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1
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Zhou M, Guan B, Liu Y, Gu Q, Chen W, Xie B, Zhou M, Xiang J, Zhao S, Zhao Q, Yan D. Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation. Cancer Lett 2025; 618:217642. [PMID: 40097065 DOI: 10.1016/j.canlet.2025.217642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 03/01/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
Investigating the mechanisms underlying the development of an immunosuppressive microenvironment within colorectal liver metastases (CRLM) is important for identifying synergistic targets for immunotherapy. The regulatory role of tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) in the immune microenvironment of CRLM has not yet been fully explored. Here, we found that TAM-EVs shaped the immunosuppressive microenvironment at the invasive front in murine CRLM models, thus dampening anti-PD-1 immunotherapy. This environment is characterized by an increased tumor stemness potential and abundant neutrophil extracellular traps (NETs) formation. Mechanistically, TAM-EVs-derived fibrinogen-like 2 (FGL2) interacts with the FCGR2B receptor in tumor cells, which further activates a p-STAT3/IL-1β positive feedback loop to increase the stemness potential of cancer cells, whereas IL-1β mediates the communication between cancer cells and neutrophils. The use of an anti-IL-1β monoclonal antibody can reduce NETs production and synergize with anti-PD-1 immunotherapy, which offers clinical translational significance for CRLM therapy. The FGL2/p-STAT3/IL-1β loop correlates with an immunosuppressive microenvironment and poor prognosis in human patients with CRLM. Our results revealed the potential of enhancing the efficacy of immunotherapy via the targeted clearance of NETs using anti-IL-1β monoclonal antibodies, which have significant clinical translational value in the treatment of CRLM.
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Affiliation(s)
- Menghua Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingjie Guan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Youdong Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qi Gu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiwei Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bowen Xie
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mantang Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianjun Xiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Senlin Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qian Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Dongwang Yan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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2
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Hu S, Ai Y, Hu C, Cassim Bawa FN, Xu Y. Transcription factors, metabolic dysfunction-associated fatty liver disease, and therapeutic implications. Genes Dis 2025; 12:101372. [PMID: 39911797 PMCID: PMC11795806 DOI: 10.1016/j.gendis.2024.101372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 03/27/2024] [Accepted: 06/21/2024] [Indexed: 02/07/2025] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a spectrum of liver diseases ranging from metabolic dysfunction-associated fatty liver to metabolic dysfunction-associated steatohepatitis, which may progress to liver cirrhosis and hepatocellular carcinoma. Several mechanisms, including obesity, insulin resistance, dyslipidemia, inflammation, apoptosis, mitochondrial dysfunction, and reactive oxygen species, have been proposed to underlie the progression of MAFLD. Transcription factors are proteins that specifically bind to DNA sequences to regulate the transcription of target genes. Numerous transcription factors regulate MAFLD by modulating the transcription of genes involved in steatosis, inflammation, apoptosis, and fibrosis. Here, we review the pathological factors associated with MAFLD, with a particular emphasis on the transcription factors that contribute to the progression of MAFLD and their therapeutic implications.
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Affiliation(s)
- Shuwei Hu
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
| | - Yingjie Ai
- Department of Pathology of School of Basic Medical Sciences, Department of Gastroenterology and Hepatology of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chencheng Hu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Fathima N. Cassim Bawa
- Institute of Diabetes, Obesity and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yanyong Xu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Frontier Innovation Center, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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3
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Wang Y, Wang M, Kang J, Zhang Y. Role of fibrinogen-like 2 (FGL2) proteins in implantation: Potential implications and mechanism. Gene 2025; 946:149284. [PMID: 39884406 DOI: 10.1016/j.gene.2025.149284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
Fibrinogen-like (Fgl2) protein belongs to fibrinogen super family, which catalyzes the conversion of prothrombin to thrombin and is involved in the coagulation process. There are two different forms of functional Fgl2 protein: membrane associated Fgl2 (mFgl2) and soluble Fgl2 (sFgl2). mFgl2, as a type II transmembrane protein with property with prothrombinase activity from its N-terminal fragment, was extensively secreted or expressed by inflammatory macrophages, dendritic cells (DCs), Th1 cells and endothelial cells. While sFgl2 was mainly produced by regulatory T cells (Tregs) and then secreted into the vasculature, which contributes to autoimmune disease by regulating maturation of (DCs), polarization of macrophage, inhibiting T cell proliferation and differentiation and inducing apoptosis of B cells. In particular, emerging evidence has shown that Fgl2 is implicated in female reproductive system that contributes to embryo development, ovarian granulosa cells differentiation and implantation failure. This article summarizes the role and potential mechanisms of Fgl2 in reproduction and identifies research gaps along with the future directions.
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Affiliation(s)
- Yueying Wang
- Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China; Department of Reproductive Medicine, Jining No.1 People's Hospital, Jining 272002, China; Key Laboratory of Pregnancy Disorder Research of Jining, 272002, China
| | - Mei Wang
- Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China
| | - Jiawei Kang
- Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China; Department of Obstetrical, Zhongnan Hospital of Wuhan University, Wuhan 430062, China
| | - Yuanzhen Zhang
- Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China.
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4
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Zhang H, Kong X, Qu H, Gao Y, Guan Z, Zhou H, Yin Z, Lu K, Wang W, Zhai X, Jin B. MYCBP2-mediated HNF4α ubiquitination reprogrammed lipid metabolism in MASH-associated hepatocellular carcinoma. Oncogene 2025:10.1038/s41388-025-03373-5. [PMID: 40181155 DOI: 10.1038/s41388-025-03373-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/27/2025] [Accepted: 03/25/2025] [Indexed: 04/05/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major global health burden, with metabolic dysfunction-associated steatohepatitis (MASH) emerging as a significant risk factor. The scarcity of effective pharmacological treatments for MASH and its progression to HCC underscores the need for deeper molecular insights. Our study identifies Myc-binding protein 2 (MYCBP2), an E3 ubiquitin ligase, as a potential tumor suppressor in MASH-related HCC. Through transcriptomic and proteomic analyses, we observed significant downregulation of MYCBP2 in HCC tissues. In vitro and in vivo experiments demonstrate that MYCBP2 inhibits HCC cell proliferation, migration, and invasion by modulating lipid metabolism pathways. Mechanistically, MYCBP2 promotes the ubiquitination and degradation of Hepatocyte Nuclear Factor 4 Alpha (HNF4α). This ubiquitination occurs via K33- and K48-linked polyubiquitin chains at lysines 300 and 307 of HNF4α. The results showed that MYCBP2 influences the expression of lipid metabolism-related genes and attenuates HNF4α's regulatory role in lipid metabolism through the mediated ubiquitination and degradation of HNF4α. Our findings elucidate the MYCBP2-HNF4α axis as a novel regulatory pathway in MASH-related HCC and highlight the broader implications of ubiquitination in cancer metabolism, offering a promising metabolic target for therapeutic intervention.
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Affiliation(s)
- Hao Zhang
- Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Xiangxu Kong
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
- The Second Clinical Medical School of Shandong University, Jinan, China
| | - Haoran Qu
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
- The Second Clinical Medical School of Shandong University, Jinan, China
| | - Yi Gao
- Medical Integration and Practice Center, Shandong University, Jinan, China
| | - Zhengyao Guan
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
- The Second Clinical Medical School of Shandong University, Jinan, China
| | - Huaxin Zhou
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
- The Second Clinical Medical School of Shandong University, Jinan, China
| | - Zhaoqing Yin
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
- The Second Clinical Medical School of Shandong University, Jinan, China
| | - Kangping Lu
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
- The Second Clinical Medical School of Shandong University, Jinan, China
| | - Wei Wang
- Medical Integration and Practice Center, Shandong University, Jinan, China.
| | - Xiangyu Zhai
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China.
- The Second Clinical Medical School of Shandong University, Jinan, China.
| | - Bin Jin
- Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China.
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China.
- The Second Clinical Medical School of Shandong University, Jinan, China.
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Wu Y, Song W, Su M, He J, Hu R, Zhao Y. The Role of Cholesterol Metabolism and Its Regulation in Tumor Development. Cancer Med 2025; 14:e70783. [PMID: 40145543 PMCID: PMC11948085 DOI: 10.1002/cam4.70783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 02/27/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Within the tumor microenvironment, tumor cells undergo metabolic reprogramming of cholesterol due to intrinsic cellular alterations and changes in the extracellular milieu. Furthermore, cholesterol reprogramming within this microenvironment influences the immune landscape of tumors, facilitating immune evasion and consequently promoting tumorigenesis. These biological changes involve modifications in numerous enzymes associated with cholesterol uptake and synthesis, including NPC1L1, SREBP, HMGCR, SQLE, and PCSK9. REVIEW This review systematically summarizes the role of cholesterol metabolism and its associated enzymes in cancer progression, examines the mechanisms through which dysregulation of cholesterol metabolism affects immune cells within the tumor microenvironment, and discusses recent advancements in cancer therapies that target cholesterol metabolism. CONCLUSION Targeting cholesterol metabolism-related enzymes can inhibit tumor growth, reshape immune landscapes, and rejuvenate antitumor immunity, offering potential therapeutic avenues in cancer treatment.
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Affiliation(s)
- Yongmei Wu
- Department of Human Histology and EmbryologyGuizhou Medical UniversityGuiyangGuizhouChina
| | - Wenqian Song
- Department of Human Histology and EmbryologyGuizhou Medical UniversityGuiyangGuizhouChina
| | - Min Su
- Department of Human Histology and EmbryologyGuizhou Medical UniversityGuiyangGuizhouChina
- Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine in Guizhou ProvinceGuizhou Medical UniversityGuiyangGuizhouChina
| | - Jing He
- Characteristic Key Laboratory of Translational Medicine Research of Cardiovascular and Cerebrovascular Diseases in Guizhou ProvinceGuizhou Medical UniversityGuiyangGuizhouChina
| | - Rong Hu
- Department of Human Histology and EmbryologyGuizhou Medical UniversityGuiyangGuizhouChina
- Characteristic Key Laboratory of Translational Medicine Research of Cardiovascular and Cerebrovascular Diseases in Guizhou ProvinceGuizhou Medical UniversityGuiyangGuizhouChina
| | - Youbo Zhao
- Department of Human Histology and EmbryologyGuizhou Medical UniversityGuiyangGuizhouChina
- Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine in Guizhou ProvinceGuizhou Medical UniversityGuiyangGuizhouChina
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Bennion KB, Miranda R.Bazzano J, Liu D, Wagener M, Paulos CM, Ford ML. Macrophage-derived Fgl2 dampens antitumor immunity through regulation of FcγRIIB+CD8+ T cells in melanoma. JCI Insight 2025; 10:e182563. [PMID: 40125553 PMCID: PMC11949062 DOI: 10.1172/jci.insight.182563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 02/05/2025] [Indexed: 03/25/2025] Open
Abstract
Cancer immunotherapy has emerged as a promising therapeutic modality but heterogeneity in patient responsiveness remains. Thus, greater understanding of the immunologic factors that dictate response to immunotherapy is critical to improve patient outcomes. Here, we show that fibrinogen-like protein 2 (Fgl2) is elevated in the setting of melanoma in humans and mice and plays a functional role in inhibiting the CD8+ T cell response. Surprisingly, the tumor itself is not the major cellular source of Fgl2. Instead, we found that macrophage-secreted Fgl2 dampens the CD8+ T cell response through binding and apoptosis of FcγRIIB+CD8+ T cells. This regulation was CD8+ T cell autonomous and not via an antigen-presenting cell intermediary, as absence of Fcgr2b from the CD8+ T cells rendered T cells insensitive to Fgl2 regulation. Fgl2 is robustly expressed by macrophages in 10 cancer types in humans and in 6 syngeneic tumor models in mice, underscoring the clinical relevance of Fgl2 as a therapeutic target to promote T cell activity and improve patient immunotherapeutic response.
