PHYTOMEDICINE
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2026
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IF 11.3
Rui Yin,Lu He,Liangli Dai,Ling Chen,Tao Liang,Jinli Han,Juan Chen
Background Hypoxic–ischemic encephalopathy (HIE) is a serious neonatal neurological disorder in which microglia-mediated acute neuroinflammation serves as a critical driver of disease progression. Our previous work revealed that H3K9 lactylation-driven microglial M1 polarization promotes neuroinflammation as a key mechanism in HIE. Baicalin, a natural compound isolated from the traditional Chinese herb Scutellaria baicalensis , is well known for its anti-inflammatory effect, but whether it can treat HIE through this anti-inflammatory effect remains unclear. Purpose This study aimed to determine whether baicalin can inhibit H3K9 lactylation-mediated microglial M1 polarization and neuroinflammation in HIE. Methods In vivo, an HIE rat model was established in which rats were treated with intraperitoneal injections of baicalin. In vitro, an oxygen‒glucose deprivation model was constructed using BV2 microglia. Network pharmacology and molecular docking were employed to predict and validate the potential targets of baicalin, after which functional assays were performed. Co-immunoprecipitation combined with mass spectrometry was further used to explore the underlying molecular mechanisms. Results Through network pharmacology analysis, molecular docking and validation experiments, we revealed that baicalin exerts its anti-inflammatory effects via the activation of adenosine 5′-monophosphate-activated protein kinase α subunit 1 (AMPKα1). Further co-immunoprecipitation and mass spectrometry analyses revealed that AMPKα1 activation promotes the phosphorylation of histone deacetylase 1 (HDAC1), a key delactylase, thus inhibiting the degradation of HDAC1 mediated by the E3 ligase ubiquitin protein ligase E3A (UBE3A). Finally, baicalin increases HDAC1 protein levels to inhibit H3K9 lactylation-mediated microglial M1 polarization via targeting AMPKα1. Conclusion These findings suggest that, when administered at an early stage after HIE, baicalin may contribute to the attenuation of HIE pathology, at least in part by increasing HDAC1 stability through AMPKα1- and UBE3A-mediated “phosphorylation–ubiquitination hierarchical regulation”, thereby reducing H3K9 lactylation and suppressing microglial M1 polarization. Download: Download high-res image (186KB) Download: Download full-size image
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高影响因子
Translational Oncology
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2026
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IF 4.9
Zhuo Chen,Meng-Lei Wang,Zhuo-Wen Zhang,Peng-Cheng Zhang,Qing-fang Yang,Yu-jing Weng,Jia-Long Shen,Wenxian Wang,Lan Shao
Background PD-1 blockade has become an important immunotherapeutic strategy, its clinical efficacy in non-small cell lung cancer (NSCLC) remains suboptimal. This study explores the effect and mechanism of sodium butyrate (NaB) and Clostridium butyricum ( C. butyricum ) combined with PD-1 inhibitors in NSCLC. Methods We established an NSCLC mouse model and evaluated tumor size, histopathology, apoptosis, cell proliferation, inflammatory factors, immune cell populations, and proteins of the HDAC1/ID2/IL-12R axis in the tumor, along with gut microbiome profiling. Results A combination of NaB or C. butyricum with PD-1 inhibitors significantly inhibited tumor growth and increased spleen and thymus indices. The combinations promoted tumor cell apoptosis, reduced the number of Ki67-positive proliferating cells, and increased IL-2, IL-6, IL-12, TNF-α, and IFN-γ levels in tumor tissues and serum. Additionally, the infiltration of CD4 + and CD8 + T cells in the tumor increased, while the Treg cells decreased. Importantly, the expressions of HDAC1 were markedly decreased, whereas ID2 and IL-12R levels increased in tumor tissues from NaB or C. butyricum with PD-1 inhibitor groups. Meanwhile, the combination of NaB or C. butyricum with PD‑1 inhibitors could alleviate the disturbance of gut microbiota by decreasing the Gordonibacter and increasing the WCHB1-32 . Significantly, the anti-CD8 antibody attenuated the inhibition of tumor growth conferred by NaB and PD‑1 inhibitors in vivo. Conclusions Collectively, NaB and C. butyricum enhanced the therapeutic action of PD‑1 inhibitors in murine models of NSCLC, possibly by modulating the HDAC1/ID2/IL-12R pathway, impacting intestinal microbiota and immune microenvironment.
