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Diao S, Li L, Zhang J, Ji M, Sun L, Shen W, Wu S, Chen Z, Huang C, Li J. Macrophage-derived CCL1 targets CCR8 receptor in hepatic stellate cells to promote liver fibrosis through JAk/STAT pathway. Biochem Pharmacol 2025; 237:116884. [PMID: 40122149 DOI: 10.1016/j.bcp.2025.116884] [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: 06/05/2024] [Revised: 02/18/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Shaoxi Diao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Liangyun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Jintong Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Minglu Ji
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Lijiao Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Wenwen Shen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Shuai Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China
| | - Zixiang Chen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, PR China; Institute for Liver Diseases of Anhui Medical University, PR China.
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Yang H, Li J, Niu Y, Zhou T, Zhang P, Liu Y, Li Y. Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment. Front Immunol 2025; 16:1494788. [PMID: 40028341 PMCID: PMC11868052 DOI: 10.3389/fimmu.2025.1494788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/29/2025] [Indexed: 03/05/2025] Open
Abstract
Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.
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Affiliation(s)
- Haoqiang Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Jinghui Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yiting Niu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Tao Zhou
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Pengyu Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yang Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yanjun Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, TongjiShanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Liu Y, Li Y, Chen L, Zha W, Zhang J, Wang K, Hao C, Gan J. Construction of an Oxidative Stress Risk Model to Analyze the Correlation Between Liver Cancer and Tumor Immunity. Curr Cancer Drug Targets 2025; 25:49-63. [PMID: 38375834 DOI: 10.2174/0115680096284532231220061048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/11/2023] [Accepted: 11/17/2023] [Indexed: 02/21/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment. METHODS This study utilized the TCGA dataset and a collection of oxidative stress genes to identify the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures. RESULTS Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines. CONCLUSION The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as an oxidative stress risk model for assessing HCC prognosis. Furthermore, there is a correlation between the expression of these risk model genes and tumor immunity.
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Affiliation(s)
- Ying Liu
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yufeng Li
- Hebei Key Laboratory of Molecular Oncology, Tangshan People's Hospital, Tangshan, Hebei, 063001, China
- Institute of Cancer Research, Tangshan People's Hospital, Tangshan, China
| | - Li Chen
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weina Zha
- Department of Endocrine, TangShan GongRen Hospital, Tangshan, China
| | - Jing Zhang
- Department of Hepatobiliary Medicine, Tangshan People's Hospital, Tangshan, China
| | - Kun Wang
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunhai Hao
- Department of Hepatobiliary Medicine, Tangshan People's Hospital, Tangshan, China
| | - Jianhe Gan
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
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Malhotra K, Malik A, Almalki WH, Sahebkar A, Kesharwani P. Reactive Oxygen Species and its Manipulation Strategies in Cancer Treatment. Curr Med Chem 2025; 32:55-73. [PMID: 37303173 DOI: 10.2174/0929867330666230609110455] [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: 04/01/2023] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 06/13/2023]
Abstract
Cancer is one of the serious diseases of modern times, occurring in all parts of the world and shows a wide range of effects on the human body. Reactive Oxygen Species (ROS) such as oxide and superoxide ions have both advantages and disadvantages during the progression of cancer, dependent on their concentration. It is a necessary part of the normal cellular mechanisms. Changes in its normal level can cause oncogenesis and other relatable problems. Metastasis can also be controlled by ROS levels in the tumor cells, which can be prevented by the use of antioxidants. However, ROS is also used for the initiation of apoptosis in cells by different mediators. There exists a cycle between the production of oxygen reactive species, their effect on the genes, role of mitochondria and the progression of tumors. ROS levels cause DNA damage by the oxidation process, gene damage, altered expression of the genes and signalling mechanisms. They finally lead to mitochondrial disability and mutations, resulting in cancer. This review summarizes the important role and activity of ROS in developing different types of cancers like cervical, gastric, bladder, liver, colorectal and ovarian cancers.
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Affiliation(s)
- Kabil Malhotra
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Arzoo Malik
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Waleed H Almalki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
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Filatov NS, Khismatullin RR, Bilyalov AI, Khabirova AI, Salyakhutdinova SM, Ursan RV, Kasimova RN, Peshkova AD, Gazizov II, Shagimardanova EI, Woroncow MV, Kiyasov AP, Litvinov RI, Gusev OA. Distinct Hemostasis and Blood Composition in Spiny Mouse Acomys cahirinus. Int J Mol Sci 2024; 25:12867. [PMID: 39684578 DOI: 10.3390/ijms252312867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
The spiny mouse (Acomys species) is capable of scarless wound regeneration through largely yet unknown mechanisms. To investigate whether this capacity is related to peculiarities of the hemostatic system, we studied the blood of Acomys cahirinus in comparison to Mus musculus (Balb/c) to reveal differences in blood composition and clotting in both males and females. In response to surgical manipulations, blood clots formed in wounds of Acomys comprised a stronger hemostatic seal with reduced surgical bleeding in comparison with Balb/c. Acomys demonstrated notably shorter tail bleeding times and elevated clottable fibrinogen levels. Histological analysis revealed that clots from Acomys blood had densely packed fibrin-rich clots with pronounced fibrin segregation from erythrocytes. Acomys exhibited superior plasma clot stiffness as revealed with thromboelastography. The latter two characteristics are likely due to hyperfibrinogenemia. Light transmission platelet aggregometry demonstrated that ADP-induced platelet aggregates in Acomys males are stable, unlike the aggregates formed in the plasma of Balb/c undergoing progressive disaggregation over time. There were no apparent distinctions in platelet contractility and baseline expression of phosphatidylserine. Hematological profiling revealed a reduced erythrocytes count but increased mean corpuscular volume and hemoglobin content in Acomys. These results demonstrate the distinctive hemostatic potential of Acomys cahirinus, which may contribute to their remarkable regenerative capacity.
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Affiliation(s)
- Nikita S Filatov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Rafael R Khismatullin
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Airat I Bilyalov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
| | - Alina I Khabirova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | | | - Roman V Ursan
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | | | - Alina D Peshkova
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Insaf I Gazizov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Elena I Shagimardanova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
| | - Mary V Woroncow
- Institute for Regenerative Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Andrey P Kiyasov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Rustem I Litvinov
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Oleg A Gusev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- LIFT, Life Improvement by Future Technologies Institute, 121205 Moscow, Russia
- Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
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Saito T, Tsuchishima M, Tsutsumi M, George J. Molecular pathogenesis of metabolic dysfunction-associated steatotic liver disease, steatohepatitis, hepatic fibrosis and liver cirrhosis. J Cell Mol Med 2024; 28:e18491. [PMID: 38894579 PMCID: PMC11187936 DOI: 10.1111/jcmm.18491] [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: 02/15/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by intense deposition of fat globules in the hepatic parenchyma that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Here, we evaluated a rat model to study the molecular pathogenesis of the spectrum of MASLD and to screen therapeutic agents. SHRSP5/Dmcr rats were fed a high-fat and cholesterol (HFC) diet for a period of 12 weeks and evaluated for the development of steatosis (MASLD), steatohepatitis, fibrosis and cirrhosis. A group of animals were sacrificed at the end of the 4th, 6th, 8th and 12th weeks from the beginning of the experiment, along with the control rats that received normal diet. Blood and liver samples were collected for biochemical and histopathological evaluations. Immunohistochemical staining was performed for α-SMA and Collagen Type I. Histopathological examinations demonstrated steatosis at the 4th week, steatohepatitis with progressive fibrosis at the 6th week, advanced fibrosis with bridging at the 8th week and cirrhosis at the 12th week. Biochemical markers and staining for α-SMA and Collagen Type I demonstrated the progression of steatosis to steatohepatitis, hepatic fibrosis and liver cirrhosis in a stepwise manner. Control animals fed a normal diet did not show any biochemical or histopathological alterations. The results of the present study clearly demonstrated that the HFC diet-induced model of steatosis, steatohepatitis, hepatic fibrosis and cirrhosis is a feasible, quick and appropriate animal model to study the molecular pathogenesis of the spectrum of MASLD and to screen potent therapeutic agents.
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Affiliation(s)
- Takashi Saito
- Department of HepatologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | | | - Mikihiro Tsutsumi
- Department of HepatologyKanazawa Medical UniversityUchinadaIshikawaJapan
- Center for Regenerative MedicineKanazawa Medical University HospitalUchinadaIshikawaJapan
| | - Joseph George
- Department of HepatologyKanazawa Medical UniversityUchinadaIshikawaJapan
- Center for Regenerative MedicineKanazawa Medical University HospitalUchinadaIshikawaJapan
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Ouyang H, Miao H, Li Z, Wu D, Gao SC, Dai YY, Gao XD, Chai HS, Hu WY, Zhu JF. Yinhuang granule alleviates carbon tetrachloride-induced liver fibrosis in mice and its mechanism. World J Hepatol 2024; 16:264-278. [PMID: 38495271 PMCID: PMC10941736 DOI: 10.4254/wjh.v16.i2.264] [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: 10/18/2023] [Revised: 01/09/2024] [Accepted: 02/01/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Liver fibrosis is a formidable global medical challenge, with no effective clinical treatment currently available. Yinhuang granule (YHG) is a proprietary Chinese medicine comprising Scutellariae Radix and Lonicerae Japonicae Flos. It is frequently used for upper respiratory tract infections, pharyngitis, as well as acute and chronic tonsillitis. AIM To investigate the potential of YHG in alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. METHODS To induce a hepatic fibrosis model in mice, this study involved intraperitoneal injections of 2 mL/kg of CCl4 twice a week for 4 wk. Meanwhile, liver fibrosis mice in the low dose of YHG (0.4 g/kg) and high dose of YHG (0.8 g/kg) groups were orally administered YHG once a day for 4 wk. Serum alanine/aspartate aminotransferase (ALT/AST) activity and liver hydroxyproline content were detected. Sirius red and Masson's trichrome staining assay were conducted. Real-time polymerase chain reaction, western-blot and enzyme-linked immunosorbent assay were conducted. Liver glutathione content, superoxide dismutase activity level, reactive oxygen species and protein carbonylation amount were detected. RESULTS The administration of YHG ameliorated hepatocellular injury in CCl4-treated mice, as reflected by decreased serum ALT/AST activity and improved liver histological evaluation. YHG also attenuated liver fibrosis, evident through reduced liver hydroxyproline content, improvements in Sirius red and Masson's trichrome staining, and lowered serum hyaluronic acid levels. Furthermore, YHG hindered the activation of hepatic stellate cells (HSCs) and ameliorated oxidative stress injury and inflammation in liver from CCl4-treated mice. YHG prompted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-dependent downstream antioxidant genes. In addition, YHG promoted mitochondrial biogenesis in liver from CCl4-treated mice, as demonstrated by increased liver adenosine triphosphate content, mitochondrial DNA levels, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and nuclear respiratory factor 1. CONCLUSION YHG effectively attenuates CCl4-induced liver fibrosis in mice by inhibiting the activation of HSCs, reducing inflammation, alleviating liver oxidative stress damage through Nrf2 activation, and promoting liver mitochondrial biogenesis.
