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1
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Schwabe RF, Brenner DA. Hepatic stellate cells: balancing homeostasis, hepatoprotection and fibrogenesis in health and disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01068-6. [PMID: 40404839 DOI: 10.1038/s41575-025-01068-6] [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] [Accepted: 04/03/2025] [Indexed: 05/24/2025]
Abstract
In the past decades, the pathogenic role of hepatic stellate cells (HSCs) in the development of liver fibrosis and its complications has been deeply characterized, rendering HSCs a primary target for antifibrotic therapies. By contrast, the beneficial roles of HSCs in liver homeostasis and liver disease are only beginning to emerge, revealing critical regulatory and fibrosis-independent functions in hepatic zonation, metabolism, injury, regeneration and non-parenchymal cell identity. Here, we review how HSC mediators, such as R-spondin 3, hepatocyte growth factor and bone morphogenetic proteins, regulate critical and homeostatic liver functions in health and disease via cognate receptors in hepatocytes, Kupffer cells and endothelial cells. We highlight how the balance shifts from protective towards fibropathogenic HSC mediators during the progression of chronic liver disease (CLD) and the impact of this shifted balance on patient outcomes. Notably, the protective roles of HSCs are not accounted for in current therapeutic concepts for CLD. We discuss the concept that reverting the HSC balance from fibrogenesis towards hepatoprotection might represent a novel holistic treatment approach to inhibit fibrogenesis and restore epithelial health in CLD simultaneously.
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Affiliation(s)
- Robert F Schwabe
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
- Columbia University Digestive and Liver Disease Research Center, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
- Institute of Human Nutrition, New York, NY, USA.
| | - David A Brenner
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, UC San Diego, La Jolla, CA, USA
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2
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Cui X, Sun Q, Wang H. Targeting fibroblast growth factor (FGF)-21: a promising strategy for metabolic dysfunction-associated steatotic liver disease treatment. Front Pharmacol 2025; 16:1510322. [PMID: 40331190 PMCID: PMC12052895 DOI: 10.3389/fphar.2025.1510322] [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: 10/12/2024] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Metabolic dysfunction-associated steatitic liver disease (MASLD) is the predominant chronic liver disease, with its incidence increasing year by year. It has emerged as the most rapidly increasing contributor to liver-related mortality worldwide and is becoming a principal cause of end-stage liver disorders, primarily cancer of the liver and liver transplantation, hence putting a substantial economic burden on public health. The approval of Resmetirom signifies significant advancement in the treatment of metabolic dysfunction-associated steatohepatitis (MASH); nonetheless, the heterogeneity of MASLD renders it challenging for a single medication to address the requirements of all patients. Consequently, it is essential to formulate varied therapeutic approaches for distinct pathogenic causes and phases of disease. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factor family, plays a positive and protective role in MASLD. It attenuates hepatic steatosis and lipotoxicity, ameliorates insulin resistance (IR), reduces oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, as well as possesses anti-fibrotic effects. As a result, FGF21 has the potential to treat MASLD. In this review, we will address the possible mechanisms of FGF21 therapy for MASLD to facilitate the development of clinical therapies targeting FGF21 for MASLD.
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Affiliation(s)
- Xinyue Cui
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Quanhao Sun
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haiqiang Wang
- Department of Gastroenterology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Wang Z, Gao H, Ma X, Zhu D, Zhao L, Xiao W. Adrenic acid: A promising biomarker and therapeutic target (Review). Int J Mol Med 2025; 55:20. [PMID: 39575474 PMCID: PMC11611323 DOI: 10.3892/ijmm.2024.5461] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/06/2024] [Indexed: 01/05/2025] Open
Abstract
Adrenic acid is a 22‑carbon unsaturated fatty acid that is widely present in the adrenal gland, liver, brain, kidney and vascular system that plays a regulatory role in various pathophysiological processes, such as inflammatory reactions, lipid metabolism, oxidative stress, vascular function, and cell death. Adrenic acid is a potential biomarker for various ailments, including metabolic, neurodegenerative and cardiovascular diseases and cancer. In addition, adrenic acid is influenced by the pharmacological properties of several natural products, such as astragaloside IV, evodiamine, quercetin, kaempferol, Berberine‑baicalin and prebiotics, so it is a promising new target for clinical treatment and drug development. However, the molecular mechanisms by which adrenic acid exerts are unclear. The present study systematically reviewed the biosynthesis and metabolism of adrenic acid, focusing on intrinsic mechanisms that influence the progression of metabolic, cardiovascular and neurological disease. These mechanisms regulate several key processes, including immuno‑inflammatory response, oxidative stress, vascular function and cell death. In addition, the present study explored the potential clinical translational value of adrenic acid as a biomarker and therapeutic target. To the best of our knowledge, the present study is first systematic summary of the mechanisms of action of adrenic acid across a range of diseases. The present study provides understanding of the wide range of metabolic activities of adrenic acid and a basis for further exploring the pathogenesis and therapeutic targets of various diseases.
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Affiliation(s)
- Ze Wang
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Haoyang Gao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Xiaotong Ma
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Danlin Zhu
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Linlin Zhao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
- School of Physical Education, Shanghai Normal University, Shanghai 200234, P.R. China
| | - Weihua Xiao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
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Taga M, Yoshida K, Yano S, Takahashi K, Kyoizumi S, Sasatani M, Suzuki K, Ogawa T, Kusunoki Y, Tsuruyama T. Hepatic Stellate Cell-mediated Increase in CCL5 Chemokine Expression after X-ray Irradiation Determined In Vitro and In Vivo. Radiat Res 2024; 202:862-869. [PMID: 39449628 DOI: 10.1667/rade-23-00127.1] [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: 06/30/2023] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
Radiation exposure causes hepatitis which induces hepatic steatosis and fibrosis. Although hepatic stellate cells (HSCs) have been considered potential pathological modulators for the development of hepatitis due to viral and microbial infections, their involvement in radiation-induced hepatitis is yet to be determined. This study aimed to clarify the relationship between radiation exposure and expressions of inflammatory cytokines and chemokines in HSCs in vitro and in vivo. HSCs were obtained from 1-week-old mice, known to be highly sensitive to radiation-induced hepatocellular carcinoma, using a newly established method combining liver perfusion, cell dissociation, and density gradient centrifugation, followed by magnetic negative selection of hematopoietic and endothelial cells with anti-CD45.2 and CD146 antibodies. The isolated HSCs were confirmed by the expression of desmin and glial fibrillary acidic protein (GFAP). We demonstrated that primary cultured HSCs, exposed to X-ray irradiation (0, 1.9, and 3.8 Gy) and cultured for 3 and 7 days, produced elevated levels of C-C motif chemokine ligand 5 (CCL5, also known as RANTES) inflammatory chemokine in a dose-dependent manner. An in vivo immunofluorescence method confirmed that increased CCL5 signals were observed in GFAP-positive HSCs in mouse livers 7 days after whole-body X-ray irradiation (1.9 and 3.8 Gy). Adequate expression of C-C motif chemokine receptor 5 (Ccr5), a receptor for CCL5, was also detected using real-time PCR in the liver of both irradiated and non-irradiated mice. Taken together, our data suggest that HSCs may drive hepatitis via CCL5/CCR5 axis in the liver under radiation-induced stress. Furthermore, this newly established experimental protocol can help evaluate the expression of other inflammatory cytokines in primary cultures of HSCs isolated from infant mice.
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Affiliation(s)
- Masataka Taga
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
| | - Kengo Yoshida
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
| | - Shiho Yano
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
| | - Keiko Takahashi
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
| | - Seishi Kyoizumi
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
| | - Megumi Sasatani
- Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Keiji Suzuki
- Radiation Risk Control Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Tomohiro Ogawa
- Center for the Advancement of Higher Education, Faculty of Engineering, Kindai University, Hiroshima, Japan
| | - Yoichiro Kusunoki
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
| | - Tatsuaki Tsuruyama
- Department of Molecular Biosciences, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima City, Hiroshima, Japan
- Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [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: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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López CAM, Freiberger RN, Sviercz FA, Jarmoluk P, Cevallos C, Quarleri J, Delpino MV. HIV and gp120-induced lipid droplets loss in hepatic stellate cells contribute to profibrotic profile. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167084. [PMID: 38368823 DOI: 10.1016/j.bbadis.2024.167084] [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: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024]
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins, primarily collagen, in response to liver injury caused by chronic liver diseases. HIV infection accelerates the progression of liver fibrosis in patients co-infected with HCV or HBV compared to those who are only mono-infected. The early event in the progression of liver fibrosis involves the activation of hepatic stellate cells (HSCs), which entails the loss of lipid droplets (LD) to fuel the production of extracellular matrix components crucial for liver tissue healing. Thus, we are examining the mechanism by which HIV stimulates the progression of liver fibrosis. HIV-R5 tropic infection was unable to induce the expression of TGF-β, collagen deposition, α-smooth muscle actin (α-SMA), and cellular proliferation. However, this infection induced the secretion of the profibrogenic cytokine IL-6 and the loss of LD. This process involved the participation of peroxisome proliferator-activated receptor (PPAR)-α and an increase in lysosomal acid lipase (LAL), along with the involvement of Microtubule-associated protein 1 A/1B-light chain 3 (LC3), strongly suggesting that LD loss could occur through acid lipolysis. These phenomena were mimicked by the gp120 protein from the R5 tropic strain of HIV. Preincubation of HSCs with the CCR5 receptor antagonist, TAK-779, blocked gp120 activity. Additionally, experiments performed with pseudotyped-HIV revealed that HIV replication could also contribute to LD loss. These results demonstrate that the cross-talk between HSCs and HIV involves a series of interactions that help explain some of the mechanisms involved in the exacerbation of liver damage observed in co-infected individuals.
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Affiliation(s)
- Cinthya Alicia Marcela López
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Rosa Nicole Freiberger
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Franco Agustín Sviercz
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Patricio Jarmoluk
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Cintia Cevallos
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Victoria Delpino
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina.
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Li H, Pan T, Gao L, Ding R, Yu Y, Ma M, Wang Y, Jin S, Chen Y, Ding C, Xu L. Chemokine receptor CCR1 regulates macrophage activation through mTORC1 signaling in nonalcoholic steatohepatitis. Metabolism 2024; 151:155758. [PMID: 38070823 DOI: 10.1016/j.metabol.2023.155758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND AND AIMS Chemokine (CC motif) receptor 1 (CCR1) promotes liver fibrosis in mice. However, its effects on nonalcoholic steatohepatitis (NASH) remain unclear. Therefore, the present study aimed to investigate the role of CCR1 in the progression of NASH. METHODS Human serum and liver tissues were obtained from patients with NASH and controls. Systemic (Ccr1-/-) and liver macrophage-knockout Ccr1 (Ccr1LKD) mice were fed a high-cholesterol and high-fat (CL) diet for 12 weeks or a methionine/choline-deficient (MCD) diet for 4 weeks. BX471 was used to pharmacologically inhibit CCR1 in CL-fed mice. RESULTS CCR1 was significantly upregulated in liver samples from patients with NASH and in animal models of dietary-induced NASH. In the livers of mice fed a CL diet for 12 weeks, the CCR1 protein colocalized with F4/80+ macrophages rather than with hepatic stellate cells. Compared to their wild-type littermates, Ccr1-/- mice fed with the CL or MCD diet showed inhibition of NASH-associated hepatic steatosis, inflammation, and fibrosis. Mechanistically, Ccr1 deficiency suppressed macrophage infiltration and activation by attenuating the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar results were observed in Ccr1LKD mice administered the CL diet. Moreover, CCR1 inhibition by BX471 effectively suppressed NASH progression in CL-fed mice. CONCLUSIONS Ccr1 deficiency mitigated macrophage activity by inhibiting mTORC1 signaling, thereby preventing the development of NASH. Notably, the CCR1 inhibitor BX471 protected against NASH. These findings would help in developing novel strategies for the treatment of NASH.
