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Jiang L, Tian CB, Ye RH, Shi N, He XC, Zhao YL, Luo XD. Kakuol and asarinin protecting liver injury via HSP90AA1/CDK2/mTOR signaling pathway. Fitoterapia 2025; 180:106297. [PMID: 39551106 DOI: 10.1016/j.fitote.2024.106297] [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: 05/27/2024] [Revised: 10/30/2024] [Accepted: 11/10/2024] [Indexed: 11/19/2024]
Abstract
Drug-induced liver injury caused acute hepatic failure and hepatitis frequently. In this investigation, kakuol and asarinin reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST) and malondialdehyde (MDA) dramatically, and ameliorated the pathological damage of liver tissues in APAP-induced mice. Furthermore, both compounds increased the viabilities of APAP-induced L-O2 cells and extracellular glutathione (GSH) levels accompanied significantly by reducing the level of intracellular ROS in vitro. In addition, HSP90AA1/CDK2/mTOR signaling pathway and five target proteins (CDK2, HSP90AA1, HRAS, MMP1, mTOR) were proposed from network pharmacology and molecular docking prediction, and then the up-regulation of protein expression of CDK2, mTOR and down-regulation of HSP90AA1, HRAS, MMP1 by kakuol and asarinin in western blotting supported their mechanism.
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Affiliation(s)
- Ling Jiang
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Cai-Bo Tian
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Rui-Han Ye
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Nian Shi
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Xing-Chao He
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Yun-Li Zhao
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
| | - Xiao-Dong Luo
- Yunnan Characteristic Plant Extraction Laboratory, Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China.
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Chen L, Guo W, Mao C, Shen J, Wan M. Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents. J Mater Chem B 2024; 12:1446-1466. [PMID: 38265305 DOI: 10.1039/d3tb02790b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
Liver fibrosis is a reversible damage-repair response, the pathological features of which mainly include damage to hepatocytes, sinusoid capillarization, hepatic stellate cells activation, excessive accumulation of extracellular matrix and inflammatory response. Although some treatments (including drugs and stem cell therapy) for these pathological features have been shown to be effective, more clinical trials are needed to confirm their effectiveness. In recent years, nanomaterials-based therapies have emerged as an innovative and promising alternative to traditional drugs, being explored for the treatment of liver fibrosis diseases. Natural nanomaterials (including extracellular vesicles) and synthetic nanomaterials (including inorganic nanomaterials and organic nanomaterials) are developed to facilitate drug targeting delivery and combination therapy. In this review, the pathological features of liver fibrosis and the current anti-fibrosis drugs in clinical trials are briefly introduced, followed by a detailed introduction of the therapeutic nanoagents for the precise delivery of anti-fibrosis drugs. Finally, the future development trend in this field is discussed.
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Affiliation(s)
- Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Wenyan Guo
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Jian Shen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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Fajloun Z, Khattar ZA, Sabatier JM. The Intriguing Connection between Cholestasis and the Renin-Angiotensin System Dysregulation Induced by SARS-CoV-2 and/or the Vaccinal Spike Protein. Infect Disord Drug Targets 2024; 24:e080324227802. [PMID: 38465438 DOI: 10.2174/0118715265304515240220105152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 01/31/2024] [Indexed: 03/12/2024]
Affiliation(s)
- Ziad Fajloun
- Department of Biology, Faculty of Sciences, Lebanese University, Campus Michel Slayman Ras Maska, 1352 Tripoli, Lebanon
- Laboratory of Applied Biotechnology (LBA3B), Azm Center for Research in Biotechnology and its Applications, EDST, Lebanese University, Hadath, Lebanon
| | - Ziad Abi Khattar
- Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Tripoli P.O. Box 100, Lebanon
| | - Jean-Marc Sabatier
- Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13385 Marseille, France
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Hassani B, Attar Z, Firouzabadi N. The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies. Cancer Cell Int 2023; 23:254. [PMID: 37891636 PMCID: PMC10604988 DOI: 10.1186/s12935-023-03080-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.
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Affiliation(s)
- Bahareh Hassani
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Attar
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Suzuki J, Kaji K, Nishimura N, Kubo T, Tomooka F, Shibamoto A, Iwai S, Tsuji Y, Fujinaga Y, Kitagawa K, Namisaki T, Akahane T, Yoshiji H. A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation. Biomedicines 2023; 11:1295. [PMID: 37238965 PMCID: PMC10215948 DOI: 10.3390/biomedicines11051295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/12/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
The renin-angiotensin-aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis.