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Affiliation(s)
- Hao Ouyang
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Miao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 201203, China
| | - Zhen Li
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Duan Wu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Si-Cheng Gao
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yao-Yao Dai
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Di Gao
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hai-Sheng Chai
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Ye Hu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jun-Feng Zhu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Zhang H, Xia T, Xia Z, Zhou H, Li Z, Wang W, Zhai X, Jin B. KIF18A inactivates hepatic stellate cells and alleviates liver fibrosis through the TTC3/Akt/mTOR pathway. Cell Mol Life Sci 2024; 81:96. [PMID: 38372748 PMCID: PMC10876760 DOI: 10.1007/s00018-024-05114-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 12/03/2023] [Accepted: 01/04/2024] [Indexed: 02/20/2024]
Abstract
Activation of hepatic stellate cells (HSCs) has been demonstrated to play a pivotal role in the process of liver fibrogenesis. In this study, we observed a decrease in the expression of KIF18A in fibrotic liver tissues compared to healthy liver tissues, which exhibited a negative correlation with the activation of HSCs. To elucidate the molecular mechanisms underlying the involvement of KIF18A, we performed in vitro proliferation experiments and established a CCl4-induced liver fibrosis model. Our results revealed that KIF18A knockdown enhanced HSCs proliferation and reduced HSCs apoptosis in vitro. Mouse liver fibrosis grade was evaluated with Masson's trichrome and alpha-smooth muscle actin (α-SMA) staining. In addition, the expression of fibrosis markers Col1A1, Stat1, and Timp1 were detected. Animal experiments demonstrated that knockdown of KIF18A could promote liver fibrosis, whereas overexpression of KIF18A alleviated liver fibrosis in a CCl4-induced mouse model. Mechanistically, we found that KIF18A suppressed the AKT/mTOR pathway and exhibited direct binding to TTC3. Moreover, TTC3 was found to interact with p-AKT and could promote its ubiquitination and degradation. Our findings provide compelling evidence that KIF18A enhances the protein binding between TTC3 and p-AKT, promoting TTC3-mediated ubiquitination and degradation of p-AKT. These results refine the current understanding of the mechanisms underlying the pathogenesis of liver fibrosis and may offer new targets for treating this patient population.
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Affiliation(s)
- Hao Zhang
- Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Tong Xia
- Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China
| | - Zhijia Xia
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Huaxin Zhou
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Zhipeng Li
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China
| | - Wei Wang
- Medical Integration and Practice Center, Shandong University, Jinan, China.
| | - Xiangyu Zhai
- Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China.
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China.
| | - Bin Jin
- Organ Transplant Department, Qilu Hospital of Shandong University, Jinan, China.
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China.
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9
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Ren H, Yang D, Xu H, Tong X, Zhao X, Wang Q, Sun Y, Ou X, Jia J, You H, Wang Z, Yang Z. The staging of nonalcoholic fatty liver disease fibrosis: A comparative study of MR elastography and the quantitative DCE-MRI exchange model. Heliyon 2024; 10:e24558. [PMID: 38312594 PMCID: PMC10835329 DOI: 10.1016/j.heliyon.2024.e24558] [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: 10/16/2023] [Revised: 12/18/2023] [Accepted: 01/10/2024] [Indexed: 02/06/2024] Open
Abstract
Objectives To evaluate the efficacy and image processing time of the dynamic contrast-enhanced MRI (DCE-MRI) exchange model in liver fibrosis staging and compare it to the efficacy of magnetic resonance elastography (MRE). Methods The subjects were 45 patients with nonalcoholic fatty liver disease (NAFLD) who underwent MRE and DCE-MRI in our hospital. Liver biopsy results were available for all patients. Spearman rank correlation coefficients were used to compare the correlations among MRE, DCE-MRI and liver fibrosis parameters. Quantitative DCE-MRI parameters, MRE-derived liver stiffness measurement (LSM), and the results of a combined DCE-MRI + MRE logistic regression model were compared in terms of the area under the receiver operating characteristic curve (AUC). We also compared the scanning and postprocessing times of the MRE and DCE-MRI techniques. Results The correlation coefficients between the following parameters of interest and liver fibrosis were as follows: capillary permeability-surface area product (PS; DCE-MRI parameter), -0.761; portal blood flow (Fp; DCE-MRI parameter), -0.754; MRE-LSM, 0.835. Some DCE-MRI parameters (PS, Fp) had slightly greater AUC values than MRE-LSM for diagnosing the presence or absence of liver fibrosis, and the combined model had the highest AUC value for all stages except F4, but there was no significant difference in the diagnostic efficacy of the DCE-MRI, MRE, and combined models for any stage of fibrosis. The average scanning times for MRE and DCE-MRI were 17 s and 330 s, respectively, and the average postprocessing times were 45.5 s and 342.7 s, respectively. Conclusions In the absence of MRE equipment, DCE-MRI represents an alternative technique. However, MRE is a quicker and simpler method for assessing fibrosis than DCE-MRI in the clinic.
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Affiliation(s)
- Hao Ren
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Dawei Yang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Hui Xu
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Xiaofei Tong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Qianyi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Yameng Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, West District, Beijing, 100050, China
| | - Zhenchang Wang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Zhenghan Yang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
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10
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Mancak M, Altintas D, Balaban Y, Caliskan UK. Evidence-based herbal treatments in liver diseases. HEPATOLOGY FORUM 2024; 5:50-60. [PMID: 38283267 PMCID: PMC10809338 DOI: 10.14744/hf.2022.2022.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 01/30/2024]
Abstract
The liver is the main organ for metabolic and detoxification reactions in the body. Therefore, its diseases can be associated with both metabolic disorders, such as insulin resistance, obesity, diabetes, or dyslipidemia, and exogenous insults such as drugs, xenobiotics, or alcohol. Indeed, lifestyle changes are the primary approaches for the prevention and treatment of liver diseases. Since ancient times, herbals have also been used for preventive and therapeutic purposes, because of their anti-apoptotic, anti-inflammatory, and antioxidant effects. Here, the literature was reviewed for potential therapeutic effects of plants and their compounds by including in vitro and in vivo studies, as well as clinical trials. Although the available data imply some beneficial roles of herbals on the liver, the indications and posology of specific plants need to be clarified through multicenter, randomized clinical trials.
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Affiliation(s)
- Methiye Mancak
- Department of Pharmacognosy and Pharmaceutical Botany, Gazi University Faculty of Pharmacy, Ankara, Turkiye
| | - Dudu Altintas
- Department of Pharmacognosy, Duzce University Faculty of Pharmacy, Duzce, Turkiye
| | - Yasemin Balaban
- Division of Gastroenterology, Department of Internal Medical Sciences, Hacettepe University School of Medicine, Ankara, Turkiye
| | - Ufuk Koca Caliskan
- Department of Pharmacognosy and Pharmaceutical Botany, Gazi University Faculty of Pharmacy, Ankara, Turkiye
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11
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Shen X, Xie A, Li Z, Jiang C, Wu J, Li M, Yue X. Research Progress for Probiotics Regulating Intestinal Flora to Improve Functional Dyspepsia: A Review. Foods 2024; 13:151. [PMID: 38201179 PMCID: PMC10778471 DOI: 10.3390/foods13010151] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/05/2023] [Accepted: 12/08/2023] [Indexed: 01/12/2024] Open
Abstract
Functional dyspepsia (FD) is a common functional gastrointestinal disorder. The pathophysiology remains poorly understood; however, alterations in the small intestinal microbiome have been observed. Current treatments for FD with drugs are limited, and there are certain safety problems. A class of active probiotic bacteria can control gastrointestinal homeostasis, nutritional digestion and absorption, and the energy balance when taken in certain dosages. Probiotics play many roles in maintaining intestinal microecological balance, improving the intestinal barrier function, and regulating the immune response. The presence and composition of intestinal microorganisms play a vital role in the onset and progression of FD and serve as a critical factor for both regulation and potential intervention regarding the management of this condition. Thus, there are potential advantages to alleviating FD by regulating the intestinal flora using probiotics, targeting intestinal microorganisms. This review summarizes the research progress of probiotics regarding improving FD by regulating intestinal flora and provides a reference basis for probiotics to improve FD.
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Affiliation(s)
- Xinyu Shen
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (X.S.); (Z.L.); (C.J.); (J.W.)
| | - Aijun Xie
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 119077, Singapore;
| | - Zijing Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (X.S.); (Z.L.); (C.J.); (J.W.)
| | - Chengxi Jiang
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (X.S.); (Z.L.); (C.J.); (J.W.)
| | - Jiaqi Wu
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (X.S.); (Z.L.); (C.J.); (J.W.)
| | - Mohan Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (X.S.); (Z.L.); (C.J.); (J.W.)
| | - Xiqing Yue
- Shenyang Key Laboratory of Animal Product Processing, Shenyang Agricultural University, Shenyang 110866, China
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12
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Sun X, Lin Z, Xu N, Chen Y, Bian S, Zheng W. Identifying Dental Pulp Stem Cell as a Novel Therapeutic trategy for Digestive Diseases. Curr Stem Cell Res Ther 2024; 19:1293-1302. [PMID: 38018204 DOI: 10.2174/011574888x275737231120045815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 11/30/2023]
Abstract
Mesenchymal stem cells (MSCs) have been identified as potential therapeutics for various diseases. In contrast to other sources of MSCs, dental stem cells (DSCs) have received increased attention due to their high activity and easy accessibility. Among them, dental pulp stem cells (DPSCs) exhibit superior self-renewal, multipotency, immunomodulatory, and regenerative capacities. Following their inspiring performance in animal models and clinical trials, DPSCs show pharmacological potential in regenerative medicine. In this review, we have generalized the sources, heterogeneity, and biological characteristics of DPSCs, as well as compared them with other types of dental stem cells. In addition, we summarized the application of DPSCs in digestive diseases (such as liver, esophageal, and intestinal diseases), highlighting their regenerative and pharmacological potential based on the existing preclinical and clinical evidence. Specifically, DPSCs can be home to injured or inflamed tissues and exert repair and regeneration functions by facilitating immune regulation, anti-inflammation, and directional differentiation. Although DPSCs have a rosy prospect, future studies should handle the underlying drawbacks and pave the way for the identification of DPSCs as novel regenerative medicine.
