LABORATORY INVESTIGATION
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2024
·
IF 5.1
Jianfeng Yi,Weilong Qu,Xinkun Huang,Guangze Zhang,Hanxu Gao,Jiancheng He,Wanjiang Xue
E3 ubiquitin ligases, crucial enzymes in the ubiquitination pathway, significantly influence the development of malignant tumors, including gastric cancer (GC), by regulating the stability of oncogenic and tumor-suppressive proteins. This study employed bioinformatics analysis of public databases alongside various experimental techniques—tissue arrays, qRT-PCR, Western blot, immunofluorescence, and co-immunoprecipitation—to identify and explore the role of HECW1, a pivotal NEDD4 family E3 ubiquitin ligase, in GC progression. Results demonstrated that HECW1 is markedly overexpressed in GC tissues relative to normal gastric tissues, and its elevated expression correlates with poor prognosis in GC patients. In vitro experiments revealed that HECW1 overexpression significantly enhances the metastatic capabilities of GC cells. Mechanistically, HECW1 interacts with HIPK2 to facilitate its ubiquitination and degradation, thereby activating AKT and promoting the expression of downstream epithelial mesenchymal transition related genes. In vivo experiments confirmed HECW1’s role in promoting GC cell metastasis, highlighting the HECW1-HIPK2-AKT signaling axis as critical in GC metastasis. These findings not only elucidate a novel metastasis mechanism of GC but also suggest potential molecular targets for developing new therapeutic strategies against GC.
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
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yanhua Zhen,Dongdong Li,Yulu Meng,Zeyu Xing,Jiahe Zheng
Atherosclerosis is a disorder of lipid metabolism, but its pathogenesis has not yet been fully elucidated. This study aimed to clarify the roles of homeodomain interacting protein kinase 2 (HIPK2) in atherosclerosis. Atherosclerotic model was constructed by feeding apolipoprotein E knockout (ApoE -/- ) mice with a high-fat diet. Human THP-1 macrophages and mouse RAW 264.7 macrophages were stimulated with IFN-γ to establish an in vitro model. We showed an upregulation of HIPK2 in the aorta of atherosclerotic mice. HIPK2 knockdown reduced macrophage infiltration, M1 polarization, and attenuates atherosclerosis development. Downregulation of HIPK2 in macrophages led to a significant suppression in the expression of pro-inflammatory factors, which was accompanied by an enhancement in the phosphorylation and degradation of β-catenin, as well as the activation of the signal transducer and activator of transcription 1 (STAT1) signaling pathway. Silencing of HIPK2 alone in THP-1 macrophages resulted in anti-inflammatory effects and suppression of M1 macrophage polarization. However, simultaneous silencing of HIPK2 and β-catenin (CTNNB1) reversed these effects, counteracting the outcomes observed with HIPK2 silencing alone. We validated that small ubiquitin-like modifier (SUMO)-specific peptidase 1 (SENP1) regulated HIPK2 function by affecting the SUMOylation of HIPK2 at the K32 site. SENP1 knockdown promoted HIPK2 SUMOylation, impairing its protein stability. In the rescue experiments, IFN-γ-induced inflammation and M1 polarization were resumed upon restoration of HIPK2 expression in SENP1-silenced macrophages. Our work demonstrated that HIPK2 accelerated the progression of atherosclerosis by regulating β-catenin/STAT1 signaling cascade to promote macrophage infiltration and M1 polarization. HIPK2 was regulated by SENP1-mediated de-SUMOylation.
研究领域:
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
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2026
·Vol. 58
·期 3
·1-13
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IF 8.5
Mingkun Xu,Linhang Fu,Yulong Zhang,Xiuli Guo,Han Wu,Sijing Gao,Fei Xiao,Li Xu
International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2020
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IF 5.162
Hang Qu,Xin Gao,Cuilin Cheng,Haitian Zhao,Zhenyu Wang,Juanjuan Yi
Previous studies have shown that Pinus koraiensis pine nut polysaccharide PNP80b-2 exerts widely protective effects against liver injury induced by chemical pollutants, alcohol and drugs. By comparison, PNP80b-2 exhibits the strongest hepatoprotection against alcohol-induced liver injury (AILI). Thus, the purpose of this study is to investigate the hepatoprotection mechanisms of PNP80b-2 against AILI in vivo . The results indicated that PNP80b-2 alleviated oxidative stress induced by alcohol through enhancing antioxidant capacity of hepatocytes via NRF2/HO-1 pathway. PNP80b-2 also effectively suppressed the secretion of pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, exhibiting anti-inflammatory effects via NF-κB signaling pathway in AILI. In addition, PNP80b-2 protected mice from severe DNA damage induced by alcohol through regulating the expression of Hipk2 , P53 , Hp1γ and Wip1 . Taken together all the results, PNP80b-2 exerts hepatoprotective activity against AILI in vivo through enhancing antioxidant capacity, suppressing inflammation response and promoting DNA damage repair in livers. Furthermore, the structural features of PNP80b-2 were also characterized. PNP80b-2, with molecular weight of 23.0 kDa, was found to be composed of 1,2-linked Gal f , 1,2-linked Rha p , 1,4-linked Xyl p , 1,6-linked Glc p , 1,4-linked Glc p A, 1,2,6-linked Gal p , 1,4,6-linked Glc p , 1,2,3,4-linked Ara p , 1-linked Gal p and Leu- and Ile-linked O-glycopeptide bonds, based on the GC–MS and NMR results.
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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毒理学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2024
·Vol. 17
·期 11
·1420
·
IF 4.3
Xinlan Hu,Yan Wu,Hanyi Ouyang,Jiayan Wu,Mengmeng Yao,Zhuo Chen,Qianbin Li
Background/Objectives:Homeodomain-interacting protein kinase 2 (HIPK2) is critically involved in the progression of renal fibrosis. This study aims to identify and characterize a novel HIPK2 inhibitor, CHR-6494, and investigate its therapeutic potential.Methods:Using structure-based virtual screening and molecular dynamics simulations, we identified CHR-6494 as a potent HIPK2 inhibitor with an IC50of 0.97 μM. The effects of CHR-6494 on the phosphorylation of p53 in Normal Rattus norvegicus kidney cells (NRK-49F) induced by transforming growth factor-β (TGF-β) were assessed, along with its impact on TGF-β signaling and downstream profibrotic markers.Results:CHR-6494 significantly reduces p53 phosphorylation induced by TGF-β and enhances the interaction between HIPK2 and seven in absentia 2 (SIAH2), facilitating HIPK2 degradation via proteasomal pathways. Both CHR-6494 and Abemaciclib inhibit NRK-49F cell proliferation and migration induced by TGF-β, suppressing TGF-β/Smad3 signaling and decreasing profibrotic markers such as Fibronectin I (FN-I) Collagen I and α-smooth muscle actin (α-SMA). Additionally, these compounds inhibit nuclear factor kappa-B (NF-κB) signaling and reduce inflammatory cytokine expression.Conclusions:The study highlights the dual functionality of HIPK2 kinase inhibitors like CHR-6494 and Abemaciclib as promising therapeutic candidates for renal fibrosis and inflammation. The findings provide new insights into HIPK2 inhibition mechanisms and suggest pathways for the design of novel HIPK2 inhibitors in the future.
研究领域:
药理学
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分子生物学
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肾脏生理学
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药物发现
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产品关联
DOI
PubMed
高影响因子
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