell injury in UC. Methods Differentially expressed genes in the colonic tissues of UC mice were screened using the Gene Expression Omnibus database, and IGFBP5 was identified. UC mice were developed using dextran sulfate sodium, and IGFBP5 expression in the colonic tissues of UC mice was confirmed by immunohistochemistry and RT-qPCR. The effects of IGFBP 5 in vivo and in vitro were investigated by intraperitoneal injection of adeno-associated virus into UC mice or by transfection with an IGFBP5 overexpression plasmid into lipopolysaccharide-treated colonic mucosal epithelial cells. The mechanisms causing IGFBP5 deletion in UC were predicted by bioinformatics analysis and ChIP-qPCR and verified by rescue experiments. Results IGFBP5 was reduced in UC. IGFBP5 impaired the NFκB pathway in the colonic tissue of UC mice and ameliorated inflammatory infiltration and colonic mucosal cell injury. IGFBP5 depletion was associated with H3K27me3 modification, which was induced by EZH2. CTCF was responsible for recruiting EZH2 to the promoter region of IGFBP5. CTCF inhibition repressed UC progression by reducing H3K27me3 modification via the discouragement of the enrichment of EZH2 in the IGFBP5 promoter. Conclusions CTCF modulates H3K27me3 modification of the IGFBP5 promoter by recruiting EZH2, thereby downregulating IGFBP5 to accentuate colonic mucosal epithelial cell injury in UC mice.
研究领域:
免疫学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2025
·
IF 4.7
Nan Li,Feng-xiang Pang,Yu-wan Zhou,Shou-chang Ding,Chuan-jian Shi,Rui-jia Wen,Yong-xin Mai,Xian-lin Wu,Jin-fang Zhang
Background Osteosarcoma (OS) is a malignant primary tumor in bone tissues, and Methotrexate (MTX) is widely used as a chemotherapeutic drug for OS in clinical treatment. However, MTX resistance is a major challenge for OS patients. Polydatin (PD) is an extract derived from Reynoutria japonica Houtt and has been identified as a potential agent for reversing chemotherapy resistance in cancer. We therefore wondered whether PD could alleviate MTX resistance in OS. Methods The effect of PD on MTX resistance was investigated. And H19 expression was examined in the PD-treated OS cells. The association between H19 and MTX resistance in osteosarcoma was investigated.The effects of H19 on MTX resistance in osteosarcoma were evaluated by cell proliferation, colony formation, ChIP and western blotting assays. In order to investigate the molecular mechanism of PD underlying methotrexate resistance in OS, the cell proliferation, colony formation, q-PCR and western blotting were examined. Results In the present study, PD was found to act as a novel MTX sensitizer, and significantly enhanced the suppressive effects of MTX on OS in vitro and in vivo . Mechanically, PD was demonstrated to suppress the expression of long non-coding RNA H19 as well as its binding protein histone methyltransferase Enhancer of zeste homolog 2 (EZH2), and thus reduced the trimethylation of histone H3K9 (H3K9me3) and K27 (H3K27me3). Furthermore, H19 knowndown increased the binding ability of H3K9me3 and H3K27me3 with the folate metabolism-related genes RFC-1 and PCFT's promoter, and influenced folate metabolism and MTX resistance. Conclusion In conclusion, our results indicated that PD alleviated MTX resistance in OS via the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis. The translational potential of this article The findings of this study validate the function of PD in alleviating MTX resistance, and provide the new insight into developing PD as a promising drug candidate for the MTX resistant OS patients.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
iScience
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2022
·
IF 6.107
Hui Wen,Huanbin Shi,Nan Jiang,Jiehua Qiu,Fucheng Lin,Yanjun Kou
Summary Ustilaginoidea virens , which causes rice false smut disease, is a destructive filamentous fungal pathogen, attracting more attention to search for effective fungicides against U . virens . Here, the results showed that the inhibition of 2 nm AgNPs on U . virens growth and virulence displayed concentration-dependent manner. Abnormalities of fungal morphology were observed upon exposure to AgNPs. RNA-sequencing (RNA-seq) analysis revealed that AgNPs treatment up-regulated 1185 genes and down-regulated 937 genes, which significantly overlapped with the methyltransferase UvKmt6-regulated genes. Furthermore, we found that AgNPs reduced the UvKmt6-mediated H3K27me3 modification, resulting in the up-regulation of ustilaginoidin biosynthetic genes The decrease of H3K27me3 level was associated with the inhibition of mycelial growth by AgNPs treatment. These results suggested that AgNPs are an effective nano-fungicide for the control of rice false smut disease, but when using AgNPs, it needs to be combined with mycotoxin-reducing fungicides to reduce the risk of toxin pollution.