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Affiliation(s)
- Xieyin Sun
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
| | - Zhaoyi Lin
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
| | - Nuo Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
| | - Yinqi Chen
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
| | - Saiyan Bian
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
- Research Institute of Stem Cells, Center of Clinical Trials, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
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13
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Sharieff S, Idrees A, Rafai W, Bukhari SUS. Use of Oral N-Acetylcysteine (NAC) in Non-Acetaminophen-Induced Acute Hepatic Failure. Cureus 2023; 15:e35852. [PMID: 37033589 PMCID: PMC10077496 DOI: 10.7759/cureus.35852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Acute liver failure (ALF) is a syndrome rather than a specific disease with several possible causes, and viral hepatitis is a major cause. The objective of the study was to assess the benefit of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). METHODS A total of six patients with a diagnosis of acute liver failure (ALF) were included in the study. All six patients received oral NAC for 72 hrs. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of ICU and hospital stay. The primary outcome was a reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate the safety of NAC and assess factors predicting mortality. RESULTS All patients improved and returned to normal or near-normal liver function with the use of NAC. No side effects were noted, and the use of NAC was associated with a shorter hospital stay. CONCLUSION In patients with non-acetaminophen-related acute liver failure, N-acetyl-L-cysteine (NAC) significantly improves overall survival and also decreases the length of hospital stay.
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14
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Sun J, Wu M, Wang L, Wang P, Xiao T, Wang S, Liu Q. miRNA-21, which disrupts metabolic reprogramming to facilitate CD4 + T cell polarization toward the Th2 phenotype, accelerates arsenite-induced hepatic fibrosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 248:114321. [PMID: 36427370 DOI: 10.1016/j.ecoenv.2022.114321] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/02/2022] [Accepted: 11/19/2022] [Indexed: 06/16/2023]
Abstract
Elevated levels of arsenic may be present in groundwater, and long-term exposure to arsenic increases hepatic fibrosis. T helper 2 (Th2) cells are involved in the fibrotic cascade, and cell metabolism is a regulatory factor participating in CD4+ T cell differentiation and function. However, the mechanism for Th2 cell regulation of arsenite-induced hepatic fibrosis is not fully understood. In present study, for arsenite-fed mice, activated hepatic stellate cells may be involved in the infiltration of CD4+ T cells, accompanied by up-regulation of GATA3, a transcription factor, and IL-13, the major Th2 cytokine. Exposed to arsenite, Jurkat cells had increased aerobic glycolysis to promote the cell cycle and cell proliferation. Further, this process elevated levels of marker molecules, including those of the Th2 paradigm characterized by GATA3, IL-4, and IL-13. LX-2 cells were activated when treated with culture medium from Jurkat cells exposed to arsenite. miR-21 may be a therapeutic target for arsenite-induced hepatic fibrosis. In vitro, miR-21 knock-down caused inhibition of the PTEN/PI3K/AKT pathway induced by arsenite. It also reversed the elevated glycolysis and the accelerated cell cycle and cell proliferation. Indeed, this alteration led to diminished expression of GATA3, IL-4, and IL-13 in T cells differentiated under Th2 conditions, which inhibits activation of LX-2 cells. Consistent with the results in vitro, miR-21 knock-out in mice reversed hepatic fibrosis and attenuated the levels of GATA3 and IL-13 induced by arsenite. These findings indicate that miR-21 regulates the glycolysis of CD4+ T cells through the PTEN/PI3K/AKT pathway to accelerate the cell cycle, thereby facilitating CD4+ T cell polarization toward Th2 and releasing the fibrogenic factor IL-13, which participates in arsenite-associated hepatic fibrosis. Inhibition of Th2 polarization of CD4+T cells or miR-21 could be a therapeutic strategy to combat hepatic fibrosis caused by exposure to arsenic.
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Affiliation(s)
- Jing Sun
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Department of Nutrition, Clinical Assessment Center of Functional Food, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu, People's Republic of China
| | - Meng Wu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Li Wang
- Department of Toxicology, School of Public Health, Baotou Medical College, Baotou 014040, Inner Mongolia, People's Republic of China
| | - Peiwen Wang
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Tian Xiao
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China
| | - Suhua Wang
- Department of Toxicology, School of Public Health, Baotou Medical College, Baotou 014040, Inner Mongolia, People's Republic of China.
| | - Qizhan Liu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
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15
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Peng Y, Yin Q, Yuan M, Chen L, Shen X, Xie W, Liu J. Role of hepatic stellate cells in liver ischemia-reperfusion injury. Front Immunol 2022; 13:891868. [PMID: 35967364 PMCID: PMC9366147 DOI: 10.3389/fimmu.2022.891868] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/27/2022] [Indexed: 12/13/2022] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is a major complication of liver trauma, resection, and transplantation. IRI may lead to liver dysfunction and failure, but effective approach to address it is still lacking. To better understand the cellular and molecular mechanisms of liver IRI, functional roles of numerous cell types, including hepatocytes, Kupffer cells, neutrophils, and sinusoidal endothelial cells, have been intensively studied. In contrast, hepatic stellate cells (HSCs), which are well recognized by their essential functions in facilitating liver protection and repair, have gained less attention in their role in IRI. This review provides a comprehensive summary of the effects of HSCs on the injury stage of liver IRI and their associated molecular mechanisms. In addition, we discuss the regulation of liver repair and regeneration after IRI by HSCs. Finally, we highlight unanswered questions and future avenues of research regarding contributions of HSCs to IRI in the liver.
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Affiliation(s)
- Yuming Peng
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
- *Correspondence: Yuming Peng, ; Qiang Yin,
| | - Qiang Yin
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
- *Correspondence: Yuming Peng, ; Qiang Yin,
| | - Miaoxian Yuan
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Lijian Chen
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Xinyi Shen
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Weixin Xie
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Jinqiao Liu
- Department of Ultrasound, Hunan Children’s Hospital, Changsha, China
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16
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George J, Tsuchishima M, Tsutsumi M. Epigallocatechin-3-gallate inhibits osteopontin expression and prevents experimentally induced hepatic fibrosis. Biomed Pharmacother 2022; 151:113111. [PMID: 35594711 DOI: 10.1016/j.biopha.2022.113111] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/26/2022] [Accepted: 05/10/2022] [Indexed: 11/28/2022] Open
Abstract
Osteopontin (OPN) is a matricellular cytokine and a stress-induced profibrogenic molecule that promotes activation of stellate cells during the pathogenesis of hepatic fibrosis. We studied the protective effects of epigallocatechin-3-gallate (EGCG) to suppress oxidative stress, inhibit OPN expression, and prevent experimentally induced hepatic fibrosis. Liver injury was induced with intraperitoneal injections of N-nitrosodimethylamine (NDMA) in a dose of 1 mg/100 g body weight on 3 consecutive days of a week for 28 days. A group of rats received 0.2 mg EGCG/100 g body weight orally everyday during the study. The animals were sacrificed on day 28th from the beginning of exposure. Serum levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid were measured. Immunohistochemistry and/or real-time PCR were performed for α-SMA, 4-HNE, OPN, collagen type I, and type III. Serial administrations of NDMA produced well developed fibrosis and early cirrhosis in rat liver. Treatment with EGCG significantly reduced serum/plasma levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid and prevented deposition of collagen fibers in the hepatic tissue. Protein and/or mRNA levels demonstrated marked decrease in the expression of α-SMA, 4-HNE, OPN, collagen type I, and type III. Treatment with EGCG prevented excessive generation of reactive oxygen species, suppressed oxidative stress, significantly reduced serum and hepatic OPN levels, and markedly attenuated hepatic fibrosis. The results indicated that EGCG could be used as a potent therapeutic agent to prevent hepatic fibrogenesis and related adverse events.
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Affiliation(s)
- Joseph George
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Center for Regenerative Medicine, Kanazawa Medical University Hospital, Uchinada, Ishikawa 920-0293, Japan.
| | - Mutsumi Tsuchishima
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
| | - Mikihiro Tsutsumi
- Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan; Center for Regenerative Medicine, Kanazawa Medical University Hospital, Uchinada, Ishikawa 920-0293, Japan
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17
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Ghanim M, Amer J, Salhab A, Jaradat N. Ecballium elaterium improved stimulatory effects of tissue-resident NK cells and ameliorated liver fibrosis in a thioacetamide mice model. Biomed Pharmacother 2022; 150:112942. [PMID: 35429743 DOI: 10.1016/j.biopha.2022.112942] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/26/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022] Open
Abstract
Ecballium elaterium (EE), widely used plant in Mediterranean medicine, showed anticancer activity. This study aimed to investigate EE effects on liver fibrosis in an animal model of thioacetamide (TAA). Intraperitoneal administration of TAA was performed twice weekly for four weeks in C57BL6J mice. Livers were extracted and serum were evaluated for inflammatory markers (H&E staining, ALT, AST, ALP), pro-inflammatory cytokines, fibrosis (Sirius red staining, Masson's trichrome, α-smooth muscle actin and collagen III), and metabolic (cholesterol, triglyceride, C-peptide, and fasting-blood-sugar) profiles. Glutathione, glutathione peroxidase, and catalase liver antioxidant markers were assessed. Tissue-resident NK cells from mice livers were functionally assessed for activating receptors and cytotoxicity. Compared to vehicle-treated mice, the TAA-induced liver injury showed attenuation in the histopathology outcome following EE treatment. In addition, EE-treated mice resulted in decreased serum levels of ALT, AST, and ALP, associated with a decrease in IL-20, TGF-β, IL-17, IL-22 and MCP-1 concentrations. Moreover, EE-treated mice exhibited improved lipid profile of cholesterol, triglycerides, C-peptide, and FBS. EE treatment maintained GSH, GPX, and CAT liver antioxidant activity and led to elevated counts of tissue-resident NK (trNK) cells in the TAA-mice. Consequently, trNK demonstrated an increase in CD107a and IFN-γ with improved potentials to kill activated hepatic-stellate cells in an in vitro assay. EE exhibited antifibrotic and antioxidative effects, increased the number of trNK cells, and improved metabolic outcomes. This plant extract could be a targeted therapy for patients with advanced liver injury.
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Affiliation(s)
- Mustafa Ghanim
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine.
| | - Johnny Amer
- Department of Allied and Applied Medical Sciences, Division of Anatomy Biochemistry and Genetics, An-Najah National University, P.O. Box 7, Nablus, Palestine.
| | - Ahmad Salhab
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine
| | - Nidal Jaradat
- Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine
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18
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Feng SS, Li W, Hu YJ, Feng JX, Deng J. The biological activity and application of Monascus pigments: a mini review. INTERNATIONAL JOURNAL OF FOOD ENGINEERING 2022. [DOI: 10.1515/ijfe-2021-0235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Abstract
Monascus pigments (MPs), as secondary metabolites of Monascus, are microbial pigments which have been used for thousands of years. MPs are widely used in food industry as food pigments and preservatives, which have the stability of light resistance, high temperature resistance and acid-base change resistance. In addition, the antioxidant, antibacterial, antiviral and anti-tumor biological activities of MPs have also attracted people’s attention. Moreover, Due to the presence of citrinin, the safety of MPs still needs to be discussed and explored. In this paper, the production, biological activity, application in various fields and methods of detection and reduction of citrinin of MPs were reviewed, which provide new insights into the study and safe application related to human different diseases, medicines or health care products with MPs as active substances.
