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Geng W, Liao W, Cao X, Yang Y. Therapeutic Targets and Approaches to Manage Inflammation of NAFLD. Biomedicines 2025; 13:393. [PMID: 40002806 PMCID: PMC11853636 DOI: 10.3390/biomedicines13020393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.
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Affiliation(s)
- Wanying Geng
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China;
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Wanying Liao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Xinyuan Cao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Yingyun Yang
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
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2
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Nascimento Júnior JXD, Gomes JDC, Imbroisi Filho R, Valença HDM, Branco JR, Araújo AB, Moreira ADOE, Crepaldi LD, Paixão LP, Ochioni AC, Demaria TM, Leandro JGB, Casanova LM, Sola-Penna M, Zancan P. Dietary caloric input and tumor growth accelerate senescence and modulate liver and adipose tissue crosstalk. Commun Biol 2025; 8:18. [PMID: 39775048 PMCID: PMC11707351 DOI: 10.1038/s42003-025-07451-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/31/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic alterations are related to tumorigenesis and other age-related diseases that are accelerated by "Westernized" diets. In fact, hypercaloric nutrition is associated with an increased incidence of cancers and faster aging. Conversely, lifespan-extending strategies, such as caloric restriction, impose beneficial effects on both processes. Here, we investigated the metabolic consequences of hypercaloric-induced aging on tumor growth in female mice. Our findings indicate that a high-fat high-sucrose diet increases tumor growth mainly due to the boosted oxidation of glucose and fatty acids. Consequently, through an increased expression of lactate, IGFBP3, and PTHLH, tumors modulate liver and white adipose tissue metabolism. In the liver, the induced tumor increases fibrosis and accelerates the senescence process, despite the lower systemic pro-inflammatory state. Importantly, the induced tumor induces the wasting and browning of white adipose tissue, thereby reversing diet-induced insulin resistance. Finally, we suggest that tumor growth alters liver-adipose tissue crosstalk that upregulates Fgf21, induces senescence, and negatively modulates lipids and carbohydrates metabolism even in caloric-restricted-fed mice.
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Affiliation(s)
- José Xavier do Nascimento Júnior
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Júlia da Conceição Gomes
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ricardo Imbroisi Filho
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Helber de Maia Valença
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jéssica Ristow Branco
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Amanda Bandeira Araújo
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Amanda de Oliveira Esteves Moreira
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Letícia Diniz Crepaldi
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Pereira Paixão
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alan C Ochioni
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thainá M Demaria
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - João Gabriel Bernardo Leandro
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Livia Marques Casanova
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mauro Sola-Penna
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patricia Zancan
- The MetaboliZSm GrouP, Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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3
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Lin L, Yang S, Li X, Zhang W, Zheng J. Unveiling the role of Pafah1b3 in liver fibrosis: A novel mechanism revealed. J Pharm Anal 2025; 15:101158. [PMID: 39906692 PMCID: PMC11791357 DOI: 10.1016/j.jpha.2024.101158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/15/2024] [Accepted: 12/01/2024] [Indexed: 02/06/2025] Open
Abstract
Liver fibrosis is a common outcome of various chronic hepatic insults, characterized by excessive extracellular matrix (ECM) deposition. The precise mechanisms, however, remain largely undefined. This study identified an elevated expression of platelet-activating factor acetylhydrolase 1B3 (Pafah1b3) in liver tissues from both carbon tetrachloride (CCl4)-treated mice and patients with cirrhosis. Deletion of Pafah1b3 significantly attenuated CCl4-induced fibrosis, hepatic stellate cell (HSC) activation, and activation of transforming growth factor-β (TGF-β) signaling. Mechanistically, PAFAH1B3 binds to mothers against decapentaplegic homolog 7 (SMAD7), disrupting SMAD7's interaction with TGF-β receptor 1 (TβR1), which subsequently decreases TβR1 ubiquitination and degradation. Pharmacological inhibition using 3-IN-P11, a specific Pafah1b3 inhibitor, conferred protective effects against CCl4-induced fibrosis in mice. Furthermore, Pafah1b3 deficiency reduced hepatic inflammation. Overall, these results establish a pivotal role for Pafah1b3 in modulating TGF-β signaling and driving HSC activation.
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Affiliation(s)
- Lifan Lin
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Shouzhang Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Xinmiao Li
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Weizhi Zhang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Jianjian Zheng
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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Wu J, Wen L, Liu X, Li Q, Sun Z, Liang C, Xie F, Li X. Silybin: A Review of Its Targeted and Novel Agents for Treating Liver Diseases Based on Pathogenesis. Phytother Res 2024; 38:5713-5740. [PMID: 39310970 DOI: 10.1002/ptr.8347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/02/2024] [Accepted: 09/09/2024] [Indexed: 12/13/2024]
Abstract
Liver disease represents a significant global public health concern. Silybin, derived from Silybum marianum, has been demonstrated to exhibit a range of beneficial properties, including anti-inflammatory, antioxidative, antifibrotic, antiviral, and cytoprotective effects. These attributes render it a promising candidate for the treatment of liver fibrosis, cirrhosis, liver cancer, viral hepatitis, non-alcoholic fatty liver disease, and other liver conditions. Nevertheless, its low solubility and low bioavailability have emerged as significant limitations in its clinical application. To address these limitations, researchers have developed a number of silybin formulations. This study presents a comprehensive review of the results of research on silybin for the treatment of liver diseases in recent decades, with a particular focus on novel formulations based on the pathogenesis of the disease. These include approaches targeting the liver via the CD44 receptor, folic acid, vitamin A, and others. Furthermore, the study presents the findings of studies that have employed nanotechnology to enhance the low bioavailability and low solubility of silybin. This includes the use of nanoparticles, liposomes, and nanosuspensions. This study reviews the application of silybin preparations in the treatment of global liver diseases. However, further high-quality and more complete experimental studies are still required to gain a more comprehensive understanding of the efficacy and safety of these preparations. Finally, the study considers the issues that arise during the research of silybin formulations.
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Affiliation(s)
- Jijiao Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lin Wen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolian Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zihao Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuipeng Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Li P, Ma X, Huang D, Gu X. Exploring the roles of non-coding RNAs in liver regeneration. Noncoding RNA Res 2024; 9:945-953. [PMID: 38680418 PMCID: PMC11046251 DOI: 10.1016/j.ncrna.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/26/2024] [Accepted: 04/16/2024] [Indexed: 05/01/2024] Open
Abstract
Liver regeneration (LR) is a complex process encompassing three distinct phases: priming, proliferation phase and restoration, all influenced by various regulatory factors. After liver damage or partial resection, the liver tissue demonstrates remarkable restorative capacity, driven by cellular proliferation and repair mechanisms. The essential roles of non-coding RNAs (ncRNAs), predominantly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNA (circRNA), in regulating LR have been vastly studied. Additionally, the impact of ncRNAs on LR and their abnormal expression profiles during this process have been extensively documented. Mechanistic investigations have revealed that ncRNAs interact with genes involved in proliferation to regulate hepatocyte proliferation, apoptosis and differentiation, along with liver progenitor cell proliferation and migration. Given the significant role of ncRNAs in LR, an in-depth exploration of their involvement in the liver's self-repair capacity can reveal promising therapeutic strategies for LR and liver-related diseases. Moreover, understanding the unique regenerative potential of the adult liver and the mechanisms and regulatory factors of ncRNAs in LR are crucial for improving current treatment strategies and exploring new therapeutic approaches for various liver-related diseases. This review provides a brief overview of the LR process and the ncRNA expression profiles during this process. Furthermore, we also elaborate on the specific molecular mechanisms through which multiple key ncRNAs regulate the LR process. Finally, based on the expression characteristics of ncRNAs and their interactions with proliferation-associated genes, we explore their potential clinical application, such as developing predictive indicators reflecting liver regenerative activity and manipulating LR processes for therapeutic purposes.
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Affiliation(s)
- Penghui Li
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
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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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7
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Qin D, Han C, Gao Y, Li H, Zhu L. Lactucin reverses liver fibrosis by inhibiting TGF-β1/STAT3 signaling pathway and regulating short-chain fatty acids metabolism. Sci Rep 2024; 14:19323. [PMID: 39164375 PMCID: PMC11336071 DOI: 10.1038/s41598-024-70253-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/14/2024] [Indexed: 08/22/2024] Open
Abstract
TGF-β1 activation of hepatic stellate cells (HSCs), transcriptional activator 3 (Stat3) activation and short chain fatty acids (SCFAs), metabolite of intestinal bacteria, is closely associated with hepatic fibrosis. Previous studies have shown that Lactucin has significant anti-inflammatory and hepatoprotective effects; however, the mechanism of Lactucin's role in liver fibrosis associated with SCFAs remains unknown. This study was intended to investigate whether effect of Lactucin on liver fibrosis was mediated by TGF-β1/Stat3 and SCFAs. We found that Lactucin induced apoptosis in HSC-T6 cells, and inhibition of nuclear translocation of Stat3 and p-Stat3. And Smad3 and TGF-β1 protein expression was significantly inhibited, while TLR4 and Smad7 protein expression was significantly enhanced. For in vivo experiments, we demonstrated that Lactucin alleviated liver fibrosis in mice, as evidenced by a reduction in inflammatory factors, collagen deposition, liver injury and fibrosis-related factors expression, especially the expression of Smad3 and TGF-β1 proteins was significantly suppressed and Smad7 protein expression was significantly increased in the liver. In addition, the levels of acetic acid, butyric acid and valeric acid in the intestine of Lactucin-treated mice were significantly higher than those in the intestine of liver fibrosis mice. In conclusion, based on the results of in vivo and in vitro experiments, preventive mechanism of Lactucin against liver fibrosis in mice may be to improve the enterohepatic circulation by regulating the metabolites of intestinal microorganisms, acetic acid and butyric acid, and to further regulate the Stat3 and TGF-β1 signaling pathway through the "gut-liver axis" to combat liver fibrosis.
