Physiological Reports
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2024
·Vol. 12
·期 3
·e15939
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IF 2.2
Li Ji,Ziying Jiao,Lin Zhang,Jia Shi,Qianqian Wan,Chunzhi Qian,Han Wang,Xiaoyan Cao,Bing Shen,Lijuan Jiang
Recurrent spontaneous abortion (RSA) is a serious condition that adversely affects women's health. Differentially expressed proteins (DEPs) in plasma of patients experiencing RSA is helpful to find new therapeutic targets and identified with mass spectrometry. In 57 DEPs, 21 were upregulated and 36 were downregulated in RSA. Gene ontology analyses indicated that identified DEPs were associated with cell proliferation, including significantly downregulated insulin-like growth factor binding protein 2 (IGFBP2). Immunohistochemical result using clinical decidual tissues also showed that IGFBP2 expression was significantly decreased in RSA trophoblasts. Cell proliferation assay indicated that IGFBP2 treatment increased the proliferation and mRNA expressions of PCNA and Ki67 in trophoblast cells. Transcriptome sequencing experiments and Kyoto Encyclopedia of Genes and Genomes analyses revealed that gene expression for components in PI3K-Akt pathway in trophoblasts was significantly upregulated following IGFBP2 treatment. To confirm bioinformatics findings, we did cell-based experiments and found that treatment of inhibitors for insulin-like growth factor (IGF)-1 receptor-PI3K-Akt pathway significantly reduced IGFBP2-induced trophoblast cell proliferation and mRNA expressions of PCNA and Ki67. Our findings suggest that IGFBP2 may increase trophoblast proliferation through the PI3K-Akt signaling pathway to affect pregnancy outcomes and that IGFBP2 may be a new target for future research and treatment of RSA.
研究领域:
妇产科学
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分子生物学
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细胞生物学
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生物信息学
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DOI
PubMed
高影响因子
Cancer Communications
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2023
·Vol. 43
·期 5
·562-581
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IF 16.2
Zhaowei Wen,Huiying Sun,Zhihua Zhang,Yannan Zheng,Siting Zheng,Jianping Bin,Yulin Liao,Min Shi,Rui Zhou,Wangjun Liao
Background Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor (ICI) treatment. This study aimed to uncover the specific mechanisms underlying the difference in sensitivity to ICI treatment between tumors with high (HTB) and low (LTB) tumor burden. Methods For in vivo studies, several mouse models of subcutaneous tumors were established, and transcriptome sequencing, immunohistochemistry, and flow cytometry assays were used to detect the immune status in these subcutaneous tumors. For in vitro experiments, co-culture models, cytokine antibody arrays, western blotting, flow cytometry, and enzyme-linked immunosorbent assays were used to explore the underlying molecular mechanisms Results We found that MC38 or B16 subcutaneous tumors from the HTB group did not show any response to anti-programmed cell death protein-1 (PD-1) therapy. Through flow cytometry assays, we found that the infiltration with CD8 + T cells was significantly decreased whereas M2-like macrophages were enriched in subcutaneous tumors of HTB groups compared with those of LTB group. These changes were not affected by the initial number of injected tumor cells or tumor age, nor could they be reversed by surgical tumor reduction. Intraperitoneal colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX3397 injection at different time points of tumor growth only had an effect when administered in the early tumor stage to maintain the “heat” of the tumor microenvironment during the process of tumor growth, thereby achieving a response to ICI treatment when the tumor grew to a large size. Mechanistically, we found that insulin-like growth factor binding protein 2 (IGFBP2) expression levels were significantly elevated in HTB tumor tissues. IGFBP2 promoted the programmed death-ligand 1 (PD-L1) expression in M2-like macrophages by activating signal transducer and activator of transcription 3 (STAT3), and PD-L1 + M2-like macrophages exerted an immunosuppressive effect by inhibiting the proliferation and activation of CD8 + T cells in a PD-L1-dependent fashion. Conclusions This study suggested that the low efficacy of ICI treatment in HTB tumors is mainly attributed to the intratumoral accumulation of PD-L1 + M2-like macrophages via the IGFBP2-STAT3-PD-L1 signaling pathway and their substantial inhibitory effects on T cell proliferation and activation.
