FASEB JOURNAL
·
2024
·Vol. 38
·期 4
·e23470
·
IF 4.4
Guangyu Zhou,Pai Liu,Chen Zhang,Qun Huang,Zixia Zhao,Si Wu,Detian Li,Hongbo Liu
Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An in vivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an in vitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with β-glycerophosphate (β-GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and β-GP-induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α-SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The in vitro results also demonstrated that β-GP-induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3-MA blocked HDAC2's protective effect on osteogenic differentiation in β-GP-treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.
研究领域:
心血管疾病
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慢性肾病
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2018
·Vol. 19
·期 10
·3184
·
IF 3.687
Zhiwen Qi,Chengzhang Wang,Jianxin Jiang,Caie Wu
A series of novel C15 urushiol derivatives were designed by introducing a pechmann structure and F-, Cl-, and Br-nitro substituents with different electronic properties into its alkyl side chain, as well as a triazolyl functional group in its aromatic oxide. Their chemical structures were determined based on the analysis of the NMR (nuclear magnetic resonance) spectroscopic and mass spectrometric data. The results showed that compound4exhibited a strong inhibition of the HepG2 cell proliferation (half maximal inhibitory concentration (IC50): 2.833 μM to human hepatocellular carcinoma (HepG2), and 80.905 μM to human normal hepatocytes (LO2)). Furthermore, it had an excellent synergistic effect with levopimaric acid. The nitrogen atom of the triazole ring formed a hydrogen-bonding interaction with Gly103, Gly154, and Tyr308, which made compound4bind to histone deacetylase (HDAC)2 more tightly. One triazole ring and His33 formed a π–π stacking effect; the other, whose branches were deep into the pocket, further enhanced the interaction with HDAC2. Meanwhile, compound4involved a hydrophobic interaction with the residues Phe210 and Leu276. The hydrophobic interaction and π–π stacking provided powerful van der Waals forces for the compounds.Keywords:urushiol;triazole;diels-alder;pechmann;anti-tumor;HDAC2
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
APOPTOSIS
·
2023
·
IF 7.2
Pei Lipeng,Zhao Feng,Zhang Yi
Epithelial ovarian cancer (EOC) is the leading cause of cancer death all over the world. USP43 functions as a tumor promoter in various malignant cancers. Nevertheless, the biological roles and mechanisms of USP43 in EOC remain unknown. In this study, USP43 was highly expressed in EOC tissues and cells, and high expression of USP43 were associated with a poor prognosis of EOC. USP43 overexpression promoted EOC cell proliferation, enhanced the ability of migration and invasion, decreased cisplatin sensitivity and inhibited apoptosis. Knockdown of USP43 in vitro effectively retarded above malignant progression of EOC. In vivo xenograft tumors, silencing USP43 slowed tumor growth and enhanced cisplatin sensitivity. Mechanistically, USP43 inhibited HDAC2 degradation and enhanced HDAC2 protein stability through its deubiquitylation function. USP43 diminished the sensitivity of EOC cells to cisplatin through activation of the Wnt/β-catenin signaling pathway mediated by HDAC2. Taken together, the data in this study revealed the functions of USP43 in proliferation, migration, invasion, chemoresistance of EOC cells, and the mechanism of HDAC2-mediated Wnt/β-catenin signaling pathway. Thus, USP43 might serve as a potential target for the control of ovarian cancer progression.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2019
·Vol. 42
·期 4
·1404-1412
·
IF 3.041
Jiafeng Tong,Ying Shen,Xi Chen,Renjie Wang,Ye Hu,Xu Zhang,Zhenghua Zhang,Li Han
Colorectal cancer (CRC), a commonly occurring malignant tumor in the gastrointestinal tract, is the third leading cause of cancer‑related deaths worldwide. FK506‑binding proteins (FKBPs) comprise an immunophilin family that are involved in the carcinogenesis, progression and chemoresistance of cancers, including CRC. FKBP3 (also known as FKBP25) is a nuclear protein that is a member of the FKBP family and is correlated with the activity of histone deacetylase 2 (HDAC2). However, the role of FKBP3 and HDAC2 in oxaliplatin resistance in CRC and the potential molecular mechanisms are still poorly understood. In the present study, the expression of FKBP3, HDAC2 and related‑genes was detected by real‑time PCR and western blot analysis. Furthermore, cell apoptosis was detected by flow cytometry (FCM). We found high expression of FKBP3 and HDAC2 in CRC tissues. In vitro, primary CRC cells with high expression of FKBP3 and HDAC2 were insensitive to oxaliplatin. Downregulation of FKBP3 significantly increased the sensitivity of primary CRC cells to oxaliplatin, reduced expression of HDAC2, permeability glycoprotein (P‑gp) and phosphorylated AKT (p‑AKT), and increased expression of phosphatase and tensin homolog (PTEN) and cleaved caspase‑3. Accordingly, upregulation of FKBP3 had the opposite effect. Furthermore, downregulation of HDAC2 significantly counteracted FKBP3‑induced oxaliplatin resistance in CRC cells. Our data revealed that oxaliplatin resistance in CRC cells is positively associated with FKBP3 and HDAC2 expression, and FKBP3 downregulation could attenuate oxaliplatin resistance in CRC cells by reducing HDAC2 expression and possibly through regulation of the PTEN/AKT pathway.