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Affiliation(s)
- Shan-Shan Feng
- Hunan Province Key Laboratory of Edible Forestry Resources Safety and Processing Utilization , National Engineering Research Center of Rice and Byproduct Deep Processing , College of Food Science and Engineering , Central South University of Forestry and Technology , Changsha , China
- College of Life Sciences and Chemistry , Hunan University of Technology, Zhuzhou , China
| | - Wen Li
- Hunan Province Key Laboratory of Edible Forestry Resources Safety and Processing Utilization , National Engineering Research Center of Rice and Byproduct Deep Processing , College of Food Science and Engineering , Central South University of Forestry and Technology , Changsha , China
- College of Life Sciences and Chemistry , Hunan University of Technology, Zhuzhou , China
| | - Yong-Jun Hu
- Department of Ultrasound , Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University , Changsha , Hunan 410002 , China
| | - Jian-Xiang Feng
- College of Life Sciences and Chemistry , Hunan University of Technology, Zhuzhou , China
| | - Jing Deng
- Hunan Province Key Laboratory of Edible Forestry Resources Safety and Processing Utilization , National Engineering Research Center of Rice and Byproduct Deep Processing , College of Food Science and Engineering , Central South University of Forestry and Technology , Changsha , China
- College of Life Sciences and Chemistry , Hunan University of Technology, Zhuzhou , China
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19
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Bandopadhyay S, Anand U, Gadekar VS, Jha NK, Gupta PK, Behl T, Kumar M, Shekhawat MS, Dey A. Dioscin: A review on pharmacological properties and therapeutic values. Biofactors 2022; 48:22-55. [PMID: 34919768 DOI: 10.1002/biof.1815] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/27/2021] [Indexed: 02/06/2023]
Abstract
Dioscin has gained immense popularity as a natural, bioactive steroid saponin, which offers numerous medical benefits. The growing global incidence of disease-associated morbidity and mortality continues to compromise human health, facilitating an increasingly urgent need for nontoxic, noninvasive, and efficient treatment alternatives. Natural compounds can contribute vastly to this field. Over recent years, studies have demonstrated the remarkable protective actions of dioscin against a variety of human malignancies, metabolic disorders, organ injuries, and viral/fungal infections. The successful usage of this phytocompound has been widely seen in medical treatment procedures under traditional Chinese medicine, and it is becoming progressively prevalent worldwide. This review provides an insight into the wide spectrum of pharmacological activities of dioscin, as reported and compiled in recent literature. The various novel approaches and applications of dioscin also verify the advantages exhibited by plant extracts against commercially available drugs, highlighting the potential of phytochemical agents like dioscin to be further incorporated into clinical practice.
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Affiliation(s)
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Vijaykumar Shivaji Gadekar
- Zoology Department, Sangola College (affiliated to Punyashlok Ahilyadevi Holkar Solapur University), Solapur, Maharashtra, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Tapan Behl
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR - Central Institute for Research on Cotton Technology, Mumbai, Maharashtra, India
| | - Mahipal S Shekhawat
- Plant Biotechnology Unit, Kanchi Mamunivar Government Institute for Postgraduate Studies and Research, Puducherry, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, India
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20
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Landerer S, Kalthoff S, Strassburg CP. UDP-glucuronosyltransferases mediate coffee-associated reduction of liver fibrosis in bile duct ligated humanized transgenic UGT1A mice. Hepatobiliary Surg Nutr 2021; 10:766-781. [PMID: 35004944 DOI: 10.21037/hbsn-20-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Coffee consumption has been shown to reduce the risk of liver fibrosis and is capable of inducing human UDP-glucuronosyltransferase (UGT) 1A genes. UGT1A enzymes act as indirect antioxidants catalyzing the elimination of reactive metabolites, which in turn are potent initiators of profibrotic mechanisms. The aim of this study was to analyze the role of UGT1A genes as effectors of the protective properties of coffee in bile duct ligation (BDL) induced liver fibrosis. METHODS Fourteen days BDL with and without coffee pre- and co-treatment was performed in htgUGT1A-WT and htgUGT1A-SNP mice. Hepatic UGT1A mRNA expression levels, serum bilirubin and aminotransferase activities were determined. Liver fibrosis was assessed by collagen deposition, computational analysis of Sirius red tissue staining and expression of profibrotic marker genes. Oxidative stress was measured by hepatic peroxidase concentrations and immunofluorescence staining. RESULTS UGT1A transcription was differentially activated in the livers of htgUGT1A-WT mice after BDL, in contrast to a reduced or absent induction in the presence of SNPs. Co-treated (coffee + BDL) htgUGT1A-WT-mice showed significantly increased UGT1A expression and protein levels and a considerably higher induction compared to water drinking WT mice (BDL), whereas in co-treated htgUGT1A-SNP mice absolute expression levels remained below those observed in htgUGT1A-WT mice. Collagen deposition, oxidative stress and the expression of profibrotic markers inversely correlated with UGT1A expression levels in htgUGT1A-WT and SNP mice after BDL and coffee + BDL co-treatment. CONCLUSIONS Coffee exerts hepatoprotective and antioxidative effects via activation of UGT1A enzymes. Attenuated hepatic fibrosis as a result of coffee-mediated UGT1A induction during cholestasis was detected, while the protective action of coffee was lower in a common low-function UGT1A SNP haplotype present in 10% of the Caucasian population. This study suggests that coffee consumption might constitute a potential strategy to support the conventional treatment of cholestasis-related liver diseases.
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Affiliation(s)
- Steffen Landerer
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Sandra Kalthoff
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
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21
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Hepatoprotective Effect and Potential Mechanism of Aqueous Extract from Phyllanthus emblica on Carbon-Tetrachloride-Induced Liver Fibrosis in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5345821. [PMID: 34712342 PMCID: PMC8548103 DOI: 10.1155/2021/5345821] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/05/2021] [Indexed: 12/29/2022]
Abstract
Liver fibrosis is a pathological variation caused by almost all chronic liver injuries. As an edible and medicinal natural resource, Phyllanthus emblica (PE) has been reported to possess hepatoprotective, antioxidant, and anti-inflammatory activities and may have an ameliorating effect on hepatic fibrosis. To investigate the protective effect of the aqueous extract of PE (AEPE) against liver fibrosis and to uncover its related mechanisms, the chemical profile of AEPE was characterized by high performance liquid chromatography (HPLC) and sulfuric acid-phenol method. Ameliorative effects of different doses of AEPE were investigated in carbon-tetrachloride- (CCl4-) induced liver fibrosis rats by analyzing biochemical markers, morphologic pathology, and related proteins expression in liver tissue. The results indicated that AEPE (1.8, 3.6 g/kg) could significantly reduce levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (Col IV), type III precollagen (PCIII), hyaluronic acid (HA), laminin (LN), malondialdehyde (MDA), nitric oxide (NO), protein carbonyl (PC), tumor necrosis factor-α(TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and hydroxyproline (Hyp) and increase the levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Hematoxylin-eosin (H&E), Sirius red, and Masson staining showed AEPE-treated improved fibrotic lesions and inflammatory cell infiltration. Meanwhile, AEPE treatment also significantly downregulates the expression of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) in the liver tissue and serum, respectively. In conclusion, AEPE possesses curative efficacy against liver fibrosis through its antioxidant, anti-inflammatory, and antifibrotic effects.
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22
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Huang J, Li Y, Xu D, Zhang X, Zhou X. RUNX1 regulates SMAD1 by transcriptionally activating the expression of USP9X, regulating the activation of hepatic stellate cells and liver fibrosis. Eur J Pharmacol 2021; 903:174137. [PMID: 33933467 DOI: 10.1016/j.ejphar.2021.174137] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 01/12/2023]
Abstract
Liver fibrosis (LF) is a common pathological process with high morbidity and mortality. Runt-related transcription factor 1 (RUNX1) is a transcription factor that could cause nephropathy and renal fibrosis, but its role in LF is unclear. Therefore, this study aimed to investigate the role RUNX1 in LF. Briefly, hepatic fibrosis was detected by Sirius Red staining. Transcript levels were quantified by qPCR, and proteins were assessed by western blotting or immunofluorescence. Cell viability and cell migration were measured by CCK8 assays and wound healing assays, respectively. The binding of RUNX1 and ubiquitin-specific protease 9X (USP9X) promoter was validated by ChIP assays and luciferase report assays, while the binding of USP9X and SMAD1 was confirmed by co-immunoprecipitation (Co-IP). Our studies found that the expression of RUNX1 was upregulated in LF mice, and RUNX1 knockdown alleviated CCl4-induced LF. RUNX1 silencing reduced the viability and migration of HSCs. Besides, RUNX1, as a transcription factor, bound to the promoter of USP9X and regulated the expression of USP9X. USP9X is a deubiquitination enzyme and was found to be up-regulated in LF mice. USP9X silencing reduced the viability and migration of HSCs, thereby inhibiting LF. Further studies showed that USP9X could stabilize downstream Smad1 expression. Furthermore, we also found that RUNX1 regulated the expression of SMAD1 by transcriptionally activating the expression of USP9X, thereby regulating the activation of hepatic stellate cells and liver fibrosis.
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Affiliation(s)
- Jie Huang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunan Province, 650101, China.
| | - Yan Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunan Province, 650101, China
| | - Dingwei Xu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunan Province, 650101, China
| | - Xiao Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunan Province, 650101, China
| | - Xiaoyang Zhou
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunan Province, 650101, China
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23
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Ghanbarinejad V, Ommati MM, Jia Z, Farshad O, Jamshidzadeh A, Heidari R. Disturbed mitochondrial redox state and tissue energy charge in cholestasis. J Biochem Mol Toxicol 2021; 35:e22846. [PMID: 34250697 DOI: 10.1002/jbt.22846] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 05/23/2021] [Accepted: 07/01/2021] [Indexed: 12/17/2022]
Abstract
The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications.