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高影响因子
Arabian Journal of Chemistry
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2024
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IF 5.3
Dong Xie,Guangfu Lv,Yuchen Wang,Wenjing Zhang,Nian Li,Yao Duan,Qing Huang,Ge Chen,Zifeng Pi,Hao Yue
Tenghuang Jiangu Wan (THJGW) is a commonly utilized treatment for osteoarthritis (OA), yet its pharmacodynamic material basis and molecular mechanism remain inadequately understood. This study systematically characterized the in vitro and in vivo chemical components of THJGW using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The pharmacodynamic material basis of THJGW in the treatment of OA was explored through a target network pharmacology approach and molecular docking technology. Cellular experiments were subsequently employed to validate the molecular mechanisms. Consequently, a total of 134 components from THJGW were identified in vitro , comprising 45 flavonoids, 10 iridoid glycosides, 39 phenylethanoid glycosides, 9 phenylpropanoids, 11 organic acids, 4 phenolics, and 16 other compounds. Additionally, 38 prototype absorbed components in serum were characterized for the purpose of network construction. 11 key components and 10 core targets (VEGFA, STAT3, RELA/NF-κB p65, PIK3R1, PIK3CA, MMP9, MMP1, IL-6, HDAC1, and FGF2) were determined by the target network pharmacology. Through Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, it was found that these intersection targets are associated with various signaling pathways such as pathways in cancer, lipid and atherosclerosis, and prostate cancer. Notably, the lipid and atherosclerosis pathway was closely linked to OA. The molecular docking results demonstrated strong binding affinities of the three core targets: IL-6, STAT3, and RELA/NF-κB p65. These results suggest that these targets may play a significant role for THJGW in treating OA. In vitro experiments showed that THJGW had notable protective effects on LPS-induced RAW264.7 macrophages by reducing levels of TNF-α and IL-6, and inhibiting phosphorylation expression of STAT3 and NF-κB p65 proteins related to the lipid and atherosclerosis pathway. This study provides insight into the pharmacodynamic material basis and mechanism of action for THJGW in the treatment of OA, which provide scientific evidence for the scientific application and improvement of quality standards for THJGW.
研究领域:
药理学
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生物化学
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分子生物学
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中医药
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DOI
高影响因子
JOURNAL OF INVESTIGATIVE DERMATOLOGY
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2020
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IF 7.143
Xiaoxuan Yu,Hui Li,Mengyuan Zhu,Po Hu,Xiao Liu,Yingjie Qing,Xiangyuan Wang,Hongzheng Wang,Zhanyu Wang,Jingyan Xu,Renxiang Tan,Qinglong Guo,Hui Hui
Cutaneous T-cell lymphomas (CTCLs) represent a rare form of non-Hodgkin lymphomas characterized by an accumulation of malignant CD4 + T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with histone deacetylase (HDAC) 1 and HDAC8, and was subsequently deacetylated to lose its function in CTCL cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on p53 status. However, recent studies have reported that HDAC inhibitors could induce a wide variety of drug-resistant characteristics in cancer cells by regulating ATP-binding cassette transporters. Moreover, we discovered that Baicalein, a natural product, exhibited an inhibitory effect on HDAC1 and HDAC8. Though the inhibition of HDAC1 was mild, Baicalein could induce the degradation of HDAC1 through the ubiquitin proteasome pathway, thereby markedly upregulating the acetylation of histone H3 without promoting ATP-binding cassette transporter gene expression. In terms of the mechanism, Baicalein showed better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC1 and HDAC8 and p53 in T-cell lymphoma cells and identifies a potential and safe natural HDAC inhibitor for the treatment of CTCLs.
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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免疫学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Miao Jiefei,Meng Chi,Wu Hongmei,Shan Wenpei,Wang Haoran,Ling Changchun,Zhang Jinlin,Yang Tao
A novel hybrid CHC was designed and synthesized by conjugating β-carboline with an important active fragment N-hydroxyacrylamide of histone deacetylase (HDAC) inhibitor by an amide linkage to enhance antitumor efficacy/potency or even block drug resistance. CHC displayed high antiproliferative effects against drug-sensitive SUMM-7721, Bel7402, Huh7, and HCT116 cells and drug-resistant Bel7402/5FU cells with IC50 values ranging from 1.84 to 3.27 μM, which were two-to four-fold lower than those of FDA-approved HDAC inhibitor SAHA. However, CHC had relatively weak effect on non-tumor hepatic LO2 cells. Furthermore, CHC exhibited selective HDAC1/6 inhibitory effects and simultaneously augmented the acetylated histone H3/H4 and α-tubulin, which may make a great contribution to their antiproliferative effects. In addition, CHC also electrostatically interacted with CT-DNA, exerted remarkable cellular apoptosis by regulating the expression of apoptosis-related proteins and DNA damage proteins in Bel7402/5FU cells, and significantly accumulated cancer cells at the G2/M phase of the cell cycle by suppressing CDK1 and cyclin B protein with greater potency than SAHA-treated groups. Finally, CHC displayed strong inhibitory potency to drug-resistant hepatic tumors in mice. Our designed and synthetic hybrid CHC could be further developed as a significant and selective anticancer agent to potentially treat drug-resistant hepatocellular carcinoma.
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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产品关联
DOI
PubMed
高影响因子
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