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Affiliation(s)
- Kelsey B. Bennion
- Cancer Biology PhD program
- Department of Surgery
- Winship Cancer Institute
| | | | - Danya Liu
- Department of Surgery
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Maylene Wagener
- Department of Surgery
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | | | - Mandy L. Ford
- Cancer Biology PhD program
- Department of Surgery
- Winship Cancer Institute
- Immunology and Molecular Pathogenesis PhD program, and
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA
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7
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Fu Y, Hu P, Hu Y, Fang Y, Zhou Y, Shi Y, Yang K, Fu T, Li W, Gritskevitch ER, Jin L, Lyu J, Zhao Q. Hepatocyte-specific RAP1B deficiency ameliorates high-fat diet-induced obesity and liver inflammation in mice. Diabetes Obes Metab 2025. [PMID: 40083059 DOI: 10.1111/dom.16309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/12/2025] [Accepted: 02/24/2025] [Indexed: 03/16/2025]
Abstract
AIM This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines. MATERIALS AND METHODS Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers. RESULTS We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation. CONCLUSIONS This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.
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Affiliation(s)
- Yinxu Fu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Pingyi Hu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yanyang Hu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yu Fang
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Yaping Zhou
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yu Shi
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Kaiqiang Yang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ting Fu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
| | - Weijia Li
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
- International Sakharov Environmental Institute, Belarusian State University, Minsk, Republic of Belarus
| | | | - Liqin Jin
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Jianxin Lyu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Qiongya Zhao
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
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Zhang Y, Li Z, Zhang J, Mafa T, Zhang J, Zhu H, Chen L, Zong Z, Yang L. Fibrinogen: A new player and target on the formation of pre-metastatic niche in tumor metastasis. Crit Rev Oncol Hematol 2025; 207:104625. [PMID: 39826884 DOI: 10.1016/j.critrevonc.2025.104625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/05/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025] Open
Abstract
Tumor metastasis involves a series of complex and coordinated processes, which is the main cause of patient death and still a significant challenge in cancer treatment. Pre-metastatic niches (PMN), a specialized microenvironment that develops in distant organs prior to the arrival of metastatic cancer cells, plays a crucial role in driving tumor metastasis. The development of PMN depends on a complex series of cellular and molecular components including tumor-derived factors, bone marrow-derived cells, resident immune cells, and extracellular matrix. Fibrinogen, a key factor in the typical blood clotting process, is related to tumor metastasis and prognosis, according to a growing body of evidence in recent years. Fibrinogen has emerged as an important factor in mediating the formation of tumor microenvironment. Nevertheless, a clear and detailed mechanism by which fibrinogen promotes tumor metastasis remains unknown. In this review, we first explore the roles of fibrinogen in the development of PMN from four perspectives: immunosuppression, inflammation, angiogenesis, and extracellular matrix remodeling. We highlight the significance of fibrinogen in shaping PMN and discuss its potential therapeutic values, opening new avenues for targeting fibrinogen to prevent or treat metastasis.
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Affiliation(s)
- Yuxin Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Rd, Nanchang, Jiangxi 330006, China; The Second Clinical Medical College, Nanchang University, No. 1299 Xuefu Ave, Nanchang, Jiangxi 330031, China
| | - Zelin Li
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Rd, Nanchang, Jiangxi 330006, China; The First Clinical Medical College, Nanchang University, No. 1299 Xuefu Ave, Nanchang, Jiangxi 330031, China
| | - Jiamao Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Rd, Nanchang, Jiangxi 330006, China; The Second Clinical Medical College, Nanchang University, No. 1299 Xuefu Ave, Nanchang, Jiangxi 330031, China
| | - Tatenda Mafa
- Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA
| | - Jingyu Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang, Jiangxi 330006, China
| | - Hui Zhu
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Rd, Nanchang, Jiangxi 330006, China
| | - Lifang Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Rd, Nanchang, Jiangxi 330006, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, No.1 MinDe Road, Nanchang, Jiangxi 330006, China
| | - Lingling Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Rd, Nanchang, Jiangxi 330006, China; Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA.
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Dong X, Xu H, He B, Zhang M, Miu W, Huang Z, Chen C. FIBRINOGEN-LIKE PROTEIN 2 PROTECTS THE AGGRAVATION OF HYPERTRIGLYCERIDEMIA ON THE SEVERITY OF HYPERTRIGLYCERIDEMIA ACUTE PANCREATITIS BY REGULATING MACROPHAGES. Shock 2025; 63:327-337. [PMID: 39527492 DOI: 10.1097/shk.0000000000002503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
ABSTRACT Objective: The mechanisms underlying the increased severity of hypertriglyceridemia acute pancreatitis (HTG-AP) remain poorly understood. Fibrinogen-like protein 2 (FGL2) has been identified as a regulator of macrophage activity, mediating immune suppression. This study aims to examine the role of FGL2 in the susceptibility to severe conditions of HTG-AP. Methods: Both wild-type and FGL2 gene knockout C57BL/6 mice were utilized to establish HTG, AP, and HTG-AP models using P-407 and/or caerulein. Serum levels of triglycerides, total cholesterol, amylase, and lipase were assessed via biochemical analysis. Pancreatic and lung tissue injuries were evaluated using hematoxylin and eosin staining. TNF-α, IL-1β, and IL-6 levels in serum and pancreatic tissues were quantified using enzyme-linked immunosorbent assay. Immunohistochemistry was used to assess the expression of FGL2, the macrophage marker CD68, and M1/M2 macrophage markers iNOS/CD163. Results: The animal models were successfully established. Compared to wild-type mice, FGL2 knockout resulted in increased pathological injury scores in the pancreas and lungs, as well as elevated TNF-α, IL-1β, and IL-6 levels in serum and pancreatic tissue in the HTG group, with more pronounced effects observed in the HTG-AP group. The AP group alone did not exhibit significant changes due to FGL2 knockout. Further analysis revealed that FGL2 knockout increased CD68 expression but reduced CD163 expression in the pancreatic tissues in the HTG group. In the HTG-AP group, there was a marked increase in CD68 and iNOS expressions, coupled with a reduction in CD163 expression. Conclusion: FGL2 knockout in HTG and HTG-AP mice resulted in increased inflammatory responses and a significant imbalance in M2 macrophages. These findings suggest that FGL2 plays a crucial role in mitigating the aggravation of HTG on the severity of HTG-AP by modulating macrophage activity.
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Affiliation(s)
- Xiuli Dong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Haibo Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interventional Pulmonology of Zhejiang Province, Wenzhou, Zhejiang Province, China
| | - Baiqi He
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interventional Pulmonology of Zhejiang Province, Wenzhou, Zhejiang Province, China
| | - Meijuan Zhang
- Department of Medical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wanqi Miu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interventional Pulmonology of Zhejiang Province, Wenzhou, Zhejiang Province, China
| | - Zhiming Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Chengshui Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interventional Pulmonology of Zhejiang Province, Wenzhou, Zhejiang Province, China
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10
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Zhao H, Zhou J, Yuan L, Sun Z, Liu Y, Zhao X, Ye F. Exploring the alleviating effects of Bifidobacterium metabolite lactic acid on non-alcoholic steatohepatitis through the gut-liver axis. Front Microbiol 2025; 15:1518150. [PMID: 39850131 PMCID: PMC11756523 DOI: 10.3389/fmicb.2024.1518150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/16/2024] [Indexed: 01/25/2025] Open
Abstract
Objective This study investigates the protective effects of lactic acid, a metabolite of Bifidobacterium, on non-alcoholic fatty liver disease (NAFLD) induced by a high-sugar, high-fat diet (HFD) in mice, in the context of the gut-liver axis. Methods A NAFLD mouse model was established using a HFD, and different intervention groups were set up to study the protective effects of Bifidobacterium and its metabolite lactic acid. The groups included a control group, NAFLD group, Bifidobacterium treatment group, Glyceraldehyde-3-P (G-3P) co-treatment group, and NOD-like receptor family pyrin domain containing 3 (NLRP3) overexpression group. The evaluation of liver function and lipid metabolism was conducted using the liver-to-body weight ratio, histological staining, and biochemical assays. Enzyme-linked immunosorbent assay (ELISA) was performed to measure inflammatory cytokines, and western blotting was used to analyze the expression of NLRP3 inflammasome and autophagy-related molecules. In vitro, an NAFLD cell model was established using oleic acid, with cells treated with lactic acid and NLRP3 overexpression to assess lipid droplet accumulation and inflammation. Results In vivo findings indicated that, in comparison to CBX group (Control group without antibiotic treatment), NAFLD/CBX group (NAFLD group without antibiotic administration) and NAFLD/ABX group (NAFLD group with antibiotic administration) exhibited increased liver-to-body weight ratio, higher lipid droplet accumulation, aggravated liver histopathological damage, and elevated levels of AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase), TC (Total Cholesterol), TG (Triglycerides), LDL-C (Low-Density Lipoprotein Cholesterol), IL-6 (Interleukin-6), TNF-α (Tumor Necrosis Factor-alpha), IL-1β (Interleukin-1 beta), and NLRP3-related molecules, while HDL-C (High-Density Lipoprotein Cholesterol) levels significantly decreased. Intervention with Bifidobacterium significantly reversed these adverse changes. Further addition of G-3P led to more pronounced improvement in NAFLD symptoms, while overexpression of NLRP3 weakened the protective effects of Bifidobacterium. In vitro results indicated that Ole group exhibited heightened lipid droplet accumulation and expression of NLRP3 inflammasome-related molecules relative to the control group. Treatment with lactic acid effectively reversed these changes; however, the protective effect of lactic acid was significantly weakened with NLRP3 overexpression. Conclusion Lactic acid can alleviate lipid metabolism disorders in NAFLD induced by diet through the inhibition of inflammation mediated by the NLRP3 inflammasome and the regulation of the autophagy process.
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Affiliation(s)
- Hongmei Zhao
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Gastroenterology and Nutrition, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, China
| | - Juan Zhou
- Department of Gastroenterology and Nutrition, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, China
| | - Lingzhi Yuan
- Department of Gastroenterology and Nutrition, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, China
| | - Zhiyi Sun
- University of Michigan Medical School, Ann Arbor, MI, United States
| | - Yi Liu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinyu Zhao
- Department of Pediatrics, Changsha County Maternal and Child Health Hospital, Changsha, China
| | - Feng Ye
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Liu M, Wang C, Liu R, Wang Y, Wei B. Association between cardiometabolic index and all-cause and cause-specific mortality among the general population: NHANES 1999-2018. Lipids Health Dis 2024; 23:425. [PMID: 39731068 DOI: 10.1186/s12944-024-02408-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/15/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND Cardiometabolic index (CMI) is a comprehensive clinical parameter which integrates overweight and abnormal lipid metabolism. However, its relationship with all-cause, cardiovascular disease (CVD), and cancer mortality is still obscure. Thus, a large-scale cohort study was conducted to illustrate the causal relation between CMI and CVD, cancer, and all-cause mortality among the common American population. METHODS Our research was performed on the basis of National Health and Nutrition Examination Survey (NHANES) database, involving 40,275 participants ranging from 1999 to 2018. The formula of CMI is [waist circumference (cm) / height (cm)] × [triglyceride (mg/dL) / high-density lipoprotein cholesterol (mg/dL)]. Outcome variables consisted of CVD, cancer, and all-cause mortality, which were identified by the International Classification of Diseases (ICD)-10. The correlation between CMI and mortality outcomes was analyzed utilizing the Kaplan-Meier survival modeling, univariate/multivariate Cox regression analysis, smooth curve fitting analysis, threshold effect analysis, and subgroup analysis. Stratification factors for subgroups included age, race/ethnicity, sex, smoking behavior, drinking behavior, BMI, hypertension, and diabetes. RESULTS The baseline characteristics table includes 4,569 all-cause-induced death cases, 1,113 CVD-induced death cases, and 1,066 cancer-induced death cases. Without adjustment for potential covariates, significantly positive causal correlation existed between CMI and all-cause mortality (HR = 1.03, 95% CI 1.02,1.04, P-value<0.05), CVD mortality (HR = 1.04, 95% CI 1.03, 1.05, P-value<0.05) and cancer mortality(HR = 1.03, 95% CI 1.02, 1.05, P-value<0.05); whereas, after confounding factors were completely adjusted, the relationship lost statistical significance in CMI subgroups (P for trend>0.05). Subgroup analysis found no specific subgroups. Under a fully adjusted model, a threshold effect analysis was performed combined with smooth curve fitting, and the findings suggested an L-shaped nonlinear association within CMI and all-cause mortality (the Inflection point was 0.98); in particular, when the baseline CMI was below 0.98, there existed a negative correlation with all-cause mortality with significance (HR 0.59, 95% CI 0.43, 0.82, P-value<0.05). A nonlinear relation was observed between CMI and CVD mortality. Whereas, the correlation between CMI and cancer mortality was linear. CONCLUSIONS Among the general American population, baseline CMI levels exhibited an L-shaped nonlinear relationship with all-cause mortality, and the threshold value was 0.98. What's more, CMI may become an effective indicator for CVD, cancer, and all-cause mortality prediction. Further investigation is essential to confirm our findings.