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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DOI
PubMed
高影响因子
Aging-US
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2019
·
IF 5.515
Yanhua Du,Jun Lin,Rulin Zhang,Wanli Yang,Heng Quan,Lijuan Zang,Yaqin Han,Bing Li,Hong Sun,Jun Wu
Globally, epithelial ovarian cancer (EOC) is the most common gynecological malignancy with poor prognosis. The expression and oncogenic roles of ubiquitin specific peptidase 5 (USP5) have been reported in several cancers except EOC. In the current study, USP5 amplification was highly prevalent in patients with EOC and associated with higher mRNA expression of USP5. USP5 amplification and overexpression was positively correlated with poor prognosis of patients of ovarian serous carcinomas. Disruption of USP5 profoundly repressed cell proliferation by inducing cell cycle G0/G1 phase arrest in ovarian cancer cells. Additionally, USP5 knockdown inhibited xenograft growth in nude mice. Knockdown of USP5 decreased histone deacetylase 2 (HDAC2) expression and increased p27 (an important cell cycle inhibitor) expression in vitro and in vivo . The promoting effects of USP5 overexpression on cell proliferation and cell cycle transition, as well as the inhibitory effects of USP5 overexpression on p27 expression were mediated by HDAC2. Moreover, USP5 interacted with HDAC2, and disruption of USP5 enhanced the ubiquitination of HDAC2. HDAC2 protein was positively correlated USP5 protein, and negatively correlated with p27 protein in ovarian serous carcinomas tissues. Collectively, our data suggest the oncogenic function of USP5 and the potential regulatory mechanisms in ovarian carcinogenesis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2022
·
IF 9.995
Tian Wang,Jinchun Xu,Yi Xu,Jie Xiao,Nanxi Bi,Xiaozhen Gu,Hui-Li Wang
Summary Social dominance is a ubiquitous phenomenon among social animals, including humans. To date, individual attributes leading to dominance (after a contest) remain largely elusive. Here, we report that socially dominant rats can be distinguished from subordinates based on their intestinal microbiota. When dysbiosis is induced, rats are predisposed to a subordinate state, while dysbiotic rats reclaim social dominance following microbiota transplantation. Winning hosts are characterized by core microbes, a majority of which are associated with butyrate production, and the sole colonization of Clostridium butyricum is sufficient to restore dominance. Regarding molecular aspects, a histone deacetylase, HDAC2, is responsive to microbial status and mediates competition outcome; however, this occurs only in a restricted population of cells in the medial prefrontal cortex (mPFC). Furthermore, HDAC2 acts by modulating synaptic activity in mPFC. Together, these findings uncover a link between commensals and host dominance, providing insight into the gut-brain mechanisms underlying dominance determination.
研究领域:
神经科学
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微生物学
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行为科学
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DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2025
·Vol. 48
·期 12
·1897-1905
·
IF 1.7
Xiaojun Zhang,Fang Wang,Yuna Dai,Zhaoyu Gao,Jianchao He
Platycodon grandiflorum (P. grandiflorum), a traditional Chinese herbal medicine, possesses various biological activities. Among its constituents, polygalacin D (PGD) stands out as one of the principal compounds. This study determined the regulatory effect of PGD on breast cancer progression. Breast cancer cells MCF-7 and BT474 were treated with different concentrations of PGD. Colony formation assays, the detection of Ki67 expression, and cell cycle analysis were performed to verify the effect of PGD on the proliferation of breast cancer cells. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, flow cytometry, and examination of caspase-3 activity were conducted to assess the changes in apoptosis following PGD treatment. In addition, the co-treatment of PGD and cisplatin (DDP) on cells was performed to explore the effect of PGD on the chemosensitivity of DDP. Furthermore, bioinformation analysis suggested that histone deacetylase 1 (HDAC1) and HDAC2 were the downstream factors of PGD, and the effect of PGD on their expression was assessed. PGD inhibited breast cancer cell proliferation, as evidenced by reduced colony formation, downregulation of Ki67 expression, and induction of cell cycle arrest. Additionally, PGD treatment significantly increased caspase-3 activity and elevated the rate of cell apoptosis and TUNEL-positive cells. Furthermore, PGD was found to enhance the chemosensitivity to DDP. Mechanistically, PGD reduced the expression of HDAC1 and HDAC2 by promoting their protein degradation. Cell proliferation induced by HDAC1 or HDAC2 was also overcome by PGD. In conclusion, PGD was confirmed as an effective tumor inhibitor that suppressed the development of breast cancer by regulating HDAC1 and HDAC2.