研究领域:
植物病理学
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分子生物学
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纳米技术
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真菌遗传学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Wenkai Yu,Xinyu Li,Chan Zhang,Pengpeng Niu,Jinghao Wu,Wenjun He,Kai Gao,Yuming Xu,Yusheng Li
Cerebral amyloid angiopathy (CAA) is a neurological disorder in the elderly, involving the deposition of vascular amyloid-β (Aβ). Sleep deprivation (SD) causes memory deficits during CAA. Lysine specific demethylase 6B (KDM6B) is a histone H3 lysine 27-specific demethylase associated with neuronal injury and inflammation. However, the role of KDM6B in CAA has yet to be studied. In the current study, the multi-platform over-water method was used to induce chronic SD in APP/PS1 mice. Pathological analysis revealed that SD exacerbated vascular lesions in this model, as manifested by extensive formation of Aβ-positive deposits. In addition, SD led to a significant increase in the expression of KDM6B in the cerebral cortex of APP/PS1 mice. Next, the effect of KDM6B on CAA progression was explored through loss of function. Further experiments illustrated that KDM6B knockdown diminished SD-induced memory impairment, neuronal injury and vascular lesions in vivo . Additionally, isolated primary cortical neurons were treated with 10 µM Aβ 1-42 for 48 h to induce the cell model. As expected, knockdown of KDM6B inhibited the Aβ 1-42 -induced cytotoxicity in primary neurons. Mechanistically, our results demonstrated that KDM6B knockdown downregulated poly (ADP-ribose) polymerase16 (PARP16) expression by increasing trimethylated lysine 27 on histone 3 (H3K27me3) levels, indicating that KDM6B epigenetically regulated PARP16 expression. Function recovery experiment results further proved that PARP16 overexpression negated the effect of KDM6B knockdown on Aβ 1-42 -induced cytotoxicity. Overall, our findings uncover an unanticipated role of KDM6B in CAA, and KDM6B may serve as a potential therapeutic target for CAA. Abbreviations: CAA, cerebral amyloid angiopathy; Aβ, amyloid-β; SD, sleep deprivation; KDM6B, lysine specific demethylase 6B; AD, Alzheimer’s disease; H3K27me3, trimethylated lysine 27 on histone 3; PARP16, poly (ADP-ribose) polymerase16; AAV2, adeno-associated virus 2; CHIP, chromatin immunoprecipitation; ANOVA, one-way analysis of variance.