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Affiliation(s)
- Mingjie Liu
- Department of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Chendong Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Rundong Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Yan Wang
- Department of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Bai Wei
- Department of Oncology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
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Zhang T, Li B, Wang J, Wu X, Song L, Wang Y, Zhang Y, Li Y. Introduced paeoniflorin reduces the main toxicity induced by diosbulbin B, the major toxic compound of Dioscorea bulbifera L.: involved inhibiting inflammation and ferroptosis. Drug Chem Toxicol 2024:1-10. [PMID: 39686661 DOI: 10.1080/01480545.2024.2440451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/22/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024]
Abstract
Rhizoma Dioscoreae Bulbiferae (HYZ) is a widely utilized herb in clinical practice, known for its significant biological activities. However, the associated hepatotoxicity poses limitations to its application. Our previous research indicated that the effective mitigation of HYZ-induced hepatotoxicity through the concoction with Radix Paeoniae Alba medicinal juice involves the incorporation of paeoniflorin (Pae) and a reduction in diosbulbin B (DB), the primary toxic compound in HYZ. This finding suggests that the introduced Pae may exert a direct attenuating effect on DB. In light of this, this study represents the first investigation into Pae's detoxification effect against DB-induced hepatotoxicity after administration for 2 months in mice vivo while also exploring underlying mechanisms related to inflammation and ferroptosis based on network pharmacology results. Our findings demonstrate that Pae significantly alleviates DB-induced hepatotoxicity in a dose-dependent manner. Western blotting and ELISA analyses revealed that Pae effectively reversed elevated levels of hepatic inflammation-related markers-such as NF-κB, p38 MAPK, NLRP3, TNF-α, and IL-1β-as well as excessively high concentrations of ferroptosis-related MDA and Fe2+. Furthermore, it restored low levels of GSH, SOD, GPX4, and FTH1. In summary, introduced Pae substantially mitigated DB-induced hepatotoxicity by inhibiting both hepatocyte inflammation and ferroptosis.
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Affiliation(s)
- Tianzhu Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Bingyin Li
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Junming Wang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
- Co-Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, China
- Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Medicine, Zhengzhou, China
| | - Xiaohui Wu
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Lingling Song
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yanmei Wang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yueyue Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yamin Li
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
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Li N, Maimaitireyimu A, Shi T, Feng Y, Liu W, Xue S, Gao F. Proteomic analysis of plasma and duodenal tissue in celiac disease patients reveals potential noninvasive diagnostic biomarkers. Sci Rep 2024; 14:29872. [PMID: 39622892 PMCID: PMC11612483 DOI: 10.1038/s41598-024-80391-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 11/18/2024] [Indexed: 12/06/2024] Open
Abstract
The pathogenesis of celiac disease (CeD) remains incompletely understood. Traditional diagnostic techniques for CeD include serological testing and endoscopic examination; however, they have limitations. Therefore, there is a need to identify novel noninvasive biomarkers for CeD diagnosis. We analyzed duodenal and plasma samples from CeD patients by four-dimensional data-dependent acquisition (4D-DIA) proteomics. Differentially expressed proteins (DEPs) were identified for functional analysis and to propose blood biomarkers associated with CeD diagnosis. In duodenal and plasma samples, respectively, 897 and 140 DEPs were identified. Combining weighted gene co-expression network analysis(WGCNA) with the DEPs, five key proteins were identified across three machine learning methods. FGL2 and TXNDC5 were significantly elevated in the CeD group, while CHGA expression showed an increasing trend, but without statistical significance. The receiver operating characteristic curve results indicated an area under the curve (AUC) of 0.7711 for FGL2 and 0.6978 for TXNDC5, with a combined AUC of 0.8944. Exploratory analysis using Mfuzz and three machine learning methods identified four plasma proteins potentially associated with CeD pathological grading (Marsh classification): FABP, CPOX, BHMT, and PPP2CB. We conclude that FGL2 and TXNDC5 deserve exploration as potential sensitive, noninvasive diagnostic biomarkers for CeD.
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Affiliation(s)
- Na Li
- Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Ayinuer Maimaitireyimu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center for Digestive Diseases, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Tian Shi
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center for Digestive Diseases, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center for Digestive Diseases, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Weidong Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Clinical Research Center for Digestive Diseases, Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Shenglong Xue
- College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Feng Gao
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Uygur Autonomous Region, Urumqi, China.
- Xinjiang Clinical Research Center for Digestive Diseases, Xinjiang Uygur Autonomous Region, Urumqi, China.
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Luo L, Zhuang X, Fu L, Dong Z, Yi S, Wang K, Jiang Y, Zhao J, Yang X, Hei F. The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome. Clin Transl Med 2024; 14:e70098. [PMID: 39623879 PMCID: PMC11612265 DOI: 10.1002/ctm2.70098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 10/26/2024] [Accepted: 11/04/2024] [Indexed: 12/06/2024] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe respiratory condition associated with elevated morbidity and mortality. Understanding their complex pathophysiological mechanisms is crucial for developing new preventive and therapeutic strategies. Recent studies highlight the significant role of inflammation involved in ALI/ARDS, particularly the hyperactivation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in macrophages. This activation drives pulmonary inflammation by releasing inflammatory signalling molecules and is linked to metabolic reprogramming, marked by increased glycolysis and reduced oxidative phosphorylation. However, the relationship between NLRP3 inflammasome activation and macrophage glycolytic reprogramming in ALI/ARDS, as well as the molecular mechanisms regulating these processes, remain elusive. This review provides a detailed description of the interactions and potential mechanisms linking NLRP3 inflammasome activation with macrophage glycolytic reprogramming, proposing that glycolytic reprogramming may represent a promising therapeutic target for mitigating inflammatory responses in ALI/ARDS. KEY POINTS: NLRP3 inflammasome activation is pivotal in mediating the excessive inflammatory response in ALI/ARDS. Glycolytic reprogramming regulates NLRP3 inflammasome activation. Therapeutic potential of targeting glycolytic reprogramming to inhibit NLRP3 inflammasome activation in ALI/ARDS.
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Affiliation(s)
- Lan Luo
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Xiaoli Zhuang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Lin Fu
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Ziyuan Dong
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Shuyuan Yi
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Kan Wang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Yu Jiang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Ju Zhao
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Xiaofang Yang
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Feilong Hei
- Department of Extracorporeal Circulation and Mechanical Circulation AssistantsCenter for Cardiac Intensive CareBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
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Cao Z, Liu X, Yan J. Prognostic significance and gene co-expression network of CD16A and FGL2 in gliomas. Front Oncol 2024; 14:1447113. [PMID: 39629005 PMCID: PMC11611834 DOI: 10.3389/fonc.2024.1447113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 10/29/2024] [Indexed: 12/06/2024] Open
Abstract
Introduction The CD16A protein encoding gene FcγRIIIa (FCGR3A) and its potential ligand Fibrinogen-like protein 2 (FGL2) are involved in various cell physiological activities on the extracellular surface. Aberrant expression of these genes has been linked to tumorigenesis. Methods To assess the prognostic significance of FCGR3A and FGL2 transcription expression in glioma and explore their roles in glioma initiation and progression, we utilized multiple online databases, including TCGA, GEPIA, CGGA, cBioPortal, TISCH, LinkedOmics, Ivy Glioblastoma Atlas Project, and Human Protein Atlas. Results Our analysis revealed that FCGR3A and FGL2 expression was significantly correlated with clinical variables such as age, tumor type, WHO grade, histology, IDH-1 mutation, and 1p19q status. A strong correlation was also observed between the transcriptional expression levels of FCGR3A and FGL2. High expression of both genes predicted poor prognosis in primary and recurrent glioma patients, particularly those with lower grade gliomas. Cox regression analysis further confirmed that elevated expression of FCGR3A and FGL2 were independent prognostic factors for shorter overall survival in glioma patients. Gene co-expression network analysis suggested that FCGR3A, FGL2, and their co-expressed genes were involved in inflammatory activities and tumor-related signaling pathways. Additionally, tissue microarrays from glioma patients at Tiantan Hospital showed significantly higher FCGR3A protein expression in high-grade gliomas compared to low-grade gliomas. Discussion In conclusion, our findings suggest that FCGR3A and FGL2 could serve as promising prognostic biomarkers and potential therapeutic targets for glioma patients.
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Affiliation(s)
- Ziwen Cao
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
| | - Xing Liu
- Department of Neuropathology, Beijing Neurosurgical Institute, Beijing, China
| | - Jun Yan
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
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Zhang H, Wang Y, Feng K, Niu Q, Xin Y, Xuan S, Liu S. MiR-146a-5p-enriched exosomes inhibit M1 macrophage activation and inflammatory response by targeting CD80. Mol Biol Rep 2024; 51:1133. [PMID: 39514136 DOI: 10.1007/s11033-024-10088-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Previous studies have demonstrated that miR-146a-5p negatively regulated the intrinsic immune and inflammatory responses, whether the miR-146a-5p-enriched exosomes possess the anti-inflammation effect remains unclear. This study aimed to investigate the effect of miR-146a-5p-enriched exosomes on M1 macrophage activation and inflammatory response and the potential molecular mechanism. METHODS GEO database was used to analyze the expression of miR-146a-5p in serum exosomes of MASH patients. MiR-146a-5p levels in primary hepatocytes, macrophages, and serum exosomes of MASH mice were measured. MiR-146a-5p-enriched exosomes were constructed and the effects on M1 macrophages activation and inflammatory factors release were investigated. The target gene of miR-146a-5p was predicted and verified. RESULTS Serum exosomal miR-146a-5p level was decreased in MASH patients analyzed by GEO database. The miR-146a-5p levels in primary cultured hepatocytes and macrophages of MASH mice were decreased. Serum exosomal miR-146a-5p level was decreased and negatively correlated with the concentrations of IL-6 in MASH mice. Furthermore, miR-146a-5p-enriched exosomes inhibited the M1 macrophages activation and the expression of pro-inflammatory factors MCP-1, IL-6, and TNF-α. CD80 was predicted as the potential target gene of miR-146a-5p, and the expression of CD80 was regulated by miR-146a-5p. In addition, the inhibitory effect of miR-146a-5p on M1 macrophages activation and inflammatory factors release was restored when CD80 was over-expressed. CONCLUSIONS This study demonstrated that miR-146a-5p-enriched exosomes can inhibit the M1 macrophages activation and reduce the release of pro-inflammatory factors by targeting CD80.