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Affiliation(s)
- Dongmei Qin
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, No. 59, North Second Road, Shihezi, 832002, Xinjiang Uygur Autonomous Region, People's Republic of China.
| | - Chang Han
- Department of Pharmacy, The Seventh Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
| | - Yuefeng Gao
- College of Applied Engineering, Henan University of Science and Technology, Sanmenxia, People's Republic of China
| | - Hong Li
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, No. 59, North Second Road, Shihezi, 832002, Xinjiang Uygur Autonomous Region, People's Republic of China
| | - Liping Zhu
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, No. 59, North Second Road, Shihezi, 832002, Xinjiang Uygur Autonomous Region, People's Republic of China
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [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: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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9
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Liu QQ, Chen J, Ma T, Huang W, Lu CH. DCDC2 inhibits hepatic stellate cell activation and ameliorates CCl 4-induced liver fibrosis by suppressing Wnt/β-catenin signaling. Sci Rep 2024; 14:9425. [PMID: 38658618 PMCID: PMC11043443 DOI: 10.1038/s41598-024-59698-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024] Open
Abstract
Liver fibrosis, as a consequence of chronic liver disease, involves the activation of hepatic stellate cell (HSC) caused by various chronic liver injuries. Emerging evidence suggests that activation of HSC during an inflammatory state can lead to abnormal accumulation of extracellular matrix (ECM). Investigating novel strategies to inhibit HSC activation and proliferation holds significant importance for the treatment of liver fibrosis. As a member of the doublecortin domain-containing family, doublecortin domain containing 2 (DCDC2) mutations can lead to neonatal sclerosing cholangitis, but its involvement in liver fibrosis remains unclear. Therefore, this study aims to elucidate the role of DCDC2 in liver fibrosis. Our findings revealed a reduction in DCDC2 expression in both human fibrotic liver tissues and carbon tetrachloride (CCl4)-induced mouse liver fibrotic tissues. Furthermore, exposure to transforming growth factor beta-1(TGF-β1) stimulation resulted in a dose- and time-dependent decrease in DCDC2 expression. The overexpression of DCDC2 inhibited the expression of α-smooth muscle actin (α-SMA) and type I collagen alpha 1 (Col1α1), and reduced the activation of HSC stimulated with TGF-β1. Additionally, we provided evidence that the Wnt/β-catenin signaling pathway was involved in this process, wherein DCDC2 was observed to inhibit β-catenin activation, thereby preventing its nuclear translocation. Furthermore, our findings demonstrated that DCDC2 could attenuate the proliferation and epithelial-mesenchymal transition (EMT)-like processes of HSC. In vivo, exogenous DCDC2 could ameliorate CCl4-induced liver fibrosis. In summary, DCDC2 was remarkably downregulated in liver fibrotic tissues of both humans and mice, as well as in TGF-β1-activated HSC. DCDC2 inhibited the activation of HSC induced by TGF-β1 in vitro and fibrogenic changes in vivo, suggesting that it is a promising therapeutic target for liver fibrosis and warrants further investigation in clinical practice.
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Affiliation(s)
- Qing-Qing Liu
- Suzhou Medical College of Soochow University, Suzhou, 215000, China
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Tao Ma
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Wei Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
| | - Cui-Hua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
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10
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Braczkowski MJ, Kufel KM, Kulińska J, Czyż DŁ, Dittmann A, Wiertelak M, Młodzik MS, Braczkowski R, Soszyński D. Pleiotropic Action of TGF-Beta in Physiological and Pathological Liver Conditions. Biomedicines 2024; 12:925. [PMID: 38672279 PMCID: PMC11048627 DOI: 10.3390/biomedicines12040925] [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: 03/10/2024] [Revised: 04/12/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The aim of this study is to review and analyze the pleiotropic effects of TGF-β in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-β is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-β plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-β levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-β has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases.
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Affiliation(s)
- Michał Jakub Braczkowski
- Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland;
| | - Klaudia Maria Kufel
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Julia Kulińska
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Daniel Łukasz Czyż
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Aleksander Dittmann
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Michał Wiertelak
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Marcin Sławomir Młodzik
- Department of Pathology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland;
| | | | - Dariusz Soszyński
- Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland;
- Department of Human Physiology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87100 Torun, Poland
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11
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Márton RA, Sebők C, Mackei M, Tráj P, Vörösházi J, Kemény Á, Neogrády Z, Mátis G. Cecropin A: investigation of a host defense peptide with multifaceted immunomodulatory activity in a chicken hepatic cell culture. Front Vet Sci 2024; 11:1337677. [PMID: 38496311 PMCID: PMC10940386 DOI: 10.3389/fvets.2024.1337677] [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: 11/13/2023] [Accepted: 02/20/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction Host defense peptides (HDPs) are increasingly referred to as promising candidates for the reduction of the use of conventional antibiotics, thereby combating antibiotic resistance. As HDPs have been described to exert various immunomodulatory effects, cecropin A (CecA) appears to be a potent agent to influence the host inflammatory response. Methods In the present study, a chicken primary hepatocyte-non-parenchymal cell co-culture was used to investigate the putative immunomodulatory effects of CecA alone and in inflammatory conditions evoked by polyinosinic-polycytidylic acid (Poly I:C). To examine the viability of the cells, the extracellular lactate dehydrogenase (LDH) activity was determined by colorimetric assay. Inflammatory markers interleukin (IL)-8 and transforming growth factor-ß1 (TGF-ß1) were investigated using the ELISA method, whereas concentrations of IL-6, IL-10, and interferon-γ (IFN-γ) were assayed by Luminex xMAP technology. Extracellular H2O2 and malondialdehyde levels were measured by fluorometric and colorimetric methods, respectively. Results Results of the lower concentrations suggested the safe application of CecA; however, it might contribute to hepatic cell membrane damage at its higher concentrations. We also found that the peptide alleviated the inflammatory response, reflected by the decreased production of the pro-inflammatory IL-6, IL-8, and IFN-γ. In addition, CecA diminished the levels of anti-inflammatory IL-10 and TGF-ß1. The oxidative markers measured remained unchanged in most cases of CecA exposure. Discussion CecA displayed a multifaceted immunomodulatory but not purely anti-inflammatory activity on the hepatic cells, and might be suggested to maintain the hepatic inflammatory homeostasis in Poly I:C-triggered immune response. To conclude, our study suggests that CecA might be a promising molecule for the development of new immunomodulatory antibiotic-substitutive agents in poultry medicine; however, there is still a lot to clarify regarding its cellular effects.
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Affiliation(s)
- Rege Anna Márton
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
- National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, Budapest, Hungary
| | - Csilla Sebők
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
| | - Máté Mackei
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
- National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, Budapest, Hungary
| | - Patrik Tráj
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
| | - Júlia Vörösházi
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
| | - Ágnes Kemény
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- Department of Medical Biology, Medical School, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Neogrády
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
| | - Gábor Mátis
- Division of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, Budapest, Hungary
- National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, Budapest, Hungary
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12
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Martini A, Turato C, Cannito S, Quarta S, Biasiolo A, Ruvoletto M, Novo E, Marafatto F, Guerra P, Tonon M, Clemente N, Bocca C, Piano SS, Guido M, Gregori D, Parola M, Angeli P, Pontisso P. The polymorphic variant of SerpinB3 (SerpinB3-PD) is associated with faster cirrhosis decompensation. Aliment Pharmacol Ther 2024; 59:380-392. [PMID: 37990490 DOI: 10.1111/apt.17804] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/24/2023] [Accepted: 10/28/2023] [Indexed: 11/23/2023]
Abstract
BACKGROUND SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3-PD (SB3-PD), presents a substitution in its reactive centre loop, determining the gain of function. AIMS To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3-PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro. METHODS We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH-7 cells transfected to overexpress either wild-type SB3 (SB3-WT) or SB3-PD to assess their endogenous effect, while LX2 and THP-1 cells were treated with exogenous SB3-WT or SB3-PD proteins. RESULTS Patients carrying SB3-PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3-WT. In multivariate analysis, SB3-PD was an independent predictor of cirrhosis complications. Patients with SB3-PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3-PD showed higher TGF-β1 expression than controls. The addition of recombinant SB3-PD induced an up-regulation of TGF-β1 in LX2 cells and a more prominent inflammatory profile in THP-1 cells, compared to the effect of SB3-WT protein. CONCLUSIONS The polymorphic variant SB3-PD is highly effective in determining activation of TGF-β1 and inflammation in vitro. Patients with cirrhosis who carry SB3-PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.
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Affiliation(s)
- Andrea Martini
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Cristian Turato
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Stefania Cannito
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Santina Quarta
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Alessandra Biasiolo
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Mariagrazia Ruvoletto
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Erica Novo
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Filippo Marafatto
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Pietro Guerra
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Nausicaa Clemente
- Department of Health Science, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy
| | - Claudia Bocca
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Salvatore Silvio Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Maria Guido
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Dario Gregori
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Maurizio Parola
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
| | - Patrizia Pontisso
- Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
- European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy
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Zhang C, Teng Y, Li F, Ho W, Bai X, Xu X, Zhang XQ. Nanoparticle-Mediated RNA Therapy Attenuates Nonalcoholic Steatohepatitis and Related Fibrosis by Targeting Activated Hepatic Stellate Cells. ACS NANO 2023; 17:14852-14870. [PMID: 37490628 DOI: 10.1021/acsnano.3c03217] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/27/2023]
Abstract
Chronic liver injury and inflammation triggered by metabolic abnormalities initiate the activation of hepatic stellate cells (HSCs), driving fibrosis and parenchymal dysfunction, culminating in disorders such as nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs capable of effectively treating NASH due to the challenges in addressing fibrosis and restoring extracellular matrix (ECM) homeostasis. We discovered a significant up-regulation of interleukin-11 (IL-11) in fibrotic livers using two well-established murine models of NASH. To leverage this signaling pathway, we developed a nanoparticle (NP)-assisted RNA interfering approach that specifically targets activated HSCs (aHSCs), blocking IL-11/ERK signaling to regulate HSC transdifferentiation along with fibrotic remodeling. The most potent NP, designated NP-AEAA, showed enhanced accumulation in fibrotic livers with NASH and was primarily enriched in aHSCs. We further investigated the therapeutic efficacy of aHSC-targeting NP-AEAA encapsulating small interfering RNA (siRNA) against IL11 or its cognate receptor IL11ra1 (termed siIL11@NP-AEAA or siIL11ra1@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both siIL11@NP-AEAA and siIL11ra1@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, siIL11ra1@NP-AEAA exhibits a superior therapeutic effect over siIL11@NP-AEAA, in terms of reducing liver steatosis and fibrosis as well as recovering liver function. These results constitute a targeted nanoparticulate siRNA therapeutic approach against the IL-11 signaling pathway of aHSCs in the fibrotic liver, offering a promising therapeutic intervention for NASH and other diseases.