研究领域:
肿瘤学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-20
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IF 11.4
Xu Wenjing,Li Yingqiu,Liu Lumei,Xie Jing,Hu Zongren,Kuang Shida,Fu Xinying,Li Bonan,Sun Tiansong,Zhu Congxu,He Qinghu,Sheng Wen
Background Prostate cancer (PCa) incidence and mortality rates are rising. Our previous research has shown that the combination of icariin (ICA) and curcumol (CUR) induced autophagy and ferroptosis in PCa cells, and altered lipid metabolism. We aimed to further explore the effects of the combination of ICA and CUR on gut microbiota, metabolism, and immunity in PCa. Methods A mouse subcutaneous RM-1 cell tumor model was established. 16 S rRNA sequencing was performed to detect changes in fecal gut microbiota. SCFAs in mouse feces, and the effect of ICA-CUR on T-cell immunity, IGFBP2, and DNMT1 were examined. Fecal microbiota transplantation (FMT) was conducted to explore the mechanism of ICA-CUR. Si-IGFBP2 and si/oe-DNMT1 were transfected into RM-1 and DU145 cells, and the cells were treated with ICA-CUR to investigate the mechanism of ICA-CUR on PCa development. Results After treatment with ICA-CUR, there was a decrease in tumor volume and weight, accompanied by changes in gut microbiota. ICA-CUR affected SCFAs and DNMT1/IGFBP2/EGFR/STAT3/PD-L1 pathway. ICA-CUR increased the positive rates of CD3 + CD8 + IFN-γ, CD3 + CD8 + Ki67 cells, and the levels of IFN-γ and IFN-α in the serum. After FMT (with donors from the ICA-CUR group), tumor volume and weight were decreased. SCFAs promote tumor development and the expression of IGFBP2. In vitro, DNMT1/IGFBP2 promotes cell migration and proliferation. ICA-CUR inhibits the expression of DNMT1/IGFBP2. Conclusions ICA-CUR mediates the interaction between gut microbiota and the DNMT1/IGFBP2 axis to inhibit the progression of PCa by regulating immune response and metabolism, suggesting a potential therapeutic strategy for PCa.
研究领域:
肿瘤学
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免疫学
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微生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
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IF 3.1
Ling Chen,Zhongwen Li,Wumei Wei,Bin An,Yao Tian,Wenjing Liu,Shuaishuai Niu,Yukai Wang,Liu Wang,Wei Li,Jie Hao,Jun Wu
Acute liver failure (ALF) is a clinical syndrome characterized by the accelerated development of hepatocyte necrosis and significant mortality. Given that liver transplantation is now the only curative treatment available for ALF, there is an urgent need to explore innovative therapies. Mesenchymal stem cells (MSCs) have been applied in preclinical studies for ALF. It had been demonstrated that human embryonic stem cell-derived immunity-and-matrix regulatory cells (IMRCs) met the properties of MSCs and had been employed in a wide range of conditions. In this study, we conducted a preclinical evaluation of IMRCs in the treatment of ALF and investigated the mechanism involved. ALF was induced in C57BL/6 mice via intraperitoneal administration of 50% CCl 4 (6 mL/kg) mixed with corn oil, followed by intravenous injection of IMRCs (3 × 10 6 cells/each). IMRCs improved histopathological changes in the liver and reduced alanine transaminase (ALT) or aspartate transaminase (AST) levels in serum. IMRCs also promoted cell renewal in the liver and protected it from CCl 4 damage. Furthermore, our data indicated that IMRCs protected against CCl 4 -induced ALF by regulating the IGFBP2-mTOR-PTEN signaling pathway, which is associated with the repopulation of intrahepatic cells. Overall, IMRCs offered protection against CCl 4 -induced ALF and were capable of preventing apoptosis and necrosis in hepatocytes, which provided a new perspective for treating and improving the prognosis of ALF.
研究领域:
肝病学
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干细胞生物学
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再生医学
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DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2024
·Vol. 30
·期 10
·e70076
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IF 4.8
Jing An,Lulu Wen,Haiyang Yu,Zhongqi Bu,Juan Feng
Aims Insulin-like growth factor binding protein 2 (IGFBP2) is implicated in various neurodegenerative diseases. However, its role in Parkinson's disease (PD) is unclear. Methods PD rat model was established by 6-OHDA injection. After 3 weeks, mRNA-seq was conducted. Rats received rIGFBP2 via intra-MFB injection 6 h prior to 6-OHDA infusion, and the effect of IGFBP2 in PD rats was investigated by western blotting, IHC, specific kits, JC-1 staining, and TUNEL analysis. In vitro, PC12 cells were treated with 6-OHDA, and CCK-8, specific kits, Hoechst 33258 staining, Western blotting, and JC-1 staining were performed to assess the IGFBP2's role. Results mRNA-seq revealed DEGs in PD, with attention to downregulated IGFBP2. rIGFBP2 treatment aggravated neurobehavioral deficits, decreased TH expression, Ψm, ATP level and SOD, GSH-Px activities but increased α-synuclein, ROS, MDA, mitochondrial cytochrome c contents, cell apoptosis in 6-OHDA-lesioned rats, which might be mediated through inactivating IGF-1R/AKT pathway. In 6-OHDA-treated PC12 cells, rIGFBP2 aggravated cell injury, demonstrated by decreased cell viability and increased apoptosis, oxidative stress, and mitochondrial dysfunction. Co-treatment with rIGFBP2 and rIGF-1 partially reversed the effect of rIGFBP2 on cell damage. Conclusion IGFBP2 exacerbates neurodegeneration in PD through increasing oxidative stress, mitochondrial dysfunction, and apoptosis via inhibiting IGF-1R/AKT pathway.
研究领域:
神经科学
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分子生物学
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药理学
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病理学
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产品关联
DOI
PubMed
高影响因子
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