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Affiliation(s)
- Haoran Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Tongtong Pan
- Hepatology Diagnosis and Treatment Center, The First Affiliated Hospital of Wenzhou Medical University & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou 325035, Zhejiang, China
| | - Lingjia Gao
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Rongxiu Ding
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Yanwen Yu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Mengchen Ma
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Yajiao Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Shengnan Jin
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Yongping Chen
- Hepatology Diagnosis and Treatment Center, The First Affiliated Hospital of Wenzhou Medical University & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou 325035, Zhejiang, China.
| | - Chunming Ding
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
| | - Liang Xu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
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Bhattacharjee J, Beaton G, Ravula SB, Lee SJ, Bacon KB, Jenkinson CP, Warren M, Tucci FC, Kohli R. Lysophosphatidic acid receptor 1 antagonist (EPGN2154) causes regression of NASH in preclinical NASH models. Hepatol Commun 2023; 7:e0323. [PMID: 37994050 PMCID: PMC10666985 DOI: 10.1097/hc9.0000000000000323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/28/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND NASH causes a tremendous health care burden in the United States. A glucagon-like peptide-1 agonist, semaglutide (Sema), treatment resulted in hepatic steatosis reduction in clinical trials of NASH. Lysophosphatidic acid receptor 1 antagonists are known to have antifibrotic effects in several organs. We tested Sema and a novel lysophosphatidic acid receptor 1 antagonist, EPGN2154, individually and in combination to evaluate their efficacy for NASH remission in preclinical models. METHODS In the present study, we used (1) C57Bl6/J wild-type mice fed on a high-fat, high-carbohydrate (HFHC) diet for 16 weeks and (2) leptin-deficient mice (ob/ob) fed on an Amylin liver NASH diet for 16 weeks. After 16 weeks, the mice were randomly distributed in equal numbers in (1) no-drug, (2) EPGN2154, (3) Sema, and (4) EPGN2154+Sema treatment groups for 8 additional weeks at a dosage of 10 mg/kg body weight for EPGN2154 (oral gavage, 5 days a week) and 6.17 μg/kg body weight of Sema (subcutaneous injection every alternate day, 3 days a week). RESULTS In the wild-type-high-fat, high-carbohydrate model, we observed the most body weight loss in the EPGN2154+Sema combination group compared to the other treatment groups. All groups led to a significant reduction in alanine transaminase levels when compared to high-fat, high-carbohydrate-fed wild type. However, no significant difference in alanine transaminase levels was observed among the treatment groups. In the ob/ob mice study, Sema did not cause body weight loss. Moreover, the EPGN2154 and the combination groups had a lower NAFLD Activity Score and incidence of advanced-stage hepatic fibrosis than the Sema group. CONCLUSIONS EPGN2154 demonstrated a hepato-protective effect independent of body weight loss in preclinical NASH models.
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Affiliation(s)
- Jashdeep Bhattacharjee
- Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | | | | | | | | | | | - Mikako Warren
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | | | - Rohit Kohli
- Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, California, USA
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Hassan GS, Flores Molina M, Shoukry NH. The multifaceted role of macrophages during acute liver injury. Front Immunol 2023; 14:1237042. [PMID: 37736102 PMCID: PMC10510203 DOI: 10.3389/fimmu.2023.1237042] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/15/2023] [Indexed: 09/23/2023] Open
Abstract
The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.
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Affiliation(s)
- Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Manuel Flores Molina
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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Bradshaw D, Abramowicz I, Bremner S, Verma S, Gilleece Y, Kirk S, Nelson M, Housman R, Miras H, Orkin C, Fox A, Curnock M, Jennings L, Gompels M, Clarke E, Robinson R, Lambert P, Chadwick D, Perry N. Hepmarc: A 96 week randomised controlled feasibility trial of add-on maraviroc in people with HIV and non-alcoholic fatty liver disease. PLoS One 2023; 18:e0288598. [PMID: 37450478 PMCID: PMC10348519 DOI: 10.1371/journal.pone.0288598] [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: 02/02/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023] Open
Abstract
OBJECTIVES Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration. METHODS We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores. RESULTS Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores. CONCLUSIONS This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis. TRIAL REGISTRATION Clinical trial registry: ISCRTN, registration number 31461655.
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Affiliation(s)
- Daniel Bradshaw
- The Lawson Unit, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom
| | - Iga Abramowicz
- Brighton and Sussex Clinical Trials Unit, University of Sussex, Brighton, United Kingdom
| | - Stephen Bremner
- Brighton and Sussex Clinical Trials Unit, University of Sussex, Brighton, United Kingdom
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
| | - Sumita Verma
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
| | - Yvonne Gilleece
- The Lawson Unit, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom
| | - Sarah Kirk
- The Lawson Unit, University Hospitals Sussex NHS Foundation Trust, Brighton, United Kingdom
| | - Mark Nelson
- Department of HIV and Sexual Health, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
| | - Rosalie Housman
- Department of HIV and Sexual Health, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
| | - Helena Miras
- Grahame Hayton Unit, Barts Health NHS Trust, London, United Kingdom
| | - Chloe Orkin
- Grahame Hayton Unit, Barts Health NHS Trust, London, United Kingdom
| | - Ashini Fox
- Department of Genitourinary Medicine and HIV, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
| | - Michael Curnock
- Department of Genitourinary Medicine and HIV, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
| | - Louise Jennings
- Department of HIV, North Bristol NHS Trust, Bristol, United Kingdom
| | - Mark Gompels
- Department of HIV, North Bristol NHS Trust, Bristol, United Kingdom
| | - Emily Clarke
- Department of Genitourinary Medicine and HIV, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Rachel Robinson
- Department of Genitourinary Medicine and HIV, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Pauline Lambert
- Department of Infectious Diseases, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom
| | - David Chadwick
- Department of Infectious Diseases, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom
| | - Nicky Perry
- Brighton and Sussex Clinical Trials Unit, University of Sussex, Brighton, United Kingdom
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11
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Montori M, Baroni GS, Santori P, Di Giampaolo C, Ponziani F, Abenavoli L, Scarpellini E. Liver Damage and COVID-19: At Least a “Two-Hit” Story in Systematic Review. Curr Issues Mol Biol 2023; 45:3035-3047. [PMID: 37185723 PMCID: PMC10136465 DOI: 10.3390/cimb45040199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
COVID-19 pandemic waves have hit on our lives with pulmonary and, also, gastrointestinal symptoms. The latter also includes acute liver damage linked to direct SARS-CoV-2 action and/or drug-induced (DILI) in the frame of pre-existing chronic liver disease. We aimed to review literature data regarding liver damage during COVID-19. We conducted a systematic search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: liver disease, COVID-19, acute liver damage, drug-induced liver injury, antivirals. Acute liver damage due to SARS-CoV-2 infection is common among COVID-19 patients and is generally self-limiting. However, chronic hepatic diseases, such as metabolic-associated fatty liver disease (MAFLD), are associated with a less favorable prognosis, especially when alkaline phosphatases show a significant rise. Pathophysiology of COVID-19 liver damage is multifaceted and helps understand differences in liver derangement among patients. Thus, early recognition, monitoring and treatment of liver damage are crucial in these patients. In the frame of a not-ending pandemic sustained by SARS-CoV-2, it is crucial to recognize acute hepatic decompensation due to the virus and/or drugs used for COVID-19 treatment.
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Affiliation(s)
- Michele Montori
- Transplant and Hepatic Damage Unit, Polytechincs University of Marche, 60121 Ancona, Italy
| | | | - Pierangelo Santori
- Hepatology and Internal Medicine Unit, Madonna del Soccorso General Hospital, 00168 San Benedetto del Tronto, Italy
| | - Catia Di Giampaolo
- Hepatology and Internal Medicine Unit, Madonna del Soccorso General Hospital, 00168 San Benedetto del Tronto, Italy
| | - Francesca Ponziani
- Digestive Disease Center (C.E.M.A.D.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Græcia, 88100 Catanzaro, Italy
| | - Emidio Scarpellini
- Hepatology and Internal Medicine Unit, Madonna del Soccorso General Hospital, 00168 San Benedetto del Tronto, Italy
- Translational Research Center for Gastrointestinal Disorders, Gasthuisberg University Hospital, KULeuven, 3000 Lueven, Belgium
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12
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Choaib A, Issa E, El Choueiry F, Eldin JN, Shbaklo K, Alhajj M, Sawaya RT, Assi G, Nader M, Chatila R, Faour WH. SARS-CoV-2-mediated liver injury: pathophysiology and mechanisms of disease. Inflamm Res 2022; 72:301-312. [PMID: 36539655 PMCID: PMC9767399 DOI: 10.1007/s00011-022-01683-y] [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: 11/15/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND SARS-CoV-2-induced severe inflammatory response can be associated with severe medical consequences leading to multi-organ failure, including the liver. The main mechanism behind this assault is the aggressive cytokine storm that induces cytotoxicity in various organs. Of interest, hepatic stellate cells (HSC) respond acutely to liver injury through several molecular mechanisms, hence furthering the perpetuation of the cytokine storm and its resultant tissue damage. In addition, hepatocytes undergo apoptosis or necrosis resulting in the release of pro-inflammatory and pro-fibrogenic mediators that lead to chronic liver inflammation. AIMS The aim of this review is to summarize available data on SARS-CoV-2-induced liver inflammation in addition to evaluate the potential effect of anti-inflammatory drugs in attenuating SARS-CoV-2-induced liver inflammation. METHODS Thorough PubMed search was done to gather and summarize published data on SARS-CoV-2-induced liver inflammation. Additionally, various anti-inflammatory potential treatments were also documented. RESULTS Published data documented SARS-CoV-2 infection of liver tissues and is prominent in most liver cells. Also, histological analysis showed various features of tissues damage, e.g., hepatocellular necrosis, mitosis, cellular infiltration, and fatty degeneration in addition to microvesicular steatosis and inflammation. Finally, the efficacy of the different drugs used to treat SARS-CoV-2-induced liver injury, in particular the anti-inflammatory remedies, are likely to have some beneficial effect to treat liver injury in COVID-19. CONCLUSION SARS-CoV-2-induced liver inflammation is a serious condition, and drugs with potent anti-inflammatory effect can play a major role in preventing irreversible liver damage in COVID-19.
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Affiliation(s)
- Ali Choaib
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Elio Issa
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Francesca El Choueiry
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Jade Nasser Eldin
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Khodor Shbaklo
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Maryline Alhajj
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Ramy Touma Sawaya
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Ghaith Assi
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Moni Nader
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, P.O. Box 127788, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Rajaa Chatila
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
- Internal Medicine-Gastroenterology, Lebanese American University Medical Center-Rizk Hospital (LAUMC-RH), Beirut, Lebanon
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon.