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Affiliation(s)
- Chenshuang Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Yilong Teng
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | | | | | - Xin Bai
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | | | - Xue-Qing Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
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14
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Laurent C, Rayar M, Maulat C, Muscari F, Marichez A, Gregoire E, Chopinet S, Mabrut JY, Boudjema K, Lesurtel M, Adam JP, Mohkam K, Chiche L. Liver transplantation and hepatocellular carcinoma: is TIPS deleterious? A multicentric retrospective study of the ARCHET research group with propensity score matching. Langenbecks Arch Surg 2023; 408:149. [PMID: 37052722 DOI: 10.1007/s00423-023-02875-8] [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: 12/16/2021] [Accepted: 03/30/2023] [Indexed: 04/14/2023]
Abstract
PURPOSE A transjugular intrahepatic portosystemic shunt (TIPS) before the liver transplantation (LT) has been considered a contraindication in cases of hepatocellular carcinoma (HCC) because of the risk of tumour growth. We aimed to assess the impact of TIPS on incidental HCC and oncological outcomes in transplanted patients with pre-existing HCC. METHODS All consecutive transplanted patients for cirrhosis who had a previous TIPS with or without HCC were included. Between 2007 and 2014, 1912 patients were transplanted. We included 122 (6.3%) patients having TIPS before LT. A 1:3 matched cohort of 366 patients (18.9%) having LT without previous TIPS was selected using a propensity score. Incidental HCC rate and risk factor of HCC recurrence were evaluated using multivariate analysis with a competing risk model. RESULTS Before LT, in the TIPS group, 27 (22.1%) had an HCC vs. 81 (22.1%) in the control group (p = 1). The incidental HCC rate was similar: 10.5% (10/95) in the TIPS group vs. 6.3% (18/285) in the control group (p = 0.17). Recurrence occurred in 1/27 (3.7%) patient in the TIPS group and in 7/81 (8.6%) patients in the control group, without significant difference (p = 0.51). After multivariate regression, patient's gender (p < 0.01) was significantly associated with HCC recurrence while a tumour within Milan criteria (p = 0.01, sHR: 0.17 [0.04; 0.7]) and an incidental HCC (p<0.01) were found to be protector factors against HCC recurrence. CONCLUSION TIPS did not worsen the prognosis of transplanted patients for HCC. TIPS should no longer be contraindicated for oncological reasons in patients with HCC waiting for an LT.
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Affiliation(s)
- Christophe Laurent
- Department of Digestive Surgery and Liver Transplantation, Bordeaux University Hospital, Pessac, France.
| | - Michel Rayar
- Department of Visceral Surgery, University Hospital of Rennes, Rennes, France
| | - Charlotte Maulat
- Department of Visceral Surgery, Toulouse-Rangueil University Hospital, Toulouse, France
| | - Fabrice Muscari
- Department of Visceral Surgery, Toulouse-Rangueil University Hospital, Toulouse, France
| | - Arthur Marichez
- Department of Digestive Surgery and Liver Transplantation, Bordeaux University Hospital, Pessac, France
| | - Emilie Gregoire
- Department of General Surgery and Liver Transplantation, Hôpital de la Timone, Aix-Marseille University, Marseille, France
| | - Sophie Chopinet
- Department of General Surgery and Liver Transplantation, Hôpital de la Timone, Aix-Marseille University, Marseille, France
| | - Jean Yves Mabrut
- Department of General Surgery & Liver Transplantation, Hospices Civils de Lyon, Croix-Rousse University Hospital, Claude-Bernard Lyon 1 University, Lyon, France
| | - Karim Boudjema
- Department of Visceral Surgery, University Hospital of Rennes, Rennes, France
| | - Mickael Lesurtel
- Department of General Surgery & Liver Transplantation, Hospices Civils de Lyon, Croix-Rousse University Hospital, Claude-Bernard Lyon 1 University, Lyon, France
| | - Jean-Philippe Adam
- Department of Digestive Surgery and Liver Transplantation, Bordeaux University Hospital, Pessac, France
| | - Kayvan Mohkam
- Department of General Surgery & Liver Transplantation, Hospices Civils de Lyon, Croix-Rousse University Hospital, Claude-Bernard Lyon 1 University, Lyon, France
| | - Laurence Chiche
- Department of Digestive Surgery and Liver Transplantation, Bordeaux University Hospital, Pessac, France
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15
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Desregulación inmunológica y fisiopatología del consumo de alcohol y la enfermedad hepática alcohólica. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2023; 88:136-154. [DOI: 10.1016/j.rgmx.2023.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2023; 88:136-154. [PMID: 36973122 DOI: 10.1016/j.rgmxen.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 01/13/2023] [Indexed: 03/28/2023] Open
Abstract
Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.
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Shan S, Liu Z, Liu Z, Zhang C, Song F. MitoQ alleviates carbon tetrachloride-induced liver fibrosis in mice through regulating JNK/YAP pathway. Toxicol Res (Camb) 2022; 11:852-862. [PMID: 36337246 PMCID: PMC9618106 DOI: 10.1093/toxres/tfac062] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/11/2022] [Accepted: 08/07/2022] [Indexed: 08/15/2023] Open
Abstract
Background Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown. Methods and results In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, intervention experiments were achieved by CCl4 combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl4 exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-β as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl4-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP. Conclusion In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease.
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Affiliation(s)
- Shulin Shan
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, P. R. China
| | - Zhaoxiong Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, P. R. China
| | - Zhidan Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, P. R. China
| | - Cuiqin Zhang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, P. R. China
| | - Fuyong Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, P. R. China
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18
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Song C, Li W, Wang Z. The Landscape of Liver Chromatin Accessibility and Conserved Non-coding Elements in Larimichthys crocea, Nibea albiflora, and Lateolabrax maculatus. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2022; 24:763-775. [PMID: 35895229 DOI: 10.1007/s10126-022-10142-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/08/2022] [Indexed: 06/15/2023]
Abstract
Large yellow croaker (Larimichthys crocea), yellow drum (Nibea albiflora), and Chinese seabass (Lateolabrax maculatus) are important economic marine fishes in China. The conserved non-coding elements (CNEs) in the liver tissues of the three kinds of fish are directly or indirectly involved in the regulation of gene expression and affect liver functions. However, the fishes' CNEs and even chromatin accessibility landscape have not been effectively investigated. Hence, this study established the landscapes of the fishes' genome-wide chromatin accessibility and CNEs by detecting regions of the open chromatin in their livers using an assay for transposase-accessible chromatin by high-throughput sequencing (ATAC-seq) and comparative genomics approach. The results showed that Smad1, Sp1, and Foxl1 transcription factor binding motifs were considerably enriched in the chromatin accessibility landscape in the liver of the three species, and the three transcription factors (TFs) had a wide range of common targets. The hypothetical gene set was targeted by one, two, or all three TFs, which was much higher than would be expected for an accidental outcome. The gene sets near the CNEs were mainly enriched through processes such as a macromolecule metabolic process and ribonucleoprotein complex biogenesis. The active CNEs were found in the promoter regions of genes such as ap1g1, hax1, and ndufs2. And 5 CNEs were predicted to be highly conserved active enhancers. These results demonstrated that Smad1, Sp1, and Foxl1 might be related to the liver function in the three fishes. In addition, we found a series of ATAC-seq-labeled CNEs located in the gene promoter regions, and highly conserved H3k27ac + -labeled CNEs located in the liver function genes. The highly conserved nature of these regulatory elements suggests that they play important roles in the liver in fish. This study mined the landscape of chromatin accessibility and CNEs of three important economic fishes to fill the knowledge gaps in this field. Moreover, the work provides useful data for the industrial application and theoretical research of these three fish species.
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Affiliation(s)
- Chaowei Song
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Jimei University, Xiamen, China
| | - Wanbo Li
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Jimei University, Xiamen, China
| | - Zhiyong Wang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Jimei University, Xiamen, China.
- Laboratory for Marine Fisheries Science and Food Production Processes, National Laboratory for Marine Science and Technology, Qingdao, China.
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Zhang XL, Zhang XY, Ge XQ, Liu MX. Mangiferin prevents hepatocyte epithelial-mesenchymal transition in liver fibrosis via targeting HSP27-mediated JAK2/STAT3 and TGF-β1/Smad pathway. Phytother Res 2022; 36:4167-4182. [PMID: 35778992 DOI: 10.1002/ptr.7549] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 06/08/2022] [Accepted: 06/17/2022] [Indexed: 12/11/2022]
Abstract
Hepatocytes has been confirmed to undergo EMT and can be converted into myofibroblasts during hepatic fibrogenesis. However, the mechanism of hepatocyte EMT regulation in hepatic fibrosis, particularly through HSP27 (human homologue of rodent HSP25), remains unclear. Mangiferin (MAN), a compound extracted from Mangifera indica L, has been reported to attenuate liver injury. This study aimed to investigate the mechanisms underlying HSP27 inhibition and the anti-fibrotic effect of MAN in liver fibrosis. Our results revealed that the expression of HSP27 was remarkably increased in the liver tissues of patients with liver cirrhosis and CCl4 -induced fibrotic rats. However, HSP27 shRNA treatment significantly alleviated fibrosis. Furthermore, MAN was found to inhibit CCl4 - and TGF-β1-induced liver fibrosis and reduced hepatocyte EMT. More importantly, MAN decreased HSP27 expression to suppress the JAK2/STAT3 pathway, and subsequently blocked TGF-β1/Smad signaling, which were consistent with its protection against CCl4 -induced EMT and liver fibrosis. Together, these results suggest that HSP27 may play a crucial role in hepatocyte EMT and liver fibrosis by activating JAK2/STAT3 signaling and TGF-β1/Smad pathway. The suppression of HSP27 expression by MAN may be a novel strategy for attenuating the hepatocyte EMT in liver fibrosis.
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Affiliation(s)
- Xiao-Ling Zhang
- College of Pharmacy, Nantong University, Nantong, PR China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Xiao-Yan Zhang
- Department of Pharmacology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, PR China
| | - Xiao-Qun Ge
- Department of Pharmacology, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, PR China
| | - Ming-Xuan Liu
- College of Pharmacy, Nantong University, Nantong, PR China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
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20
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Signaling cascades in the failing heart and emerging therapeutic strategies. Signal Transduct Target Ther 2022; 7:134. [PMID: 35461308 PMCID: PMC9035186 DOI: 10.1038/s41392-022-00972-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/13/2022] [Accepted: 03/20/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.
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21
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Choi JW, Shin JY, Zhou Z, Kim DU, Kweon B, Oh H, Kim YC, Song HJ, Bae GS, Park SJ. Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-β/Smad signaling pathway. J Investig Med 2022; 70:1285-1292. [PMID: 35078865 DOI: 10.1136/jim-2021-002169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 11/04/2022]
Abstract
Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative and antitumor activities. Although FR possesses numerous properties associated with the regulation of diverse diseases, the effects of FR on CP remain unknown. Herein, we examined the effects of FR on CP. For CP induction, mice were intraperitoneally administered cerulein (50 μg/kg) 6 times a day, 4 days per week for 3 weeks. FR extract (100 or 400 mg/kg) or saline (control group) was intraperitoneally injected 1 hour before the first cerulein injection. After 3 weeks, the pancreas was harvested for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of FR. Administration of FR significantly inhibited histological damage in the pancreas, increased pancreatic acinar cell survival, decreased PSC activation and collagen deposition, and decreased pro-inflammatory cytokines. Moreover, FR treatment inhibited the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, fibronectin 1, and decreased pro-inflammatory cytokines in isolated PSCs stimulated with transforming growth factor (TGF)-β. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-β-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.