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Affiliation(s)
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Nara, Japan
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Hartl L, Rumpf B, Domenig O, Simbrunner B, Paternostro R, Jachs M, Poglitsch M, Marculescu R, Trauner M, Reindl-Schwaighofer R, Hecking M, Mandorfer M, Reiberger T. The systemic and hepatic alternative renin-angiotensin system is activated in liver cirrhosis, linked to endothelial dysfunction and inflammation. Sci Rep 2023; 13:953. [PMID: 36653504 PMCID: PMC9849268 DOI: 10.1038/s41598-023-28239-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.
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Affiliation(s)
- Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Rumpf
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Department of Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Rodrig Marculescu
- Department for Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Roman Reindl-Schwaighofer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Manfred Hecking
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. .,Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria. .,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
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Gui Z, Zhang Y, Zhang A, Xia W, Jia Z. CARMA3: A potential therapeutic target in non-cancer diseases. Front Immunol 2022; 13:1057980. [PMID: 36618379 PMCID: PMC9815110 DOI: 10.3389/fimmu.2022.1057980] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
Caspase recruitment domain and membrane-associated guanylate kinase-like protein 3 (CARMA3) is a scaffold protein widely expressed in non-hematopoietic cells. It is encoded by the caspase recruitment domain protein 10 (CARD10) gene. CARMA3 can form a CARMA3-BCL10-MALT1 complex by recruiting B cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), thereby activating nuclear factor-κB (NF-κB), a key transcription factor that involves in various biological responses. CARMA3 mediates different receptors-dependent signaling pathways, including G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Inappropriate expression and activation of GPCRs and/or RTKs/CARMA3 signaling lead to the pathogenesis of human diseases. Emerging studies have reported that CARMA3 mediates the development of various types of cancers. Moreover, CARMA3 and its partners participate in human non-cancer diseases, including atherogenesis, abdominal aortic aneurysm, asthma, pulmonary fibrosis, liver fibrosis, insulin resistance, inflammatory bowel disease, and psoriasis. Here we provide a review on its structure, regulation, and molecular function, and further highlight recent findings in human non-cancerous diseases, which will provide a novel therapeutic target.
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Affiliation(s)
- Zhen Gui
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Zhang
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Aihua Zhang
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Weiwei Xia
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China,Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China,*Correspondence: Zhanjun Jia, ; Weiwei Xia,
| | - Zhanjun Jia
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China,*Correspondence: Zhanjun Jia, ; Weiwei Xia,
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The compound losartan cream inhibits scar formation via TGF-β/Smad pathway. Sci Rep 2022; 12:14327. [PMID: 35995975 PMCID: PMC9395380 DOI: 10.1038/s41598-022-17686-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/29/2022] [Indexed: 11/12/2022] Open
Abstract
The role of angiotensin receptor blocker in wound healing and cutaneous fibrosis has become a hotspot in recent years. We have developed a losartan cream that is comparable to triamcinolone ointment in inhibiting scarring. Considering the effects of chitosan and asiaticoside on wound healing and scarring, we added them to the losartan cream this time and improved the formula, expecting to get a better anti-scarring effect. The effects of creams were investigated on mouse scar model with triamcinolone ointment, onion extract gel, and commercial asiaticoside cream set as positive controls. A preliminary exploration of the mechanism involved in TGF-β/Smad pathway was performed in vivo and in vitro. With all results of anti-scarring, the compound losartan cream (containing chitosan, asiaticoside, and losartan) shows the best effect, followed by the chitosan asiaticoside cream. The treatment of the compound losartan cream inhibited expression of TGF-β1, collagen, and Smads, and decreased phosphorylation of Smad in vivo. These inhibitory effects were also confirmed in vitro. Our findings indicated that the compound losartan cream could inhibit scarring via TGF-β/Smad pathway. This cream might be an effective option for scar treatment.