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Affiliation(s)
- Vahid Ghanbarinejad
- Toxicology Laboratory, Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad M Ommati
- Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Zhipeng Jia
- Department of Veterinary Medicine, College of Animal Sciences and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Omid Farshad
- Toxicology Laboratory, Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Toxicology Laboratory, Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Toxicology Laboratory, Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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24
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Dai X, Zeng Y, Zhang H, Gu Z, Gong Q, Luo K. Advances on Nanomedicines for Diagnosis and Theranostics of Hepatic Fibrosis. ADVANCED NANOBIOMED RESEARCH 2021. [DOI: 10.1002/anbr.202000091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Xinghang Dai
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- West China School of Medicine Sichuan University Chengdu 610041 China
| | - Yujun Zeng
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
| | - Hu Zhang
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- Amgen Bioprocessing Centre Keck Graduate Institute CA 91711 USA
| | - Zhongwei Gu
- Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
| | - Kui Luo
- Huaxi MR Research Center (HMRRC) Department of Radiology Functional and molecular imaging Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu 610041 China
- Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China
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25
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Lee HA, Chu KB, Moon EK, Quan FS. Histone Deacetylase Inhibitor-Induced CDKN2B and CDKN2D Contribute to G2/M Cell Cycle Arrest Incurred by Oxidative Stress in Hepatocellular Carcinoma Cells via Forkhead Box M1 Suppression. J Cancer 2021; 12:5086-5098. [PMID: 34335925 PMCID: PMC8317537 DOI: 10.7150/jca.60027] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/13/2021] [Indexed: 01/03/2023] Open
Abstract
Forkhead box protein M1 (FOXM1) is a pivotal regulator of G2/M cell cycle progression in many types of cancer. Previously, our study demonstrated that histone deacetylase inhibition (HDACi) sensitizes hepatocellular carcinoma cells (HCC) to oxidative stress through FOXM1 suppression. However, the mechanism underlying its suppression by HDACi still requires elucidation. We hypothesized that HDACi induce genes responsible for destabilizing and inactivating FOXM1. The transcriptome in the HepG2 was revealed by massive analysis of cDNA end (MACE). Expression of mRNA and proteins were analyzed by quantitative real-time PCR (qPCR) and western blot, respectively. Cell cycle was analyzed by fluorescence-activated cell sorting (FACS). Oxidative stress and HDACi suppressed CDK4/6 levels while enhancing CDK inhibitor 2B and 2D (CDKN2B and CDKN2D) expressions in HCC. Palbociclib, a specific inhibitor of CDK4/6, induced G2/M cell cycle arrest in HCC by down-regulating phosphorylation level of FOXM1, and its downstream target genes such as aurora kinase A (AURKA) and polo-like kinase 1 (PLK1). HDACi treatment increased the ubiquitination level of FOXM1 by suppressing ubiquitin-specific peptidase 21 (USP21), which deubiquitinates FOXM1. Inhibiting FOXM1 degradation with MG132 treatment affected neither palbociclib-induced G2/M cell cycle arrest nor expression of its target genes. Double knockdown of CDKN2B and CDKN2D reduced the oxidative stress and HDACi-induced G/2M cell cycle arrest. In conclusion, oxidative stress and HDACi synergistically cause G2/M cell cycle arrest via CDKN2 induction, which sequentially inhibits CDK4/6, FOXM1, and its downstream target genes AURKA, PLK1, and CCNB1 phosphorylation in HCC.
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Affiliation(s)
- Hae-Ahm Lee
- Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Ki-Back Chu
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Eun-Kyung Moon
- Department of Medical Zoology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Fu-Shi Quan
- Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea.,Department of Medical Zoology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
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26
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Ghanbarinejad V, Jamshidzadeh A, Khalvati B, Farshad O, Li H, Shi X, Chen Y, Ommati MM, Heidari R. Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:1191-1203. [PMID: 33527194 DOI: 10.1007/s00210-020-02041-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/13/2020] [Indexed: 02/07/2023]
Abstract
Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.
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Affiliation(s)
- Vahid Ghanbarinejad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran
- Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran
- Department of Pharmacology and Toxicology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahman Khalvati
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran
| | - Huifeng Li
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Xiong Shi
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Yuanyu Chen
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China.
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran.
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27
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Yang J, Xu C, Wu M, Wu Y, Jia X, Zhou C, Zhang X, Ge S, Li Z, Zhang L. MicroRNA-124 inhibits hepatic stellate cells inflammatory cytokines secretion by targeting IQGAP1 through NF-κB pathway. Int Immunopharmacol 2021; 95:107520. [PMID: 33743313 DOI: 10.1016/j.intimp.2021.107520] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 01/01/2023]
Abstract
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. To date, there was no direct approved antifibrotic therapy, and current treatment was mainly the removal of the causative factor. Recent studies demonstrated that aberrant expression of miR-124 was involved in the progression of various liver diseases including hepatocellular carcinoma (HCC). However, whether miR-124 could function as a transcriptional regulator in the inflammatory cytokines secretion of liver fibrosis remains unclear. In this study, we demonstrated that the expression of miR-124 was downregulated in liver fibrosis tissues and TNF-α-induced LX-2 cells, concomitant with the upregulated expression of IQGAP1, suggesting that miR-124 and IQGAP1 might be associated with the development of inflammation in liver fibrosis. Therefore, we demonstrated that the overexpression of miR-124 and knockdown of IQGAP1 could lead to the downregulation of TNF-α, IL-1β and IL-6. While knockdown of miR-124 or overexpression of IQGAP1 showed reversed results. Moreover, dual luciferase reporter assays demonstrated that miR-124 specifically targeted the 3'-UTR of IQGAP1, and thus inhibited the expression of IQGAP1. Mechanistically, we found that the expression changes of miR-124 and IQGAP1 could be involved in inhibition or activation of NF-κB signaling pathway in response to TNF-α. In conclusion, these results indicated that miR-124 plays a crucial role in TNF-α-induced LX-2 cells via regulating NF-κB signaling pathway.
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Affiliation(s)
- Junfa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Changqing Xu
- The Third People's Hospital of Hefei (Hefei Third Clinical College of Anhui Medical University), Hefei, Anhui Province, China
| | - Maomao Wu
- Department of Pharmacy, Anhui Chest Hospital, Hefei, Anhui Province, China
| | - Ying Wu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Xiaodi Jia
- Fujian Normal University, Fuzhou 350007, China
| | - Chang Zhou
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Xianzheng Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Shenglin Ge
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
| | - Zeng Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China.
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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28
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Ommati MM, Amjadinia A, Mousavi K, Azarpira N, Jamshidzadeh A, Heidari R. N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats. Stress 2021; 24:213-228. [PMID: 32510264 DOI: 10.1080/10253890.2020.1777970] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, Peoples' Republic of China
| | - Ali Amjadinia
- Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khadijeh Mousavi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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29
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Wu SY, Wang WJ, Dou JH, Gong LK. Research progress on the protective effects of licorice-derived 18β-glycyrrhetinic acid against liver injury. Acta Pharmacol Sin 2021; 42:18-26. [PMID: 32144337 PMCID: PMC7921636 DOI: 10.1038/s41401-020-0383-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 02/19/2020] [Indexed: 12/15/2022]
Abstract
The first description of the medical use of licorice appeared in "Shennong Bencao Jing", one of the well-known Chinese herbal medicine classic books dated back to 220-280 AD. As one of the most commonly prescribed Chinese herbal medicine, licorice is known as "Guo Lao", meaning "a national treasure" in China. Modern pharmacological investigations have confirmed that licorice possesses a number of biological activities, such as antioxidation, anti-inflammatory, antiviral, immune regulation, and liver protection. 18β-glycyrrhetinic acid is one of the most extensively studied active integrants of licorice. Here, we provide an overview of the protective effects of 18β-glycyrrhetinic acid against various acute and chronic liver diseases observed in experimental models, and summarize its pharmacological effects and potential toxic/side effects at higher doses. We also make additional comments on the important areas that may warrant further research to support appropriate clinical applications of 18β-glycyrrhetinic acid and avoid potential risks.
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Affiliation(s)
- Shou-Yan Wu
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wen-Jie Wang
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jin-Hui Dou
- National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, Oxford, MS, 38677, USA
| | - Li-Kun Gong
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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30
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Zhang J, Li R, Liu Q, Zhou J, Huang H, Huang Y, Zhang Z, Wu T, Tang Q, Huang C, Zhao Y, Zhang G, Mo L, Li Y, He J. SB431542-Loaded Liposomes Alleviate Liver Fibrosis by Suppressing TGF-β Signaling. Mol Pharm 2020; 17:4152-4162. [PMID: 33089693 DOI: 10.1021/acs.molpharmaceut.0c00633] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Rui Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jian Zhou
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Hui Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ya Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Zijing Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Tong Wu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Qin Tang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Cuiyuan Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yingnan Zhao
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Guorong Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
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Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models. J Mol Med (Berl) 2020; 98:1203-1213. [PMID: 32666246 DOI: 10.1007/s00109-020-01950-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/04/2020] [Accepted: 07/09/2020] [Indexed: 12/15/2022]
Abstract
Hepatic fibrosis and cirrhosis are chronic diseases affecting liver and a major health problem throughout the world. The hallmark of fibrosis and cirrhosis is inordinate synthesis and deposition of fibril forming collagens in the extracellular matrix of the liver leading to nodule formation and loss of normal architecture. Hepatic stellate cells play a crucial role in the pathogenesis and progression of liver fibrosis through secretion of several potent fibrogenic factors that trigger hepatocytes, portal fibrocytes, and bone marrow-derived fibroblasts to synthesize and deposit several connective tissue proteins, especially collagens between hepatocytes and space of Disse. Regulation of various events involved in the activation and transformation of hepatic stellate cells seems to be an appropriate strategy for the arrest of hepatic fibrosis and liver cirrhosis. In order to unravel the molecular mechanisms involved in the pathogenesis and progression of hepatic fibrosis, to determine proper and potent targets to arrest fibrosis, and to discover powerful therapeutic agents, a quick and reproducible animal model of hepatic fibrosis and liver cirrhosis that display all decompensating features of human condition is required. This review thoroughly evaluates the biochemical, histological, and pathological features of N-nitrosodimethylamine-induced model of liver injury, hepatic fibrosis, and early cirrhosis in rodents.
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Li J, Kong L, Huang H, Luan S, Jin R, Wu F. ASIC1a inhibits cell pyroptosis induced by acid-induced activation of rat hepatic stellate cells. FEBS Open Bio 2020; 10:1044-1055. [PMID: 32237041 PMCID: PMC7262943 DOI: 10.1002/2211-5463.12850] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/11/2020] [Accepted: 03/25/2020] [Indexed: 12/19/2022] Open
Abstract
The activation of hepatic stellate cells (HSCs) is associated with liver fibrosis, the pathological feature of most forms of chronic hepatic damage, and is accompanied by abnormal deposition of the extracellular matrix (ECM). During the pathological process, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is involved in the activation of HSCs. It has previously been identified that ASIC1a is related to pyroptosis in articular chondrocytes. However, it remains unclear whether ASIC1a restrains pyroptosis during liver fibrosis. Here, we determined that the levels of pyroptosis-associated speck-like protein, gasdermin D, caspase-1, nucleotide-binding oligomerization domain (NOD)-like receptor 3, and apoptosis-associated speck-like protein (ASC) decreased, while the level of α-smooth muscle actin and collagen-I increased upon introduction of ASIC1a into an acid-induced model. Inhibition or silencing of ASIC1a and the use of Ca2+ -free medium were able to promote the pyroptosis of activated HSCs, which reduced their deposition. In summary, our study indicates that ASIC1a inhibits pyroptosis of HSCs and that inhibition of ASIC1a may be able to promote pyroptosis to relieve liver fibrosis.
