CELL PROLIFERATION
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2024
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IF 5.9
Yaqing Chen,Yi Yan,Yujing Li,Liang Zhang,Tingting Luo,Xinlong Zhu,Dan Qin,Ning Chen,Wendong Huang,Xiangmei Chen,Liqiang Wang,Xianmin Zhu,Lisheng Zhang
Transglutaminase 2 (Tgm2) plays an essential role in hepatic repair following prolonged toxic injury. During cholestatic liver injury, the intrahepatic cholangiocytes undergo dynamic tissue expansion and remodelling, referred to as ductular reaction (DR), which is crucial for liver regeneration. However, the molecular mechanisms governing the dynamics of active cells in DR are still largely unclear. Here, we generated Tgm2-knockout mice (Tgm2 −/− ) and Tgm2- CreERT2 -Rosa26-mTmG flox/flox (Tgm2 CreERT2 -R26T/G f/f ) mice and performed a three-dimensional (3D) collagen gel culture of mouse hepatocytes to demonstrate how Tgm2 signalling is involved in DR to remodel intrahepatic cholangiocytes. Our results showed that the deletion of Tgm2 adversely affected the functionality and maturity of the proliferative cholangiocytes in DR, thus leading to more severe cholestasis during DDC-induced liver injury. Additionally, Tgm2 hepatocytes played a crucial role in the regulation of DR through metaplasia. We unveiled that Tgm2 regulated H3K4me3Q5ser via serotonin to promote BMP signalling activation to participate in DR. Besides, we revealed that the activation or inhibition of BMP signalling could promote or suppress the development and maturation of cholangiocytes in DDC-induced DR. Furthermore, our 3D collagen gel culture assay indicated that Tgm2 was vital for the development of cholangiocytes in vitro. Our results uncovered a considerable role of BMP signalling in controlling metaplasia of Tgm2 hepatocytes in DR and revealed the phenotypic plasticity of mature hepatocytes.
研究领域:
肝病学
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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
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Runfeng Sun,Hua Li,Yun Chen,Ming Hu,Jiaping Wang
Cardiac fibrosis is associated with myocardial remodeling following myocardial infarction (MI), which can lead to heart failure, arrhythmias, and even death. This study aimed to determine the effects of tubuloside A (TA) on cardiac fibrosis after MI and elucidate their underlying molecular mechanisms. Rats were divided into the following groups: sham (fake surgery), MI, MI + 1 mg/kg TA, and MI + 3 mg/kg TA. Compared with MI, the addition of TA significantly reduced mortality, improved cardiac function, decreased infarct size, and inhibited myocardial injury and fibrosis. To verify the direct targets of TA, we used cellular thermal shift assay and drug affinity responsive target stability to analyze drug–protein interactions and discovered that TA can bind directly to TGM2 and inhibit its enzymatic activity. Furthermore, to investigate whether TA can inhibit the TGF-β1-mediated activation of cardiac fibroblasts (CFs) through TGM2, we overexpressed TGM2 in CF cells and treated them with TA. We found that TA inhibited the activity of TGM2 in CF cells and reduced α-SMA, collagen-I, and collagen-III levels, thereby inhibiting the progression of fibrosis. Similarly, we found that TA could exert anti-inflammatory and antiapoptotic effects by inhibiting TGM2. Overall, we demonstrated that TA is a potential candidate drug for inhibiting the impacts of myocardial infarction and cardiac fibrosis, reducing postinfarction fibrosis by inhibiting the NF-κB signaling pathway and suppressing mitochondrial pathway-mediated apoptosis. Therefore, focusing on drug discovery strategies for TA may provide a promising therapeutic approach for MI.
研究领域:
药理学
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心脏病学
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分子生物学
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炎症研究
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细胞凋亡
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DOI
PubMed
高影响因子
Translational Research
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2024
·
IF 6.4
Shan-Shan Li,Qiao-Juan Liu,Jia-Xin Bao,Meng-ting Lu,Bing-Quan Deng,Wen-Wen Li,Chang-Chun Cao
Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence ‘YEVEDYR’) from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to β-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro , overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.