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13
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Association between Immunologic Markers and Cirrhosis in Individuals from a Prospective Chronic Hepatitis C Cohort. Cancers (Basel) 2022; 14:cancers14215280. [PMID: 36358697 PMCID: PMC9657502 DOI: 10.3390/cancers14215280] [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: 09/09/2022] [Revised: 10/19/2022] [Accepted: 10/23/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Chronic hepatitis C virus (HCV) infection can affect immune response and inflammatory pathways, leading to severe liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Methods: In a prospective cohort of chronically HCV-infected individuals, we sampled 68 individuals who developed cirrhosis, 91 controls who did not develop cirrhosis, and 94 individuals who developed HCC. Unconditional odds ratios (ORs) from polytomous logistic regression models and canonical discriminant analyses (CDAs) were used to compare categorical (C) baseline plasma levels for 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. Leave-one-out cross validation was used to produce receiver operating characteristic curves to assess predictive ability of markers. Lastly, biological pathways were assessed in association with cirrhotic development compared to controls. Results: After multivariable adjustment, DEFA-1 (OR: C2v.C1 = 7.73; p < 0.0001), ITGAM (OR: C2v.C1 = 4.03; p = 0.0002), SCF (OR: C4v.C1 = 0.19; p-trend = 0.0001), and CCL11 (OR: C4v.C1 = 0.31; p-trend= 0.002) were all associated with development of cirrhosis compared to controls; these markers, together with clinical/demographics variables, improved prediction of cirrhosis from 55.7% (in clinical/demographic-only model) to 74.9% accuracy. A twelve-marker model based on CDA results further increased prediction of cirrhosis to 88.0%. While six biological pathways were found to be associated with cirrhosis, cell adhesion was the only pathway associated with cirrhosis after Bonferroni correction. In contrast to cirrhosis, DEFA-1 and ITGAM levels were inversely associated with HCC risk. Conclusions: Pending validation, these findings highlight the important role of immunological markers in predicting HCV-related cirrhosis even 11 years post-enrollment.
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14
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Wallace SJ, Tacke F, Schwabe RF, Henderson NC. Understanding the cellular interactome of non-alcoholic fatty liver disease. JHEP Rep 2022; 4:100524. [PMID: 35845296 PMCID: PMC9284456 DOI: 10.1016/j.jhepr.2022.100524] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. Non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, has become the leading indication for liver transplantation in both Europe and the USA. Liver fibrosis is the consequence of sustained, iterative liver injury, and the main determinant of outcomes in NASH. The liver possesses remarkable inherent plasticity, and liver fibrosis can regress when the injurious agent is removed, thus providing opportunities to alter long-term outcomes through therapeutic interventions. Although hepatocyte injury is a key driver of NASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cellular components of the fibrotic niche include endothelial cells, macrophages, passaging immune cell populations and myofibroblasts. In this review, we will describe how rapidly evolving technologies such as single-cell genomics, spatial transcriptomics and single-cell ligand-receptor analyses are transforming our understanding of the cellular interactome in NAFLD/NASH, and how this new, high-resolution information is being leveraged to develop rational new therapies for patients with NASH.
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Key Words
- BAs, bile acids
- CCL, C-C motif chemokine ligand
- CCR, C-C motif chemokine receptor
- CLD, chronic liver disease
- CTGF, connective tissue growth factor
- CXCL, C-X-C motif chemokine ligand
- CXCR, C-X-C motif chemokine receptor
- DAMP, damage-associated molecular pattern
- ECM, extracellular matrix
- ER, endoplasmic reticulum
- FGF, fibroblast growth factor
- FXR, farnesoid X receptor
- HSCs, hepatic stellate cells
- IL, interleukin
- ILC, innate lymphoid cell
- KCs, Kupffer cells
- LSECs, liver sinusoidal endothelial cells
- MAIT, mucosal-associated invariant T
- MAMPS, microbiota-associated molecular patterns
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NK(T), natural killer (T)
- NLR, Nod like receptors
- Non-alcoholic fatty liver disease (NAFLD)
- PDGF, platelet-derived growth factor
- PFs, portal fibroblasts
- SASP, senescence-associated secretory phenotype
- TGF, transforming growth factor
- TLR, Toll-like receptor
- TNF, tumour necrosis factor
- VEGF, vascular endothelial growth factor
- antifibrotic therapies
- cellular interactome
- cirrhosis
- fibrosis
- single-cell genomics
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Affiliation(s)
- Sebastian J. Wallace
- Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Robert F. Schwabe
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
- Department of Medicine, Columbia University, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
- Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Neil C. Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, UK
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15
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Ramírez-Vélez R, García-Hermoso A, Correa-Rodríguez M, Fernández-Irigoyen J, Palomino-Echeverría S, Santamaría E, Correa-Bautista JE, González-Ruíz K, Izquierdo M. Effects of Different Doses of Exercise on Inflammation Markers Among Adolescents With Overweight/Obesity: HEPAFIT Study. J Clin Endocrinol Metab 2022; 107:e2619-e2627. [PMID: 35038337 PMCID: PMC9472258 DOI: 10.1210/clinem/dgac021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Indexed: 11/30/2022]
Abstract
PROPOSE Obesity-related metabolic risk factors in adolescents who are overweight/obese may be associated with systemic low-grade inflammation; therefore, we investigated whether 6 months of exercise training altered markers of inflammation. METHODS Secondary analyses of a randomized controlled exercise-based intervention trial (September 2017-December 2018). Adolescents aged 11 to 17 years (Tanner stage II-V), 70% girls, with a body mass index z-score at or above the 85th percentile, and/or with excess of adiposity (body fat ≥ 30%). The participants were randomly assigned to the following 4 groups for 6 months: (1) standard physical education lessons, as a control (CTRL); (2) high-intensity physical education class (HIPE); (3) low-to-moderate intensity physical education class (LIPE); (4) a combined group (PLUS). Inflammatory markers and immune molecules including chemokines, cytokines, and growth factors (n = 65 biomarkers) were determined by cytokine antibody array. RESULTS Of the 120 randomly assigned participants, 95 were included in the analysis. Considering these 22 proteins, the LIPE group shows statistical significance in 9 proteins with log-fold change (logFC) and P < 0.05 (in BLC, eotaxin, fibroblast growth factor-6 [FGF-6], GCP-2, I-309, IGFBP-4, MCP-4, NAP-2, and PARC), followed by the PLUS group in 9 proteins (BLC, pro-epidermal growth factor, eotaxin, FGF-6, MCP-4, NAP-2, osteopontin, PARC, and RANTES), the HIPE group in 7 proteins (FGF-4, FGF-7, GCP-2, IGF-1, IGFBP-1, IGFBP-4, and MIP-1 delta), and the CTRL group in 6 proteins (FGF-4, IP-10, Leptin, MCP-1, MIG, and MIP-1 delta). However, subanalysis performed to detect differentially expressed proteins at baseline and after intervention, with significance at an adjusted P value ≤ 0.05 and absolute log fold-change (logFC) ≥ 1.0, showed 3 downregulated proteins in the LIPE group (BLC(logFC) = 1.27, eotaxin(logFC) = 1.18, and MCP-4(logFC) = 1.14), and 4 proteins in the HIPE group (BLC(logFC) = 1.45, FGF-6(logFC) = 1.20, MCP-4(logFC) = 1.50, and PARC(logFC) = 1.33), supporting that the changes we observed in the exercise groups were not time-related changes but occurred in response to exercise. CONCLUSIONS Implementing a 6-month physical exercise program in overweight/obese adolescents, based on LIPE and PLUS groups, significantly change several circulating inflammatory levels. Interventions involving supervised physical exercise may reduce the associated effects of systemic low-grade inflammation, thus preventing the development of obesity-related metabolic diseases in adolescents with overweight/obesity.
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Affiliation(s)
- Robinson Ramírez-Vélez
- Navarrabiomed, Hospital Universitario de Navarra (HUN), Navarra Institute for Health Research (IdiSNA), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Antonio García-Hermoso
- Navarrabiomed, Hospital Universitario de Navarra (HUN), Navarra Institute for Health Research (IdiSNA), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain
- Escuela de Ciencias de la Actividad Física, el Deporte y la Salud, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, USACH, Santiago 9170022, Chile
| | - María Correa-Rodríguez
- Department of Nursing, Faculty of Health Sciences, University of Granada, 18016 Granada, Spain
- Biosanitary Research Institute (ibs.GRANADA), Granada, Spain
| | - Joaquín Fernández-Irigoyen
- Proteored-Institute of Health Carlos III (ISCIII), Clinical Neuroproteomics Unit, Navarrabiomed, Navarra Health Department, Public University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
| | - Sara Palomino-Echeverría
- Translational Bioinformatics Unit (TransBio), Navarrabiomed, Navarra Health Department, Public University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
| | - Enrique Santamaría
- Proteored-Institute of Health Carlos III (ISCIII), Clinical Neuroproteomics Unit, Navarrabiomed, Navarra Health Department, Public University of Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
| | - Jorge Enrique Correa-Bautista
- Grupo Rendimiento Físico Militar “RENFIMIL”, Escuela Militar de Cadetes “General José María Córdova”, Bogotá, 111711, Colombia
| | - Katherine González-Ruíz
- Grupo de Investigación Salud y Movimiento. Programa de Fisioterapia. Facultad de Salud, Universidad Santiago de Cali, 760035, Colombia
- Programa de Doctorado en Ciencias Biomédicas y Biológicas, Escuela de Medicina y Ciencias de la Salud - Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario, Bogotá, 111221, Colombia
| | - Mikel Izquierdo
- Navarrabiomed, Hospital Universitario de Navarra (HUN), Navarra Institute for Health Research (IdiSNA), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: Mikel Izquierdo, PhD, Department of Health Sciences, Public University of Navarra, Avenida de Barañain s/n, 31008, Pamplona, Spain.
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16
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Cucarull B, Tutusaus A, Rider P, Hernáez-Alsina T, Cuño C, García de Frutos P, Colell A, Marí M, Morales A. Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances. Cancers (Basel) 2022; 14:cancers14030621. [PMID: 35158892 PMCID: PMC8833604 DOI: 10.3390/cancers14030621] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. Fortunately, advances in systemic treatment options are finally arriving for HCC patients. After a decade of sorafenib as a standard therapy for advanced HCC, several tyrosine kinase inhibitors (TKIs), antiangiogenic antibodies, and immune checkpoint inhibitors have reached the clinic. Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non- alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. In addition, markers of treatment efficacy are needed to speed the movement of patients towards other potentially effective treatments. Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.
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Affiliation(s)
- Blanca Cucarull
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | | | - Carlos Cuño
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Unidad Asociada (IMIM), IIBB-CSIC, CIBERCV, IDIBAPS, 08036 Barcelona, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08036 Barcelona, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, IDIBAPS, 08036 Barcelona, Spain
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
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17
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Zhang P, The E, Luo Z, Zhai Y, Yao Q, Ao L, Fullerton DA, Xu D, Meng X. Pro-inflammatory mediators released by activated monocytes promote aortic valve fibrocalcific activity. Mol Med 2022; 28:5. [PMID: 35062861 PMCID: PMC8780233 DOI: 10.1186/s10020-022-00433-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/07/2022] [Indexed: 11/24/2022] Open
Abstract
Background Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Valvular fibrocalcification is a characteristic pathological change. In diseased valves, monocyte accumulation is evident, and aortic valve interstitial cells (AVICs) display greater fibrogenic and osteogenic activities. However, the impact of activated monocytes on valular fibrocalcification remains unclear. We tested the hypothesis that pro-inflammatory mediators from activated monocytes elevate AVIC fibrogenic and osteogenic activities.