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Affiliation(s)
- Ji-Won Choi
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea.,Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Joon Yeon Shin
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Ziqi Zhou
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Dong-Uk Kim
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Bitna Kweon
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Hyuncheol Oh
- Institute of Pharmaceutical Research and Development, College of Pharmacy, WonkwangUniversity, Iksan, Jeollabuk-do, Republic of Korea
| | - Youn-Chul Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, WonkwangUniversity, Iksan, Jeollabuk-do, Republic of Korea
| | - Ho-Joon Song
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Gi-Sang Bae
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea .,Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea.,Research Center of Traditional Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Sung-Joo Park
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea .,Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
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22
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Rao S, Yang X, Ohshiro K, Zaidi S, Wang Z, Shetty K, Xiang X, Hassan I, Mohammad T, Latham PS, Nguyen BN, Wong L, Yu H, Al-Abed Y, Mishra B, Vacca M, Guenigault G, Allison MED, Vidal-Puig A, Benhammou JN, Alvarez M, Pajukanta P, Pisegna JR, Mishra L. β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Sci Transl Med 2021; 13:eabk2267. [PMID: 34910547 PMCID: PMC8941321 DOI: 10.1126/scitranslmed.abk2267] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.
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Affiliation(s)
- Shuyun Rao
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Sobia Zaidi
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Zhanhuai Wang
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Kirti Shetty
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, 21201, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Patricia S. Latham
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
- Department of Pathology, The George Washington University, DC, 20037, USA
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
| | - Linda Wong
- Cancer Biology department, University of Hawaii Cancer Center, HI, 96813, USA
- Dept of Surgery, University of Hawaii John A. Burns School of Medicine, HI, 96813, USA
| | - Herbert Yu
- Epidemiology Program, University of Hawaii Cancer Center, HI, 96813, USA
| | - Yousef Al-Abed
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Bibhuti Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Department of Neurology, Northwell Health, Manhasset, NY, 11030, USA
| | - Michele Vacca
- TVP Lab, Metabolic Research Laboratories, WT/MRC Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
| | | | - Michael ED Allison
- Liver Unit, Cambridge Biomedical Research Centre, Cambridge University Hospitals, CB2 0QQ, United Kingdom
| | - Antonio Vidal-Puig
- TVP Lab, Metabolic Research Laboratories, WT/MRC Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
- Welcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom
- Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei Area, Nanjing, 210000, China
| | - Jihane N Benhammou
- Vatche and Tamar Manoukian Division of Digestive Diseases and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, 90095, USA
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Joseph R. Pisegna
- Department of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, 90095, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
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23
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Cho SS, Lee JH, Kim KM, Park EY, Ku SK, Cho IJ, Yang JH, Ki SH. REDD1 attenuates hepatic stellate cell activation and liver fibrosis via inhibiting of TGF-β/Smad signaling pathway. Free Radic Biol Med 2021; 176:246-256. [PMID: 34614448 DOI: 10.1016/j.freeradbiomed.2021.10.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 09/27/2021] [Accepted: 10/01/2021] [Indexed: 12/20/2022]
Abstract
Liver fibrosis is caused by repetitive hepatic injury. Regulated in development and DNA damage response 1 (REDD1) gene is induced by various stresses and has been studied in cell proliferation and survival. However, the role of REDD1 in hepatic stellate cell activation and hepatic fibrogenesis has not yet been investigated. In the current study, we examined the effect of REDD1 on hepatic fibrogenesis and the underlying molecular mechanism. REDD1 protein was upregulated in the activated primary hepatic stellate cells and transforming growth factor-β (TGF-β)-treated LX-2 cells. REDD1 mRNA levels were also elevated by TGF-β treatment. TGF-β signaling is primarily transduced via the activation of the Smad transcription factor. However, TGF-β-mediated REDD1 induction was not Smad-dependent. Thus, we investigated the transcription factors that influence the REDD1 expression by TGF-β. We found that c-JUN, a component of AP-1, upregulated the REDD1 expression that was specifically suppressed by p38 inhibitor. In silico analysis of the REDD1 promoter region showed putative AP-1-binding sites; additionally, its deletion mutants demonstrated that the AP-1-binding site between -716 and -587 bp within the REDD1 promoter is critical for TGF-β-mediated REDD1 induction. Moreover, REDD1 overexpression markedly inhibited TGF-β-induced plasminogen activator inhibitor-1 (PAI-1) expression and Smad phosphorylation. REDD1 adenovirus infection inhibited CCl4-induced hepatic injury in mice, which was demonstrated by reduced ALT/AST levels and collagen accumulation. In addition, we observed that REDD1 inhibited CCl4-induced fibrogenic gene induction and restored GSH and malondialdehyde levels. Our findings implied that REDD1 has the potential to inhibit HSC activation and protect against liver fibrosis.
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Affiliation(s)
- Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do, 58554, Republic of Korea
| | - Sae Kwang Ku
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Il Je Cho
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea.
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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24
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Tavakoli A, Mirzababaei A, Sajadi F, Mirzaei K. Circulating inflammatory markers may mediate the relationship between low carbohydrate diet and circadian rhythm in overweight and obese women. BMC WOMENS HEALTH 2021; 21:87. [PMID: 33648476 PMCID: PMC7923314 DOI: 10.1186/s12905-021-01240-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 02/22/2021] [Indexed: 12/29/2022]
Abstract
Background Low carbohydrate diet (LCD) can improve inflammation and obesity and also circadian rhythm disorders can lead to increased inflammation in obese individuals. The purpose of this study is to evaluate the association between adherence of LCD and circadian rhythm mediated by inflammatory markers including transforming growth factor-β (TGF-β), interleukin-1β (IL-1β) and Galectin-3 in overweight and obese women. Methods 304 women affected by overweight and obesity were enrolled. We evaluated LCD scores by Semi-quantitative food frequency questionnaire (FFQ) of 147 items. The morning-evening questionnaire (MEQ) was applied to evaluate the circadian rhythm. Biochemical parameters such as inflammatory markers and anthropometric components were assessed. Results There was a negative significant correlation between adherence of LCD and circadian rhythm status. In other words, as the LCD scores increased, the odds of circadian rhythm disturbance in intermediate group and morning type persons decreased compared to evening type. It was showed that, IL-1β and Galectin-3 in intermediate and morning type groups, destroyed the significance of this relationship and may be considered as mediating markers. Conclusion Adherence of LCD can improve the circadian rhythm by reducing levels of inflammatory markers and may be considered as a treatment for obesity.
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Affiliation(s)
- Atefeh Tavakoli
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
| | - Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
| | - Forough Sajadi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box 14155-6117, Tehran, Iran.
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25
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Raza S, Rajak S, Upadhyay A, Tewari A, Anthony Sinha R. Current treatment paradigms and emerging therapies for NAFLD/NASH. FRONT BIOSCI-LANDMRK 2021; 26:206-237. [PMID: 33049668 PMCID: PMC7116261 DOI: 10.2741/4892] [Citation(s) in RCA: 199] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one the fastest emerging manifestations of the metabolic syndrome worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, may culminate into cirrhosis and hepatocellular cancer (HCC) and is presently a leading cause of liver transplant. Although a steady progress is seen in understanding of the disease epidemiology, pathogenesis and identifying therapeutic targets, the slowest advancement is seen in the therapeutic field. Currently, there is no FDA approved therapy for this disease and appropriate therapeutic targets are urgently warranted. In this review we discuss the role of lifestyle intervention, pharmacological agents, surgical approaches, and gut microbiome, with regard to therapy for NASH. In particular, we focus the role of insulin sensitizers, thyroid hormone mimetics, antioxidants, cholesterol lowering drugs, incretins and cytokines as therapeutic targets for NASH. We highlight these targets aiming to optimize the future for NASH therapy.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Aditya Upadhyay
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Archana Tewari
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India,
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26
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Wang R, Zhang D, Tang D, Sun K, Peng J, Zhu W, Yin S, Wu Y. Amygdalin inhibits TGFβ1-induced activation of hepatic stellate cells (HSCs) in vitro and CCl 4-induced hepatic fibrosis in rats in vivo. Int Immunopharmacol 2021; 90:107151. [PMID: 33296784 DOI: 10.1016/j.intimp.2020.107151] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/22/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023]
Abstract
The activation of hepatic stellate cells (HSCs) has been considered one of the major events in hepatic fibrosis. Amygdalin has been used to treat cancers and alleviate pain; however, its role and mechanism in HSC activation and hepatic fibrosis remain unclear. In the present study, transforming growth factor-beta 1 (TGF-β1) stimulated the activation of HSCs, as indicated by significantly increased alpha-smooth muscle actin (α-SMA), desmin, collagen I, and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein levels. Amygdalin treatment dramatically suppressed TGF-β1-induced HSC proliferation and activation. Moreover, amygdalin treatment also reduced the TGF-β1-induced secretion of cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), platelet-derived growth factor (PDGF), and chemokine (C-C motif) ligand 2 (CCL2), as well as the phosphorylation of Smad2, Smad3, and p65. In the CCl4-stimulated liver fibrosis rat model, amygdalin treatment improved liver fibrosis and liver damage by reducing focal necrosis, collagen fiber accumulation, and the protein levels of α-SMA, desmin, collagen I, and TIMP-1 in hepatic tissue samples and reducing serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. In conclusion, we demonstrated the suppressive effects of amygdalin in TGF-β1-induced HSC activation through modulating proliferation, fibrogenesis, and inflammation signaling in vitro and the antifibrotic effects of amygdalin in CCl4-stimulated hepatic fibrosis in rats in vivo.
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Affiliation(s)
- Ruoyu Wang
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Dong Zhang
- Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine in Zhuhai, Zhuhai, Guangdong 519015, China
| | - Dan Tang
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Kewei Sun
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Jianping Peng
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Wenfang Zhu
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Sihan Yin
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Yunan Wu
- Department of Hepatology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
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27
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Nilsson J, Hörnberg M, Schmidt-Christensen A, Linde K, Nilsson M, Carlus M, Erttmann SF, Mayans S, Holmberg D. NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis. Sci Rep 2020; 10:21778. [PMID: 33311540 PMCID: PMC7732838 DOI: 10.1038/s41598-020-78688-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 11/27/2020] [Indexed: 12/27/2022] Open
Abstract
Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. We have found that a transgenic NKT (tgNKT) cell population produced in the immunodeficient 2,4αβNOD.Rag2−/− mice, but not in 2,4αβNOD.Rag2+/− control mice, promoted a type 1 inflammatory response with engagement of the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome. The induction of the type 1 inflammatory response was followed by an altered cytokine profile of the tgNKT cell population with a biased production of anti-inflammatory/profibrotic cytokines and development of liver fibrosis. These findings illustrate how the plasticity of NKT cells modulates the inflammatory response, suggesting a key role for the NKT cell population in the control of sterile liver inflammation.