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Affiliation(s)
- Han Zhang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, 5 Donghaizhong Road, Qingdao, Shandong Province, 266071, China
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266071, China
| | - Yifen Wang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, 5 Donghaizhong Road, Qingdao, Shandong Province, 266071, China
- Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, 030009, China
| | - Keqing Feng
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
| | - Qinghui Niu
- Department of Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, 266071, China
| | - Yongning Xin
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, 5 Donghaizhong Road, Qingdao, Shandong Province, 266071, China
| | - Shiying Xuan
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, 5 Donghaizhong Road, Qingdao, Shandong Province, 266071, China.
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, 5 Donghaizhong Road, Qingdao, Shandong Province, 266011, China.
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He L, Wang W, Wang X, Zhang D, Zhang Y, Zhao Y, Zhao L, Li X, Cheng J, Xu D, Ma Z, Yang X, Huang Z, Cai Y, Liu X, Chen Z, Weng X, Lin C, Gong P, Zhang X. Identification of the FGB gene polymorphism and analysis of its association with fat deposition traits in Hu sheep. Anim Biotechnol 2024; 35:2344207. [PMID: 38669223 DOI: 10.1080/10495398.2024.2344207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
As a crucial economic trait, fat deposition is directly related to carcass quality and feed efficiency in sheep. The purpose of this study was to investigate the polymorphisms of the FGB gene related to fat deposition and detect the expression features of the FGB gene in different adipose tissues of sheep by using Sanger sequencing, MassARRAY® SNP technique, and quantitative real-time PCR (qRT-PCR). Results showed that in the intron region of the FGB gene, a SNP g. 3378953 A > T has been identified, and significant association was found between perirenal fat weight, perirenal fat relative weight, mesenteric fat weight, and mesenteric fat relative weight (P < 0.05). Moreover, qRT-PCR analysis showed that FGB was expressed in all three adipose tissues, and FGB gene expression level in the AA genotype was significantly lower than that in the AT or TT genotypes (P < 0.05). Therefore, the FGB gene can be used as a candidate gene to reduce fat deposition in Hu sheep breeding, and the selection of the AA genotype in Hu sheep in production practice is more conducive to improving production efficiency.
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Affiliation(s)
- Lijuan He
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Weimin Wang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaojuan Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Deyin Zhang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Yukun Zhang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Yuan Zhao
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Liming Zhao
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaolong Li
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Jiangbo Cheng
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Dan Xu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Zongwu Ma
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Xiaobin Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Zhiqiang Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Youxin Cai
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Xiaoqiang Liu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Zhanyu Chen
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
| | - Xiuxiu Weng
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu, China
| | - Changchun Lin
- Institute of Animal Husbandry Quality Standards, Xinjiang Academy of Animal Science, Urumqi, China
| | - Ping Gong
- Institute of Animal Husbandry Quality Standards, Xinjiang Academy of Animal Science, Urumqi, China
| | - Xiaoxue Zhang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, Gansu, China
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Ullah A, Chen Y, Singla RK, Cao D, Shen B. Exploring cytokines dynamics: Uncovering therapeutic concepts for metabolic disorders in postmenopausal women- diabetes, metabolic bone diseases, and non-alcohol fatty liver disease. Ageing Res Rev 2024; 101:102505. [PMID: 39307315 DOI: 10.1016/j.arr.2024.102505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/18/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024]
Abstract
Menopause is an age-related change that persists for around one-third of a woman's life. Menopause increases the risk of metabolic illnesses such as diabetes, osteoporosis (OP), and nonalcoholic fatty liver disease (NAFLD). Immune mediators (pro-inflammatory cytokines), such as interleukin-1 (IL-1), IL-6, IL-17, transforming growth factor (TGF), and tumor necrosis factor (TNF), exacerbate the challenges of a woman undergoing menopause by causing inflammation and contributing to the development of these metabolic diseases in postmenopausal women. Furthermore, studies have shown that anti-inflammatory cytokines such as interleukin-1 receptor antagonists (IL-1Ra), IL-2, and IL-10 have a double-edged effect on diabetes and OP. Likewise, several interferon (IFN) members are double-edged swords in the OP. Therefore, addressing these immune mediators precisely may be an approach to improving the health of postmenopausal women. Hence, considering the significant changes in these cytokines, the present review focuses on the latest findings concerning the molecular mechanisms by which pro- and anti-inflammatory cytokines (interleukins) impact postmenopausal women with diabetes, OP, and NAFLD. Furthermore, we comprehensively discuss the therapeutic approaches that identify cytokines as therapeutic targets, such as hormonal therapy, physical activities, natural inhibitors (drugs), and others. Finally, this review aims to provide valuable insights into the role of cytokines in postmenopausal women's diabetes, OP, and NAFLD. Deeply investigating the mechanisms and therapeutic interventions involved will address the characteristics of immune mediators (cytokines) and improve the management of these illnesses, thereby enhancing the general quality of life and health of the corresponding populations of women.
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Affiliation(s)
- Amin Ullah
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yongxiu Chen
- Gynecology Department, Guangdong Women and Children Hospital, No. 521, Xingnan Road, Panyu District, Guangzhou 511442, China
| | - Rajeev K Singla
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Dan Cao
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bairong Shen
- Department of Abdominal Oncology, Cancer Center of West China Hospital and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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Tan Q, Chu H, Wei J, Yan S, Sun X, Wang J, Zhu L, Yang F. Astaxanthin Alleviates Hepatic Lipid Metabolic Dysregulation Induced by Microcystin-LR. Toxins (Basel) 2024; 16:401. [PMID: 39330859 PMCID: PMC11435617 DOI: 10.3390/toxins16090401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/09/2024] [Accepted: 09/12/2024] [Indexed: 09/28/2024] Open
Abstract
Microcystin-LR (MC-LR), frequently generated by cyanobacteria, has been demonstrated to raise the likelihood of liver disease. Few previous studies have explored the potential antagonist against MC-LR. Astaxanthin (ASX) has been shown to possess various beneficial effects in regulating lipid metabolism in the liver. However, whether ASX could alleviate MC-LR-induced hepatic lipid metabolic dysregulation is as yet unclear. In this work, the important roles and mechanisms of ASX in countering MC-LR-induced liver damage and lipid metabolic dysregulation were explored for the first time. The findings revealed that ASX not only prevented weight loss but also enhanced liver health after MC-LR exposure. Moreover, ASX effectively decreased triglyceride, total cholesterol, aspartate transaminase, and alanine aminotransferase contents in mice that were elevated by MC-LR. Histological observation showed that ASX significantly alleviated lipid accumulation and inflammation induced by MC-LR. Mechanically, ASX could significantly diminish the expression of genes responsible for lipid generation (Srebp-1c, Fasn, Cd36, Scd1, Dgat1, and Pparg), which probably reduced lipid accumulation induced by MC-LR. Analogously, MC-LR increased intracellular lipid deposition in THLE-3 cells, while ASX decreased these symptoms by down-regulating the expression of key genes in the lipid synthesis pathway. Our results implied that ASX played a crucial part in lipid synthesis and effectively alleviated MC-LR-induced lipid metabolism dysregulation. ASX might be developed as a novel protectant against hepatic impairment and lipid metabolic dysregulation associated with MC-LR. This study offers new insights for further management of MC-LR-related metabolic diseases.
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Affiliation(s)
- Qinmei Tan
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Q.T.); (S.Y.); (X.S.)
| | - Hanyu Chu
- Hengyang Maternal and Child Health Hospital, Hengyang 421001, China;
| | - Jia Wei
- Xiangya School of Public Health, Central South University, Changsha 410078, China;
| | - Sisi Yan
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Q.T.); (S.Y.); (X.S.)
| | - Xiaoya Sun
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Q.T.); (S.Y.); (X.S.)
| | - Jiangping Wang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China;
| | - Lemei Zhu
- School of Public Health, Changsha Medical University, Changsha 410219, China;
| | - Fei Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; (Q.T.); (S.Y.); (X.S.)
- Affiliated Nanhua Hospital University of South China, Hengyang 421000, China
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20
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Zou Y, Liu C, Wang Z, Li G, Xiao J. Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies. J Orthop Translat 2024; 48:123-132. [PMID: 39220678 PMCID: PMC11363721 DOI: 10.1016/j.jot.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 07/18/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024] Open
Abstract
Pain is the leading symptom for most individuals with osteoarthritis (OA), a complex condition marked by joint discomfort. Recently, the dynamic interplay between the nervous and immune systems has become a focal point for understanding pain regulation. Despite this, there is still a substantial gap in our comprehensive understanding of the neuroimmune interactions and their effects on pain in OA. This review examines the bidirectional influences between immune cells and nerves in OA progression. It explores current approaches that target neuroimmune pathways, including promoting M2 macrophage polarization and specific neuronal receptor targeting, for effective pain reduction. Translational potential statement This review provides a comprehensive overview of the mechanisms underlying the interplay between the immune system and nervous system during the progression of OA, as well as their contributions to pain. Additionally, it compiles existing intervention strategies targeting neuroimmunity for the treatment of OA pain. This information offers valuable insights for researchers seeking to address the challenge of OA pain.
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Affiliation(s)
- Yi Zou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Changyu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Zhenggang Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Guanghui Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Jun Xiao
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
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21
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Yan L, Wang J, Cai X, Liou Y, Shen H, Hao J, Huang C, Luo G, He W. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm (Beijing) 2024; 5:e658. [PMID: 39092292 PMCID: PMC11292402 DOI: 10.1002/mco2.658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 08/04/2024] Open
Abstract
Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.
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Affiliation(s)
- Lingfeng Yan
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Damage Repair and RegenerationChongqingChina
| | - Jue Wang
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Damage Repair and RegenerationChongqingChina
| | - Xin Cai
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Damage Repair and RegenerationChongqingChina
| | - Yih‐Cherng Liou
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- National University of Singapore (NUS) Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore
| | - Han‐Ming Shen
- Faculty of Health SciencesUniversity of MacauMacauChina
| | - Jianlei Hao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University)Jinan UniversityZhuhaiGuangdongChina
- The Biomedical Translational Research InstituteFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospitaland West China School of Basic Medical Sciences and Forensic MedicineSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Gaoxing Luo
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Damage Repair and RegenerationChongqingChina
| | - Weifeng He
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Damage Repair and RegenerationChongqingChina
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Shen X, Zheng W, Du X, Chen Y, Song X, Yang L, Yuan Q. The role of C5aR1-mediated hepatic macrophage efferocytosis in NASH. Sci Rep 2024; 14:17232. [PMID: 39060563 PMCID: PMC11282180 DOI: 10.1038/s41598-024-68207-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/22/2024] [Indexed: 07/28/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the first major chronic liver disease in developed countries. 10-20% of NAFLD patients will progress to non-alcoholic steatohepatitis (NASH), and up to 25% of NASH patients may develop cirrhosis within 10 years. Therefore, it is critical to find key targets that may treat this disease. Here, we identified C5aR1 as a highly-expressed gene in NASH mouse model through analyzing Gene Expression Omnibus (GEO) database and confirmed its higher expression in livers of NASH patients than that of NAFL patients. Meanwhile, we verified its positive correlation with patients' serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. In vivo and in vitro experiments revealed that knocking down C5aR1 in liver significantly reduced liver weight ratio and serum ALT and AST levels and attenuated inflammatory cell infiltration and cell apoptosis in the liver of NASH mice as well as enhanced the efferocytotic ability of liver macrophages, suggesting that C5aR1 may play a crucial role in the efferocytosis of liver macrophages. Furthermore, we also found that the expression levels of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3), caspase-1, IL-1β and other inflammation-related factors in the liver were significantly reduced. Our work demonstrates a potential mechanism of how C5aR1 deficiency protects against diet-induced NASH by coordinating the regulation of inflammatory factors and affecting hepatic macrophage efferocytosis.