Methods and results Picro-sirius red staining and Alizarin red staining revealed collagen and calcium depositions in cultured human AVICs exposed to conditioned media derived from Pam3CSK4-stimulated monocytes (Pam3 CM). Pam3 CM up-regulated alkaline phosphatase (ALP), an osteogenic biomarker, and extracellular matrix proteins collagen I and matrix metalloproteinase-2 (MMP-2). ELISA analysis identified high levels of RANTES and TNF-α in Pam3 CM. Neutralizing RANTES in the Pam3 CM reduced its effect on collagen I and MMP-2 production in AVICs while neutralizing TNF-α attenuated the effect on AVIC ALP production. In addition, Pam3 CM induced NF-κB and JNK activation. While JNK mediated the effect of Pam3 CM on collagen I and MMP-2 production, NF-κB was critical for the effect of Pam3 CM on ALP production in AVICs. Conclusions This study demonstrates that activated monocytes elevate the fibrogenic and osteogenic activities in human AVICs through a paracrine mechanism. TNF-α and RANTES mediate the pro-fibrogenic effect of activated monocytes on AVICs through activation of JNK, and TNF-α also activates NF-κB to elevate AVIC osteogenic activity. The results suggest that infiltrated monocytes elevate AVIC fibrocalcific activity to promote CAVD progression.
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Affiliation(s)
- Peijian Zhang
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA.,Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Erlinda The
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Zichao Luo
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA.,Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yufeng Zhai
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Qingzhou Yao
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Lihua Ao
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA
| | - David A Fullerton
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Dingli Xu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Xianzhong Meng
- Department of Surgery, University of Colorado Denver, Aurora, CO, 80045, USA.
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18
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Lim AR, Ghajar CM. Thorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse. Semin Cancer Biol 2022; 78:104-123. [PMID: 33979673 PMCID: PMC9595433 DOI: 10.1016/j.semcancer.2021.05.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 02/07/2023]
Abstract
Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
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Affiliation(s)
- Andrea R Lim
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Graduate Program in Molecular and Cellular Biology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Cyrus M Ghajar
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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19
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Carter JK, Friedman SL. Hepatic Stellate Cell-Immune Interactions in NASH. Front Endocrinol (Lausanne) 2022; 13:867940. [PMID: 35757404 PMCID: PMC9218059 DOI: 10.3389/fendo.2022.867940] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a more aggressive presentation of NAFLD, is characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation and heightened immune cell activity have emerged as hallmark features of NASH and key drivers of fibrosis through the activation of hepatic stellate cells (HSCs). Recent advances in our understanding of the molecular and cellular pathways in NASH have highlighted extensive crosstalk between HSCs and hepatic immune populations that strongly influences disease activity. Here, we review these findings, emphasizing the roles of HSCs in liver immunity and inflammation, key cell-cell interactions, and exciting areas for future investigation.
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Affiliation(s)
- James K Carter
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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20
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Xu L, Chen Y, Nagashimada M, Ni Y, Zhuge F, Chen G, Li H, Pan T, Yamashita T, Mukaida N, Kaneko S, Ota T, Nagata N. CC chemokine ligand 3 deficiency ameliorates diet-induced steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice. Metabolism 2021; 125:154914. [PMID: 34656648 DOI: 10.1016/j.metabol.2021.154914] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/06/2021] [Accepted: 10/12/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. Chemokines and their receptors have potential as therapeutic targets of NAFLD. We investigated the role of CC chemokine ligand 3 (CCL3) in the development of murine and human NAFLD. METHODS CCL3-knockout mice (CCL3-/-) and littermate CCL3 wild-type control mice (WT) were fed a high-cholesterol and high-fat (CL) diet for 16 weeks to induce NAFLD. We investigated the impact of CCL3 gene deletion in bone marrow cells and leptin-deficient ob/ob mice on CL diet-induced steatohepatitis. We assayed the serum CCL3 levels in 36 patients with biopsy-proven NAFLD and nine healthy control subjects. RESULTS Compared with normal chow (NC), the CL diet induced steatohepatitis and hepatic fibrosis and elevated the plasma CCL3 level. In the liver, CCL3 protein colocalized with F4/80+ macrophages, especially CD11c+ M1-like macrophages, rather than other cell types. CCL3-/- attenuated CL diet-induced steatohepatitis and fibrosis associated with M2-dominant liver macrophages compared with the WT. The reconstitution of bone marrow (BM) cells from CCL3-/- attenuated steatohepatitis in WT mice fed a CL diet. Furthermore, crossing CCL3-/- onto the ob/ob background prevented CL diet-induced NAFLD in ob/ob mice, which was associated with a lesser inflammatory phenotype of liver macrophages. Also, the serum and hepatic levels of CCL3 were significantly increased in patients with non-alcoholic steatohepatitis (NASH) compared to those with simple fatty liver (NAFL) and healthy subjects. CONCLUSION Our data indicate that CCL3 facilitates macrophage infiltration into the liver and M1 polarization in the progression of steatohepatitis and highlight the need for further studies to determine the effect of CCL3-CCR1 and -CCR5 signaling blockade on the treatment of NAFLD.
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Affiliation(s)
- Liang Xu
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
| | - Yongping Chen
- First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Mayumi Nagashimada
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Yinhua Ni
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Fen Zhuge
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Guanliang Chen
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Haoran Li
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Tongtong Pan
- First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Tatsuya Yamashita
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Tsuguhito Ota
- Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Naoto Nagata
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
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21
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Schinagl M, Tomin T, Gindlhuber J, Honeder S, Pfleger R, Schittmayer M, Trauner M, Birner-Gruenberger R. Proteomic Changes of Activated Hepatic Stellate Cells. Int J Mol Sci 2021; 22:ijms222312782. [PMID: 34884585 PMCID: PMC8657869 DOI: 10.3390/ijms222312782] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatic stellate cells (HSC) are the major cellular drivers of liver fibrosis. Upon liver inflammation caused by a broad range of insults including non-alcoholic fatty liver, HSC transform from a quiescent into a proliferating, fibrotic phenotype. Although much is known about the pathophysiology of this process, exact cellular processes which occur in HSC and enable this transformation remain yet to be elucidated. In order to investigate this HSC transformation, we employed a simple, yet reliable model of HSC activation via an increase in growth medium serum concentration (serum activation). For that purpose, immortalized human LX-2 HSC were exposed to either 1% or 10% fetal bovine serum (FBS). Resulting quiescent (1% FBS) and activated (10% FBS) LX-2 cells were then subjected to in-depth mass spectrometry-based proteomics analysis as well as comprehensive phenotyping. Protein network analysis of activated LX-2 cells revealed an increase in the production of ribosomal proteins and proteins related to cell cycle control and migration, resulting in higher proliferation and faster migration phenotypes. Interestingly, we also observed a decrease in the expression of cholesterol and fatty acid biosynthesis proteins in accordance with a concomitant loss of cytosolic lipid droplets during activation. Overall, this work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analyses and presents an accessible model for HSC activation. Data are available via ProteomeXchange with identifier PXD029121.
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Affiliation(s)
- Maximilian Schinagl
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
| | - Tamara Tomin
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
| | - Juergen Gindlhuber
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
| | - Sophie Honeder
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
| | - Raphael Pfleger
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
| | - Matthias Schittmayer
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria;
| | - Ruth Birner-Gruenberger
- Institute of Chemical Technologies and Analytics, Technische Universität Wien, 1060 Vienna, Austria; (M.S.); (T.T.); (R.P.); (M.S.)
- Department of Pathology, Medical University of Graz, 8010 Graz, Austria; (J.G.); (S.H.)
- Correspondence:
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22
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Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
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23
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Shrivastava S, Kottilil S, Sherman KE, Masur H, Tang L. CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV/HCV-Coinfected Patients. Viruses 2021; 13:v13102074. [PMID: 34696504 PMCID: PMC8539814 DOI: 10.3390/v13102074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/08/2021] [Accepted: 10/10/2021] [Indexed: 11/16/2022] Open
Abstract
Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis.
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Affiliation(s)
- Shikha Shrivastava
- Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA;
| | - Shyam Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
| | - Kenneth E. Sherman
- Division of Digestive Diseases, University of Cincinnati, Cincinatti, OH 45267, USA;
| | - Henry Masur
- National Institutes of Health, Bethesda, MD 20892, USA;
| | - Lydia Tang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
- Correspondence:
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24
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Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model. Cancers (Basel) 2021; 13:cancers13194935. [PMID: 34638423 PMCID: PMC8508380 DOI: 10.3390/cancers13194935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/20/2021] [Accepted: 09/26/2021] [Indexed: 01/01/2023] Open
Abstract
Simple Summary Liver stem cells and activated macrophages have been implicated as contributors to liver cancer; hence, reducing their abundance is a potential avenue for therapy. In this article, we demonstrate that Maraviroc, a drug approved for human use, reduces the liver stem cell response and macrophage activation in a mouse model of liver cancer. These findings underline the preventive potential of this drug in liver cancer, a deadly disease for which there are few effective treatments. Abstract Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.
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25
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Lin SN, Mao R, Qian C, Bettenworth D, Wang J, Li J, Bruining D, Jairath V, Feagan B, Chen M, Rieder F. Development of Anti-fibrotic Therapy in Stricturing Crohn's Disease: Lessons from Randomized Trials in Other Fibrotic Diseases. Physiol Rev 2021; 102:605-652. [PMID: 34569264 DOI: 10.1152/physrev.00005.2021] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Intestinal fibrosis is considered an inevitable complication of Crohn's disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective anti-fibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver and skin. In this review, we summarized data from randomized controlled trials (RCT) of anti-fibrotic therapies in these conditions. Multiple compounds have been tested for the anti-fibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylgultaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.
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Affiliation(s)
- Si-Nan Lin
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Ren Mao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Chenchen Qian
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, Pennsylvania, United States
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Jie Wang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Jiannan Li
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - David Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States
| | - Vipul Jairath
- Alimentiv Inc., London, ON, Canada.,Department of Medicine, Western University, London, ON, Canada.,Department of Biostatistics and Epidemiology, Western University, London, ON, Canada
| | - Brian Feagan
- Alimentiv Inc., London, ON, Canada.,Department of Medicine, Western University, London, ON, Canada.,Department of Biostatistics and Epidemiology, Western University, London, ON, Canada
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | | | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, United States
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26
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Lee DH, Ku EJ, Oh TK, Jeon HJ. RANTES 59029A/G Polymorphisms Associated with Diabetic Compilations in Korean Patients with Type 2 Diabetes for over 15 Years. Genes (Basel) 2021; 12:genes12091445. [PMID: 34573427 PMCID: PMC8468929 DOI: 10.3390/genes12091445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/14/2021] [Accepted: 09/18/2021] [Indexed: 11/25/2022] Open
Abstract
Background: Polymorphisms in the RANTES gene are known to be associated with several diseases related to insulin resistance. In this study, we investigated the association between RANTES 59029A/G polymorphisms and the prevalence of diabetic complications relative to obesity in Korean patients who had type 2 diabetes (T2D) for over 15 years. Methods: A single-center, retrospective case-control study was performed. We included 271 patients with a duration of diabetes greater than 15 years. Polymerase chain reaction-restriction fragment length polymorphism was used to analyze RANTES polymorphisms, identifying genotypes as GG, AG, or AA. Obesity was defined using the body mass index with a cutoff value of 25 kg/m2. Both microvascular (retinopathy and nephropathy) and macrovascular (coronary artery disease and cerebrovascular disease) complications were evaluated. Results: The duration of T2D and hemoglobin A1c values at enrollment were 24.4 ± 5.0 years and 7.8 ± 1.6%, respectively, in the non-obese group, and 25.4 ± 6.1 years and 7.7 ± 1.7%, respectively, in the obese group. The prevalence of microvascular complications was significantly higher in the obese group compared with that in the non-obese group (83.5% vs. 72.0%, p = 0.039). Compared to the non-obese group, the obese group showed a higher proportion of the patients with AA or AG genotypes (64.3% vs. 84.5%, p = 0.001). Conclusions: The A allele of the RANTES gene is associated with obesity and may affect diabetic microvascular complications in patients with T2D for over 15 years.