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Affiliation(s)
- Julia Nilsson
- Department of Experimental Medical Sciences, Lund University Diabetes Center, Clinical Research Center, Lund University, Jan Waldenströms gata 35, 214 28, Malmö, Sweden.,InfiCure Bio AB, Tvistevägen 48 C, 907 36, Umeå, Sweden
| | | | - Anja Schmidt-Christensen
- Department of Experimental Medical Sciences, Lund University Diabetes Center, Clinical Research Center, Lund University, Jan Waldenströms gata 35, 214 28, Malmö, Sweden
| | - Kajsa Linde
- InfiCure Bio AB, Tvistevägen 48 C, 907 36, Umeå, Sweden
| | - Maria Nilsson
- Department of Experimental Medical Sciences, Lund University Diabetes Center, Clinical Research Center, Lund University, Jan Waldenströms gata 35, 214 28, Malmö, Sweden
| | - Marine Carlus
- Carlus Pathology Consulting, 2 rue de la Libération, 76630, Bellengreville, France
| | - Saskia F Erttmann
- Department of Molecular Biology, Umeå University, 901 87, Umeå, Sweden
| | - Sofia Mayans
- InfiCure Bio AB, Tvistevägen 48 C, 907 36, Umeå, Sweden
| | - Dan Holmberg
- Department of Experimental Medical Sciences, Lund University Diabetes Center, Clinical Research Center, Lund University, Jan Waldenströms gata 35, 214 28, Malmö, Sweden. .,InfiCure Bio AB, Tvistevägen 48 C, 907 36, Umeå, Sweden.
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Xiang D, Zou J, Zhu X, Chen X, Luo J, Kong L, Zhang H. Physalin D attenuates hepatic stellate cell activation and liver fibrosis by blocking TGF-β/Smad and YAP signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 78:153294. [PMID: 32771890 DOI: 10.1016/j.phymed.2020.153294] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/14/2020] [Accepted: 07/24/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Hepatic fibrosis is considered integral to the progression of chronic liver diseases, as it leads to the development of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. The transforming growth factor-β1 (TGF-β1) and Yes-associated protein (YAP) pathways play a pivotal role in HSC activation, hepatic fibrosis and cirrhosis progression. Therefore, targeting the TGF-β/Smad and YAP signaling pathways is a promising strategy for antifibrotic therapy. PURPOSE The present study investigated the protective effects of Physalin D (PD), a withanolide isolated from Physalis species (Solanaceae), against liver fibrosis and further elucidated the mechanisms involved in vitro and in vivo. STUDY DESIGN/METHODS We conducted a series of experiments using carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced fibrotic mice and cultured LX-2 cells. Serum markers of liver injury, and the morphology, histology and fibrosis of liver tissue were investigated. Western blot assays and quantitative real-time PCR were used to investigate the mechanisms underlying the antifibrotic effects of PD. RESULT PD decreased TGF-β1-induced COL1A1 promoter activity. PD inhibited TGF-β1-induced expression of Collagen I and α-smooth muscle actin (α-SMA) in human hepatic stellate LX-2 cells. PD significantly ameliorated hepatic injury, including transaminase activities, histology, collagen deposition and α-SMA, in CCl4- or BDL-induced mice. Moreover, PD markedly decreased the expression of phosphorylated Smad2/3 in vitro and in vivo. Furthermore, PD significantly decreased YAP protein levels, and YAP knockdown did not further enhance the effects of PD, namely α-SMA inhibition, Collagen I expression and YAP target gene expression in LX-2 cells. CONCLUSION These results clearly show that PD ameliorated experimental liver fibrosis by inhibiting the TGF-β/Smad and YAP signaling pathways, indicating that PD has the potential to effectively treat liver fibrosis.
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Affiliation(s)
- Dejuan Xiang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jie Zou
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoyun Zhu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xinling Chen
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jianguang Luo
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lingyi Kong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Peng F, Tian Y, Ma J, Xu Z, Wang S, Tang M, Lei J, Gong G, Jiang Y. CAT1 silencing inhibits TGF-β1-induced mouse hepatic stellate cell activation in vitro and hepatic fibrosis in vivo. Cytokine 2020; 136:155288. [PMID: 32980687 DOI: 10.1016/j.cyto.2020.155288] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 09/03/2020] [Accepted: 09/04/2020] [Indexed: 12/31/2022]
Abstract
Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM). Hepatic stellate cells (HSCs) are the primary cells that produce ECM in response to hepatic injury, and transforming growth factor-beta (TGF-β) has been regarded as the central stimulus responsible for HSC-mediated ECM production. In the present study, we attempted to identify a critical factor in HSC activation and the underlying mechanism. By analyzing online microarray expression profiles, we found that the expression of high-affinity cationic amino acid transporter 1 (CAT1) was upregulated in hepatic fibrosis models and activated HSCs. We isolated and identified mouse HSCs (MHSCs) and found that in these cells, CAT1 was most highly upregulated by TGF-β1 stimulation in both time- and dose-dependent manners. In vitro, CAT1 overexpression further enhanced, while CAT1 silencing inhibited, the effect of TGF-β1 in promoting MHSC activation. In vivo, CAT1 silencing significantly improved the hepatic fibrosis induced by both CCl4 and non-alcoholic fatty liver disease (NAFLD). In summary, CAT1 was significantly upregulated in TGF-β1-activated MHSCs and mice with hepatic fibrosis. CAT1 silencing inhibited TGF-β1-induced MHSC activation in vitro and fibrogenic changes in vivo. CAT1 is a promising target for hepatic fibrosis treatment that requites further investigation in human cells and clinical practice.
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Affiliation(s)
- Feng Peng
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yi Tian
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jing Ma
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Zhenyu Xu
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Sujuan Wang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Min Tang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Jianhua Lei
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Guozhong Gong
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yongfang Jiang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
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30
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Su DN, Wu SP, Xu SZ. Mesenchymal stem cell-based Smad7 gene therapy for experimental liver cirrhosis. Stem Cell Res Ther 2020; 11:395. [PMID: 32928296 PMCID: PMC7489041 DOI: 10.1186/s13287-020-01911-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 01/17/2023] Open
Abstract
Background Bone mesenchymal stem cells (MSCs) can promote liver regeneration and inhibit inflammation and hepatic fibrosis. MSCs also can serve as a vehicle for gene therapy. Smad7 is an essential negative regulatory gene in the TGF-β1/Smad signalling pathway. Activation of TGF-β1/Smad signalling accelerates liver inflammation and fibrosis; we therefore hypothesized that MSCs overexpressing the Smad7 gene might be a new cell therapy approach for treating liver fibrosis via the inhibition of TGF-β1/Smad signalling. Methods MSCs were isolated from 6-week-old Wistar rats and transduced with the Smad7 gene using a lentivirus vector. Liver cirrhosis was induced by subcutaneous injection of carbon tetrachloride (CCl4) for 8 weeks. The rats with established liver cirrhosis were treated with Smad7-MSCs by direct injection of cells into the main lobes of the liver. The expression of Smad7, Smad2/3 and fibrosis biomarkers or extracellular matrix proteins and histopathological change were assessed by quantitative PCR, ELISA and Western blotting and staining. Results The mRNA and protein level of Smad7 in the recipient liver and serum were increased after treating with Smad-MSCs for 7 and 21 days (P < 0.001). The serum levels of collagen I and III and collagenase I and III were significantly (P < 0.001) reduced after the treatment with Smad7-MSCs. The mRNA levels of TGF-β1, TGFBR1, α-SMA, TIMP-1, laminin and hyaluronic acid were decreased (P < 0.001), while MMP-1 increased (P < 0.001). The liver fibrosis score and liver function were significantly alleviated after the cell therapy. Conclusions The findings suggest that the MSC therapy with Smad7-MSCs is effective in the treatment of liver fibrosis in the CCl4-induced liver cirrhosis model. Inhibition of TGF-β1 signalling pathway by enhancement of Smad-7 expression could be a feasible cell therapy approach to mitigate liver cirrhosis.
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Affiliation(s)
- Dong-Na Su
- Department of Infectious Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), 1017 Dong Men Bei Road, Luo Hu District, Shenzhen, 518020, Guangdong Province, People's Republic of China
| | - Shi-Pin Wu
- Department of Infectious Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), 1017 Dong Men Bei Road, Luo Hu District, Shenzhen, 518020, Guangdong Province, People's Republic of China.
| | - Shang-Zhong Xu
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
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31
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Yang J, Gao J, Yu W, Hao R, Fan J, Wei J. The effects and mechanism of Aronia melanocarpa Elliot anthocyanins on hepatic fibrosis. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103897] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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32
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Liu X, Huang K, Zhang RJ, Mei D, Zhang B. Isochlorogenic Acid A Attenuates the Progression of Liver Fibrosis Through Regulating HMGB1/TLR4/NF-κB Signaling Pathway. Front Pharmacol 2020; 11:582. [PMID: 32425800 PMCID: PMC7206717 DOI: 10.3389/fphar.2020.00582] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 04/15/2020] [Indexed: 01/17/2023] Open
Abstract
Liver fibrosis, a chronic damage process related to further progression of hepatic cirrhosis, has yet no truly effective treatment. Isochlorogenic acid A (ICQA), isolated from a traditional Chinese herbal medicine named Laggera alata (DC.) Sch.Bip. ex Oliv. (Asteraceae), is proved to exhibit anti-inflammatory, hepatoprotective and antiviral properties. However, the actions of ICQA on liver fibrosis are poorly understood. The purpose of this study was to evaluate the actions of ICQA on liver fibrosis and clarify the underlying mechanism. It was found that ICQA had significant protective actions on liver injury, inflammation as we as fibrosis in rats. Meanwhile, ICQA prevented hepatic stellate cells (HSC) activation, indicated by its inhibitory effect on the overexpression of α-smooth muscle actin (α-SMA). In addition, the reduced fibrosis was found to be associated with the decreased protein expression of high-mobility group box 1 (HMGB1) as well as toll like receptor (TLR) 4. Simultaneously, ICQA can suppress the cytoplasmic translocation of HMGB1 in rat liver. Further investigations indicated that ICQA treatment dramatically attenuated the nuclear translocation of the nuclear factor-kB (NF-κB) p65 and suppressed the hepatic expression of p−IκBα in rats with liver fibrosis. Taken together, our study indicated that ICQA could protect against CCl4-induced liver fibrosis probably through suppressing the HMGB1/TLR4/NF-κB signaling pathways.