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Perramón M, Carvajal S, Reichenbach V, Fernández‐Varo G, Boix L, Macias‐Muñoz L, Melgar‐Lesmes P, Bruix J, Melmed S, Lamas S, Jiménez W. The pituitary tumour-transforming gene 1/delta-like homologue 1 pathway plays a key role in liver fibrogenesis. Liver Int 2022; 42:651-662. [PMID: 35050550 PMCID: PMC9303549 DOI: 10.1111/liv.15165] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS PTTG1 is almost undetectable in adult livers but is highly expressed in hepatocarcinoma. While little is known about its involvement in liver fibrosis, PTTG1 expression is associated with DLK1. We assessed the role of the PTTG1/DLK1 pathway in fibrosis progression and the potential therapeutic effect of PTTG1 silencing in fibrosis. METHODS Pttg1 and Dlk1 were studied in liver and isolated cell populations of control and fibrotic rats and in human liver biopsies. The fibrotic molecular signature was analysed in Pttg1-/- and Pttg1+/+ fibrotic mice. Finally, Pttg1 silencing was evaluated in rats as a novel antifibrotic therapy. RESULTS Pttg1 and Dlk1 mRNA selectively increased in fibrotic rats paralleling fibrosis progression. Serum DLK1 concentrations correlated with hepatic collagen content and systemic and portal haemodynamics. Human cirrhotic livers showed greater PTTG1 and DLK1 transcript abundance than non-cirrhotic, and reduced collagen was observed in Pttg1 Pttg1-/- mice. The liver fibrotic molecular signature revealed lower expression of genes related to extracellular matrix remodelling including Mmp8 and 9 and Timp4 and greater eotaxin and Mmp13 than fibrotic Pttg1+/+ mice. Finally, interfering Pttg1 resulted in reduced liver fibrotic area, lower α-Sma and decreased portal pressure than fibrotic animals. Furthermore, Pttg1 silencing decreased the transcription of Dlk1, collagens I and III, Pdgfrβ, Tgfrβ, Timp1, Timp2 and Mmp2. CONCLUSIONS Pttg1/Dlk1 are selectively overexpressed in the cirrhotic liver and participate in ECM turnover regulation. Pttg1 disruption decreases Dlk1 transcription and attenuates collagen deposition. PTTG1/DLK1 signalling is a novel pathway for targeting the progression of liver fibrosis.
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Affiliation(s)
- Meritxell Perramón
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain
| | - Silvia Carvajal
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain
| | - Vedrana Reichenbach
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain
| | - Guillermo Fernández‐Varo
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain
| | - Loreto Boix
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain,Department of MedicineUniversity of BarcelonaBarcelonaSpain,Barcelona‐Clínic Liver Cancer GroupHospital Clínic UniversitariBarcelonaSpain
| | - Laura Macias‐Muñoz
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain
| | - Pedro Melgar‐Lesmes
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain,Department of BiomedicineUniversity of BarcelonaBarcelonaSpain,Institute for Medical Engineering and ScienceMassachusetts Institute of TechnologyCambridgeMAUSA
| | - Jordi Bruix
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain,Department of MedicineUniversity of BarcelonaBarcelonaSpain,Barcelona‐Clínic Liver Cancer GroupHospital Clínic UniversitariBarcelonaSpain
| | - Shlomo Melmed
- Department of Medicine, Cedars‐Sinai Research InstituteUniversity of California School of MedicineLos AngelesCAUSA
| | - Santiago Lamas
- Centro de Biología Molecular Severo Ochoa (CSIC‐UAM)MadridSpain
| | - Wladimiro Jiménez
- Biochemistry and Molecular Genetics ServiceHospital Clínic UniversitariBarcelonaSpain,Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD)BarcelonaSpain,Department of BiomedicineUniversity of BarcelonaBarcelonaSpain
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Hasan HF, Mohmed HK, Galal SM. Scorpion bradykinin potentiating factor mitigates lung damage induced by γ-irradiation in rats: Insights on AngII/ACE/Ang(1-7) axis. Toxicon 2021; 203:58-65. [PMID: 34626598 DOI: 10.1016/j.toxicon.2021.10.001] [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: 07/21/2021] [Revised: 08/22/2021] [Accepted: 10/01/2021] [Indexed: 10/20/2022]
Abstract
The goal of this research is to study the mitigating impact of bradykinin potentiating factor (BPF) found in scorpion Androctonus bicolor venom on irradiation-induced lung damage as a new functional target for angiotensin-converting enzyme inhibitors (ACEIs). Male rats were exposed to 7 Gy of γ-radiation as a single dose, with a biweekly intraperitoneal injection of 1 μg/g BPF. Gamma irradiation not only boosted the ACE activity and angiotensin II (Ang II) level, in lung tissue but also significantly depressed the angiotensin (1-7) (Ang (1-7)) that, lead to lung toxicity through a significant elevation of pulmonary levels of CXC-chemokine receptor 4 (CXCR4), toll-like receptor 4 (TLR4), nitric oxide (NO) and lactate dehydrogenase (LDH) activity with a marked disruption in oxidative stress markers, via a reduction in the level of total thiol (tSH) and superoxide dismutase (SOD) activity associated with an elevation in protein carbonyl (PCO) contents. In addition, apoptotic consequences of gamma irradiation were evidenced by raising the levels of mitogen-activated protein kinase (MAPK), C-Jun N-Terminal Kinases (JNK), and cleaved caspase-3. BPF administration leads to ACE inhibition, consequently sustaining decreased Ang II alongside increased Ang (1-7) production. Those sensitive molecules reduce irradiated lung issues. In conclusion, BPF significantly diminished the biochemical and histopathological consequences of radiation through renin-angiotensin system (RAS) control and ACE suppression in the lung.