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Affiliation(s)
| | | | | | - Hyun-Jeong Jeon
- Correspondence: ; Tel.: +82-43-269-6352; Fax: +82-43-273-3252
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27
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Cao S, Liu M, Sehrawat TS, Shah VH. Regulation and functional roles of chemokines in liver diseases. Nat Rev Gastroenterol Hepatol 2021; 18:630-647. [PMID: 33976393 PMCID: PMC9036964 DOI: 10.1038/s41575-021-00444-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/18/2021] [Indexed: 02/03/2023]
Abstract
Inflammation is a major contributor to the pathogenesis of almost all liver diseases. Low-molecular-weight proteins called chemokines are the main drivers of liver infiltration by immune cells such as macrophages, neutrophils and others during an inflammatory response. During the past 25 years, tremendous progress has been made in understanding the regulation and functions of chemokines in the liver. This Review summarizes three main aspects of the latest advances in the study of chemokine function in liver diseases. First, we provide an overview of chemokine biology, with a particular focus on the genetic and epigenetic regulation of chemokine transcription as well as on the cell type-specific production of chemokines by liver cells and liver-associated immune cells. Second, we highlight the functional roles of chemokines in liver homeostasis and their involvement in progression to disease in both human and animal models. Third, we discuss the therapeutic opportunities targeting chemokine production and signalling in the treatment of liver diseases, such as alcohol-associated liver disease and nonalcoholic steatohepatitis, including the relevant preclinical studies and ongoing clinical trials.
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Affiliation(s)
- Sheng Cao
- GI Research Unit, Mayo Clinic, Rochester, MN, USA.
| | - Mengfei Liu
- GI Research Unit, Mayo Clinic, Rochester, MN, USA
| | | | - Vijay H Shah
- GI Research Unit, Mayo Clinic, Rochester, MN, USA.
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28
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Borgia M, Dal Bo M, Toffoli G. Role of Virus-Related Chronic Inflammation and Mechanisms of Cancer Immune-Suppression in Pathogenesis and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13174387. [PMID: 34503196 PMCID: PMC8431318 DOI: 10.3390/cancers13174387] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma pathogenesis is dependent on a chronic inflammation caused by several factors, including hepatotropic viruses, such as HCV and HBV. This chronic inflammation is established in the context of the immunotolerogenic environment peculiar of the liver, in which the immune system can be stimulated by HCV and HBV viral antigens. This complex interaction can be influenced by direct-acting antiviral drug treatments, capable of (almost totally) rapidly eradicating HCV infection. The influence of anti-viral treatments on HCC pathogenesis and progression remains to be fully clarified. Abstract Hepatocellular carcinoma (HCC) can be classified as a prototypical inflammation-driven cancer that generally arises from a background of liver cirrhosis, but that in the presence of nonalcoholic steatohepatitis (NASH), could develop in the absence of fibrosis or cirrhosis. Tumor-promoting inflammation characterizes HCC pathogenesis, with an epidemiology of the chronic liver disease frequently encompassing hepatitis virus B (HBV) or C (HCV). HCC tumor onset and progression is a serial and heterogeneous process in which intrinsic factors, such as genetic mutations and chromosomal instability, are closely associated with an immunosuppressive tumor microenvironment (TME), which may have features associated with the etiopathogenesis and expression of the viral antigens, which favor the evasion of tumor neoantigens to immune surveillance. With the introduction of direct-acting antiviral (DAA) therapies for HCV infection, sustained virological response (SVR) has become very high, although occurrence of HCC and reactivation of HBV in patients with co-infection, who achieved SVR in short term, have been observed in a significant proportion of treated cases. In this review, we discuss the main molecular and TME features that are responsible for HCC pathogenesis and progression. Peculiar functional aspects that could be related to the presence and treatment of HCV/HBV viral infections are also dealt with.
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Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab 2021; 50:101122. [PMID: 33220492 PMCID: PMC8324683 DOI: 10.1016/j.molmet.2020.101122] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/30/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly due to the worldwide obesity and diabetes epidemics. SCOPE OF REVIEW This review summarizes the knowledge on the pathogenesis underlying NAFLD by focusing on studies in humans and on hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, and oxidative stress, and highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials. MAJOR CONCLUSIONS Recent studies have provided evidence that certain conditions, for example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance.
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Affiliation(s)
- Kalliopi Pafili
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Michael Roden
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
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30
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Colucci G, Invernizzi F, Uceda Renteria S, Perbellini R, Degasperi E, D'Ambrosio R, Galmozzi E, Lunghi G, Sguazzini E, Lampertico P, Donato MF. The CCR5 and CXCR3 Pathways in Hepatitis C Virus Liver Transplanted Recipients Treated by a Direct Antiviral Agent Regimen: Informative Kinetics Profiles. Viral Immunol 2021; 34:542-551. [PMID: 34252334 DOI: 10.1089/vim.2021.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R (p > 0.01) and CHC (p > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC (p > 0.05 and p = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R (p < 0.01) and in CHC, but only at FU (p < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R (p < 0.03) and CHC (p < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.
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Affiliation(s)
- Giuseppe Colucci
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Federica Invernizzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Sara Uceda Renteria
- Virology Unit, Division of Clinical Laboratory, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Riccardo Perbellini
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Elisabetta Degasperi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Roberta D'Ambrosio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Enrico Galmozzi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Giovanna Lunghi
- Virology Unit, Division of Clinical Laboratory, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Enrico Sguazzini
- Department of Medical Biotechnology, Università Degli Studi di Milano, Milan, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy.,Department of Medical Surgical Physiopatology and Transplantation, University of Milan, Milan, Italy
| | - Maria Francesca Donato
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
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31
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Getachew A, Abbas N, You K, Yang Z, Hussain M, Huang X, Cheng Z, Tan S, Tao J, Yu X, Chen Y, Yang F, Pan T, Xu Y, Xu G, Zhuang Y, Wu F, Li Y. SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury. iScience 2021; 24:102483. [PMID: 34113824 PMCID: PMC8169952 DOI: 10.1016/j.isci.2021.102483] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/03/2021] [Accepted: 04/25/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.
SAA1 serves as a chemokine to guide migration of HSCs toward injury locus TLR2 acts as a functional receptor for SAA1 in HSCs SAA1/TLR2 axis-mediated migration of HSCs operates through PI3K/Rac1 signaling SAA1/TLR2 axis provides a link for the cross talk between hepatocytes and HSCs
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Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Nasir Abbas
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Kai You
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Zhen Yang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- University of China Academy of Sciences, Beijing 100049, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Ziqi Cheng
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shenglin Tan
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Jiawang Tao
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xiaorui Yu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yan Chen
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Fan Yang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Tingcai Pan
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yingying Xu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Guosheng Xu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yuanqi Zhuang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - FeiMa Wu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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Nathwani R, Mullish BH, Kockerling D, Forlano R, Manousou P, Dhar A. A Review of Liver Fibrosis and Emerging Therapies. EUROPEAN MEDICAL JOURNAL 2020. [DOI: 10.33590/emj/10310892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
With the increasing burden of liver cirrhosis, the most advanced stage of hepatic fibrosis, there is a need to better understand the pathological processes and mechanisms to target specific treatments to reverse or cease fibrosis progression. Antiviral therapy for hepatitis B and C has effectively treated underlying causes of chronic liver disease and has induced fibrosis reversal in some; however, this has not been targeted for the majority of aetiologies for cirrhosis including alcohol or nonalcoholic steatohepatitis. Fibrosis, characterised by the accumulation of extracellular matrix proteins, is caused by chronic injury from toxic, infectious, or metabolic causes. The primary event of fibrogenesis is increased matrix production and scar formation mediated by the hepatic stellate cell, which is the principal cell type involved. Experimental models using rodent and human cell lines of liver injury have assisted in better understanding of fibrogenesis, especially in recognising the role of procoagulant factors. This has led to interventional studies using anticoagulants in animal models with reversal of fibrosis as the primary endpoint. Though these trials have been encouraging, no antifibrotic therapies are currently licenced for human use. This literature review discusses current knowledge in the pathophysiology of hepatic fibrosis, including characteristics of the extracellular matrix, signalling pathways, and hepatic stellate cells. Current types of experimental models used to induce fibrosis, as well as up-to-date anticoagulant therapies and agents targeting the hepatic stellate cell that have been trialled in animal and human studies with antifibrotic properties, are also reviewed.
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Affiliation(s)
- Rooshi Nathwani
- Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
| | - Benjamin H. Mullish
- Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
| | - David Kockerling
- Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
| | - Roberta Forlano
- Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
| | - Pinelopi Manousou
- Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
| | - Ameet Dhar
- Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
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Odagiri N, Matsubara T, Sato-Matsubara M, Fujii H, Enomoto M, Kawada N. Anti-fibrotic treatments for chronic liver diseases: The present and the future. Clin Mol Hepatol 2020; 27:413-424. [PMID: 33317250 PMCID: PMC8273638 DOI: 10.3350/cmh.2020.0187] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/07/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis reflects tissue scarring in the liver due to the accumulation of excessive extracellular matrix in response to chronically persistent liver injury. Hepatocyte cell death can trigger capillarization of liver sinusoidal endothelial cells, stimulation of immune cells including macrophages and Kupffer cells, and activation of hepatic stellate cells (HSCs), resulting in progression of liver fibrosis. Liver cirrhosis is the terminal state of liver fibrosis and is associated with severe complications, such as liver failure, portal hypertension, and liver cancer. Nevertheless, effective therapy for cirrhosis has not yet been established, and liver transplantation is the only radical treatment for severe cases. Studies investigating HSC activation and regulation of collagen production in the liver have made breakthroughs in recent decades that have advanced the knowledge regarding liver fibrosis pathophysiology. In this review, we summarize molecular mechanisms of liver fibrosis and discuss the development of novel anti-fibrotic therapies.
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Affiliation(s)
- Naoshi Odagiri
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Misako Sato-Matsubara
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.,Department of Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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Abstract
The worldwide prevalence of non-alcoholic fatty liver disease is around 25%, and that of nonalcoholic steatohepatitis (NASH) ranges from 1.5% to 6.45%. Patients with NASH, especially those with fibrosis, are at higher risk for adverse outcomes such as cirrhosis and liver-related mortality. Although vitamin E, pioglitazone, and liraglutide improved liver histology in randomized trials, there are currently no Food and Drug Administration-approved drugs for NASH. Five pharmacologic agents-obeticholic acid, elafibranor, cenicriviroc, resmetirom, and aramchol-are being evaluated in large, histology-based phase 3 trials. Within 2 to 4 years, new and effective drugs for the treatment of NASH are expected. Additionally, many phase 2 trials are ongoing for various agents. Based on the results of phase 2 and 3 trials, combination treatments are also being investigated. Future treatment strategies will comprise drug combinations and precision medicine based on the different phenotypes of NASH and treatment response of the individual patient.