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Affiliation(s)
- Jun Li
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Lingjin Kong
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Huiping Huang
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Shaohua Luan
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Rui Jin
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Fanrong Wu
- School of PharmacyAnhui Medical UniversityHefeiChina
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The Anticarcinogenic Effect of the Apple Polyphenol Phloretin in an Experimental Rat Model of Hepatocellular Carcinoma. ARABIAN JOURNAL FOR SCIENCE AND ENGINEERING 2020. [DOI: 10.1007/s13369-020-04478-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Liang H, Wang X, Si C, Duan Y, Chen B, Liang H, Yang D. Downregulation of miR‑141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway. Int J Mol Med 2020; 46:406-414. [PMID: 32319536 DOI: 10.3892/ijmm.2020.4578] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 03/27/2020] [Indexed: 01/18/2023] Open
Abstract
The activation of hepatic stellate cells (HSCs) caused by stimulating factors or fibrogenic cytokines is the critical stage of liver fibrosis. Recent studies have demonstrated the influence of microRNAs (miRNAs or miRs) on HSC activation and transformation; however, the function and underlying mechanisms of miRNAs in HSC activation have not yet been completely clarified. In the present study, transforming growth factor β1 (TGF‑β1) was used to treat human HSC lines (HSC‑T6 and LX2 cells) to simulate the activation of HSCs in vivo and whether the expression of miRNAs in HSCs was affected by TGF‑β1 treatment was examined using a miRNA microarray. It was observed that miR‑141 was one of the most upregulated miRNAs during HSC activation. Functional analyses revealed that miR‑141 knockdown suppressed the viability of HSCs and inhibited the expression levels of pro‑fibrotic markers. In addition, phosphatase and tensin homolog (PTEN), a well‑known suppressor of the AKT/mammalian target of rapamycin (mTOR) pathway, was found to be directly targeted by miR‑141 in HSCs. More importantly, the knockdown of PTEN markedly reversed the suppressive effects of miR‑141 inhibition on the viability of and the expression levels of pro‑fibrotic markers during HSC activation. Finally, it was observed that the downregulation of miR‑141 blocked the TGF‑β1‑induced activation of the AKT/mTOR pathway in HSCs. On the whole, the findings of the present study indicate that miR‑141 inhibition suppresses HSC activation via the AKT/mTOR pathway by targeting PTEN, highlighting that miR‑141 may serve as a novel therapeutic target for liver fibrosis.
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Affiliation(s)
- Haijun Liang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Xinwei Wang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Changyun Si
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yuxiu Duan
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Baoxin Chen
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Haixia Liang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Daokun Yang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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Feng Q, Guan S, Zhao JR, Zhao XY, Zhang CC, Wang L, Feng YM, Li SL, Zhu Q. Gadobenate dimeglumine-enhanced magnetic resonance imaging can accurately predict the severity of esophageal varices and portal vein pressure in patients with hepatitis B cirrhosis. J Dig Dis 2020; 21:104-111. [PMID: 31922658 DOI: 10.1111/1751-2980.12843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 01/03/2020] [Accepted: 01/06/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To explore the effectiveness of gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) in predicting portal hypertension and high-risk esophageal varices (EV) in patients with hepatitis B cirrhosis. METHODS In total, 71 and 30 patients comprising the training and validation groups, respectively, were enrolled in the study. Univariate and multivariate analyses were performed to detect their risk of developing high-risk EV to generate a formula for scoring EV. The relationships between the relative enhancement ratio (RE) of Gd-BOPTA-enhanced MRI and portal vein pressure were explored. RESULTS Platelet count, portal vein width and RE were identified as independent predictors of high-risk EV. Based on these parameters, the EV score model were calculated as: -6.483 + 15.612 × portal vein width + 2.251 × RE - 0.176 × platelet count. The area under the receiver operating characteristic curve was 0.903. At a cut-off value of ≤ -2.74, the negative predictive value was 94.00%, while the positive predictive value was as high as 93.80% when the cut-off was set at > 4.00. Gd-BOPTA-enhanced MRI was effective in predicting portal pressure. Its accuracy was confirmed with the validation set. CONCLUSIONS Gd-BOPTA-enhanced MRI was successfully applied to evaluate high-risk EV and portal hypertension. These results represent an accurate, non-invasive model for detecting high-risk EV, based on which we propose a cost-effective algorithm for EV management, eliminating the need to perform an endoscopy in all patients with cirrhosis.
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Affiliation(s)
- Qian Feng
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
| | - Shan Guan
- Department of Hepatology, Liaocheng People's Hospital, Liaocheng, China
| | - Jing Run Zhao
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
| | - Xin Ya Zhao
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Chuan Chen Zhang
- Department of Radiology, Liaocheng People's Hospital, Liaocheng, China
| | - Le Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Yue Min Feng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Sen Lin Li
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
| | - Qiang Zhu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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Lee HA, Chu KB, Moon EK, Kim SS, Quan FS. Sensitization to oxidative stress and G2/M cell cycle arrest by histone deacetylase inhibition in hepatocellular carcinoma cells. Free Radic Biol Med 2020; 147:129-138. [PMID: 31870798 DOI: 10.1016/j.freeradbiomed.2019.12.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 12/13/2022]
Abstract
Oxidative stress resistance in cancer cells has contributed to multi-drug resistance, which poses a serious challenge to cancer therapy. To surmount this, combinatorial treatment involving anticancer drugs and histone deacetylase inhibitors (HDACi) have emerged as a chemotherapeutic option. Yet, HDACi's role in redox states of cancer cells still requires elucidation. In the present study, we hypothesized that HDACi sensitizes cancer cells to oxidative stress and results in G2/M cell cycle arrest. Cell viability and cell cycle were analyzed using Cell Counting Kit 8 (CCK8) and fluorescent activated cell sorting (FACS), respectively. The transcriptomes of cells were investigated by massive analysis of cDNA end (MACE). Expression of mRNA and proteins were analyzed by quantitative real-time PCR (qPCR) and Western blot, respectively. Intracellular oxidative stress induced by tert-Butyl hydroperoxide (tBHP) reduced cell viability and resulted in G2/M cell cycle arrest in a dose-dependent manner in hepatocellular carcinoma (HCC) cells. The effects of sorafenib on cell cycle arrest and HCC viability were enhanced through HDACi treatment. MACE revealed that genes related to progression of G2/M cell cycle including Foxm1, Aurka, Plk1, and Ccnb1 were significantly down-regulated in tBHP and HDACi-treated HepG2 cells. Inhibition of FOXM1 with thiostrepton also resulted in reduced cell viability and expression of FOXM1 target genes such as Aurka, Plk1, and Ccnb1. These results indicate that HDACi sensitizes HepG2 cells to oxidative stress and results in G2/M cell cycle arrest via down-regulation of FOXM1, which plays a key role in progression of G2/M cell cycle.
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Affiliation(s)
- Hae-Ahm Lee
- Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Ki-Back Chu
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Eun-Kyung Moon
- Department of Medical Zoology, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Sung Soo Kim
- Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Biochemistry and Molecular Biology, Kyung Hee University School of Medicine, Seoul, 02447, Republic of Korea
| | - Fu-Shi Quan
- Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Medical Zoology, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
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Zhou Z, Qi J, Zhao J, Lim CW, Kim J, Kim B. Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin-induced liver fibrosis and biliary fibrosis in mice. J Cell Mol Med 2020; 24:1383-1398. [PMID: 31821710 PMCID: PMC6991653 DOI: 10.1111/jcmm.14817] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/23/2019] [Accepted: 10/26/2019] [Indexed: 12/31/2022] Open
Abstract
Although numerous studies have suggested that canonical IκB kinases (IKK) play a key role in the progression of liver fibrosis, the role of non-canonical IKKε and TANK-binding kinase 1 (TBK1) on the development and progression of liver fibrosis remains unclear. To demonstrate such issue, repeated injection of CCl4 was used to induce hepatotoxin-mediated chronic liver injury and biliary fibrosis was induced by 0.1% diethoxycarbonyl-1, 4-dihydrocollidine diet feeding for 4 weeks. Mice were orally administered with amlexanox (25, 50, and 100 mg/kg) during experimental period. Significantly increased levels of TBK1 and IKKε were observed in fibrotic livers or hepatic stellate cells (HSCs) isolated from fibrotic livers. Interestingly, amlexanox treatment significantly inhibited the phosphorylation of TBK1 and IKKε accompanied by reduced liver injury as confirmed by histopathologic analysis, decreased serum biochemical levels and fibro-inflammatory responses. Additionally, treatment of amlexanox promoted the fibrosis resolution. In accordance with these findings, amlexanox treatment suppressed HSC activation and its related fibrogenic responses by partially inhibiting signal transducer and activator of transcription 3. Furthermore, amlexanox decreased the activation and inflammatory responses in Kupffer cells. Collectively, we found that inhibition of the TBK1 and IKKε by amlexanox is a promising therapeutic strategy to cure liver fibrosis.
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Affiliation(s)
- Zixiong Zhou
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Jing Qi
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Jing Zhao
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Chae Woong Lim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Jong‐Won Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Pathology (BK21 Plus Program)College of Veterinary MedicineJeonbuk National UniversityIksanKorea
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Shahin K, Hosseini SY, Jamali H, Karimi MH, Azarpira N, Zeraatian M. The enhancing impact of amino termini of hepatitis C virus core protein on activation of hepatic stellate cells. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2020; 13:57-63. [PMID: 32190226 PMCID: PMC7069533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIM To investigate the potential effects of carboxyl and amino termini of HCV core protein on the HSCs activation. BACKGROUND The core protein is recognized as the most important fibrosis inducer of Hepatitis C virus (HCV). While the exogenous fibrotic effect of HCV core protein has been reported earlier, the endogenous effect and the role of two termini must still be investigated. METHODS Plasmids expressing full length, carboxyl-truncated (T1), or amino-truncated (T3) versions of the core were transfected into LX 2 cells. MTT assay was performed to evaluate the cytotoxicity of the endogenous expression of different regions of core protein on these cells. Afterwards, the total RNA was reversely transcribed and introduced into quantitative polymerase chain reaction (qPCR) to measure the expression level of collagen type I (COL1A1), α-smooth muscle actin (-SMA), tissue metalloproteinase inhibitor 1 (TIMP-1), and transforming growth factor-β1 (TGF-β1). In addition, TGF-β1 as a fibrotic factor, was also assessed in the supernatant of LX-2 cells using ELISA method. RESULTS The full and T1 versions of the core exhibited a measurable proliferative effect on LX 2 cells (P<0.05). Analysis of the gene expression was also showed that, in spite of amino-truncated version, these constructs represented a significant activation impact compared to the empty plasmid. Moreover, the result of TGF β assay was in agreement with the results of mRNA expression analysis. CONCLUSION The endogenous expression of the full and carboxyl-truncated versions of the core exhibited a significant activator effect on HSCs. Therefore, it can be concluded that, amino domain of HCV core protein performs a stellate cell activation role.