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Affiliation(s)
- Xuan Shen
- Department of Basic Medicine, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, 154000, Heilongjiang, China
| | - Wenxing Zheng
- Department of Endocrinology, The First Huaian Hospital Affiliated to Nanjing Medical University, Huai'an, 223300, Jiangsu, China
| | - Xinna Du
- Department of Basic Medicine, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China
| | - Yuping Chen
- Department of Basic Medicine, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China
| | - Xianping Song
- Department of Basic Medicine, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China
| | - Liucai Yang
- Department of Basic Medicine, Jiangsu Vocational College of Medicine, Yancheng, 224005, Jiangsu, China.
| | - Qi Yuan
- Department of Endocrinology, The First Huaian Hospital Affiliated to Nanjing Medical University, Huai'an, 223300, Jiangsu, China.
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Mahmoudi A, Jalili A, Butler AE, Aghaee-Bakhtiari SH, Jamialahmadi T, Sahebkar A. Exploration of the Key Genes Involved in Non-alcoholic Fatty Liver Disease and Possible MicroRNA Therapeutic Targets. J Clin Exp Hepatol 2024; 14:101365. [PMID: 38433957 PMCID: PMC10904918 DOI: 10.1016/j.jceh.2024.101365] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 02/11/2024] [Indexed: 03/05/2024] Open
Abstract
Background MicroRNAs (miRNAs) are promising therapeutic agents for non-alcoholic fatty liver disease (NAFLD). This study aimed to identify key genes/proteins involved in NAFLD pathogenesis and progression and to evaluate miRNAs influencing their expression. Methods Gene expression profiles from datasets GSE151158, GSE163211, GSE135251, GSE167523, GSE46300, and online databases were analyzed to identify significant NAFLD-related genes. Then, protein-protein interaction networks and module analysis identified hub genes/proteins, which were validated using real-time PCR in oleic acid-treated HepG2 cells. Functional enrichment analysis evaluated signaling pathways and biological processes. Gene-miRNA interaction networks identified miRNAs targeting critical NAFLD genes. Results The most critical overexpressed hub genes/proteins included: TNF, VEGFA, TLR4, CYP2E1, ACE, SCD, FASN, SREBF2, and TGFB1 based on PPI network analysis, of which TNF, TLR4, SCD, FASN, SREBF2, and TGFB1 were up-regulated in oleic acid-treated HepG2 cells. Functional enrichment analysis for biological processes highlighted programmed necrotic cell death, lipid metabolic process response to reactive oxygen species, and inflammation. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the highest adjusted P-value signaling pathways encompassed AGE-RAGE in diabetic complications, TNF, and HIF-1 signaling pathways. In gene-miRNA network analysis, miR-16 and miR-124 were highlighted as the miRNAs exerting the most influence on important NAFLD-related genes. Conclusion In silico analyses identified NAFLD therapeutic targets and miRNA candidates to guide further experimental investigation.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Amin Jalili
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | | | - Seyed H. Aghaee-Bakhtiari
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
- Bioinformatics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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24
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Gao Y, Liu MF, Li Y, Liu X, Cao YJ, Long QF, Yu J, Li JY. Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators. World J Stem Cells 2024; 16:670-689. [PMID: 38948098 PMCID: PMC11212550 DOI: 10.4252/wjsc.v16.i6.670] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/22/2024] [Accepted: 05/11/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment. AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model. METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice. RESULTS Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF. CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.
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Affiliation(s)
- Ying Gao
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial Rehabilitation Hospital, Xi'an 710000, Shaanxi Province, China
| | - Mei-Fang Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Ningxia Medical University (The First People's Hospital of Yinchuan), Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Yang Li
- School of Clinical Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi Province, China
| | - Xi Liu
- Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Yu-Jie Cao
- Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Qian-Fa Long
- Department of Neurosurgery, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Jun Yu
- Department of Emergency, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Jian-Ying Li
- Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China.
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Gao Y, Liu MF, Li Y, Liu X, Cao YJ, Long QF, Yu J, Li JY. Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators. World J Stem Cells 2024; 16:669-688. [DOI: 10.4252/wjsc.v16.i6.669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/22/2024] [Accepted: 05/11/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment.
AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model.
METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.
RESULTS Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF.
CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.
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Affiliation(s)
- Ying Gao
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial Rehabilitation Hospital, Xi’an 710000, Shaanxi Province, China
| | - Mei-Fang Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Ningxia Medical University (The First People’s Hospital of Yinchuan), Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Yang Li
- School of Clinical Medicine, Xi’an Medical University, Xi’an 710021, Shaanxi Province, China
| | - Xi Liu
- Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Yu-Jie Cao
- Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Qian-Fa Long
- Department of Neurosurgery, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Jun Yu
- Department of Emergency, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Jian-Ying Li
- Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
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Xie Y, Liu F. The role of the gut microbiota in tumor, immunity, and immunotherapy. Front Immunol 2024; 15:1410928. [PMID: 38903520 PMCID: PMC11188355 DOI: 10.3389/fimmu.2024.1410928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/20/2024] [Indexed: 06/22/2024] Open
Abstract
In recent years, with the deepening understanding of the gut microbiota, it has been recognized to play a significant role in the development and progression of diseases. Particularly in gastrointestinal tumors, the gut microbiota influences tumor growth by dysbiosis, release of bacterial toxins, and modulation of host signaling pathways and immune status. Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment efficacy by enhancing immune cell responses. Current clinical and preclinical studies have demonstrated that the gut microbiota and its metabolites can enhance the effectiveness of immunotherapy. Furthermore, certain gut microbiota can serve as biomarkers for predicting immunotherapy responses. Interventions targeting the gut microbiota for the treatment of gastrointestinal diseases, especially colorectal cancer (CRC), include fecal microbiota transplantation, probiotics, prebiotics, engineered bacteria, and dietary interventions. These approaches not only improve the efficacy of ICIs but also hold promise for enhancing immunotherapy outcomes. In this review, we primarily discuss the role of the gut microbiota and its metabolites in tumors, host immunity, and immunotherapy.
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Affiliation(s)
| | - Fang Liu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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27
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Yu L, Gao F, Li Y, Su D, Han L, Li Y, Zhang X, Feng Z. Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications. Biomed Pharmacother 2024; 175:116724. [PMID: 38761424 DOI: 10.1016/j.biopha.2024.116724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 05/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.
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Affiliation(s)
- Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Feifei Gao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Yaoxin Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Dan Su
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Liping Han
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yueming Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Xuehan Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Engineering Technology Research Center of immune checkpoint drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453000, P.R.China.
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Xu S, Lu F, Gao J, Yuan Y. Inflammation-mediated metabolic regulation in adipose tissue. Obes Rev 2024; 25:e13724. [PMID: 38408757 DOI: 10.1111/obr.13724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 11/04/2023] [Accepted: 01/17/2024] [Indexed: 02/28/2024]
Abstract
Chronic inflammation of adipose tissue is a prominent characteristic of many metabolic diseases. Lipid metabolism in adipose tissue is consistently dysregulated during inflammation, which is characterized by substantial infiltration by proinflammatory cells and high cytokine concentrations. Adipose tissue inflammation is caused by a variety of endogenous factors, such as mitochondrial dysfunction, reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, cellular senescence, ceramides biosynthesis and mediators of lipopolysaccharides (LPS) signaling. Additionally, the gut microbiota also plays a crucial role in regulating adipose tissue inflammation. Essentially, adipose tissue inflammation arises from an imbalance in adipocyte metabolism and the regulation of immune cells. Specific inflammatory signals, including nuclear factor-κB (NF-κB) signaling, inflammasome signaling and inflammation-mediated autophagy, have been shown to be involved in the metabolic regulation. The pathogenesis of metabolic diseases characterized by chronic inflammation (obesity, insulin resistance, atherosclerosis and nonalcoholic fatty liver disease [NAFLD]) and recent research regarding potential therapeutic targets for these conditions are also discussed in this review.
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Affiliation(s)
- Shujie Xu
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Feng Lu
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianhua Gao
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Yuan
- Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Chen J, Wu L, Li Y. FGL1 and FGL2: emerging regulators of liver health and disease. Biomark Res 2024; 12:53. [PMID: 38816776 PMCID: PMC11141035 DOI: 10.1186/s40364-024-00601-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 05/21/2024] [Indexed: 06/01/2024] Open
Abstract
Liver disease is a complex group of diseases with high morbidity and mortality rates, emerging as a major global health concern. Recent studies have highlighted the involvement of fibrinogen-like proteins, specifically fibrinogen-like protein 1 (FGL1) and fibrinogen-like protein 2 (FGL2), in the regulation of various liver diseases. FGL1 plays a crucial role in promoting hepatocyte growth, regulating lipid metabolism, and influencing the tumor microenvironment (TME), contributing significantly to liver repair, non-alcoholic fatty liver disease (NAFLD), and liver cancer. On the other hand, FGL2 is a multifunctional protein known for its role in modulating prothrombin activity and inducing immune tolerance, impacting viral hepatitis, liver fibrosis, hepatocellular carcinoma (HCC), and liver transplantation. Understanding the functions and mechanisms of fibrinogen-like proteins is essential for the development of effective therapeutic approaches for liver diseases. Additionally, FGL1 has demonstrated potential as a disease biomarker in radiation and drug-induced liver injury as well as HCC, while FGL2 shows promise as a biomarker in viral hepatitis and liver transplantation. The expression levels of these molecules offer exciting prospects for disease assessment. This review provides an overview of the structure and roles of FGL1 and FGL2 in different liver conditions, emphasizing the intricate molecular regulatory processes and advancements in targeted therapies. Furthermore, it explores the potential benefits and challenges of targeting FGL1 and FGL2 for liver disease treatment and the prospects of fibrinogen-like proteins as biomarkers for liver disease, offering insights for future research in this field.
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Affiliation(s)
- Jiongming Chen
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Lei Wu
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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Zhang L, Tao M, Zhang H, Zhang S, Hou X, Zong C, Sun G, Feng S, Yan H, Lu Y, Yang X, Wei L, Zhang L. Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells. Chem Biol Interact 2024; 395:111015. [PMID: 38663797 DOI: 10.1016/j.cbi.2024.111015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 04/15/2024] [Accepted: 04/21/2024] [Indexed: 05/01/2024]
Abstract
Hepatic fibrosis is a complex chronic liver disease in which both macrophages and hepatic stellate cells (HSCs) play important roles. Many studies have shown that clodronate liposomes (CLD-lipos) effectively deplete macrophages. However, no liposomes have been developed that target both HSCs and macrophages. This study aimed to evaluate the therapeutic efficacy of lipopolysaccharide-coupled clodronate liposomes (LPS-CLD-lipos) and the effects of liposomes size on hepatic fibrosis. Three rat models of hepatic fibrosis were established in vivo; diethylnitrosamine (DEN), bile duct ligation (BDL), and carbon tetrachloride (CCl4). Hematoxylin and eosin staining and serological liver function indices were used to analyze pathological liver damage. Masson's trichrome and Sirius red staining were used to evaluate the effect of liposomes on liver collagen fibers. The hydroxyproline content in liver tissues was determined. In vitro cell counting kit-8 (CCK-8) and immunofluorescence assays were used to further explore the effects of LPS modification and liposomes size on the killing of macrophages and HSCs. Both in vitro and in vivo experiments showed that 200 nm LPS-CLD-lipos significantly inhibited hepatic fibrosis and the abnormal deposition of collagen fibers in the liver and improved the related indicators of liver function. Further results showed that 200 nm LPS-CLD-lipos increased the clearance of macrophages and induced apoptosis of hepatic stellate cells, significantly. The present study demonstrated that 200 nm LPS-CLD-lipos could significantly inhibit hepatic fibrosis and improve liver function-related indices and this study may provide novel ideas and directions for hepatic fibrosis treatment.