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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天然产物化学
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表观遗传学
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DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Rujing Wang,Lan Zou,Dandan Mi,Chuan Wang,Zijian Song,Tiantian Liu,Mengnan Zhao,Dong Wang,Sanjun Shi
Tumor metastasis, a leading cause of cancer-related mortality, presents a significant challenge due to its complex, multi-step nature and tumor cells’ adaptability. Current targeted therapies often face limitations as tumor cells activate compensatory signaling pathways, leading to drug resistance. Here, we introduce a novel molecular drug pair of sorafenib (Sora) and curcumin (Cur) self-assembled into Sora-Cur@diploid nanoparticles (diNPs), which were transformed into label-free diNP@pharmaceutical dots (diNP@PDs) with enhanced fluorescence through a specialized formulation process, eliminating the need for chemical modification. diNP@PDs exhibit photoluminescence capability, simultaneously promoting cross-talk among lysosomes, mitochondria, and nuclei. This lysosomes-mitochondria-nuclei interaction induces perinuclear clustering of organelles, triggering nuclear reactive oxygen species (nuROS) generation. The nuROS epigenetically suppresses HDAC2 activity, inhibiting epithelial-mesenchymal transition (EMT) and tumor metastasis. By integrating multi-organelle targeting with molecular therapy, diNP@PDs offer an innovative strategy for both imaging and inhibiting tumor metastasis, highlighting the potential of interorganelle approaches in oncology. Download: Download high-res image (351KB) Download: Download full-size image
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DOI
高影响因子
Neural Regeneration Research
·
2024
·Vol. 19
·期 12
·2708
·
IF 5.9
Fang He,Li Mengjie,Yang Jingchen,Ma Shunping,Zhang Li,Yang Hongqi,Tang Qiongyan,Cao Jing,Yang Weimin
Thalamic hemorrhage can lead to the development of central post-stroke pain. Changes in histone acetylation levels, which are regulated by histone deacetylases, affect the excitability of neurons surrounding the hemorrhagic area. However, the regulatory mechanism of histone deacetylases in central post-stroke pain remains unclear. Here, we show that iron overload leads to an increase in histone deacetylase 2 expression in damaged ventral posterolateral nucleus neurons. Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium (Kv) channel subunit gene in a rat model of central post-stroke pain, thereby increasing Kcna2 expression and relieving central pain. However, in the absence of nerve injury, increasing histone deacetylase 2 expression decreased Kcna2 expression, decreased Kv current, increased the excitability of neurons in the ventral posterolateral nucleus area, and led to neuropathic pain symptoms. Moreover, treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage, reversed histone deacetylase 2 upregulation and Kv1.2 downregulation, and alleviated mechanical hypersensitivity in central post-stroke pain rats. These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation, mediated by iron overload, are important factors in central post-stroke pain pathogenesis and could serve as new targets for central post-stroke pain treatment.
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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神经病学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Xi Chen,Di Wang,Xuejun Guo,Xiaoming Li,Wenjing Ye,Yang Qi,Wen Gu
The present study was aim to prepare curcumin-loaded methoxypolyethylene-glycols-poly (lactic-co-glycolic acid) nanoparticles (Cur-mPEG-PLGA-NPs) and investigate curcumin's effect on reversing corticosteroid resistance induced by cigarette smoke extract (CSE) in rat tracheal epithelial (RTE) cells. The Cur-mPEG-PLGA-NPs were spherical, regular in shape with smooth surfaces, and well distributed and Cur-mPEG-PLGA-NP suspensions had good water solubility and presented prolonged release. Furthermore, we found that Cur-mPEG-PLGA-NPs were internalized more than curcumin into the cells and significantly alleviated apoptosis in RTE cells. In addition, 10% CSE reduced the maximal inhibition percentage and increased the half-inhibitory concentration of budesonide (BUD) on IL-8 secretion, and curcumin restored the efficacy of BUD inhibition. BUD in combination with Cur-mPEG-PLGA-NPs showed higher inhibitory rates for LPS- and CSE-induced IL-8 secretion than that in combination with curcumin. Moverover, the relative expression levels of HDAC2 was reduced after CSE exposure and curcumin could improve HDAC2 expression and reverse CSE-induced corticosteroid resistance. Curcumin in high concentration and Cur-mPEG-PLGA-NPs restored HDAC2 levels in RTE cells and thus Cur-mPEG-PCL-NPs have higher biological activity than curcumin.
研究领域:
药理学
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纳米技术
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呼吸医学
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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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