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Affiliation(s)
- Khashayar Shahin
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Younes Hosseini
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran,Department of Bacteriology and Virology, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Hoshang Jamali
- Department of Microbiology, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | | | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mastaneh Zeraatian
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Rao S, Xiang J, Huang J, Zhang S, Zhang M, Sun H, Li J. PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis. Cell Biosci 2019; 9:100. [PMID: 31867100 PMCID: PMC6916466 DOI: 10.1186/s13578-019-0363-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 12/09/2019] [Indexed: 02/07/2023] Open
Abstract
Background PRC1 (Protein regulator of cytokinesis 1) regulates microtubules organization and functions as a novel regulator in Wnt/β-catenin signaling pathway. Wnt/β-catenin is involved in development of liver fibrosis (LF). We aim to investigate effect and mechanism of PRC1 on liver fibrosis. Methods Carbon tetrachloride (CCl4)-induced mice LF model was established and in vitro cell model for LF was induced by mice primary hepatic stellate cell (HSC) under glucose treatment. The expression of PRC1 in mice and cell LF models was examined by qRT-PCR (quantitative real-time polymerase chain reaction), western blot and immunohistochemistry. MTT assay was used to detect cell viability, and western blot to determine the underlying mechanism. The effect of PRC1 on liver pathology was examined via measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hydroxyproline, as well as histopathological analysis. Results PRC1 was up-regulated in CCl4-induced mice LF model and activated HSC. Knockdown of PRC1 inhibited cell viability and promoted cell apoptosis of activated HSC. PRC1 expression was regulated by Wnt3a signaling, and PRC1 could regulate downstream β-catenin activation. Moreover, PRC1 could activate glioma-associated oncogene homolog 1 (GLI1)-dependent osteopontin expression to participate in LF. Adenovirus-mediated knockdown of PRC1 in liver attenuated LF and reduced collagen deposition. Conclusions PRC1 aggravated LF through regulating Wnt/β-catenin mediated GLI1-dependent osteopontin expression, providing a new potential therapeutic target for LF treatment.
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Affiliation(s)
- Shenzong Rao
- 1Department of Transfusion, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Jie Xiang
- Department of Laboratory Medicine, Wuhan Medical Treatment Center, Wuhan City, 430023 Hubei Province China
| | - Jingsong Huang
- 3Department of Transfusion, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000 Xiangan Eastroad, Xiangan District, Xiamen, 361101 China
| | - Shangang Zhang
- 4Department of Rehabilitation Medicine, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000 Xiangan Eastroad, Xiangan District, Xiamen, 361101 China
| | - Min Zhang
- 1Department of Transfusion, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Haoran Sun
- 1Department of Transfusion, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Jian Li
- 1Department of Transfusion, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
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Phaosri M, Jantrapirom S, Na Takuathung M, Soonthornchareonnon N, Sireeratawong S, Buacheen P, Pitchakarn P, Nimlamool W, Potikanond S. Salacia chinensis L. Stem Extract Exerts Antifibrotic Effects on Human Hepatic Stellate Cells Through the Inhibition of the TGF-β1-Induced SMAD2/3 Signaling Pathway. Int J Mol Sci 2019; 20:ijms20246314. [PMID: 31847284 PMCID: PMC6940887 DOI: 10.3390/ijms20246314] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/11/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022] Open
Abstract
Salacia chinensis L. (SC) stems have been used as an ingredient in Thai traditional medicine for treating patients with hepatic fibrosis and liver cirrhosis. However, there is no scientific evidence supporting the antifibrotic effects of SC extract. Therefore, this study aimed to determine the antifibrotic activity of SC stem extract in human hepatic stellate cell-line called LX-2. We found that upon TGF-β1 stimulation, LX-2 cells transformed to a myofibroblast-like phenotype with a noticeable increase in α-SMA and collagen type I production. Interestingly, cells treated with SC extract significantly suppressed α-SMA and collagen type I production and reversed the myofibroblast-like characteristics back to normal. Additionally, TGF-β1 also influenced the development of fibrogenesis by upregulation of MMP-2, TIMP-1, and TIMP-2 and related cellular signaling, such as pSmad2/3, pErk1/2, and pJNK. Surprisingly, SC possesses antifibrotic activity through the suppression of TGF-β1-mediated production of collagen type 1, α-SMA, and the phosphorylation status of Smad2/3, Erk1/2, and JNK. Taken together, the present study provides accumulated information demonstrating the antifibrotic effects of SC stem extract and revealing its potential for development for hepatic fibrosis patients.
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Affiliation(s)
- Mattareeyapar Phaosri
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (M.P.); (S.J.); (M.N.T.); (S.S.); (W.N.)
- Graduate School, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Salinee Jantrapirom
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (M.P.); (S.J.); (M.N.T.); (S.S.); (W.N.)
| | - Mingkwan Na Takuathung
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (M.P.); (S.J.); (M.N.T.); (S.S.); (W.N.)
- Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Noppamas Soonthornchareonnon
- Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Thung Phaya Thai, Rajathevi, Bangkok 10400, Thailand;
| | - Seewaboon Sireeratawong
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (M.P.); (S.J.); (M.N.T.); (S.S.); (W.N.)
| | - Pensiri Buacheen
- Graduate School, Chiang Mai University, Chiang Mai 50200, Thailand;
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Pornsiri Pitchakarn
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Wutigri Nimlamool
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (M.P.); (S.J.); (M.N.T.); (S.S.); (W.N.)
- Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Saranyapin Potikanond
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (M.P.); (S.J.); (M.N.T.); (S.S.); (W.N.)
- Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand
- Correspondence: or
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Kim KH, Lee JI, Kim OH, Hong HE, Kwak BJ, Choi HJ, Ahn J, Lee TY, Lee SC, Kim SJ. Ameliorating liver fibrosis in an animal model using the secretome released from miR-122-transfected adipose-derived stem cells. World J Stem Cells 2019; 11:990-1004. [PMID: 31768225 PMCID: PMC6851007 DOI: 10.4252/wjsc.v11.i11.990] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 09/02/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome. AIM To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs). METHODS We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared. RESULTS MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome. CONCLUSION We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.
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Affiliation(s)
- Kee-Hwan Kim
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Jae Im Lee
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
| | - Ok-Hee Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Ha-Eun Hong
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Bong Jun Kwak
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Joseph Ahn
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Tae Yun Lee
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
| | - Sang Chul Lee
- Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 34943, South Korea
| | - Say-June Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea.
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Wang JQ, Liu YR, Xia Q, Chen RN, Liang J, Xia QR, Li J. Emerging Roles for NLRC5 in Immune Diseases. Front Pharmacol 2019; 10:1352. [PMID: 31824312 PMCID: PMC6880621 DOI: 10.3389/fphar.2019.01352] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 10/25/2019] [Indexed: 12/15/2022] Open
Abstract
Innate immunity activates the corresponding immune response relying on multiple pattern recognition receptors (PRRs) that includes pattern recognition receptors (PRRs), like NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs), which could accurately recognize invasive pathogens. In particular, NLRs belong to a large protein family of pattern recognition receptors in the cytoplasm, where they are highly correlated with activation of inflammatory response system followed by rapid clearance of invasive pathogens. Among the NLRs family, NLRC5, also known as NOD4 or NOD27, accounts for a large proportion and involves in immune responses far and wide. Notably, in the above response case of inflammation, the expression of NLRC5 remarkably increased in immune cells and immune-related tissues. However, the evidence for higher expression of NLRC5 in immune disease still remains controversial. It is noted that the growing evidence further accounts for the participation of NLRC5 in the innate immune response and inflammatory diseases. Moreover, NLRC5 has also been confirmed to exert a critical role in the control of regulatory diverse signaling pathways. Together with its broad participation in the occurrence and development of immune diseases, NLRC5 can be consequently treated as a potential therapeutic target. Nevertheless, the paucity of absolute understanding of intrinsic characteristics and underlying mechanisms of NLRC5 still make it hard to develop targeting drugs. Therefore, current summary about NLRC5 information is indispensable. Herein, current knowledge of NLRC5 is summarized, and research advances in terms of NLRC5 in characteristics, biological function, and regulatory mechanisms are reviewed.
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Affiliation(s)
- Jie-Quan Wang
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.,Department of Pharmacy, Anhui Mental Health Center, Hefei, China.,Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, China.,School of Pharmacy, Anhui Medical University, Ministry of Education, Hefei, China
| | - Ya-Ru Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ruo-Nan Chen
- School of Pharmacy, Anhui Medical University, Ministry of Education, Hefei, China.,Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Liang
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.,Department of Pharmacy, Anhui Mental Health Center, Hefei, China.,Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
| | - Qing-Rong Xia
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.,Department of Pharmacy, Anhui Mental Health Center, Hefei, China.,Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Ministry of Education, Hefei, China
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Ommati MM, Farshad O, Niknahad H, Arabnezhad MR, Azarpira N, Mohammadi HR, Haghnegahdar M, Mousavi K, Akrami S, Jamshidzadeh A, Heidari R. Cholestasis-associated reproductive toxicity in male and female rats: The fundamental role of mitochondrial impairment and oxidative stress. Toxicol Lett 2019; 316:60-72. [DOI: 10.1016/j.toxlet.2019.09.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/01/2019] [Accepted: 09/09/2019] [Indexed: 02/07/2023]
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44
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Liang S, Lin X, Liang Y, Song D, Zhang L, Fan X. Killing Effects of IFN R -/- Mouse NK Cells Activated by HN Protein of NDV on Mouse Hepatoma Cells and Possible Mechanism with Syk and NF-κB. Anat Rec (Hoboken) 2019; 302:1718-1725. [PMID: 31120191 PMCID: PMC6771794 DOI: 10.1002/ar.24177] [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: 10/17/2017] [Revised: 11/27/2018] [Accepted: 12/08/2018] [Indexed: 11/07/2022]
Abstract
The objective of this article is to evaluate whether the tumoricidal activity of mouse IFN R-/- nature killer (NK) cells is induced by Newcastle disease virus hemagglutinin-neuraminidase (NDV-HN) stimulation, and to investigate what is the mechanism of the HN-stimulated NK cells to kill mouse hepatoma cell line in vitro. The mouse IFN R-/- NK cells were stimulated for 16 hr with 500 ng/mL NDV-HN in 1640 medium. Quantify the cytotoxic activities of NK cells against mouse hepatoma cells (Hepa1-6) by flow cytometry. Granzymes B (GrB) and Fas/FasL concentrations in the supernatants of IFN R-/- NK cells medium were determined by specific ELISA assay. The expression of cell surface GrB and Fas was determined by Western blot. NDV-HN stimulation enhanced tumoricidal activity of IFN R-/- NK cells toward Hepa1-6 in vitro. Treating with anti-HN neutralizing mAb induced significant decline in the cytotoxicity of IFN R-/- NK cells toward Hepa1-6 cell line (P < 0.05). After treating with anti-HN protein (1 μL/mL), Syk-specific inhibitor Herbimycin A(250 ng/mL) and NF-κB inhibitor PDTC (500 ng/mL) downregulated the tumoricidal activity of HN-stimulated IFN R-/- NK cells (P < 0.05). Moreover, significant suppressions in the production of GrB and Fas/FasL were observed in HN-stimulated IFN R-/- NK cells (P < 0.05). Thus, we concluded that killer activation receptors pathway is involved in the IFN-γ-independent GrB and Fas/FasL expression of NDV-HN-stimulated IFN R-/- NK cells, and these are activated by Syk and NF-κB. Anat Rec, 302:1718-1725, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association for Anatomy.