研究领域:
神经科学
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分子生物学
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病理学
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药理学
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产品关联
DOI
PubMed
高影响因子
Genes
·
2020
·Vol. 11
·期 5
·495
·
IF 3.759
Yuyi Zhong,Liying Li,Yingting He,Bo He,Zhonghui Li,Zhe Zhang,Hao Zhang,Xiaolong Yuan,Jiaqi Li
H3K27me3 is an epigenetic modification that results in the repression of gene transcription. The transcription factor RUNX1 (the runt-related transcription factor 1) influences granulosa cells’ growth and ovulation. This research uses ELISA, flow cytometry, EDU, ChIP-PCR, WB and qPCR to investigate steroidogenesis, cell apoptosis, and the proliferation effect ofRUNX1in porcine granulosa cells (pGCs) as regulated by H3K27me3. Decreased H3K27me3 stimulates the expression of steroidogenesis-related genes, includingCYP11A1,PTGS2, andSTAR, as well as prostaglandin. H3K27me3 transcriptionally repressesRUNX1here, whereas RUNX1 acts as an activator ofFSHR,CYP11A1, andCYP19A1, promoting the production of androgen, estrogen, and prostaglandin, as well as increasing anti-apoptotic and cell proliferation activity, but decreasing progesterone. Both the complementary recovery of the H3K27me3 antagonist with the siRUNX1 signal, and the H3K27me3 agonist with the RUNX1 signal to maintain RUNX1 lead to the activation ofCYP19A1,ER1,HSD17β4, andSTARhere. Androgen and prostaglandin are significantly repressed but progesterone is markedly increased with the antagonist and siRUNX1. Prostaglandin is significantly promoted with the agonist and RUNX1. Furthermore, H3K27me3-RUNX1 affects the anti-apoptotic activity and stimulation of proliferation in pGCs. The present work verifies the transcriptional suppression ofRUNX1by H3K27me3 during antral follicular development and maturation, which determines the levels of hormone synthesis and cell apoptosis and proliferation in the pGC microenvironment.Keywords:H3K27me3;RUNX1;granulosa cells;steroidogenesis;cell apoptosis and proliferation;antral follicles;pigs
研究领域:
分子生物学
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生殖生物学
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表观遗传学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2022
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IF 7.033
Wei Shang,Xin Zhao,Fan Yang,Dongyi Wang,Le Lu,Zihan Xu,Zhiming Zhao,Hui Cai,Junyi Shen
Background: Compared with traditional drugs, nanomaterial drugs have the benefits of improving the solubility, bioavailability, and absorption rate of insoluble drugs. Nanoporous complexes can increase the efficiency with which drugs can penetrate the blood-brain barrier and reach target organs. Ginsenoside Rg1 is an effective drug that promotes angiogenesis. Ginsenoside Rg1 composite nanoparticles were employed to induce the expression of several key epigenetic enzymes and then activate the VEGF and Notch pathways after the onset of ischemic brain lesions. Methods: We constructed nanoparticles to fully encapsulate the therapeutic drug (ginsenoside Rg1), which can be transferred into brain tissue via the receptor-mediated transfer of drug-encapsulated nanoparticles. Evaluation of the therapeutic effect of ginsenoside Rg1 complex nanovesicles (CNV) was performed by in vitro and in vivo experiments. Real-time polymerase chain reaction (RT- PCR), Western blot, immunohistochemistry staining (IHC), and Co-immunoprecipitation (co-IP) were employed to screen for epigenetic enzymes with an up-regulated expression post ginsenoside Rg1-CNV intervention. RNA sequencing, shRNA knockdown, and chromatin Immunoprecipitation (ChIP) sequencing were performed to detect the target genes of ginsenoside Rg1-CNV that regulate angiogenesis. Then, bioinformatic analysis was performed to investigate the mechanism of action of epigenetic modifying enzymes in regulating target genes. Results: The average of the synthesized ginsenoside Rg1-CNV was 203.78±6.83 nm, the polydispersion index was 0.135±0.007, and the Zeta potential was 23.13±1.65 mV. Through in vivo and in vitro experiments, we found that it promotes the proliferation, migration, and tubular formation of brain microvascular endothelial cells (BMECs). Meanwhile, the intervention of ginsenoside Rg1-CNV promoted the demethylation of H3K27me3 within the promoter region of VEGF-A and Jagged1 genes and reduced the H3K27me3 modification within this region. Conclusion: The ginsenoside Rg1 nanoparticles may be an available blood-brain barrier penetrating agent for ischemic stroke.
