DIGESTIVE DISEASES AND SCIENCES
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2022
·Vol. 68
·期 3
·778-790
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IF 3.487
Gu Dan,Cao Ting,Yi Shijie,Liu Ya,Fan Chao
Background Ulcerative colitis (UC) features chronic, non-infectious inflammation of the colon. Insulin-like growth factor binding protein 5 (IGFBP5) has been indicated to be related to various inflammation-related diseases. However, its association with UC remains largely unclear. Aims Here, we investigate the role of IGFBP5 in colonic mucosal epithelial cell injury in UC. Methods Differentially expressed genes in the colonic tissues of UC mice were screened using the Gene Expression Omnibus database, and IGFBP5 was identified. UC mice were developed using dextran sulfate sodium, and IGFBP5 expression in the colonic tissues of UC mice was confirmed by immunohistochemistry and RT-qPCR. The effects of IGFBP 5 in vivo and in vitro were investigated by intraperitoneal injection of adeno-associated virus into UC mice or by transfection with an IGFBP5 overexpression plasmid into lipopolysaccharide-treated colonic mucosal epithelial cells. The mechanisms causing IGFBP5 deletion in UC were predicted by bioinformatics analysis and ChIP-qPCR and verified by rescue experiments. Results IGFBP5 was reduced in UC. IGFBP5 impaired the NFκB pathway in the colonic tissue of UC mice and ameliorated inflammatory infiltration and colonic mucosal cell injury. IGFBP5 depletion was associated with H3K27me3 modification, which was induced by EZH2. CTCF was responsible for recruiting EZH2 to the promoter region of IGFBP5. CTCF inhibition repressed UC progression by reducing H3K27me3 modification via the discouragement of the enrichment of EZH2 in the IGFBP5 promoter. Conclusions CTCF modulates H3K27me3 modification of the IGFBP5 promoter by recruiting EZH2, thereby downregulating IGFBP5 to accentuate colonic mucosal epithelial cell injury in UC mice.
研究领域:
免疫学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 5
·5056
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IF 5.6
Xunshan Ren,Huangming Zhuang,Fuze Jiang,Yuelong Zhang,Panghu Zhou
Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles (CeNP) have exhibited therapeutic effects in multiple age-related diseases due to their unique capability of ROS scavenging. However, the role of CeNP in OA remains unknown. Our results revealed that CeNP could inhibit the expression of senescence and SASP biomarkers in multiple passaged and hydrogen-peroxide-treated synoviocytes by removing ROS. In vivo, the concentration of ROS in the synovial tissue was remarkably suppressed after the intra-articular injection of CeNP. Likewise, CeNP reduced the expression of senescence and SASP biomarkers as determined by immunohistochemistry analysis. The mechanistic study showed that CeNP inactivated the NFκB pathway in senescent synoviocytes. Finally, safranin O–fast green staining showed milder destruction of articular cartilage in the CeNP-treated group compared with the OA group. Overall, our study suggested that CeNP attenuated senescence and protected cartilage from degeneration via scavenging ROS and inactivating the NFκB signaling pathway. This study has potentially significant implications in the field of OA as it provides a novel strategy for OA treatment.Keywords:osteoarthritis;senescence;synoviocytes;ceria
研究领域:
骨科
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纳米技术
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衰老研究
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风湿病学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Xin Yan,Jun Huang,Youjie Zeng,Xuefeng Zhong,Yangxia Fu,Haiyan Xiao,Xia Wang,Huilin Lian,Hui Luo,Dai Li,Ren Guo
Background Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NFκB pathway and secretes pro-inflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and anti-inflammatory effects. Methods The role of the cGAS-STING-NFκB signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NFκB signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. Results Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NFκB pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NFκB pathway through PKA. Conclusion This study identifies that CGRP attenuates cGAS-STING-NFκB axis-mediated vascular remodeling in PAH through PKA.
研究领域:
心脏病学
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肺医学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
CANCER LETTERS
·
2024
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IF 9.1
Ying Ning,Yu Chen,Tian Tian,Xinyan Gao,Xiaolan Liu,Jia Wang,Huijun Chu,Chenyang Zhao,Yufei Yang,Ke Lei,He Ren,Zhumei Cui
Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.
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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癌症治疗
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DOI
PubMed
高影响因子
Journal of Advanced Research
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2024
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IF 11.4
Dongwei Guan,Pengju Huang,Xinlei Liu,Qing Li,Xiaoxun Zhang,Nan Liu,Yong Wang,Ying Wan,Jin Chai,Shiying Cai,Rui Chen,Zhijia Ye
Introduction Niemann-Pick C1 (NPC1), a lysosomal cholesterol transport protein, is required for efficient efferocytosis. Patients with Npc1 mutation are frequently accompanied with hepatic symptoms, including hepatomegaly, elevated liver transaminases, or even acute liver failure, but the pathogenic mechanism remains unknown. Objectives Our work aims to characterize the functional role of myeloid NPC1 in liver injury and elucidate its underlying mechanism. Methods Analyses of injured livers from patients with liver diseases and mouse models were conducted to examine NPC1 expression. Myeloid cell-specific Npc1 knockout mice were constructed to determine the functional role of macrophage NPC1 in liver injury. Isolated macrophages were subjected to in vitro mechanistical assays. Results We found that NPC1 is mainly expressed in hepatic macrophages. Its mRNA and protein expression are significantly elevated in injured livers from both patients and mouse models. Tissue-specific deletion of myeloid Npc1 increased liver inflammation, levels of serum liver function enzymes, and liver fibrosis in mouse models of liver injury induced by carbon tetrachloride (CCl 4 ) injection and methionine-and-choline-deficient (MCD) diets. Further analyses indicate that Npc1 deficiency in mouse models of liver injury resulted in increased levels of serum HMGB1 and mitochondrial DNA, promoted hepatic macrophage proinflammatory activation, M1 polarization, led to overproduction of hepatic inflammatory cytokines/chemokines, e.g. CCL2 and STING/NFκB pathway activation. In vitro mechanistical studies reveal that Npc1 -deficient macrophages exhibited inefficient efferocytosis, partly due to impaired cargo degradation. Conclusions These findings indicate that elevated expression of myeloid NPC1 in liver diseases protects liver from injury by promoting macrophage efferocytosis of damaged cells. Dysfunction of NPC1 aggravates liver injury, suggesting that NPC1 may be a potential therapeutic target for treating liver diseases.
研究领域:
肝病学
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免疫学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
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