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Affiliation(s)
- Soung Won Jeong
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
- Corresponding author: Soung Won Jeong Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea E-mail:
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36
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Pan X, Chiwanda Kaminga A, Liu A, Wen SW, Chen J, Luo J. Chemokines in Non-alcoholic Fatty Liver Disease: A Systematic Review and Network Meta-Analysis. Front Immunol 2020; 11:1802. [PMID: 33042108 PMCID: PMC7530185 DOI: 10.3389/fimmu.2020.01802] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 07/06/2020] [Indexed: 12/19/2022] Open
Abstract
Background: Previous results on the relationship between non-alcoholic fatty liver disease (NAFLD) and chemokine concentrations were inconsistent. The purpose of this network meta-analysis was to evaluate the link between chemokine system and NAFLD. Methods: Relevant data, published not later than June 31, 2019, were searched in the databases of PubMed, Embase, Cochrane Library, and Web of Science. A network meta-analysis was used to rank the chemokines by surface under the cumulative ranking (SUCRA) probabilities. In addition, standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated as group differences in the chemokine concentrations. Results: The search in the databases identified 46 relevant studies that investigated the relationship between 15 different chemokines and NAFLD using 4,753 patients and 4,059 controls. Results from the network meta-analysis showed that the concentrations of CCL2 and CXCL8 in the non-alcoholic fatty liver (NAFL) group was significantly higher than that in the control group (SMDs of 1.51 and 1.95, respectively), and the concentrations of CCL3, CCL4, CCL20, CXCL8, and CXCL10 in the non-alcoholic steatohepatitis (NASH) group was significantly higher than that in the control group (SMDs of 0.90, 2.05, 2.16, 0.91, and 1.46, respectively). SUCRA probabilities showed that CXCL8 had the highest rank in NAFL for all chemokines and CCL20 had the highest rank in NASH for all chemokines. Conclusion: Elevated concentrations of CCL2, CCL4, CCL20, CXCL8, and CXCL10 may be associated with NAFL or NASH. In this regard, more population-based studies are needed to ascertain this hypothesis. Systematic Review Registration: PROSPERO: CRD42020139373.
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Affiliation(s)
- Xiongfeng Pan
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Atipatsa Chiwanda Kaminga
- Xiangya School of Public Health, Central South University, Changsha, China.,Department of Mathematics and Statistics, Mzuzu University, Mzuzu, Malawi
| | - Aizhong Liu
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Shi Wu Wen
- Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa, ON, Canada.,Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Jihua Chen
- Xiangya School of Public Health, Central South University, Changsha, China.,Department of Food Science and Biotechnol, Kagoshima University, Kagoshima, Japan
| | - Jiayou Luo
- Xiangya School of Public Health, Central South University, Changsha, China
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37
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Bartneck M, Koppe C, Fech V, Warzecha KT, Kohlhepp M, Huss S, Weiskirchen R, Trautwein C, Luedde T, Tacke F. Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion. Cell Mol Gastroenterol Hepatol 2020; 11:327-347. [PMID: 32896623 PMCID: PMC7779787 DOI: 10.1016/j.jcmgh.2020.08.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 08/27/2020] [Accepted: 08/31/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. METHODS To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knock-out of the nuclear factor κB (NF-κB) essential modulator (NEMO), termed NEMOLPC-KO mice, and generated NEMOLPC-KOCcr2-/- and NEMOLPC-KOCcr5-/- mice. NEMOLPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months. RESULTS We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMOLPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8+ T cells or NK cells, significantly aggravated liver injury in NEMOLPC-KO mice and was further increased in NEMOLPC-KOCcr5-/- mice. CLL-induced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115+ immature monocytes or B cells did not reduce liver injury. CONCLUSIONS Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMOLPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis.
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Affiliation(s)
| | - Christiane Koppe
- Department of Medicine III, RWTH Aachen University, Aachen, Germany
| | - Viktor Fech
- Department of Medicine III, RWTH Aachen University, Aachen, Germany
| | | | - Marlene Kohlhepp
- Department of Medicine III, RWTH Aachen University, Aachen, Germany,Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Sebastian Huss
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
| | | | - Tom Luedde
- Department of Medicine III, RWTH Aachen University, Aachen, Germany,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frank Tacke
- Department of Medicine III, RWTH Aachen University, Aachen, Germany,Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany,Reprint requests Address requests for reprints to: Frank Tacke, MD, PhD, Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. fax: +49-30-450-553902.
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Diaz Soto MP, Lim JK. Evaluating the Therapeutic Potential of Cenicriviroc in the Treatment of Nonalcoholic Steatohepatitis with Fibrosis: A Brief Report on Emerging Data. Hepat Med 2020; 12:115-123. [PMID: 32884369 PMCID: PMC7434517 DOI: 10.2147/hmer.s230613] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 08/04/2020] [Indexed: 12/26/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with significant morbidity and mortality due to liver cirrhosis, liver failure, and hepatocellular carcinoma, and represents a leading indication for liver transplantation in the United States (U.S.). A growing spectrum of novel therapies are currently in clinical development and target several mechanisms of action which address hepatic steatosis, steatohepatitis, and hepatic fibrosis. Cenicriviroc (Allergan, Dublin, Ireland) is a novel oral antagonist of CC-motif chemokine receptors 2 and 5 (CCR2/5) which have demonstrated expression on circulating monocytes and Kupffer cells. Preclinical models have confirmed that CCR2/5 antagonism may block fat accumulation and Kupffer cell activation and disrupt monocyte/macrophage recruitment and hepatic stellate cell activation responsible for fibrogenesis. Herein we review results from the phase 2b CENTAUR trial and study designs for the phase 2b TANDEM and phase 3 AURORA trials and discuss the potential role of cenicriviroc in future pharmacotherapy for NASH fibrosis.
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Affiliation(s)
| | - Joseph K Lim
- Yale Liver Center and Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
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Bradshaw D, Gilleece Y, Verma S, Abramowicz I, Bremner S, Perry N. Protocol for a phase IV, open-label feasibility study investigating non-invasive markers of hepatic fibrosis in people living with HIV-1 and non-alcoholic fatty liver disease randomised to receiving optimised background therapy (OBT) plus maraviroc or OBT alone. BMJ Open 2020; 10:e035596. [PMID: 32636281 PMCID: PMC7342479 DOI: 10.1136/bmjopen-2019-035596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION At least 30% of people living with HIV (PLWH) infection have non-alcoholic fatty liver disease (NAFLD), which has now become a leading cause of hepatic fibrosis and cirrhosis. Management is based largely on lifestyle modifications, which are difficult to achieve, and therapeutic options are urgently needed. Maraviroc (MVC), through antagonism of CCR5 receptors, may reduce hepatic fibrosis progression and could be an effective treatment for NAFLD. However, dosing is usually two times per day, unlike most currently recommended antiretroviral therapies. This study will investigate the feasibility and acceptability of addition of MVC to combination antiretroviral therapy in PLWH and NAFLD as a treatment for NAFLD. METHODS AND ANALYSIS This is a phase IV, randomised, open-label, non-invasive feasibility study. Sixty individuals with well-controlled HIV-1 and NAFLD will be recruited from UK HIV clinics and randomised 1:1 to receive either optimised background therapy (OBT) plus MVC or OBT alone. Follow-up will be every 24 weeks for 96 weeks. The primary outcome measures will include recruitment and retention rates, adverse events and adherence. Secondary outcomes will include changes in markers of hepatic fibrosis, including the Enhanced Liver Fibrosis score, median liver stiffness measurement and controlled attenuation parameter scores on Fibroscan, and quality of life assessments. Analyses will be performed according to intention-to-treat principles. For secondary outcomes, estimated differences and 95% CIs between the groups using a t-method will be presented for continuous variables and as exact 95% binomial CIs for categorical variables. ETHICS AND DISSEMINATION Ethical approval was obtained through the London Dulwich UK Research Ethics Committee (reference 17/LO/2093). Results will be disseminated both through community groups and peer-reviewed scientific literature.Trial registration number SRCTN31461655. EudraCT number 2017-004141-24; Pre-results.
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Affiliation(s)
- Daniel Bradshaw
- Brighton and Sussex University Hospitals NHS Trust, Brighton
| | - Yvonne Gilleece
- Brighton and Sussex University Hospitals NHS Trust, Brighton
| | - Sumita Verma
- Brighton and Sussex Medical School, Brighton, UK
| | | | | | - Nicky Perry
- Brighton and Sussex Medical School, Brighton, UK
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Baeza-Raja B, Goodyear A, Liu X, Lam K, Yamamoto L, Li Y, Dodson GS, Takeuchi T, Kisseleva T, Brenner DA, Dabbagh K. Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis. PLoS One 2020; 15:e0234038. [PMID: 32492075 PMCID: PMC7269334 DOI: 10.1371/journal.pone.0234038] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular adenosine triphosphate (eATP) released by damaged cells, and its purinergic receptors, comprise a crucial signaling network after injury. Purinergic receptor P2X7 (P2RX7), a major driver of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and IL-1β processing, has been shown to play a role in liver injury in murine diet- and chemically-induced liver injury models. It is unclear, however, whether P2RX7 plays a role in non-alcoholic steatohepatitis (NASH) and which cell type is the main target of P2RX7 pharmacological inhibition. Here, we report that P2RX7 is expressed by infiltrating monocytes and resident Kupffer cells in livers from NASH-affected individuals. Using primary isolated human cells, we demonstrate that P2RX7 expression in CD14+ monocytes and Kupffer cells primarily mediates IL-1β release. In addition, we show that pharmacological inhibition of P2RX7 in monocytes and Kupffer cells, blocks IL-1β release, reducing hepatocyte caspase 3/7 activity, IL-1β-mediated CCL2 and CCL5 chemokine gene expression and secretion, and hepatic stellate cell (HSC) procollagen secretion. Consequently, in a chemically-induced nonhuman primate model of liver fibrosis, treatment with a P2RX7 inhibitor improved histological characteristics of NASH, protecting from liver inflammation and fibrosis. Taken together, these findings underscore the critical role of P2RX7 in the pathogenesis of NASH and implicate P2RX7 as a promising therapeutic target for the management of this disease.