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Affiliation(s)
- Luyao Zhang
- School of Pharmacy, Anhui Medical University, Hefei, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China; Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Min Tao
- School of Pharmacy, Anhui Medical University, Hefei, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China; Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hengyan Zhang
- Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Shichao Zhang
- Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xiaojuan Hou
- The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chen Zong
- The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Gangqi Sun
- Molecular Pathology Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shiyao Feng
- Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Haixin Yan
- Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Ying Lu
- Department of Pharmaceutical Sciences, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Xue Yang
- The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
| | - Lixin Wei
- The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
| | - Li Zhang
- School of Pharmacy, Anhui Medical University, Hefei, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China; Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
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Lian J, Xu Y, Shi J, Liu P, Hua Y, Zhang C, Ren T, Su G, Cheng S, Nie Z, Jia T. Acteoside and isoacteoside alleviate renal dysfunction and inflammation in lipopolysaccharide-induced acute kidney injuries through inhibition of NF-κB signaling pathway. PLoS One 2024; 19:e0303740. [PMID: 38748639 PMCID: PMC11095724 DOI: 10.1371/journal.pone.0303740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 04/30/2024] [Indexed: 05/19/2024] Open
Abstract
Acute kidney injury (AKI) is a sudden loss of renal function with a high mortality rate and inflammation is thought to be the underlying cause. The phenylpropanoid components acteoside (ACT) and isoacteoside (ISO), which were isolated from Cistanche deserticola Y.C.Ma, have been reported to have preventive effects against kidney disorders. This study aimed to investigate the anti-inflammatory properties and protective mechanisms of ACT and ISO. In this investigation, kidney function was assessed using a semi-automatic biochemical analyzer, histopathology was examined using Hematoxylin-Eosin staining and immunohistochemistry, and the concentration of inflammatory cytokines was assessed using an enzyme-linked immunosorbent assay (ELISA) test. In addition, using Western blot and q-PCR, the expression of proteins and genes connected to the NF-κB signaling pathway in mice with lipopolysaccharide (LPS)-induced AKI was found. The findings showed that under AKI intervention in LPS group, ACT group and ISO group, the expression of Rela (Rela gene is responsible for the expression of NFκB p65 protein) and Tlr4 mRNA was considerably elevated (P<0.01), which led to a significant improvement in the expression of MyD88, TLR4, Iκ-Bɑ and NF-κB p65 protein (P<0.001). The levels of Alb, Crea and BUN (P<0.001) increased along with the release of downstream inflammatory factors such as IL-1β, IL-6, Cys-C, SOD1 and TNF-α (P<0.001). More importantly, the study showed that ISO had a more favorable impact on LPS-induced AKI mice than ACT. In conclusion, by inhibiting NF-κB signaling pathway, ACT and ISO could relieve renal failure and inflammation in AKI, offering a fresh possibility for the therapeutic management of the condition.
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Affiliation(s)
- Jing Lian
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Yisheng Xu
- Waters Technology (Beijing) Co., Ltd., Beijing, China
| | - Ji Shi
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Pengpeng Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Yue Hua
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Chao Zhang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Tianhang Ren
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Guoming Su
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Shizan Cheng
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Zixuan Nie
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Tianzhu Jia
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
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Liu S, Wang B, Lin L, Xu W, Gong ZH, Xiao WJ. L-Theanine alleviates heat stress through modulation of gut microbiota and immunity. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:2059-2072. [PMID: 37917744 DOI: 10.1002/jsfa.13095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/23/2023] [Accepted: 11/02/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Heat stress (HS) damages the intestines, disrupting gut microbiota and immune balance. l-Theanine (LTA), found in tea, alleviates oxidative stress and cell apoptosis under HS; however, its effects on gut microbiota and immunity under HS remain unclear. To investigate this, we administered LTA doses of 100, 200, and 400 mg·kg-1 ·d-1 to C57BL/6J mice. On day 44, the model group and LTA intervention group were subjected to continuous 7-day HS treatment for 2 h per day. RESULTS The results demonstrated that LTA intervention improved food intake, body weight, and intestinal epithelium, and reduced the water intake of heat-stressed mice. It increased the abundance of Turicibacter, Faecalibaculum, Bifidobacterium, and norank_f_Muribaculaceae, while reducing that of Lachnoclostridium and Desulfovibrio. LTA intervention also increased the concentrations of amino acid and lipid metabolites, regulated macrophage differentiation stimulated by gut microbiota and metabolites, reduced the antigen presentation by macrophages to the specific immune system, promoted B-cell differentiation and sIgA secretion, inhibited pro-inflammatory factors, and enhanced intestinal defense. Mechanistically, LTA downregulated heat shock protein 70 expression and the TLR4/NF-κB/p38 MAPK signaling pathway, restoring gut microbiota and immune balance. CONCLUSION We suggest that LTA can alleviate HS by modulating gut microbiota, metabolites, and immunity, indicating its potential as a natural active ingredient for anti-HS food products. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Sha Liu
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
- Sino-Kenya Joint Laboratory of Tea Science, Hunan Agricultural University, Changsha, China
| | - Bin Wang
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
- Sino-Kenya Joint Laboratory of Tea Science, Hunan Agricultural University, Changsha, China
| | - Ling Lin
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
- Sino-Kenya Joint Laboratory of Tea Science, Hunan Agricultural University, Changsha, China
| | - Wei Xu
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
- Sino-Kenya Joint Laboratory of Tea Science, Hunan Agricultural University, Changsha, China
| | - Zhi-Hua Gong
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
- Sino-Kenya Joint Laboratory of Tea Science, Hunan Agricultural University, Changsha, China
| | - Wen-Jun Xiao
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
- Sino-Kenya Joint Laboratory of Tea Science, Hunan Agricultural University, Changsha, China
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Sun M, Zhang Y, Guo A, Xia Z, Peng L. Progress in the Correlation Between Inflammasome NLRP3 and Liver Fibrosis. J Clin Transl Hepatol 2024; 12:191-200. [PMID: 38343611 PMCID: PMC10851067 DOI: 10.14218/jcth.2023.00231] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 09/02/2023] [Accepted: 09/13/2023] [Indexed: 01/04/2025] Open
Abstract
Liver fibrosis is a reversible condition that occurs in the early stages of chronic liver disease. To develop effective treatments for liver fibrosis, understanding the underlying mechanism is crucial. The NOD-like receptor protein 3 (NLRP3) inflammasome, which is a part of the innate immune system, plays a crucial role in the progression of various inflammatory diseases. NLRP3 activation is also important in the development of various liver diseases, including viral hepatitis, alcoholic or nonalcoholic liver disease, and autoimmune liver disease. This review discusses the role of NLRP3 and its associated molecules in the development of liver fibrosis. It also highlights the signal pathways involved in NLRP3 activation, their downstream effects on liver disease progression, and potential therapeutic targets in liver fibrosis. Further research is encouraged to develop effective treatments for liver fibrosis.
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Affiliation(s)
- Meihua Sun
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Yanqing Zhang
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Anbing Guo
- Department of Gastroenterology, Linyi People’s Hospital, Linyi, Shandong, China
| | - Zongting Xia
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Lijun Peng
- Department of Gastroenterology, Linyi People’s Hospital, Linyi, Shandong, China
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Rao PL, Shen YH, Song YJ, Xu Y, Xu HX. Prunella vulgaris L. attenuates gut dysbiosis and endotoxin leakage against alcoholic liver disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117237. [PMID: 37769885 DOI: 10.1016/j.jep.2023.117237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/14/2023] [Accepted: 09/26/2023] [Indexed: 10/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Prunella vulgaris L. (PVL) is a perennial herb belonging to the Labiate family, first recorded in the "Shen Nong's Classic of the Materia Medica". PVL can enter the liver and gallbladder channel to show its function in clearing the liver fire, dispersing nodules, dissolving swelling, and improving vision. The traditional use of PVL is to protect liver function and has clinical applications in liver diseases therapy. The modern pharmacological studies have been shown to possess potential hepatoprotection, but its underlying mechanisms against alcoholic liver disease (ALD) in mice remains to be elucidated. AIM OF THE STUDY This study aimed to explore the protective effect and potential mechanism of PVL on alcohol induced liver injury. MATERIALS AND METHODS We used Lieber-DeCarli ethanol liquid diet fed Male C57BL/6 mice for four weeks plus a single binge (NIAAA modified model) to establish an ALD model and explored the protective effects of PVL extract against ALD. Western blot, Flow cytometry and RT-qPCR methods were used to detect lipid metabolism disorders and the inflammatory response induced by macrophages in ALD mice, and the gut microbiota composition changes were detected by 16s rRNA to reveal the potential mechanism of PVL against ALD. RESULTS In ALD mice, PVL can ameliorate excessive alcohol intake-induced liver injury and lipid metabolism disorders associated with improvement of gut microbiota dysbiosis and intestinal barrier damage. PVL reduced the translocation of endotoxin, which subsequently inhibits hepatic inflammation mediated by the TLR4/MyD88 signaling pathway. CONCLUSION These findings demonstrated the protective potential of PVL against gut dysbiosis and endotoxin leakage in ALD mice, which provides a theoretical basis for PVL against liver diseases.
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Affiliation(s)
- Pei-Li Rao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yun-Hui Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China
| | - Yi-Jie Song
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yu Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China.
| | - Hong-Xi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China.
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Dong T, Li J, Liu Y, Zhou S, Wei X, Hua H, Tang K, Zhang X, Wang Y, Wu Z, Gao C, Zhang H. Roles of immune dysregulation in MASLD. Biomed Pharmacother 2024; 170:116069. [PMID: 38147736 DOI: 10.1016/j.biopha.2023.116069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 12/28/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Its occurrence and progression involve the process from simple hepatic steatosis to metabolic dysfunction associated steatohepatitis (MASH), which could develop into advanced liver fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). Growing evidences support that the pathogenesis and progression of MASLD are closely related to immune system dysfunction. This review aims to summarize the association of MASLD with immune disorders and the prospect of using immunotherapy for MASLD.
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Affiliation(s)
- Tingyu Dong
- The Second Clinical Medical College of Anhui Medical University, Hefei 230032, China; Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Jiajin Li
- The Second Clinical Medical College of Anhui Medical University, Hefei 230032, China; Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Yuqing Liu
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Shikai Zhou
- The Second Clinical Medical College of Anhui Medical University, Hefei 230032, China
| | - Xiang Wei
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Hongting Hua
- Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Kechao Tang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Xiaomin Zhang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Yiming Wang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Zhen Wu
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China
| | - Chaobing Gao
- Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Huabing Zhang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei 230032, China.
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Zeng Q, Liu CH, Ampuero J, Wu D, Jiang W, Zhou L, Li H, Bai L, Romero-Gómez M, Tang H. Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance. RNA Biol 2024; 21:1-15. [PMID: 38113132 PMCID: PMC10761141 DOI: 10.1080/15476286.2023.2290769] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2023] [Indexed: 12/21/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.