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Affiliation(s)
- Shuang Liang
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
- Department of Pharmaceutical and Medical EquipmentTrading Center of Guangxi Public ResourcesNanningGuangxiChina
| | - Xiao Lin
- Guangxi Key Laboratory of Traditional Chinese Medicine Quality StandardsGuangxi Institute of Traditional Medical and Pharmaceutical SciencesNanningChina
| | - Ying Liang
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
| | - Dezhi Song
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
| | - Lei Zhang
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
| | - Xiaohui Fan
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
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A first experience of transduction for differentiated HepaRG cells using lentiviral technology. Sci Rep 2019; 9:12910. [PMID: 31501487 PMCID: PMC6733867 DOI: 10.1038/s41598-019-49402-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 07/22/2019] [Indexed: 12/23/2022] Open
Abstract
Currently, there is a lack of systems for studying the role of hepatitis B viral proteins, such as HBeAg and HBcAg, on liver injury. It is necessary to develop an original tool in order to clarify the role of these viral proteins in hepatic stellate cell activation, and to understand the molecular mechanisms of liver injury. HepaRG are the most reliable hepatocyte-like cells for studying liver functions or disorders. In this paper, we demonstrate that the transduction of differentiated HepaRG (dHepaRG) cells can be performed successfully using lentiviral particles. The production of a functional Green Fluorescent Protein (GFP) assessed by Fluorescence Activated Cell Sorting and fluorescence microscopy is up to 16% of GFP positive cells using a multiplicity of infection (MOI) of 2.4. We demonstrate that this technology can allow the stable expression of GFP during the long lifecycle of the cell (up to four weeks after the cell’s passage). With this innovative tool, we aim to express viral proteins such as HBeAg or HBcAg in dHepaRG cells. The preliminary results of this work shows that HBeAg can be efficiently produced in dHepaRG cells and that increased MOI allows a better production of this protein. Our future objective will be to study the role of HBc and HBe proteins on the induction of hepatic fibrosis.
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46
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Latief U, Umar MF, Ahmad R. Nrf2 protein as a therapeutic target during diethylnitrosamine-induced liver injury ameliorated by β-carotene-reduced graphene oxide (βC-rGO) nanocomposite. Int J Biol Macromol 2019; 137:346-357. [DOI: 10.1016/j.ijbiomac.2019.06.219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/26/2019] [Accepted: 06/27/2019] [Indexed: 12/31/2022]
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Ramos-Tovar E, Muriel P. Free radicals, antioxidants, nuclear factor-E2-related factor-2 and liver damage. J Appl Toxicol 2019; 40:151-168. [PMID: 31389060 DOI: 10.1002/jat.3880] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/03/2019] [Accepted: 07/04/2019] [Indexed: 12/11/2022]
Abstract
Oxidative/nitrosative stress is proposed to be a critical factor in various diseases, including liver pathologies. Antioxidants derived from medicinal plants have been studied extensively and are relevant to many illnesses, including liver diseases. Several hepatic disorders, such as viral hepatitis and alcoholic or nonalcoholic steatohepatitis, involve free radicals/oxidative stress as agents that cause or at least exacerbate liver injury, which can result in chronic liver diseases, such as liver fibrosis, cirrhosis and end-stage hepatocellular carcinoma. In this scenario, nuclear factor-E2-related factor-2 (Nrf2) appears to be an essential factor to counteract or attenuate oxidative or nitrosative stress in hepatic cells. In fact, a growing body of evidence indicates that Nrf2 plays complex and multicellular roles in hepatic inflammation, fibrosis, hepatocarcinogenesis and regeneration via the induction of its target genes. Inflammation is the most common feature of chronic liver diseases, triggering fibrosis, cirrhosis and hepatocellular carcinoma. Increasing evidence indicates that Nrf2 counteracts the proinflammatory process by modulating the recruitment of inflammatory cells and inducing the endogenous antioxidant response of the cell. In this review, the interactions between antioxidant and inflammatory molecular pathways are analyzed.
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Affiliation(s)
- Erika Ramos-Tovar
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico
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48
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Wang Y, Yan D. Plantamajoside exerts antifibrosis effects in the liver by inhibiting hepatic stellate cell activation. Exp Ther Med 2019; 18:2421-2428. [PMID: 31555353 PMCID: PMC6755269 DOI: 10.3892/etm.2019.7843] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 03/18/2019] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs) into muscle fiber cells and fibroblasts. The aim of the current study was to investigate whether plantamajoside (PMS) exerted antifibrosis effects by affecting HSCs activation and survival during liver fibrosis, and to investigate the underlying mechanism. HSC-T6 cells were activated by exposure to platelet-derived growth factor BB (PDGF-BB), and were subsequently treated with increasing concentrations of PMS (0, 20, 40, 80 and 160 µg/ml). Cell viability, apoptosis, migration and invasion were determined using the Cell Counting Kit-8 (CCK-8) assay, flow cytometry and the Transwell assay, respectively. Results indicated that PDGF-BB significantly activated HSC-T6 cells, demonstrated by increased cell proliferation, enhanced cell migration and invasion as well as increased expression of α-smooth muscle actin (α-SMA) and collagen type 1 α 1 (Col1α1). PMS inhibited proliferation, induced cell apoptosis and prevented cell migration and invasion in PDGF-BB-treated HSC-T6 cells in what appeared to be a dose-dependent manner. PMS appeared to dose-dependently reduce the protein and mRNA levels of α-SMA and Col1α1 in PDGF-BB-treated HSC-T6 cells. Furthermore, the results of the present study suggested that PMS administration inhibited the protein expression of phosphorylated-protein kinase B in what appeared to be a dose-dependent manner. In conclusion, the data indicated that PMS exhibited an antifibrotic effect in the liver by inhibiting hepatic stellate cell activation and survival.
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Affiliation(s)
- Yun Wang
- Department of Pharmacy, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China
| | - Dongliang Yan
- Department of General Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Li X, Zhang H, Pan L, Zou H, Miao X, Cheng J, Wu Y. Puerarin alleviates liver fibrosis via inhibition of the ERK1/2 signaling pathway in thioacetamide-induced hepatic fibrosis in rats. Exp Ther Med 2019; 18:133-138. [PMID: 31258646 DOI: 10.3892/etm.2019.7534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 03/21/2019] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a complex pathological process and an early step in the progression of liver cirrhosis, which can eventually develop into hepatocellular carcinoma. Currently, there is no effective treatment for liver fibrosis. Puerarin is a traditional Chinese herb, which is commonly used in the treatment of various diseases. In addition, it is also believed to have a therapeutic effect in liver fibrosis. However, whether puerarin reduces liver fibrosis via the ERK1/2 signaling pathway to inhibit the activation of hepatic stellate cell (HSC) and excessive collagen deposition in liver fibrosis remains unknown. The aim of the current study was to establish a liver fibrosis in vivo model by intraperitoneal injection of thioacetamide (TAA) and investigate the effect of puerarin in the treatment of liver fibrosis. Hematoxylin and eosin and Van Gieson's staining were used to examine histopathological changes associated with liver fibrosis. Liver hydroxyproline content was examined to determine the total amount of collagen in the liver. The relative protein expression levels of transforming growth factor β1 (TGFβ1), α-smooth muscle actin (α-SMA), collagen type I, fibronectin, ERK1/2 and p-ERK1/2 were determined by western blot analysis. In the TAA group, histopathological changes and collagen fiber content in rat liver tissue samples were significantly increased compared with the control group (P<0.05). In addition, treatment with puerarin significantly decreased histopathological changes and collagen fiber content in rat liver tissue samples (P<0.05). The relative protein expression levels of TGFβ1, α-SMA, collagen type I, fibronectin and p-ERK1/2 were significantly upregulated in the TAA group compared with the control group (P<0.05), whereas puerarin treatment reversed these changes. These findings suggest that treatment with puerarin may reduce HSC activation and alleviate extracellular matrix protein expression levels by inhibiting the TGF-β/ERK1/2 pathway in liver fibrosis.
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Affiliation(s)
- Xiuqing Li
- Department of Gastroenterology and Hepatology, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Hui Zhang
- Department of Gastroenterology and Hepatology, The Second Hospital of Lianyungang, Lianyungang, Jiangsu 222023, P.R. China
| | - Lijuan Pan
- Department of Gastroenterology and Hepatology, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Haiou Zou
- Department of Gastroenterology and Hepatology, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Xiaonan Miao
- Department of Gastroenterology and Hepatology, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Jing Cheng
- Department of Gastroenterology and Hepatology, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
| | - Youshan Wu
- Department of Gastroenterology and Hepatology, Lianyungang Oriental Hospital, Lianyungang, Jiangsu 222042, P.R. China
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Mi XJ, Hou JG, Jiang S, Liu Z, Tang S, Liu XX, Wang YP, Chen C, Wang Z, Li W. Maltol Mitigates Thioacetamide-induced Liver Fibrosis through TGF-β1-mediated Activation of PI3K/Akt Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:1392-1401. [PMID: 30644744 DOI: 10.1021/acs.jafc.8b05943] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-β1 (TGF-β1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-β1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.
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Affiliation(s)
- Xiao-Jie Mi
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Jin-Gang Hou
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
- Intelligent Synthetic Biology Center , Daejeon 34141 , Republic of Korea
| | - Shuang Jiang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Zhi Liu
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Shan Tang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Xiang-Xiang Liu
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Ying-Ping Wang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development , Changchun 130118 , China
| | - Chen Chen
- School of Biomedical Sciences, Queensland Brain Institute , The University of Queensland , Brisbane , Queensland 4072 , Australia
| | - Zi Wang
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
| | - Wei Li
- College of Chinese Medicinal Materials , Jilin Agricultural University , Changchun 130118 , China
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development , Changchun 130118 , China
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