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Affiliation(s)
- Bernat Baeza-Raja
- Second Genome Inc., South San Francisco, California, United States of America
| | - Andrew Goodyear
- Second Genome Inc., South San Francisco, California, United States of America
| | - Xiao Liu
- Department of Surgery, University of California San Diego, La Jolla, California, United States of America
| | - Kevin Lam
- Department of Surgery, University of California San Diego, La Jolla, California, United States of America
| | - Lynn Yamamoto
- Second Genome Inc., South San Francisco, California, United States of America
| | - Yingwu Li
- Second Genome Inc., South San Francisco, California, United States of America
| | - G. Steven Dodson
- Second Genome Inc., South San Francisco, California, United States of America
| | - Toshi Takeuchi
- Second Genome Inc., South San Francisco, California, United States of America
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, California, United States of America
| | - David A. Brenner
- Department of Medicine, University of California San Diego, La Jolla, California, United States of America
| | - Karim Dabbagh
- Second Genome Inc., South San Francisco, California, United States of America
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Sällberg M, Pasetto A. Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation. Front Immunol 2020; 11:552. [PMID: 32292409 PMCID: PMC7119224 DOI: 10.3389/fimmu.2020.00552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the third most common cause of cancer related death in the World. From an epidemiological point of view the risk factors associated to primary liver cancer are mainly viral hepatitis infection and alcohol consumption. Even though there is a clear correlation between liver inflammation, cirrhosis and cancer, other emerging liver diseases (like fatty liver) could also lead to liver cancer. Moreover, the liver is the major site of metastasis from colon, breast, ovarian and other cancers. In this review we will address the peculiar status of the liver as organ that has to balance between tolerance and immune activation. We will focus on macrophages and other key cellular components of the liver microenvironment that play a central role during tumor progression. We will also discuss how current and future therapies may affect the balance toward immune activation.
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Affiliation(s)
- Matti Sällberg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Pasetto
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
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Rzeszotarska E, Sowinska A, Stypinska B, Walczuk E, Wajda A, Lutkowska A, Felis-Giemza A, Olesinska M, Puszczewicz M, Majewski D, Jagodzinski PP, Czerewaty M, Malinowski D, Pawlik A, Jaronczyk M, Paradowska-Gorycka A. The Role of MECP2 and CCR5 Polymorphisms on the Development and Course of Systemic Lupus Erythematosus. Biomolecules 2020; 10:biom10030494. [PMID: 32214033 PMCID: PMC7175371 DOI: 10.3390/biom10030494] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/19/2020] [Accepted: 03/22/2020] [Indexed: 12/14/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease. SLE is described by production of autoantibodies and causes damage of many organs. T-cells play a crucial role in SLE pathogenesis. T-cells intensify inflammation through a number of processes, which leads to autoimmunization. CCR5 and MECP2 genes are linked with T-cells and pathogenesis of SLE. Polymorphisms in these genes are related with the prognostic factors of risk of disease onset and disease severity. The aim of this study was to estimate the influence of polymorphisms in MECP2 and CCR5 genes on the development and course of systemic lupus erythematosus. We examined 137 SLE patients and 604 healthy controls. We studied polymorphisms for CCR5 gene: rs333 and for MECP2: rs2075596, rs1734787, rs17435, and rs2239464. We genotyped our MECP2 samples and we performed a restriction fragment length polymorphism (RFLP) analysis for CCR5 samples. We showed a risk factor for allele T in rs17435 and for allele A in rs2075596 in MECP2. We noticed that MECP2 rs2075596 G/A, rs1734787 C/A, rs17435 A/T, and rs2239464 G/A polymorphisms are more prevalent in SLE patients than in healthy controls. We believe that above-mentioned MECP2 polymorphisms can be considered as SLE susceptibility factor.
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Affiliation(s)
- Ewa Rzeszotarska
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.R.); (B.S.); (E.W.); (A.W.)
| | - Anna Sowinska
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
| | - Barbara Stypinska
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.R.); (B.S.); (E.W.); (A.W.)
| | - Ewa Walczuk
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.R.); (B.S.); (E.W.); (A.W.)
| | - Anna Wajda
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.R.); (B.S.); (E.W.); (A.W.)
| | - Anna Lutkowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (A.L.); (P.P.J.)
| | - Anna Felis-Giemza
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (A.F.-G.); (M.O.)
| | - Marzena Olesinska
- Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (A.F.-G.); (M.O.)
| | - Mariusz Puszczewicz
- Department of Rheumatology and Internal Diseases, Poznan University of Medical Science, 61-545 Poznan, Poland; (M.P.); (D.M.)
| | - Dominik Majewski
- Department of Rheumatology and Internal Diseases, Poznan University of Medical Science, 61-545 Poznan, Poland; (M.P.); (D.M.)
| | - Pawel Piotr Jagodzinski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (A.L.); (P.P.J.)
| | - Michal Czerewaty
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (M.C.); (A.P.)
| | - Damian Malinowski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (M.C.); (A.P.)
| | - Malgorzata Jaronczyk
- Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 30/34 Chelmska Str., 00-725 Warsaw, Poland;
| | - Agnieszka Paradowska-Gorycka
- Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.R.); (B.S.); (E.W.); (A.W.)
- Correspondence:
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Ahn SY, Maeng YS, Kim YR, Choe YH, Hwang HS, Hyun YM. In vivo monitoring of dynamic interaction between neutrophil and human umbilical cord blood-derived mesenchymal stem cell in mouse liver during sepsis. Stem Cell Res Ther 2020; 11:44. [PMID: 32014040 PMCID: PMC6998265 DOI: 10.1186/s13287-020-1559-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/30/2019] [Accepted: 01/09/2020] [Indexed: 12/24/2022] Open
Abstract
Background Sepsis is a global inflammatory disease that causes death. It has been reported that mesenchymal stem cell (MSC) treatment can attenuate inflammatory and septic symptoms. In this study, we investigated how interactions between neutrophils and human umbilical cord blood (hUCB)-MSCs in the liver of septic mice are involved in mitigating sepsis that is mediated by MSCs. Accordingly, we aimed to determine whether hUCB-MSC application could be an appropriate treatment for sepsis. Methods To induce septic condition, lipopolysaccharide (LPS) was intraperitoneally (i.p.) injected into mice 24 h after the intravenous (i.v.) injection of saline or hUCB-MSCs. To determine the effect of hUCB-MSCs on the immune response during sepsis, histologic analysis, immunoassays, and two-photon intravital imaging were performed 6 h post-LPS injection. For the survival study, mice were monitored for 6 days after LPS injection. Results The injection (i.v.) of hUCB-MSCs alleviated the severity of LPS-induced sepsis by increasing IL-10 levels (p < 0.001) and decreasing mortality (p < 0.05) in septic mice. In addition, this significantly reduced the recruitment of neutrophils (p < 0.001) to the liver. In hUCB-MSC-treated condition, we also observed several distinct patterns of dynamic interactions between neutrophils and hUCB-MSCs in the inflamed mouse liver, as well as vigorous interactions between hepatic stellate cells (HSCs or ito cells) and hUCB-MSCs. Interestingly, hUCB-MSCs that originated from humans were not recognized as foreign in the mouse body and consequently did not cause graft rejection. Conclusions These distinct interaction patterns between innate immune cells and hUCB-MSCs demonstrated that hUCB-MSCs have beneficial effects against LPS-induced sepsis through associations with neutrophils. In addition, the immunomodulatory properties of hUCB-MSCs might enable immune evasion in the host. Taken together, our results suggest the prospects of hUCB-MSCs as a therapeutic tool to inhibit inflammation and alleviate pathological immune responses such as sepsis.
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Affiliation(s)
- Sung Yong Ahn
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Sun Maeng
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Rim Kim
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea.,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Ho Choe
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea.,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Han Sung Hwang
- Department of Obstetrics and Gynecology, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea.
| | - Young-Min Hyun
- Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea. .,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Das D, Fayazzadeh E, Li X, Koirala N, Wadera A, Lang M, Zernic M, Panick C, Nesbitt P, McLennan G. Quiescent hepatic stellate cells induce toxicity and sensitivity to doxorubicin in cancer cells through a caspase-independent cell death pathway: Central role of apoptosis-inducing factor. J Cell Physiol 2020; 235:6167-6182. [PMID: 31975386 DOI: 10.1002/jcp.29545] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/03/2020] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide and in the United States as its incidence has increased substantially within the past two decades. HCC therapy remains a challenge, primarily due to underlying liver disorders such as cirrhosis that determines treatment approach and efficacy. Activated hepatic stellate cells (A-HSCs) are the key cell types involved in hepatic fibrosis/cirrhosis. A-HSCs are important constituents of HCC tumor microenvironment (TME) and support tumor growth, chemotherapy resistance, cancer cell migration, and escaping immune surveillance. This makes A-HSCs an important therapeutic target in hepatic fibrosis/cirrhosis as well as in HCC. Although many studies have reported the role of A-HSCs in cancer generation and investigated the therapeutic potential of A-HSCs reversion in cancer arrest, not much is known about inactivated or quiescent HSCs (Q-HSCs) in cancer growth or arrest. Here we report that Q-HSCs resist cancer cell growth by inducing cytotoxicity and enhancing chemotherapy sensitivity. We observed that the conditioned media from Q-HSCs (Q-HSCCM) induces cancer cell death through a caspase-independent mechanism that involves an increase in apoptosis-inducing factor expression, nuclear localization, DNA fragmentation, and cell death. We further observed that Q-HSCCM enhanced the efficiency of doxorubicin, as measured by cell viability assay. Exosomes present in the conditioned media were not involved in the mechanism, which suggests the role of other factors (proteins, metabolites, or microRNA) secreted by the cells. Identification and characterization of these factors are important in the development of effective HCC therapy.
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Affiliation(s)
- Dola Das
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ehsan Fayazzadeh
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Section of Vascular and Interventional Radiology, Department of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
| | - Xin Li
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nischal Koirala
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, Ohio
| | - Akshay Wadera
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,School of Medicine, New York Medical College, Valhalla, New York
| | - Min Lang
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Maximilian Zernic
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Catherine Panick
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, Oregon
| | - Pete Nesbitt
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania
| | - Gordon McLennan
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Section of Vascular and Interventional Radiology, Department of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio
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New therapeutic strategies in nonalcoholic fatty liver disease: a focus on promising drugs for nonalcoholic steatohepatitis. Pharmacol Rep 2020; 72:1-12. [PMID: 32016853 DOI: 10.1007/s43440-019-00020-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 09/21/2019] [Accepted: 09/22/2019] [Indexed: 02/08/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Globally, it is currently the most common liver disease and is estimated to affect up to 25% of the population. In the first stage, NAFLD is characterized by simple hepatic steatosis (NAFL, nonalcoholic fatty liver) that might progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular carcinoma. In this review, we discuss the global burden of NAFLD, together with future perspectives on how this epidemic could be restrained. There is also an urgent need for the development of new medical strategies for NAFLD patients. We aim to present the beneficial effects of life-style modifications that should be advised to both non-obese and obese NAFLD patients. Since there are currently no medications directly used for the treatment of more advanced NAFLD stages, the central part of this review summarizes ongoing and recently completed clinical trials testing promising drugs for NASH resolution. The marketing of new therapeutic agents would greatly increase the odds of reducing the global burden of NAFLD.