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Affiliation(s)
- Xin Liu
- Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
| | - Kai Huang
- Drug Clinical Trial Institution, Wuxi People's Hospital, Nanjing Medical University, Wuxi, China
| | - Ru Jiao Zhang
- Health Science Center, Hebei University, Baoding, China
| | - Dan Mei
- Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Zhang
- Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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33
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Gong T, Zhang C, Ni X, Li X, Li J, Liu M, Zhan D, Xia X, Song L, Zhou Q, Ding C, Qin J, Wang Y. A time-resolved multi-omic atlas of the developing mouse liver. Genome Res 2020; 30:263-275. [PMID: 32051188 PMCID: PMC7050524 DOI: 10.1101/gr.253328.119] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 01/17/2020] [Indexed: 12/13/2022]
Abstract
Liver organogenesis and development are composed of a series of complex, well-orchestrated events. Identifying key factors and pathways governing liver development will help elucidate the physiological and pathological processes including those of cancer. We conducted multidimensional omics measurements including protein, mRNA, and transcription factor (TF) DNA-binding activity for mouse liver tissues collected from embryonic day 12.5 (E12.5) to postnatal week 8 (W8), encompassing major developmental stages. These data sets reveal dynamic changes of core liver functions and canonical signaling pathways governing development at both mRNA and protein levels. The TF DNA-binding activity data set highlights the importance of TF activity in early embryonic development. A comparison between mouse liver development and human hepatocellular carcinoma (HCC) proteomic profiles reveal that more aggressive tumors are characterized with the activation of early embryonic development pathways, whereas less aggressive ones maintain liver function-related pathways that are elevated in the mature liver. This work offers a panoramic view of mouse liver development and provides a rich resource to explore in-depth functional characterization.
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Affiliation(s)
- Tongqing Gong
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Chunchao Zhang
- Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Xiaotian Ni
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China.,Department of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xianju Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Jin'e Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Mingwei Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Dongdong Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China.,Department of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xia Xia
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Lei Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Quan Zhou
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, and School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China
| | - Jun Qin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China.,State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, and School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China
| | - Yi Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Institute of Lifeomics, Beijing 102206, China.,Alkek Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
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34
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Kim JY, Kim KM, Yang JH, Cho SS, Kim SJ, Park SJ, Ahn SG, Lee GH, Yang JW, Lim SC, Kang KW, Ki SH. Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. Sci Rep 2020. [PMID: 31949242 DOI: 10.1038/s41598-019-57322-w.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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Affiliation(s)
- Ji Young Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hye Yang
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.,College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Seung Jung Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Su Jung Park
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, College of Dentistry, Chosun University, Gwangju, 61452, Republic of Korea
| | - Gum Hwa Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jin Won Yang
- College of Pharmacy, Woosuk University, Wanju, Jeonbuk, 55338, Republic of Korea
| | - Sung Chul Lim
- College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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35
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Induction of E6AP by microRNA-302c dysregulation inhibits TGF-β-dependent fibrogenesis in hepatic stellate cells. Sci Rep 2020; 10:444. [PMID: 31949242 PMCID: PMC6965100 DOI: 10.1038/s41598-019-57322-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 12/27/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatic stellate cells (HSCs) are essential for liver fibrosis. E6 associated protein (E6AP) is one of the E3-ubiquitin-protein ligase and has been studied in proliferation and cellular stress. Currently, no information is available on the role of E6AP on transforming growth factor-β (TGF-β) signaling and hepatic fibrogenesis. This study examined whether E6AP is overexpressed in activated HSCs, and if so, its effect on hepatic fibrogenesis and the molecular mechanism. E6AP was expressed higher in HSCs than hepatocytes, and was up-regulated in activated HSCs, HSCs from the livers of carbon tetrachloride-injected mice, or TGF-β-treated LX-2 cells. The TGF-β-mediated E6AP up-regulation was not due to altered mRNA level nor protein stability. Thus, we performed microRNA (miRNA, miR) analysis and found that miR-302c was dysregulated in TGF-β-treated LX-2 cells or activated primary HSCs. We revealed that miR-302c was a modulator of E6AP. E6AP overexpression inhibited TGF-β-induced expression of plasminogen activator inhibitor-1 in LX-2 cells, albeit it was independent of Smad pathway. Additionally, E6AP inhibited TGF-β-mediated phosphorylation of mitogen-activated protein kinases. To conclude, E6AP overexpression due to decreased miR-302c in HSCs attenuated hepatic fibrogenesis through inhibition of the TGF-β-induced mitogen-activated protein kinase signaling pathway, implying that E6AP and other molecules may contribute to protection against liver fibrosis.
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36
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Chen Z, Wan L, Jin X, Wang W, Li D. Transforming growth factor-β signaling confers hepatic stellate cells progenitor features after partial hepatectomy. J Cell Physiol 2019; 235:2655-2667. [PMID: 31584200 DOI: 10.1002/jcp.29169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 08/26/2019] [Indexed: 12/29/2022]
Abstract
Liver regeneration involves not only hepatocyte replication but progenitor aggregation and scarring. Partial hepatectomy (PH), an established model for liver regeneration, reactivates transforming growth factor-β (TGF-β) signaling. Hepatic stellate cells (HSCs) are primarily responding cells for TGF-β and resident in stem cell niche. In the current study, PH mice were treated with SB-431542, an inhibitor of TGF-β Type I receptor, aiming to address the role of TGF-β signaling on the fate determination of HSCs during liver regeneration. After PH, control mice exhibited HSCs activation, progenitor cells accumulation, and a fraction of HSCs acquired the phenotype of hepatocyte or cholangiocyte. Blocking TGF-β signaling delayed proliferation, impaired progenitor response, and scarring repair. In SB-431542 group, merely no HSCs were found coexpressed progenitor makers, such as SOX9 and AFP. Inhibition of TGF-β pathway disturbed the epithelial-mesenchymal transitions and diminished the nuclear accumulation of β-catenin as well as the expression of cytochrome P450 2E1 in HSC during liver regeneration. We identify a key role of TGF-β signaling on promoting HSC transition, which subsequently becomes progenitor for generating liver epithelial cells after PH. This process might interact with an acknowledged stem cell function signaling, Wnt/β-catenin.
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Affiliation(s)
- Zixin Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Wan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dewei Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Cao G, Zhu R, Jiang T, Tang D, Kwan HY, Su T. Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 63:153055. [PMID: 31377585 DOI: 10.1016/j.phymed.2019.153055] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/03/2019] [Accepted: 07/26/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated. METHODS Carbon tetrachloride (CCl4)-induced rat HF model and TGF-β1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects. RESULTS We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects. CONCLUSION Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention.
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Affiliation(s)
- Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ting Jiang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dongxin Tang
- First Affiliated Hospital of Guiyang College of Traditional Chinese Medicine, Guiyang, China
| | - Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Tao Su
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Huang X, Lee F, Teng Y, Lingam CB, Chen Z, Sun M, Song Z, Balachander GM, Leo HL, Guo Q, Shah I, Yu H. Sequential drug delivery for liver diseases. Adv Drug Deliv Rev 2019; 149-150:72-84. [PMID: 31734169 DOI: 10.1016/j.addr.2019.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.
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Affiliation(s)
- Xiaozhong Huang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Fan Lee
- Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Yao Teng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Corey Bryen Lingam
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore
| | - Zijian Chen
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore; Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen 518055, China
| | - Min Sun
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Ziwei Song
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Gowri M Balachander
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Hwa Liang Leo
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore
| | - Qiongyu Guo
- Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen 518055, China
| | - Imran Shah
- National Center for Computational Toxicology, United States Environmental Protection Agency, 4930 Old Page Rd., Durham, NC 27703, USA
| | - Hanry Yu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore; Mechanobiology Institute, National University of Singapore, T-Lab, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore; CAMP, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Level 4 Enterprise Wing, Singapore 138602, Singapore; Gastroenterology Department, Southern Medical University, Guangzhou 510515, China.
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Propofol intravenous anaesthesia with desflurane compared with desflurane alone on postoperative liver function after living-donor liver transplantation. Eur J Anaesthesiol 2019; 36:656-666. [DOI: 10.1097/eja.0000000000001018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Yuan B, Liu J, Cao J, Yu Y, Zhang H, Wang F, Zhu Y, Xiao M, Liu S, Ye Y, Ma L, Xu D, Xu N, Li Y, Zhao B, Xu P, Jin J, Xu J, Chen X, Shen L, Lin X, Feng X. PTPN3 acts as a tumor suppressor and boosts TGF-β signaling independent of its phosphatase activity. EMBO J 2019; 38:e99945. [PMID: 31304624 PMCID: PMC6627230 DOI: 10.15252/embj.201899945] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 03/14/2019] [Accepted: 03/28/2019] [Indexed: 12/22/2022] Open
Abstract
TGF-β controls a variety of cellular functions during development. Abnormal TGF-β responses are commonly found in human diseases such as cancer, suggesting that TGF-β signaling must be tightly regulated. Here, we report that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates TGF-β signaling independent of its phosphatase activity. PTPN3 stabilizes TGF-β type I receptor (TβRI) through attenuating the interaction between Smurf2 and TβRI. Consequently, PTPN3 facilitates TGF-β-induced R-Smad phosphorylation, transcriptional responses, and subsequent physiological responses. Importantly, the leucine-to-arginine substitution at amino acid residue 232 (L232R) of PTPN3, a frequent mutation found in intrahepatic cholangiocarcinoma (ICC), disables its role in enhancing TGF-β signaling and abolishes its tumor-suppressive function. Our findings have revealed a vital role of PTPN3 in regulating TGF-β signaling during normal physiology and pathogenesis.
