Frontiers in Genetics
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2021
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IF 4.599
Zhang Jing,Gao Juan,Lin Dengna,Xiong Jing,Wang Jialei,Chen Junfeng,Lin Bingliang,Gao Zhiliang
Acute-on-chronic liver failure (ACLF) is a severe syndrome associated with high mortality. Alterations in the liver microenvironment are one of the vital causes of immune damage and liver dysfunction. Human bone marrow mesenchymal stem cells (hBMSCs) have been reported to alleviate liver injury via exosome-mediated signaling; of note, miRNAs are one of the most important cargoes in exosomes. Importantly, the miRNAs within exosomes in the hepatic microenvironment may mediate the mesenchymal stem cell (MSC)-derived regulation of liver function. This study investigated the hepatocyte exosomal miRNAs which are regulated by MSCs and the target genes which have potential in the treatment of liver failure. Briefly, ACLF was induced in mice using carbon tetrachloride and primary hepatocytes were isolated and co-cultured (or not) with MSCs under serum-free conditions. Exosomes were then collected, and the expression of exosomal miRNAs was assessed using next-generation sequencing; a comparison was performed between liver cells from healthy versus ACLF animals. Additionally, to identify the intracellular targets of exosomal miRNAs in humans, we focused on previously published data, i.e., microarray data and mass spectrometry data in liver samples from ACLF patients. The biological functions and signaling pathways associated with differentially expressed genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomics enrichment analyses; hub genes were also screened based on pathway analysis and the prediction of protein-protein interaction networks. Finally, we constructed the hub gene-miRNA network and performed correlation analysis and qPCR validation. Importantly, our data revealed that MSCs could regulate the miRNA content within exosomes in the hepatic microenvironment. MiR-20a-5p was down-regulated in ACLF hepatocytes and their exosomes, while the levels of chemokine C-X-C Motif Chemokine Ligand 8 (CXCL8; interleukin 8) were increased in hepatocytes. Importantly, co-culture with hBMSCs resulted in up-regulated expression of miR-20a-5p in exosomes and hepatocytes, and down-regulated expression of CXCL8 in hepatocytes. Altogether, our data suggest that the exosomal miR-20a-5p/intracellular CXCL8 axis may play an important role in the reduction of liver inflammation in ACLF in the context of MSC-based therapies and highlights CXCL8 as a potential target for alleviating liver injury.
研究领域:
肝病学
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干细胞生物学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 24
·期 1
·6
·
IF 8.9
Yang Xinyi,Ning Tingting,Zhang Wanru,Hou Songyuan,Su Jiayi,Li Wenkun,Wu Jing
Background Gastric microbiota dysbiosis is closely linked to chronic inflammation and carcinogenesis. Fusobacterium nucleatum ( Fn ), an opportunistic gastrointestinal pathogen, is implicated in perturbing the immune system and form an inflammatory microenvironment that fuels the occurrence and progression of gastric cancer (GC). However, the underlying mechanisms remain elusive. We aimd to investigate the impacts of Fn on GC cells and the crosstalk between GC cells and mast cells (MCs). Methods Fn abundance and MC infiltration were assessed in clinical GC tissues. Cell-based functional experiments, including wound healing, transwell, and ELISA, were performed using conditioned medium-based co-culture systems to explore how Fn influenced GC cell migration and the crosstalk with MC. A murine lung metastasis model was employed to evaluate Fn -driven metastasis and the effects of metronidazole and Reparixin. Results We showed that Fn and MCs were enriched and positively correlated in clinical GC tissues compared to paracancerous tissues. Fn and MCs exhibited tumor-promoting properties by facilitating GC cell migration. Besides, Fn and GC cells can recruit MCs and facilitate its activation. This crosstalk between GC cells and MCs was further enhanced by Fn , thereby amplifying this positive feedback loop between them. The production of CXCL8 in response to Fn stimulation was a significant mediator. Suppression of CXCL8 in GC cells weakened Fn ’s promoting effects on GC cell migration, MC recruitment and activation. Similarly, knocking down CXCL8 in MCs reversed the Fn -induced feedback effect of MCs on the highly invasive phenotype of GC cells. Mechanistically, the exoprotein Gbp of Fn activated CypA-NF-κB pathway in both GC cells and MCs, leading to the upregulation of CXCL8 expression. In addition, the in vivo assays substantiated Fn ’s ability to enhance tumor progression by facilitating cell migration, upregulating CXCL8 expression, and inducing MC infiltration and activation. However, these effects were reversed by metronidazole, a highly Fn -susceptible antibiotic, and Reparixin. Conclusions In summary, this study suggests that Fn contributes to GC progression by promoting tumor cell migration, MCs recruitment and activation. Simultaneously, the enhanced CXCL8-mediated crosstalk between GC cells and MCs plays a vital role in the pro-cancer effect of Fn.