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Segal-Salto M, Barashi N, Katav A, Edelshtein V, Aharon A, Hashmueli S, George J, Maor Y, Pinzani M, Haberman D, Hall A, Friedman S, Mor A. A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage. JHEP Rep 2020; 2:100064. [PMID: 32039405 PMCID: PMC7005554 DOI: 10.1016/j.jhepr.2019.100064] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 12/10/2019] [Accepted: 12/15/2019] [Indexed: 12/19/2022] Open
Abstract
Background & Aims C-C motif chemokine ligand 24 (CCL24) is a chemokine that regulates inflammatory and fibrotic activities through its receptor, C-C motif chemokine receptor (CCR3). The aim of the study was to evaluate the involvement of the CCL24-CCR3 axis in liver fibrosis and inflammation and to assess the potential of its blockade, by a monoclonal anti-CCL24 antibody, as a therapeutic strategy for non-alcoholic steatohepatitis (NASH) and liver fibrosis. Methods Expression of CCL24 and CCR3 was evaluated in liver biopsies and blood samples. CCL24 involvement in NAFLD/NASH pathogenesis was assessed in Ccl24 knockout mouse using the methionine-choline deficient (MCD) diet experimental model. Antifibrotic and anti-inflammatory effects of CM-101 were tested in the MCD and STAM mouse models and in the thioacetamide (TAA) model in rats. Liver enzymes, liver morphology, histology and collagen deposition, as well as fibrosis- and inflammation-related protein expression were assessed. Activation of hepatic stellate cells (HSCs) was evaluated in the human LX2 cell line. Results Patients with NASH and advanced NAFLD exhibited significant expression of both CCL24 and CCR3 in liver and blood samples. In the experimental MCD-diet model, Ccl24 knockout mice showed an attenuated liver damage response compared to wild-type mice, exhibiting reduced histological NAFLD activity scores and fibrosis, as well as lower levels of liver enzymes. Blocking CCL24 using CM-101 robustly reduced liver damage in 3 experimental animal models (MCD, STAM and TAA), as demonstrated by attenuation of liver fibrosis and NAFLD activity score. Furthermore, blocking CCL24 by CM-101 significantly inhibited CCL24-induced HSC motility, α-SMA expression and pro-collagen I secretion. Conclusion Our results reveal that blocking CCL24 significantly attenuates liver fibrosis and inflammation and may have a potential therapeutic effect in patients with NASH and/or liver fibrosis. Lay summary CCL24 is a chemokine that regulates inflammation and fibrosis. It was found to be significantly expressed in patients with non-alcoholic steatohepatitis, in whom it regulates profibrotic processes in the liver. Herein, we show that blockade of CCL24 using a monoclonal antibody robustly attenuated liver fibrosis and inflammation in animal models, thus suggesting a potential therapeutic role for an anti-CCL24 agent.
CCL24 is a chemokine that regulates inflammatory and fibrotic activities through its receptor, CCR3. Significant expression of CCL24 and CCR3 were found in liver biopsies and blood samples from patients with NAFLD/NASH. CM-101, a monoclonal antibody that selectively targets CCL24, significantly attenuates fibrotic and inflammatory processes. Blocking CCL24 may have a potential therapeutic effect in NASH and liver fibrosis.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Antibody
- C-C motif chemokine ligand 24
- CCL24
- CCL24, C-C motif chemokine ligand 24
- CCR3, C-C motif chemokine receptor 3
- CM-101
- Fibrosis
- HSCs, hepatic stellate cells
- IL-6, interleukin-6
- MCD, methionine-choline deficient
- MFI, median fluorescence intensity
- MMP, matrix metallopeptidase
- NAFLD, non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH, non-alcoholic steatohepatitis
- Non-alcoholic fatty liver disease
- Non-alcoholic steatohepatitis
- PBMC, peripheral blood mononuclear cells
- TAA, thioacetamide
- WT, wild-type
- α-SMA, α-smooth muscle actin
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Affiliation(s)
| | | | | | | | | | | | - Jacob George
- Heart Center, Kaplan Medical Center, Rehovot, Affiliated to the Hebrew University, Jerusalem, Israel
| | - Yaakov Maor
- Institute of Gastroenterology and Hepatology, Kaplan Medical Center, Rehovot, Israel
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, University College of London, London, UK.,Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
| | - Dan Haberman
- Heart Center, Kaplan Medical Center, Rehovot, Affiliated to the Hebrew University, Jerusalem, Israel
| | - Andrew Hall
- UCL Institute for Liver and Digestive Health, University College of London, London, UK.,Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
| | - Scott Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
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47
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Dhar D, Baglieri J, Kisseleva T, Brenner DA. Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood) 2020; 245:96-108. [PMID: 31924111 PMCID: PMC7016420 DOI: 10.1177/1535370219898141] [Citation(s) in RCA: 258] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma.
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Affiliation(s)
- Debanjan Dhar
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jacopo Baglieri
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA 92093, USA
| | - David A Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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Pérez-García A, Arroyo-Valerio AG, Bustos-Esquivel MA, Quispe-Siccha RM, Zaldívar-Fujigaki JL, Pacheco-Yepez J, Kershenobich D, López-Alvarenga JC, Hernández-Ruiz J. Young adult binge drinkers have immunophenotypical disarrangements in peripheral natural killer cells. Alcohol 2019; 81:70-78. [PMID: 31265902 DOI: 10.1016/j.alcohol.2019.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 06/17/2019] [Accepted: 06/19/2019] [Indexed: 11/18/2022]
Abstract
Alcohol consumption is an issue of worldwide relevance and a problem of national scale in Mexico. The consumption pattern of large amounts of alcohol on the weekends is rapidly increasing in young adults between 18 and 29 years. Despite various studies that have focused on the noxious effect of alcohol in immunity, the changes in the immunoprofiles of peripheral blood cells have not been completely described. Natural killer cells (NKCs) are lymphoid-origin cells of the immune system that are responsible for defense against tumors, among other functions. In homeostatic conditions, they are found to be in a state of "dynamic balance" between activation and inhibition stimuli, which, if broken, may lead to immunosuppression or activation of cytotoxic mechanisms. In this study, we evaluated the immunoprofile of peripheral NKCs of 54 young adults, 29 of whom were binge drinkers and 25 of whom were low risk (LR), as classified by validated tools. Drinking habits were assessed. Blood samples were collected to perform hematic biometry and liver enzyme tests. Peripheral NKCs were identified by FACS, and stained for CCR2, CCR4, CCR5, CXCR4, CD69, CD127, CD137, TLR4, and Granzyme B. The data were analyzed using the t test and Mann-Whitney's U test for contrasts, and the effect size was obtained in order to evaluate the impact of each immunoprofile. The binge group showed increased expression of CCR5 and PD-1 in NKCs, respective to the LR group, and decreased expression of TLR4, along with fewer CCR4+ cells. Moreover, the increase found in CCR5 and PD-1 expression was correlated with the number of drinks in the last drinking session. Our findings show that young binge drinkers have different immunoprofiles that could suggest an early status of immunosuppression and trafficking of NKCs to the liver, which could be related to the onset of early liver damage, early in a subject's lifespan.
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Affiliation(s)
- Adolfo Pérez-García
- Experimental Surgery Service, Hospital General de México "Dr. Eduardo Liceaga", Dr. Balmis 148 Colonia Doctores, Delegación, Cuauhtémoc, 06726 CDMX, Mexico
| | - América Guadalupe Arroyo-Valerio
- Research Department, Hospital General de México "Dr. Eduardo Liceaga", Dr. Balmis 148 Colonia Doctores, Delegación Cuauhtémoc, 06726 CDMX, Mexico
| | - Mayra A Bustos-Esquivel
- Research & Technological Development Unit (UIDT) UNAM-HGM, Dr. Balmis 148 Colonia, Doctores, Delegación Cuauhtémoc, 06726 CDMX, Mexico
| | - Rosa M Quispe-Siccha
- Research Department, Hospital General de México "Dr. Eduardo Liceaga", Dr. Balmis 148 Colonia Doctores, Delegación Cuauhtémoc, 06726 CDMX, Mexico; Research & Technological Development Unit (UIDT) UNAM-HGM, Dr. Balmis 148 Colonia, Doctores, Delegación Cuauhtémoc, 06726 CDMX, Mexico
| | - José Luis Zaldívar-Fujigaki
- Clinical Research, Centro Médico Nacional "20 de Noviembre", ISSSTE, Félix Cuevas 540, Col del Valle Sur, Delegación Benito Juárez, 03100 CDMX, Mexico
| | - Judith Pacheco-Yepez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Calle Salvador Díaz Mirón S/N, Santo Tomás, Alcaldia Miguel Hidalgo, 11340 CDMX, Mexico
| | - David Kershenobich
- National Institute of Medical Sciences and Nutrition, "Salvador Zubirán,", Avenida Vasco de Quiroga No. 15, Colonia Belisario Domínguez Sección XVI, Delegación Tlalpan, CDMX 14080, Mexico
| | - J C López-Alvarenga
- Department of Human Genetics, School of Medicine, University of Texas, Rio Grande Valley, Texas, United States; Research Division Mexican-American University of the North (UMAN), Reynosa, Tamaulipas, Mexico
| | - Joselín Hernández-Ruiz
- Clinical Pharmacology Unit, Hospital General de México "Dr. Eduardo Liceaga", Dr. Balmis 148 Colonia Doctores, Alcaldia Cuauhtémoc, 06726 CDMX, Mexico.
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Blackard JT, Kong L, Rouster SD, Karns R, Horn PS, Kottilil S, Shata MT, Sherman KE. CCR5 receptor antagonism inhibits hepatitis C virus (HCV) replication in vitro. PLoS One 2019; 14:e0224523. [PMID: 31661521 PMCID: PMC6818973 DOI: 10.1371/journal.pone.0224523] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022] Open
Abstract
Background and aim The hepatitis C virus (HCV) is a single-strand RNA virus that infects millions of people worldwide. Recent advances in therapy have led to viral cure using two- and three- drug combinations of direct acting inhibitors of viral replication. CCR5 is a chemokine receptor that is expressed on hepatocytes and represents a key co-receptor for HIV. We evaluated the effect of CCR5 blockade or knockdown on HCV replication in Huh7.5JFH1 cells. Methods Cells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor). Results HCV RNA was detected utilizing two qualitative strand-specific RT-PCR assays. HCV core antigen and NS3 protein was quantified in the supernatant and cell lysate, respectively. siRNA was utilized to knockdown CCR5 gene expression in hepatocytes. Alternatively, anti-CCR5 antibodies were employed to block the receptor. Supernatant levels of HCV RNA (expressed as fold change) were not reduced in the presence of raltegravir but were reduced 8.55-fold and 12.42-fold with cenicriviroc and maraviroc, respectively. Sofosbuvir resulted in a 16.20-fold change in HCV RNA levels. HCV core and NS3 protein production was also reduced in a dose-dependent manner. Two distinct anti-CCR5 antibodies also resulted in a significant reduction in HCV protein expression, as did siRNA knockdown of CCR5 gene expression. Conclusions These data provide evidence that CCR5 modulation could have a significant effect on HCV replication in an in vitro system. Further evaluation of the role of CCR5 inhibition in clinical settings may be warranted.
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Affiliation(s)
- Jason T Blackard
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Ling Kong
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Susan D Rouster
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Rebekah Karns
- Digestive Health Center, Cincinnati Children's Hospital, Cincinnati, OH, United States of America
| | - Paul S Horn
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.,Neurology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America
| | - Shyam Kottilil
- University of Maryland, Baltimore, MD, United States of America
| | - M Tarek Shata
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Kenneth E Sherman
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
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50
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Wang Z, Park H, Bae EJ. Efficacy of evogliptin and cenicriviroc against nonalcoholic steatohepatitis in mice: a comparative study. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2019; 23:459-466. [PMID: 31680767 PMCID: PMC6819900 DOI: 10.4196/kjpp.2019.23.6.459] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 08/26/2019] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.
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Affiliation(s)
- Zheng Wang
- College of Pharmacy, Woosuk University, Wanju 55338, Korea
| | - Hansu Park
- Dong-A Socio Research Center, Dong-A ST Co., Ltd., Yongin 17073, Korea
| | - Eun Ju Bae
- College of Pharmacy, Chonbuk National University, Jeonju 54896, Korea
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