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Affiliation(s)
- Bo Yuan
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Jinquan Liu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Jin Cao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Yi Yu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Hanchenxi Zhang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Fei Wang
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Yezhang Zhu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Mu Xiao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Sisi Liu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Youqiong Ye
- Department of Biochemistry and Molecular BiologyUniversity of Texas Health Science CenterHoustonTXUSA
| | - Le Ma
- Department of Molecular & Cellular BiologyBaylor College of MedicineHoustonTXUSA
| | - Dewei Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Ningyi Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Yi Li
- Department of Molecular & Cellular BiologyBaylor College of MedicineHoustonTXUSA
| | - Bin Zhao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Pinglong Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Jianping Jin
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Jianming Xu
- Department of Molecular & Cellular BiologyBaylor College of MedicineHoustonTXUSA
| | - Xi Chen
- Department of Biochemistry and Molecular BiologyUniversity of Texas Health Science CenterHoustonTXUSA
| | - Li Shen
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
| | - Xia Lin
- Michael DeBakey Department of SurgeryBaylor College of MedicineHoustonTXUSA
| | - Xin‐Hua Feng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhouZhejiangChina
- Department of Molecular & Cellular BiologyBaylor College of MedicineHoustonTXUSA
- Michael DeBakey Department of SurgeryBaylor College of MedicineHoustonTXUSA
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Ling L, Li G, Wang G, Meng D, Li Z, Zhang C. Carvedilol improves liver cirrhosis in rats by inhibiting hepatic stellate cell activation, proliferation, invasion and collagen synthesis. Mol Med Rep 2019; 20:1605-1612. [PMID: 31257490 PMCID: PMC6625452 DOI: 10.3892/mmr.2019.10401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 05/22/2019] [Indexed: 12/13/2022] Open
Abstract
Portal hypertension (PHT) is one of the most severe consequences of liver cirrhosis. Carvedilol is a first-line pharmacological treatment of PHT. However, the antifibrogenic effects of carvedilol on liver cirrhosis and the intrinsic mechanisms underlying these effects have not been thoroughly investigated. The present study aimed to investigate the antifibrogenic effects of carvedilol on liver cirrhosis in vivo and in vitro. Liver cirrhosis was induced in rats by carbon tetrachloride (CCl4) administration for 9 weeks; carvedilol was administered simultaneously in the experimental group. Blood samples were collected for serum biochemistry. Liver tissues were used for fibrosis evaluation, histological examination, immunohistochemistry and western blot analysis. The human hepatic stellate cell (HSC) line LX-2 was used for in vitro studies. The effects of carvedilol on LX-2 cell proliferation and invasion were evaluated by Cell Counting Kit-8 assay and Transwell invasion assays, respectively. The effect of carvedilol on transforming growth factor β1 (TGFβ1)-induced collagen synthesis in LX-2 cells and the molecular mechanisms were examined by western blot analysis. The results demonstrated that carvedilol improved CCl4-induced structural distortion and fibrosis in the liver. Carvedilol inhibited HSC activation, proliferation and invasion. Carvedilol inhibited HSC collagen synthesis through the TGFβ1/SMAD pathway. In conclusion, carvedilol may alleviate liver cirrhosis in rats by inhibiting HSC activation, proliferation, invasion and collagen synthesis. Carvedilol may be a potential treatment of early-stage liver cirrhosis.
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Affiliation(s)
- Liping Ling
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Guangqi Li
- Department of Oncology, Binzhou People's Hospital, Binzhou, Shandong 256603, P.R. China
| | - Guangchuan Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Dongxiao Meng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhen Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression. J Hematol Oncol 2019; 12:53. [PMID: 31142326 PMCID: PMC6542024 DOI: 10.1186/s13045-019-0739-0] [Citation(s) in RCA: 195] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 05/19/2019] [Indexed: 02/06/2023] Open
Abstract
The tumor microenvironment (TME) is an essential intrinsic portion of hepatocellular carcinoma (HCC) for the regulation of its origination, development, invasion, and metastasis. As emerging components of the tumor-host interaction, exosomes are increasingly recognized as professional carriers of information in TME and as pivotal molecular entities involved in tumorigenic microenvironment setup. However, much remains unknown about the role of the exosome communication system within TME in the development and progression of HCC. In this review, we focus on the roles and probable mechanisms of TME in HCC and show the exosome-based immune regulation in TME to promote HCC. Multiple processes are involved in HCC, including tumor survival, growth, angiogenesis, invasion, and metastasis. We also discuss the specific roles of exosomes in HCC processes by molding hospitable TME for HCC, such as providing energy, transmitting protumor signals, and evading inhibitory signals. In addition, exosomes induce angiogenesis by changing the biological characteristics of endothelial cells and directly regulating proangiogenic and propermeability factors. Furthermore, exosomes may lead to HCC metastatic invasion by epithelial-mesenchymal transformation, extracellular matrix degradation, and vascular leakage. Finally, we summarize the therapeutic usage of exosomes in the HCC microenvironment and attempt to provide a theoretical reference for modern antitumor agents designed to target these mechanisms.
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Abdallah HMI, Abdel-Rahman RF, El Awdan SA, Allam RM, El-Mosallamy AEMK, Selim MS, Mohamed SS, Arbid MS, Farrag ARH. Protective effect of some natural products against chemotherapy-induced toxicity in rats. Heliyon 2019; 5:e01590. [PMID: 31080906 PMCID: PMC6507045 DOI: 10.1016/j.heliyon.2019.e01590] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 03/01/2019] [Accepted: 04/24/2019] [Indexed: 02/07/2023] Open
Abstract
Aim There is a great interest in combining anticancer drugs with natural products aiming at maximizing their efficacy while minimizing systemic toxicity. Hence, the present study was constructed aiming to investigate the protective potential of three natural products, 1,8-cineole an essential oil from Artemisia herba alba, exopolysaccharide (EPS) from locally identified marine streptomycete, and ellagic acid (EA), against chemotherapy-induced organ toxicity. Methods Isolation, production and characterization of EPS from marine streptomycete was done. Animals were allocated into five groups, GP1: normal control, GP2: cyclophosphamide (CYC), GP3: 1,8-cineole + CYC, GP4: EPS + CYC, GP4: EA + CYC. All drugs were administered orally 1 week before and concomitantly with CYC. Electrocardiography (ECG) analysis, liver enzymes (ALT and AST), cardiac serum markers (LDH and CK), oxidative stress biomarkers in hepatic and cardiac tissues (GSH and MDA), TGF-β1 and histopathological examination of hepatic and cardiac tissues were executed. Results The isolated stain produced EPS was identified as Streptomyces xiamenensis. EPS contains uronic, sulphate groups and different monosugars with Mw 4.65 × 104 g/mol and showed antioxidant activity against DPPH. Pretreatment of rats with 1,8-cineole, EPS and EA improved ECG abnormalities, decrease serum markers of hepato- and cardiotoxicity, prevent oxidative stress and decrease TGF-β1 in liver and heart tissues. Conclusion The present results demonstrate the hepatoprotective and cardioprotective effects of the above-mentioned natural products against CYC organ toxicity.
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Affiliation(s)
- Heba M I Abdallah
- Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt
| | - Rehab F Abdel-Rahman
- Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt
| | - Sally A El Awdan
- Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt
| | - Rasha M Allam
- Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt
| | | | - Manal S Selim
- Department of Microbial Biotechnology, Genetic Engineering and Biotechnology Research Division, National Research Centre, Giza, Egypt
| | - Sahar S Mohamed
- Department of Microbial Biotechnology, Genetic Engineering and Biotechnology Research Division, National Research Centre, Giza, Egypt
| | - Mahmoud S Arbid
- Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt
| | - Abdel Razik H Farrag
- Department of Pathology, Medical Division, National Research Centre, Giza, Egypt
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Tang RZ, Gu SS, Chen XT, He LJ, Wang KP, Liu XQ. Immobilized Transforming Growth Factor-Beta 1 in a Stiffness-Tunable Artificial Extracellular Matrix Enhances Mechanotransduction in the Epithelial Mesenchymal Transition of Hepatocellular Carcinoma. ACS APPLIED MATERIALS & INTERFACES 2019; 11:14660-14671. [PMID: 30973698 DOI: 10.1021/acsami.9b03572] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Cancer progression is regulated by multiple factors of extracellular matrix (ECM). Understanding how cancer cells integrate multiple signaling pathways to achieve specific behaviors remains a challenge because of the lack of appropriate models to copresent and modulate ECM properties. Here we proposed a strategy to build a thin biomaterial matrix by poly(l-lysine) and hyaluronan as an artificial stiffness-tunable ECM. Transforming growth factor-beta 1 (TGF-β1) was used as a biochemical cue to present in an immobilized and spatially controlled manner, with a high loading efficiency of 90%. Either soft matrix with immobilized TGF-β1 (i-TGF) or bare stiff matrix could only promote HCC cells to form the epithelial phenotype, whereas stiff matrix with i-TGF was the only condition to induce the mesenchymal phenotype. Further investigation revealed that i-TGF increased the specific TGF-β1 receptor (TβRI) expression to activate PI3K pathway. i-TGF-TβRI interactions also promoted HCC cell adhesion to enlarge contact area for stiffness sensing, resulting in the raising expression of the mechano-sensor (β1 integrin). Mechanotransduction would then be enhanced by the β1 integrin/vinculin/p-FAK pathway, leading to a noble PI3K activation. Using our model, a novel mechanism was discovered to elucidate regulation of cell fates by coupling mechanotransduction and biochemical signaling.
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Affiliation(s)
| | | | | | - Li-Jie He
- Graphitene Ltd. , Flixborough , North Lincolnshire DN15 8SJ , United Kingdom
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Wang K, Fang S, Liu Q, Gao J, Wang X, Zhu H, Zhu Z, Ji F, Wu J, Ma Y, Hu L, Shen X, Gao D, Zhu J, Liu P, Zhou H. TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM. EBioMedicine 2019; 42:458-469. [PMID: 30926424 PMCID: PMC6491716 DOI: 10.1016/j.ebiom.2019.03.058] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/13/2019] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatic stellate cell (HSC) activation induced by transforming growth factor β1 (TGF-β1) plays a pivotal role in fibrogenesis, while the complex downstream mediators of TGF-β1 in such process are largely unknown. METHODS We performed pharmacoproteomic profiling of the mice liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis and NPLC0393 administrated groups. The target gene MAT2A was overexpressed or knocked down in vivo by tail vein injection of AAV vectors. We examined NF-κB transcriptional activity on MAT2A promoter via luciferase assay. Intracellular SAM contents were analyzed by LC-MS method. FINDINGS We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice, and application of NPLC0393, a known small molecule inhibitor of TGF-β1 signaling pathway, inhibits the upregulation of MAT2A. Mechanistically, TGF-β1 induces phosphorylation of p65, i.e., activation of NF-κB, thereby promoting mRNA transcription and protein expression of MAT2A and reduces S-adenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393. INTERPRETATION This study identifies TGF-β1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis. FUND: This work was supported by National Natural Science Foundation of China (No. 81500469, 81573873, 81774196 and 31800693), Zhejiang Provincial Natural Science Foundation of China (No. Y15H030004), the National Key Research and Development Program from the Ministry of Science and Technology of China (No. 2017YFC1700200) and the Key Program of National Natural Science Foundation of China (No. 8153000502).