研究领域:
肿瘤学
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微生物组学
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免疫肿瘤学
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分子肿瘤学
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炎症与癌症
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信号转导
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DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Yuan Li,Kuo Zhang,Xuezheng Ai,Qingshi Zhang,Lu Jiang,Jiang Long,Huange Xu,Chencheng Feng,Yaqing Zhang,Guoke Tang,Fanli Chong,Lei Wang,Bo Huang
Maintaining quiescence of stem cells is a potential way to decrease cell nutrition demand for restoring the organization. Herein, a biomimetic peptide to maintain quiescence of stem cells through C-X-C motif chemokine ligand 8 (CXCL8)-C-X-C motif chemokine receptor 1 (CXCR1) pathway against intervertebral disc degeneration (IVDD) is developed. First, it is confirmed that quiescence can be induced via inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in nucleus pulposus stem cells (NPSCs). Meanwhile, it is well known that CXCR1, a chemokine receptor, can be targeted by CXCL8, resulting in cell proliferation via activating PI3K/Akt/mTOR pathway. Second, a biomimetic peptide (OAFF) that can bind to CXCR1 and form fibrous networks on NPSCs, mimicking extracellular matrix formation is developed. The multivalent effect and long-term binding to CXCR1 on NPSCs of OAFF fibers offer forcefully competitive inhibition with natural CXCL8, which induces NPSCs quiescence and ultimately overcomes obstacle in intradiscal injection therapy. In rat caudal disc puncture model, OAFF nanofibers still maintain at 5 weeks after operation and inhibit degeneration process of intervertebral disc in terms of histopathology and imageology. In situ fibrillogenesis of biomimetic peptide on NPSCs provides promising stem cells for intradiscal injection therapy against IVDD.
研究领域:
生物医学工程
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干细胞生物学
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组织工程
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再生医学
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骨科
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DOI
PubMed
高影响因子
MOLECULES
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2024
·Vol. 29
·期 9
·1994
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IF 4.2
Lingfeng Du,Chunfang Ma,Bingnan Liu,Wei Liu,Yue Zhu,Zuhua Wang,Teng Chen,Luqi Huang,Yuxin Pang
In this study, we developed a green and multifunctional bioactive nanoemulsion (BBG-NEs) ofBlumea balsamiferaoil usingBletilla striatapolysaccharide (BSP) and glycyrrhizic acid (GA) as natural emulsifiers. The process parameters were optimized using particle size, PDI, and zeta potential as evaluation parameters. The physicochemical properties, stability, transdermal properties, and bioactivities of the BBG-NEs under optimal operating conditions were investigated. Finally, network pharmacology and molecular docking were used to elucidate the potential molecular mechanism underlying its wound-healing properties. After parameter optimization, BBG-NEs exhibited excellent stability and demonstrated favorable in vitro transdermal properties. Furthermore, it displayed enhanced antioxidant and wound-healing effects. SD rats wound-healing experiments demonstrated improved scab formation and accelerated healing in the BBG-NE treatment relative to BBO and emulsifier groups. Pharmacological network analyses showed that AKT1, CXCL8, and EGFR may be key targets of BBG-NEs in wound repair. The results of a scratch assay and Western blotting assay also demonstrated that BBG-NEs could effectively promote cell migration and inhibit inflammatory responses. These results indicate the potential of the developed BBG-NEs for antioxidant and skin wound applications, expanding the utility of natural emulsifiers. Meanwhile, this study provided a preliminary explanation of the potential mechanism of BBG-NEs to promote wound healing through network pharmacology and molecular docking, which provided a basis for the mechanistic study of green multifunctional nanoemulsions.
研究领域:
药学
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纳米技术
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生物技术
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药理学
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材料科学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2023
·
IF 5.6
Cao Xu,Zhang Ningyi,Chen Hening,Wang Wei,Liang Yijun,Zhang Jiaxin,Liu Ruijia,Li Shuo,Yao Yuhao,Jin Qian,Guo Ziwei,Chen Yue,Gong Yuanyuan,Li Xiaoke,Zao Xiaobin,Ye Yong’an
The JiGuCao capsule formula (JCF) has demonstrated promising curative effects in treating chronic hepatitis B (CHB) in clinical trials. Here, we aimed to investigate JCF’s function and mechanism in diseases related to the hepatitis B virus (HBV). We used mass spectrometry (MS) to identify the active metabolites of JCF and established the HBV replication mouse model by hydrodynamically injecting HBV replication plasmids into the mice’s tail vein. Liposomes were used to transfect the plasmids into the cells. The CCK-8 kit identified cell viability. We detected the levels of HBV s antigen (HBsAg) and HBV e antigen (HBeAg) by the quantitative determination kits. qRT-PCR and Western blot were used to detect the genes’ expression. The key pathways and key genes related to JCF on CHB treatment were obtained by network pharmacological analysis. Our results showed that JCF accelerated the elimination of HBsAg in mice. JCF and its medicated serum inhibited HBV replication and proliferation of HBV-replicating hepatoma cells in vitro. And the key targets of JCF in treating CHB were CASP3, CXCL8, EGFR, HSPA8, IL6, MDM2, MMP9, NR3C1, PTGS2, and VEGFA. Furthermore, these key targets were related to pathways in cancer, hepatitis B, microRNAs in cancer, PI3K-Akt signaling, and proteoglycans in cancer pathways. Finally, Cholic Acid, Deoxycholic Acid, and 3′, 4′, 7-Trihydroxyflavone were the main active metabolites of JCF that we obtained. JCF employed its active metabolites to perform an anti-HBV effect and prevent the development of HBV-related diseases.
研究领域:
药理学
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病毒学
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分子生物学
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网络药理学
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肝病学
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产品关联
DOI
PubMed
高影响因子
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