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Affiliation(s)
- Qingmin Zeng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Javier Ampuero
- Digestive Diseases Unit, Virgen del Rocío University Hospital. SeLiver group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US). University of Seville, Seville, Spain
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Manuel Romero-Gómez
- Digestive Diseases Unit, Virgen del Rocío University Hospital. SeLiver group at Institute of Biomedicine of Seville (IBIS: HUVRocío/CSIC/US). University of Seville, Seville, Spain
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China
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Ren G, Bai C, Yi S, Cong Q, Zhu Y. Mechanisms and Therapeutic Strategies for MAFLD Targeting TLR4 Signaling Pathways. J Innate Immun 2023; 16:45-55. [PMID: 38128497 PMCID: PMC10783892 DOI: 10.1159/000535524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/23/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases. The underlying pathophysiological mechanisms are intricate and involve various factors. Unfortunately, there is currently a lack of available effective treatment options. Toll-like receptors (TLRs) are a group of pattern-recognition receptors that are responsible for activating the innate immune system. Research has demonstrated that TLR4 plays a pivotal role in the progression of MAFLD by facilitating the pathophysiological mechanisms. SUMMARY Lipid peroxidation, pro-inflammatory factors, insulin resistance (IR), and dysbiosis of intestinal microbiota are considered as the pathogenic mechanisms of MAFLD. This review summarizes the impact of TLR4 signaling pathways on the progression of MAFLD, specifically in relation to lipid metabolic disorders, IR, oxidative stress, and gut microbiota disorders. Additionally, we emphasize the potential therapeutic approaches for MAFLD that target TLR4 signaling pathways, including the use of plant extracts, traditional Chinese medicines, probiotics, pharmaceuticals such as peroxisome proliferator-activated receptor antagonists and farnesol X agonists, and lifestyle modifications such as dietary changes and exercise also considered. Furthermore, TLR4 signaling pathways have also been linked to the lean MAFLD. KEY MESSAGES TLR4 plays a crucial role in MAFLD by triggering IR, buildup of lipids, imbalance in gut microbiota, oxidative stress, and initiation of immune responses. The mitigation of MAFLD can be accomplished by suppressing the TLR4 signaling pathway. In the future, it could potentially emerge as a therapeutic target for the condition.
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Affiliation(s)
- Guanghui Ren
- Department of Infectious Disease, Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China,
| | - Changchuan Bai
- Dalian Hospital of Traditional Chinese Medicine, Dalian, China
| | - Sitong Yi
- Department of Infectious Disease, Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qingwei Cong
- Department of Infectious Disease, Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ying Zhu
- Department of Infectious Disease, Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Qin J, Cao P, Ding X, Zeng Z, Deng L, Luo L. Machine learning identifies ferroptosis-related gene ANXA2 as potential diagnostic biomarkers for NAFLD. Front Endocrinol (Lausanne) 2023; 14:1303426. [PMID: 38192427 PMCID: PMC10773757 DOI: 10.3389/fendo.2023.1303426] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/14/2023] [Indexed: 01/10/2024] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease, still lacks effective therapeutic targets today. Ferroptosis, a type of cell death characterized by lipid peroxidation, has been linked to NAFLD in certain preclinical trials, yet the exact molecular mechanism remains unclear. Thus, we analyzed the relationship between ferroptosis genes and NAFLD using high-throughput data. Method We utilized a total of 282 samples from five datasets, including two mouse ones, one human one, one single nucleus dataset and one single cell dataset from Gene Expression Omnibus (GEO), as the data basis of our study. To filter robust treatment targets, we employed four machine learning methods (LASSO, SVM, RF and Boruta). In addition, we used an unsupervised consensus clustering algorithm to establish a typing scheme for NAFLD based on the expression of ferroptosis related genes (FRGs). Our study is also the first to investigate the dynamics of FRGs throughout the disease process by time series analysis. Finally, we validated the relationship between core gene and ferroptosis by in vitro experiments on HepG2 cells. Results We discovered ANXA2 as a central focus in NAFLD and indicated its potential to boost ferroptosis in HepG2 cells. Additionally, based on the results obtained from time series analysis, ANXA2 was observed to significantly define the disease course of NAFLD. Our results demonstrate that implementing a ferroptosis-based staging method may hold promise for the diagnosis and treatment of NAFLD. Conclusion Our findings suggest that ANXA2 may be a useful biomarker for the diagnosis and characterization of NAFLD.
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Affiliation(s)
- Jingtong Qin
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuexuan Ding
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Zeyao Zeng
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Liyan Deng
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Lianxiang Luo
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, China
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Wu L, Liu X, Lei J, Zhang N, Zhao H, Zhang J, Deng H, Li Y. Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells. J Immunother Cancer 2023; 11:e008081. [PMID: 38056898 PMCID: PMC10711877 DOI: 10.1136/jitc-2023-008081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer. METHODS The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs. RESULTS Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy. CONCLUSION These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.
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Affiliation(s)
- Lei Wu
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Xudong Liu
- School of Medicine, Chongqing University, Chongqing, China
| | - Juan Lei
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Nan Zhang
- School of Medicine, Chongqing University, Chongqing, China
| | - Huakan Zhao
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Jiangang Zhang
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Huan Deng
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
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Alruwaili M, Al-kuraishy HM, Alexiou A, Papadakis M, ALRashdi BM, Elhussieny O, Saad HM, Batiha GES. Pathogenic Role of Fibrinogen in the Neuropathology of Multiple Sclerosis: A Tale of Sorrows and Fears. Neurochem Res 2023; 48:3255-3269. [PMID: 37442896 PMCID: PMC10514123 DOI: 10.1007/s11064-023-03981-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/20/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating neurodegenerative disease of the central nervous system (CNS) due to injury of the myelin sheath by immune cells. The clotting factor fibrinogen is involved in the pathogenesis of MS by triggering microglia and the progress of neuroinflammation. Fibrinogen level is correlated with MS severity; consequently, inhibition of the fibrinogen cascade may reduce MS neuropathology. Thus, this review aimed to clarify the potential role of fibrinogen in the pathogenesis of MS and how targeting of fibrinogen affects MS neuropathology. Accumulation of fibrinogen in the CNS may occur independently or due to disruption of blood-brain barrier (BBB) integrity in MS. Fibrinogen acts as transduction and increases microglia activation which induces the progression of inflammation, oxidative stress, and neuronal injury. Besides, brain fibrinogen impairs the remyelination process by inhibiting the differentiation of oligodendrocyte precursor cells. These findings proposed that fibrinogen is associated with MS neuropathology through interruption of BBB integrity, induction of neuroinflammation, and demyelination with inhibition of the remyelination process by suppressing oligodendrocytes. Therefore, targeting of fibrinogen and/or CD11b/CD18 receptors by metformin and statins might decrease MS neuropathology. In conclusion, inhibiting the expression of CD11b/CD18 receptors by metformin and statins may decrease the pro-inflammatory effect of fibrinogen on microglia which is involved in the progression of MS.
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Affiliation(s)
- Mubarak Alruwaili
- Department of Internal Medicine, College of Medicine, Jouf University, Sakaka, Saudi Arabia
| | - Hayder M. Al-kuraishy
- Department of Pharmacology, Toxicology and Medicine, Medical Faculty, College of Medicine, Al-Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770 Australia
- AFNP Med, 1030 Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany
| | - Barakat M. ALRashdi
- Biology Department, College of Science, Jouf University, Sakaka, 41412 Saudi Arabia
| | - Omnya Elhussieny
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744 Egypt
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744 Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511 Egypt
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Zhu W, Xu M, Zhu M, Song Y, Zhang J, Zheng C. Cuyun Recipe ameliorates pregnancy loss by regulating macrophage polarization and hypercoagulable state during the peri-implantation period in an ovarian hyperstimulation mouse model. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 119:154974. [PMID: 37523838 DOI: 10.1016/j.phymed.2023.154974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/09/2023] [Accepted: 07/15/2023] [Indexed: 08/02/2023]
Abstract
BACKGROUND The Chinese herbal prescription Cuyun Recipe (CYR) has been widely used to treat clinical infertility and has shown good efficacy. Animal experiments have shown that CYR can promote implantation in mice, however, the exact mechanism underlying the implantation has not been elucidated. PURPOSE To investigate the effect and mechanism of CYR on regulating macrophage polarization and hypercoagulability during the peri-implantation period in mice with ovarian hyperstimulation. METHODS An ovarian hyperstimulation mouse model was developed, followed by treatment with CYR. Mice were sacrificed on day (D)4.5, D6, or D8 of gestation. The number of implantation sites, the pathological changes of the uterus and ovaries were assessed. The polarization of monocytes/macrophages in the spleen and endometrium, the expression and localization of cytokines were further detected. Furthermore, analyses of hypercoagulable state of the blood were also performed. RESULTS Treatment with CYR increased the average number of implantation sites, promoted angiogenesis in endometrial, and regulated monocytes/macrophages and the cytokine levels. Moreover, CYR downregulated the overexpression of D-dimer and fgl2 after ovarian hyperstimulation. CONCLUSION CYR facilitates embryo implantation by alleviating ovarian hyperstimulation, promoting endometrial decidualization and angiogenesis, regulating macrophage polarization, and reversing the hypercoagulable state of the blood.
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Affiliation(s)
- Wenxin Zhu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Menghao Xu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Mengdi Zhu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Yufan Song
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Jinmin Zhang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China
| | - Cuihong Zheng
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China.
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Fang H, Lin D, Li X, Wang L, Yang T. Therapeutic potential of Ganoderma lucidum polysaccharide peptide in Doxorubicin-induced nephropathy: modulation of renin-angiotensin system and proteinuria. Front Pharmacol 2023; 14:1287908. [PMID: 37841924 PMCID: PMC10570435 DOI: 10.3389/fphar.2023.1287908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/21/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction: In the Doxorubicin (DOX)-induced nephropathy model, proteinuria is a manifestation of progressive kidney injury. The pathophysiology of renal illness is heavily influenced by the renin-angiotensin system (RAS). To reduce renal RAS activation and proteinuria caused by DOX, this study evaluated the effectiveness of Ganoderma lucidum polysaccharide peptide (GL-PP), a new glycopeptide produced from Ganoderma lucidum grown on grass. Methods: Three groups of BALB/c male mice were created: control, DOX, and DOX + GL-PP. GL-PP (100 mg/kg) was administered to mice by intraperitoneal injection for 4 weeks following a single intravenous injection of DOX (10 mg/kg via the tail vein). Results: After 4 weeks, full-length and soluble pro(renin) receptor (fPRR/sPRR) overexpression in DOX mouse kidneys, which is crucial for the RAS pathway, was dramatically inhibited by GL-PP therapy. Additionally, GL-PP successfully reduced elevation of urinary renin activity and angiotensin II levels, supporting the idea that GL-PP inhibits RAS activation. Moreover, GL-PP showed a considerable downregulation of nicotinamide adenine nucleotide phosphate oxidase 4 (NOX4) expression and a decrease in hydrogen peroxide (H2O2) levels. GL-PP treatment effectively reduced glomerular and tubular injury induced by DOX, as evidenced by decreased proteinuria, podocyte damage, inflammation, oxidative stress, apoptosis, and fibrosis. Discussion: GL-PP inhibits intrarenal PRR/sPRR-RAS activation and upregulation of NOX4 and H2O2, suggesting potential therapeutic approaches against DOX-induced nephropathy.
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Affiliation(s)
- Hui Fang
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Dongmei Lin
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Xinxuan Li
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Lianfu Wang
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Teng Yang
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
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Wang J, Qu J, Liu S, Xu Q, Li X, Zhu Y, Liu X, Yi J, Yuan Z, Huang P, Yin Y, Wen L, Wu J. Tannic Acid Ameliorates Systemic Glucose and Lipid Metabolic Impairment Induced by Low-Dose T-2 Toxin Exposure. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:12574-12586. [PMID: 37525894 DOI: 10.1021/acs.jafc.3c02934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
Subacute mycotoxin exposure in food is commonly overlooked. As one of the most toxic trichothecene mycotoxins, the T-2 toxin severely pollutes human foods and animal feeds. In our study, we investigated the effects of low-dose T-2 toxin on glucose and lipid metabolic function and further investigated the protective effect of tannic acid (TA) in C57BL/6J mice. Results showed that low-dose T-2 toxin significantly impaired blood glucose and lipid homeostasis, promoted ferroptosis in the pancreas and subsequent repression of insulin secretion in β-cells, and impacted hepatic glucose and lipid metabolism by targeted inhibition of the insulin receptor substrate (IRS)/phosphatidylin-ositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, which induced insulin resistance and steatosis in the liver. TA treatment attenuated pancreatic function and hepatic metabolism by ameliorating oxidative stress and insulin resistance in mice. These findings provide new perspectives on the toxic mechanism and intervention of chronic subacute toxicity of foodborne mycotoxins.