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Affiliation(s)
- Kuifeng Wang
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China; Suzhou GenHouse Pharmaceutical Co., Ltd., 388 Ruoshui Road, Suzhou, Jiangsu 215123, China
| | - Shanhua Fang
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Qian Liu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Jing Gao
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Xiaoning Wang
- E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Hongwen Zhu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Zhenyun Zhu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Feihong Ji
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China; Suzhou GenHouse Pharmaceutical Co., Ltd., 388 Ruoshui Road, Suzhou, Jiangsu 215123, China
| | - Jiasheng Wu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Yueming Ma
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Lihong Hu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Xu Shen
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Daming Gao
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Jiansheng Zhu
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China.
| | - Ping Liu
- E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China.
| | - Hu Zhou
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
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Ganesan M, Poluektova LY, Kharbanda KK, Osna NA. Human immunodeficiency virus and hepatotropic viruses co-morbidities as the inducers of liver injury progression. World J Gastroenterol 2019; 25:398-410. [PMID: 30700937 PMCID: PMC6350175 DOI: 10.3748/wjg.v25.i4.398] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/15/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatotropic viruses induced hepatitis progresses much faster and causes more liver- related health problems in people co-infected with human immunodeficiency virus (HIV). Although treatment with antiretroviral therapy has extended the life expectancy of people with HIV, liver disease induced by hepatitis B virus (HBV) and hepatitis C virus (HCV) causes significant numbers of non-acquired immune deficiency syndrome (AIDS)-related deaths in co-infected patients. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV/HCV and HIV/HBV co-infections have been reported. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease in HIV-HCV/HBV co-infection in the era of direct acting antivirals (DAA) and antiretroviral therapy (ART). We also review the novel therapeutics for management of HIV/HCV and HIV/HBV co-infected individuals.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
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Bi JG, Zheng JF, Li Q, Bao SY, Yu XF, Xu P, Liao CX. MicroRNA-181a-5p suppresses cell proliferation by targeting Egr1 and inhibiting Egr1/TGF-β/Smad pathway in hepatocellular carcinoma. Int J Biochem Cell Biol 2018; 106:107-116. [PMID: 30503931 DOI: 10.1016/j.biocel.2018.11.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/24/2018] [Accepted: 11/27/2018] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality worldwide. Early growth response factor 1 (Egr1) plays a crucial role in cancer progression. However, its precise role in HCC has not been clear. Here, we identified the aggravating role of Egr1 in cell proliferation of HCC firstly. The expression of Egr1 was significantly increased in HCC tissues. Functionally, overexpression of Egr1 enhanced, whereas silenced Egr1 expression attenuated HCC cells proliferation in vitro. Mechanistically, up-regulated Egr1 induced cell proliferation through activating Transforming growth factor (TGF)-β1/Smad signaling pathway concomitantly with upregulation of p-Smad2 and p-Smad3. Secondly, miR-181a-5p was down-regulated in clinical HCC specimens and its expression was inversely correlated with Egr1 expression. Functionally, overexpression of miR-181a-5p inhibited, whereas decreased expression of miR-181a-5p promoted HCC cells proliferation in vitro. Furthermore, we demonstrated that miR-181a-5p overexpression directly suppressed Egr1, resulting in a down-regulated TGF-β1/Smad pathway. Besides, the silenced Egr1 expression could rescue the enhanced cell proliferation induced by miR-181a-5p inhibitor. Thus, we concluded that miR-181a-5p is a negative regulator of Egr1 that can suppress tumor proliferation in HCC through targeting Egr1/TGF-β1/Smad pathway, which may be a potential therapeutic approach of HCC.
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Affiliation(s)
- Jian-Gang Bi
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China.
| | - Jin-Feng Zheng
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China
| | - Qi Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China
| | - Shi-Yun Bao
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China
| | - Xiao-Fang Yu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China
| | - Ping Xu
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China
| | - Cai-Xian Liao
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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Chung YH, Huang YH, Chu TH, Chen CL, Lin PR, Huang SC, Wu DC, Huang CC, Hu TH, Kao YH, Tai MH. BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling. J Transl Med 2018; 98:999-1013. [PMID: 29789683 DOI: 10.1038/s41374-018-0069-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 03/16/2018] [Accepted: 04/02/2018] [Indexed: 01/08/2023] Open
Abstract
Transforming growth factor-β (TGF-β) plays a central role in hepatic fibrogenesis. This study investigated the function and mechanism of bone morphogenetic protein-2 (BMP-2) in regulation of hepatic fibrogenesis. BMP-2 expression in fibrotic liver was measured in human tissue microarray and mouse models of liver fibrosis induced by bile duct ligation surgery or carbon tetrachloride administration. Adenovirus-mediated BMP-2 gene delivery was used to test the prophylactic effect on liver fibrosis. Primary hepatic stellate cells (HSC), HSC-T6 and clone-9 cell lines were used to study the interplay between BMP-2 and TGF-β1. Hepatic BMP-2 was localized in parenchymal hepatocytes and activated HSCs and significantly decreased in human and mouse fibrotic livers, showing an opposite pattern of hepatic TGF-β1 contents. BMP-2 gene delivery alleviated the elevations of serum hepatic enzymes, cholangiocyte marker CK19, HSC activation markers, and liver fibrosis in both models. Mechanistically, exogenous TGF-β1 dose dependently reduced BMP-2 expression, whereas BMP-2 significantly suppressed expression of TGF-β and its cognate type I and II receptor peptides, as well as the induced Smad3 phosphorylation levels in primary mouse HSCs. Aside from its suppressive effects on cell proliferation and migration, BMP-2 treatment prominently attenuated the TGF-β1-stimulated α-SMA and fibronectin expression, and reversed the TGF-β1-modulated epithelial-to-mesenchymal transition marker expression in mouse HSCs. The mutual regulation between BMP-2 and TGF-β1 signaling axes may constitute the anti-fibrogenic mechanism of BMP-2 in the pathogenesis of liver fibrosis. BMP-2 may potentially serve as a novel therapeutic target for treatment of liver fibrosis.
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Affiliation(s)
- Yueh-Hua Chung
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Ying-Hsien Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chiayi Chang Gung Memorial Hospital, Puzi City, Taiwan
| | - Tien-Huei Chu
- Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chun-Lin Chen
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Pey-Ru Lin
- Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shih-Chung Huang
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Deng-Chyang Wu
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Biobank and Tissue Bank and Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ying-Hsien Kao
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. .,Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Zhang H, Ju B, Nie Y, Song B, Xu Y, Gao P. Adenovirus‑mediated knockdown of activin A receptor type 2A attenuates immune‑induced hepatic fibrosis in mice and inhibits interleukin‑17‑induced activation of primary hepatic stellate cells. Int J Mol Med 2018; 42:279-289. [PMID: 29620144 PMCID: PMC5979935 DOI: 10.3892/ijmm.2018.3600] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 03/08/2018] [Indexed: 01/20/2023] Open
Abstract
Fibrosis induces a progressive loss of liver function, thus leading to organ failure. Activins are secreted proteins that belong to the transforming growth factor (TGF)-β superfamily, which initiate signaling by binding to their two type II receptors: Activin A receptor type 2A (ACVR2A) and activin A receptor type 2B. Previous studies that have explored the mechanisms underlying immune-induced hepatic fibrosis have mainly focused on TGF-β signaling, not activin signaling. To investigate the role of the activin pathway in this disease, adenovirus particles containing short hairpin (sh)RNA targeting ACVR2A mRNA (Ad-ACVR2A shRNA) were administered to mice, which were chronically treated with concanavalin A (Con A). The pathological changes in the liver were evaluated with hematoxylin/eosin staining, Masson trichrome staining and immunohistochemical assay. The results detected an increase in serum activin A and liver ACVR2A in Con A-treated animals. Conversely, liver function was partially restored and fibrotic injury was attenuated when activin signaling was blocked. In addition, the activation of hepatic stellate cells (HSCs) in response to Con A was suppressed by Ad-ACVR2A shRNA, as evidenced by decreased α-smooth muscle actin, and type I and IV collagen expression. Furthermore, primary mouse HSCs (mHSCs) were activated when exposed to interleukin (IL)-17A or IL-17F, which are two major cytokines produced by cluster of differentiation 4+ T helper 17 cells. The levels of activin A, type I and IV collagen were determined with ELISA kits and the expression of fibrotic molecules was determined with western blot analysis. Conversely, blocking activin/ACVR2A impaired the potency of HSCs to produce collagens in response to IL-17s. In addition, C terminus phosphorylation of Smad2 on Ser465 and Ser467, induced by either Con A in the liver or by IL-17s in mHSCs, was partly inhibited when activin A/ACVR2A signaling was suppressed. Collectively, the present study demonstrated an involvement of activated activin A/ACVR2A/Smad2 signaling in immune-induced hepatic fibrosis.
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Affiliation(s)
- Hongjun Zhang
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Baoling Ju
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Ying Nie
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Baohui Song
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Yuanhong Xu
- Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Ping Gao
- Department of Gastroenterology, Mudanjiang Forestry Central Hospital, Mudanjiang, Heilongjiang 157000, P.R. China
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50
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Liu Y, Xu Y, Ma H, Wang B, Xu L, Zhang H, Song X, Gao L, Liang X, Ma C. Hepatitis B virus X protein amplifies TGF-β promotion on HCC motility through down-regulating PPM1a. Oncotarget 2018; 7:33125-35. [PMID: 27121309 PMCID: PMC5078080 DOI: 10.18632/oncotarget.8884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 04/02/2016] [Indexed: 12/26/2022] Open
Abstract
Over-activation of transforming growth factor-β (TGF-β) signaling pathway promotes cell migration and invasion in hepatocellular carcinoma (HCC). The Hepatitis B virus X protein (HBx) is involved in the enhancement of TGF-β signaling pathway in HCC while the mechanism remains unclear. Protein phosphatase magnesium dependent 1A (PPM1a) functions as a phosphatase essential for terminating the TGF-β signaling pathway by dephosphorylating p-Smad2/3. In this study, we found that HBx dose-dependently downregulated PPM1a protein level in the presence of TGF-β, while having no effect on its mRNA level. Further study showed that HBx increased the ubiquitination of PPM1a and accelerated its proteasomal degradation. Restoration of PPM1a almost completely abrogated HBx mediated promotion on HCC migration and invasion. This involvement of PPM1a in HBx-related HCC was further confirmed with immunohistochemical analysis in HCC tissue. Compared with paired pericarcinous tissue, HCC tissue showed decreased PPM1a level. Besides, PPM1a level is negatively correlated with HBx expression. Taken together, our present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-β pathway in HCC development, which might provide potential candidates for clinical diagnosis and treatment.
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Affiliation(s)
- Yuan Liu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Hongxin Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Bo Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Leiqi Xu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Hualin Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, 250012 P.R. China
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