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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药物发现
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产品关联
DOI
PubMed
高影响因子
Cell Discovery
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2026
·Vol. 12
·期 1
·30
·
IF 16.9
Bai Junping,Geng Dandan,Chen Xinwen,Li Wanting,Wang Xiaowei,Tian Luyang,Han Yi,Jin Zhao,Du Meihang,Tang Yang,Hu Weisheng,Zhu Chunxiao,Zhang Shan,Zhao Zhangting,Zhang Run,Zhang Xinru,Kang Wei,To KaFai,Nomura Sachiyo,Guo Fenghua,Jiao Shi,Xie Yixuan,Zhou Zhaocai,Dong Chao,Li Hui,An Liwei
Protein monoaminylation represents a new layer of neural–cancer regulation, but its role in gastric tumorigenesis is not understood. Using untargeted plasma metabolomics, we revealed that the level of serotonin (5-HT) is significantly elevated in gastric cancer (GC) patients. Functionally, 5-HT treatment dramatically promoted GC cell proliferation and tumor growth in a dose-dependent manner. Importantly, this oncogenic effect was abrogated by the inhibition of transglutaminase 2 (TGM2), indicating a crucial role for protein serotonylation via a receptor-independent mechanism. Using a 5-HT-based chemoproteomic probe, we identified a broad spectrum of serotonylation targets, including key ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4). Specifically, we found that GPX4 is serotonylated by TGM2 at residues Gln55 and Gln77, which increases GPX4 protein stability by attenuating its ubiquitin-mediated degradation, thereby conferring resistance to ferroptosis and facilitating tumor growth. Clinically, TGM2 levels were positively correlated with tumoral GPX4 expression in GC patient specimens. Collectively, our results establish TGM2-mediated GPX4 serotonylation as a key mechanism driving GC progression through ferroptosis resistance, highlighting its potential as both a diagnostic biomarker and a therapeutic target within the neural–tumor axis.
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2025
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IF 3
Jianbin Xiong,Jian Song,Xing Jiang,Zhuanzhuan Huang,Yijie Zhang
Chronic pancreatitis (CP) is a progressive inflammatory disorder with no effective treatment, which underscores the urgent need for novel therapeutic strategies. In this study, single-cell sequencing data retrieved from the Gene Expression Omnibus (GEO) database revealed that Prkcq and IL-4 were highly induced in group 2 innate lymphoid cells (ILC2s), while Mitf and Tgm2 were highly expressed in tissue-resident macrophages (TRMs). A mouse model of CP was established using dibutyltin dichloride (DBTC), and pathological evaluations via H&E, Masson, and Sirius Red staining confirmed typical features of CP, including acinar atrophy, inflammatory cell infiltration, and increased fibrosis. Notably, the numbers of ILC2s and TRMs in pancreatic tissues were significantly elevated in DBTC-treated mice. Functional experiments showed that the Prkcq knockdown in ILC2s suppressed the expression of IL-4, IL-5 and IL-13, while in TRMs, the transcription factor Mitf upregulated Tgm2 expression. In CP mice, Prkcq knockdown reduced TRM abundance, ultimately alleviating pancreatic fibrosis. Collectively, this study identifies Prkcq as a key regulator of CP by modulating TRM populations.
研究领域:
免疫学
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细胞生物学
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分子生物学
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病理学
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胃肠病学
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DOI
PubMed
高影响因子
Proteomics Clinical Applications
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2024
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IF 2.1
Aidi Gao,Chao He,Hengrui Chen,Qianlin Liu,Yin Chen,Jianying Sun,Chuanfeng Wu,Ya Pan,Sonia Rocha,Mu Wang,Jundong Zhou
Purpose The recurrence of esophageal squamous cell carcinoma (ESCC) in radiation therapy treatment presents a complex challenge due to its resistance to radiation. However, the mechanism underlying the development of radioresistance in ESCC remains unclear. In this study, we aim to uncover the mechanisms underlying radioresistance in ESCC cells and identify potential targets for radiosensitization. Methods We established two radio-resistant cell lines, TE-1R and KYSE-150R, from the parental ESCC cell lines TE-1 and KYSE-150 through fractionated irradiation. A TMT-based quantitative proteomic profiling approach was applied to identify changes in protein expression patterns. Cell Counting Kit-8, colony formation, γH2AX foci immunofluorescence and comet assays were utilized to validate our findings. The downstream effectors of the DNA repair pathway were confirmed using an HR/NHEJ reporter assay and Western blot analysis. Furthermore, we evaluated the expression of potential targets in ESCC tissues through immunohistochemistry combined with mass spectrometry. Results Over 2,000 proteins were quantitatively identified in the ESCC cell lysates. A comparison with radio-sensitive cells revealed 61 up-regulated and 14 down-regulated proteins in the radio-resistant cells. Additionally, radiation treatment induced 24 up-regulated and 12 down-regulated proteins in the radio-sensitive ESCC cells. Among the differentially expressed proteins, S100 calcium binding protein A6 (S100A6), glutamine gamma-glutamyltransferase 2 (TGM2), glycogen phosphorylase, brain form (PYGB), and Thymosin Beta 10 (TMSB10) were selected for further validation studies as they were found to be over-expressed in the accumulated radio-resistant ESCC cells and radio-resistant cells. Importantly, high S100A6 expression showed a positive correlation with cancer recurrence in ESCC patients. Our results suggest that several key proteins, including S100A6, TGM2, and PYGB, play a role in the development of radioresistance in ESCC. Conclusions Our results revealed that several proteins including Protein S100-A6 (S100A6), Protein-glutamine gamma-glutamyltransferase 2 (TGM2), Glycogen phosphorylase, brain form (PYGB) were involved in radio-resistance development. These proteins could potentially serve as biomarkers for ESCC radio-resistance and as therapeutic targets to treat radio-resistant ESCC cells.
研究领域:
肿瘤学
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蛋白质组学
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放射生物学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
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