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Affiliation(s)
- Ji Wang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Jianyu Qu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Sha Liu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Qiurong Xu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Xiaowen Li
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Yuanyuan Zhu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Changsha Lvye Biotechnology Co., Ltd., Changsha 410100, China
| | - Xiangyan Liu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Jine Yi
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Zhihang Yuan
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Peng Huang
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Yulong Yin
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Lixin Wen
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Jing Wu
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
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Li C, Cui Y, Zhou W, Zhang Y, Huang X, Yu F. Bone Turnover Markers in Adults with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Int J Endocrinol 2023; 2023:9957194. [PMID: 39263527 PMCID: PMC11390221 DOI: 10.1155/2023/9957194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/05/2023] [Accepted: 07/12/2023] [Indexed: 09/13/2024] Open
Abstract
Objective Previous studies suggested that the level of bone turnover markers (BTMs) could be altered in patients with nonalcoholic fatty liver disease (NAFLD). We aim to provide a comprehensive understanding on the associations between BTMs and NAFLD in adults with a meta-analysis. Methods Articles published up to January 31, 2023, were systematically searched in PubMed, Web of Science, Cochrane database, Embase, and CNKI. The search formula is as follows: "nonalcoholic fatty liver disease" combined with the terms that bone turnover markers such as "osteocalcin," "collagen type I trimeric cross-linked peptide," and "procollagen type I N-terminal peptide." Stata 15.0 software was used to calculate the pooled OR (95% CI) and perform the heterogeneity test, sensitivity analysis, and publication bias. Results We identified 18 studies with a total of 12,310 participants. Statistical differences were found between patients with NAFLD compared to the control group for osteocalcin (n = 15 studies; SMD: -0.69; 95% CI: -0.73--0.64; P=0.002), procollagen type I N-terminal propeptide (n = 5 studies; SMD: -0.40; 95% CI: -0.80--0.00; P=0.049), and collagen type I cross-linked C-telopeptide (n = 7 studies; SMD: -0.16; 95% CI: -0.23--0.09); P < 0.001). Conclusion Bone turnover markers were lower in patients with NAFLD compared to the control group.
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Affiliation(s)
- Chao Li
- Chengdu Jinjiang District Maternal and Child Healthcare Hospital, Chengdu, China
| | - Yali Cui
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- Department of Laboratory Medicine, Meishan Women and Children's Hospital, Alliance Hospital of West China Second University Hospital, Sichuan University, Meishan, China
| | - Wenjie Zhou
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Yiduo Zhang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Xiaocui Huang
- Chengdu Jinjiang District Maternal and Child Healthcare Hospital, Chengdu, China
| | - Fan Yu
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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Wang HW, Tang J, Sun L, Li Z, Deng M, Dai Z. Mechanism of immune attack in the progression of obesity-related type 2 diabetes. World J Diabetes 2023; 14:494-511. [PMID: 37273249 PMCID: PMC10236992 DOI: 10.4239/wjd.v14.i5.494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
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Affiliation(s)
- Hua-Wei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ming Deng
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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Huang L, Zhan D, Xing Y, Yan Y, Li Q, Zhang J, Li S, Ning Q, Zhang C, Luo X. FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress. Front Immunol 2023; 14:1157027. [PMID: 37051251 PMCID: PMC10083319 DOI: 10.3389/fimmu.2023.1157027] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/16/2023] [Indexed: 03/28/2023] Open
Abstract
IntroductionThe impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined.MethodsLipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying.ResultsUpon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs.ConclusionOur findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.
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Affiliation(s)
- Lianjing Huang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Di Zhan
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ying Xing
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yaqin Yan
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qing Li
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jingyi Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sujuan Li
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cai Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Xiaoping Luo, ; Cai Zhang,
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Xiaoping Luo, ; Cai Zhang,
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Fan G, Li Y, Zong Y, Suo X, Jia Y, Gao M, Yang X. GPAT3 regulates the synthesis of lipid intermediate LPA and exacerbates Kupffer cell inflammation mediated by the ERK signaling pathway. Cell Death Dis 2023; 14:208. [PMID: 36964139 PMCID: PMC10039030 DOI: 10.1038/s41419-023-05741-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 03/26/2023]
Abstract
In the process of inflammatory activation, macrophages exhibit lipid metabolism disorders and accumulate lipid droplets. Kupffer cells (KCs) are the resident hepatic macrophage with critical defense functions in the pathogenesis of several types of liver disease. How dysregulated lipid metabolism contributes to perturbed KCs functions remains elusive. Here we report that glycerol-3-phosphate acyltransferase 3 (GPAT3) plays a key role in KCs inflammation response. Our findings indicate that lipopolysaccharide (LPS)-mediated inflammatory activation markedly increased lipid droplets (LDs) accumulation in KCs. This increase could be attributed to significantly up-regulated GPAT3. The loss of GPAT3 function obviously reduced KCs inflammation reaction both in vivo and in vitro, and was accompanied by improved mitochondrial function and decreased production of lysophosphatidic acid (LPA), in turn inhibiting extracellular regulated protein kinases (ERK) signaling pathway. Overall, this study highlights the role of GPAT3 in inflammatory activation of KCs and could thus be a potential therapeutic target for the treatment of inflammation-related liver disease.
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Affiliation(s)
- Guoqiang Fan
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, 210095, P. R. China
| | - Yanfei Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, 210095, P. R. China
| | - Yibo Zong
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, 210095, P. R. China
| | - Xiaoyi Suo
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, 210095, P. R. China
| | - Yimin Jia
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, 210095, P. R. China
| | - Mingming Gao
- Laboratory of Lipid Metabolism, Hebei Medical University, Shijiazhuang, Hebei, 050017, China
| | - Xiaojing Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, 210095, P. R. China.
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, P. R. China.
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Zhang JJ, Shen Y, Chen XY, Jiang ML, Yuan FH, Xie SL, Zhang J, Xu F. Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis. Front Endocrinol (Lausanne) 2023; 14:1115890. [PMID: 37008925 PMCID: PMC10061151 DOI: 10.3389/fendo.2023.1115890] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
Introduction Non-alcoholic steatohepatitis (NASH), an advanced subtype of non-alcoholic fatty liver disease (NAFLD), has becoming the most important aetiology for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. This study were designed to explore novel genes associated with NASH. Methods Here, five independent Gene Expression Omnibus (GEO) datasets were combined into a single cohort and analyzed using network biology approaches. Results 11 modules identified by weighted gene co-expression network analysis (WGCNA) showed significant association with the status of NASH. Further characterization of four gene modules of interest demonstrated that molecular pathology of NASH involves the upregulation of hub genes related to immune response, cholesterol and lipid metabolic process, extracellular matrix organization, and the downregulation of hub genes related to cellular amino acid catabolic, respectively. After DEGs enrichment analysis and module preservation analysis, the Turquoise module associated with immune response displayed a remarkably correlation with NASH status. Hub genes with high degree of connectivity in the module, including CD53, LCP1, LAPTM5, NCKAP1L, C3AR1, PLEK, FCER1G, HLA-DRA and SRGN were further verified in clinical samples and mouse model of NASH. Moreover, single-cell RNA-seq analysis showed that those key genes were expressed by distinct immune cells such as microphages, natural killer, dendritic, T and B cells. Finally, the potential transcription factors of Turquoise module were characterized, including NFKB1, STAT3, RFX5, ILF3, ELF1, SPI1, ETS1 and CEBPA, the expression of which increased with NASH progression. Discussion In conclusion, our integrative analysis will contribute to the understanding of NASH and may enable the development of potential biomarkers for NASH therapy.
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Affiliation(s)
- Jun-jie Zhang
- Center for Molecular Pathology, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Yan Shen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Xiao-yuan Chen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Man-lei Jiang
- Department of Hepatology, The Affiliated Fifth People’s Hospital of Ganzhou, Gannan Medical University, Ganzhou, China
| | - Feng-hua Yuan
- Center for Molecular Pathology, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Shui-lian Xie
- Center for Molecular Pathology, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jie Zhang
- Department of Hepatology, The Affiliated Fifth People’s Hospital of Ganzhou, Gannan Medical University, Ganzhou, China
| | - Fei Xu
- Department of Hepatology, The Affiliated Fifth People’s Hospital of Ganzhou, Gannan Medical University, Ganzhou, China
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Tang YL, Zhu L, Tao Y, Lu W, Cheng H. Role of targeting TLR4 signaling axis in liver-related diseases. Pathol Res Pract 2023; 244:154410. [PMID: 36917917 DOI: 10.1016/j.prp.2023.154410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/05/2023] [Accepted: 03/06/2023] [Indexed: 03/09/2023]
Abstract
Toll-like receptor 4 (TLR4) plays an important role as a key signal-receiving transmembrane protein molecule in the liver, and substances that target the liver exert therapeutic effects via TLR4-related signaling pathways. This article provides a comprehensive review of targeting the TLR4 signaling axis to play an important role in the liver based on endogenous substances. Articles were divided into 5 major types of liver disease, acute liver injury, viral hepatitis, alcoholic and non-alcoholic liver disease, cirrhosis, and liver cancer, to elucidate how various endogenous substances affect the liver via the TLR4 pathway and the important role of the pathway itself in liver-related diseases to discover the potential therapeutic implications of the TLR4-related pathway in the liver. The results indicate that activation of the TLR4-related signaling axis primarily plays a role in promoting disease progression in liver-related diseases, and the TLR4/MyD88/NF-κB axis plays the most dominant role. Therefore, exploring the full effects of drugs targeting the TLR4-related signaling axis in the liver and the new use of old drugs may be a new research direction.
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Affiliation(s)
- Ying-Le Tang
- Medical College, Yangzhou University, Yangzhou, China
| | - Lin Zhu
- Medical College, Yangzhou University, Yangzhou, China
| | - Yan Tao
- Medical College, Yangzhou University, Yangzhou, China
| | - Wen Lu
- Medical College, Yangzhou University, Yangzhou, China
| | - Hong Cheng
- Yangzhou University Medical College, Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Institute of Translational Medicine, Yangzhou University, Jiangsu, Yangzhou, China.
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50
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Fu L, Liu Z, Liu Y. Fibrinogen-like protein 2 in inflammatory diseases: A future therapeutic target. Int Immunopharmacol 2023; 116:109799. [PMID: 36764282 DOI: 10.1016/j.intimp.2023.109799] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 12/09/2022] [Accepted: 01/25/2023] [Indexed: 02/10/2023]
Abstract
Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen family, exists as a membrane-bound protein with immune-associated coagulation activity and a soluble form possessing immunosuppressive functions. The immunomodulatory role of FGL2 is evident in fibrin deposition-associated inflammatory diseases and cancer, suggesting that FGL2 expression could be exploited as a disease biomarker and a therapeutic target. Recently, in vitro studies and knockout and transgenic animal FGL2 models have been used by us and others to reveal the involvement of FGL2 in the pathogenesis of various inflammatory diseases. This review summarizes our current knowledge of the immunomodulatory role of FGL2 in inflammatory diseases and examines the role of FGL2 as a potential therapeutic target.
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Affiliation(s)
- Li Fu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China
| | - Zheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China.
| | - Yang Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China.
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