研究领域:
药理学
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神经科学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Lang Chen,Chenyan Yu,Wanting Xu,Yuan Xiong,Peng Cheng,Ze Lin,Zhenhe Zhang,Leonard Knoedler,Adriana C. Panayi,Samuel Knoedler,Junqing Wang,Bobin Mi,Guohui Liu
Ongoing research has highlighted the significance of the cross-play of macrophages and mesenchymal stem cells (MSCs). Lysine-specific demethylase 6B (KDM6B) has been shown to control osteogenic differentiation of MSCs by depleting trimethylated histone 3 lysine 27 (H3K27me3). However, to date, the role of KDM6B in bone marrow-derived macrophages (BMDMs) remains controversial. Here, a chromatin immunoprecipitation assay (ChIP) proved that KDM6B derived from osteogenic-induced BMSCs could bind to the promoter region of BMDMs’ brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) gene in a coculture system and activate BMAL1. Transcriptome sequencing and experiments in vitro showed that the overexpression of BMAL1 in BMDM could inhibit the TLR2/NF-κB signaling pathway, reduce pyroptosis, and decrease the M1/M2 ratio, thereby promoting osteogenic differentiation of BMSCs. Furthermore, bone and macrophage dual-targeted GSK-J4 (KDM6B inhibitor)-loaded nanodiscs were synthesized via binding SDSSD-apoA-1 peptide analogs (APA) peptide, which indirectly proved the critical role of KDM6B in osteogenesis in vivo. Overall, we demonstrated that KDM6B serves as a positive circulation trigger during osteogenic differentiation by decreasing the ratio of M1/M2 both in vitro and in vivo. Collectively, these results provide insight into basic research in the field of osteoporosis and bone repair.
研究领域:
干细胞生物学
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免疫学
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骨生物学
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2025
·Vol. 22
·期 1
·1-20
·
IF 10.1
Hong Wenxiang,Ma Hongbo,Li Zhibin,Du Yiwen,Xia Wenjing,Yin Han,Huang Han,Sun Zebing,Gai Renhua,Tong Lexian,Zhu Hong,Wang Jincheng,Yang Bo,He Qiaojun,Weng Qinjie,Wang Jiajia
The epigenetic modification of histone H3 lysine 27 trimethylation (H3K27me3) by the embryonic ectoderm development (EED) protein is closely associated with the regulation of transcriptional programs and is implicated in autoimmune diseases. However, the efficacy of targeting H3K27me3 for the treatment of neuroinflammation remains unclear. In this study, we demonstrate that systemic administration of an EED inhibitor diminishes the inflammatory response mediated by dendritic cells (DCs), thereby alleviating experimental autoimmune encephalitis (EAE), a representative mouse model of autoimmune diseases in the central nervous system (CNS). Our findings indicate that EED inhibitors suppress DC migration by upregulating genes in the WNT signaling pathway that are epigenetically marked by H3K27me3. Conversely, inhibiting the WNT pathway partially reverses the impaired DC migration caused by EED inhibitors. Additionally, the genetic deletion of Eed inhibits DC migration and effectively mitigates autoimmune symptoms and inflammatory infiltration into the CNS in EAE. These results highlight EED as a critical regulator of DC migration and suggest its potential as a therapeutic target for autoimmune disorders.
研究领域:
免疫学
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神经科学
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表观遗传学
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自身免疫疾病
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产品关联
DOI
PubMed
高影响因子
eLife
·
2024
·
IF 6.4
Zeina Salloum,Kristin Dauner,Yun-feng Li,Neha Verma,David Valdivieso-González,Víctor Almendro-Vedia,John D Zhang,Kiran Nakka,Mei Xi Chen,Jeffrey McDonald,Chase D Corley,Alexander Sorisky,Bao-Liang Song,Iván López-Montero,Jie Luo,Jeffrey F Dilworth,Xiaohui Zha
Statins are known to be anti-inflammatory, but the mechanism remains poorly understood. Here, we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane and changes the proton gradient in the mitochondria. This activates nuclear factor kappa-B (NF-κB) and Jmjd3 expression, which removes the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (M1), macrophages, either treated with statins in vitro or isolated from statin-fed mice, express lower levels proinflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL-4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.
研究领域:
免疫学
·
药理学
·
细胞生物学
·
表观遗传学
✓ 已验证
DOI
PubMed
高影响因子
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