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Affiliation(s)
- Hesham Farouk Hasan
- Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, Cairo, Egypt.
| | - Heba Karam Mohmed
- Drug Radiation Research Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Shereen Mohamed Galal
- Health Radiation Research Department, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
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11
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Basiglio CL, Crocenzi FA, Sánchez Pozzi EJ, Roma MG. Oxidative Stress and Localization Status of Hepatocellular Transporters: Impact on Bile Secretion and Role of Signaling Pathways. Antioxid Redox Signal 2021; 35:808-831. [PMID: 34293961 DOI: 10.1089/ars.2021.0021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Significance: Most hepatopathies are primarily or secondarily cholestatic in nature. Oxidative stress (OS) is a frequent trait among them, and impairs the machinery to generate bile by triggering endocytic internalization of hepatocellular transporters, thus causing cholestasis. This is critical, since it leads to accelerated transporter degradation, which could explain the common post-transcriptional downregulation of transporter expression in human cholestatic diseases. Recent Advances: The mechanisms involved in OS-induced hepatocellular transporter internalization are being revealed. Filamentous actin (F-actin) cytoskeleton disorganization and/or detachment of crosslinking actin proteins that afford transporter stability have been characterized as causal factors. Activation of redox-sensitive signaling pathways leading to changes in phosphorylation status of these structures is involved, including Ca2+-mediated activation of "classical" and "novel" protein kinase C (PKC) isoforms or redox-signaling cascades downstream of NADPH oxidase. Critical Issues: Despite the well-known occurrence of hepatocellular transporter internalization in human hepatopathies, the cholestatic implications of this phenomenon have been overlooked. Accordingly, no specific treatment has been established in the clinical practice for its prevention/reversion. Future Directions: We need to improve our knowledge on the pro-oxidant triggering factors and the multiple signaling pathways that mediate this oxidative injury in each cholestatic hepatopathy, so as to envisage tailor-made therapeutic strategies for each case. Meanwhile, administration of antioxidants or heme oxygenase-1 induction to elevate the hepatocellular levels of the endogenous scavenger bilirubin are promising alternatives that need to be re-evaluated and implemented. They may complement current treatments in cholestasis aimed to enhance transcriptional carrier expression, by providing membrane stability to the newly synthesized carriers. Antioxid. Redox Signal. 35, 808-831.
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Affiliation(s)
- Cecilia L Basiglio
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Fernando A Crocenzi
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Enrique J Sánchez Pozzi
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
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12
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Zhang HF, Gao X, Wang X, Chen X, Huang Y, Wang L, Xu ZW. The mechanisms of renin-angiotensin system in hepatocellular carcinoma: From the perspective of liver fibrosis, HCC cell proliferation, metastasis and angiogenesis, and corresponding protection measures. Biomed Pharmacother 2021; 141:111868. [PMID: 34328104 DOI: 10.1016/j.biopha.2021.111868] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/04/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, of which the occurrence and development involve a variety of pathophysiological processes, such as liver fibrosis, hepatocellular malignant proliferation, metastasis, and tumor angiogenesis. Some important cytokines, such as TGF-β, PI3K, protein kinase B (Akt), VEGF and NF-κB, can regulate the growth, proliferation, diffusion, metastasis, and apoptosis of HCC cells by acting on the corresponding signaling pathways. Besides, many studies have shown that the formation of HCC is closely related to the main components of renin-angiotensin system (RAS), such as Ang II, ACE, ACE2, MasR, AT1R, and AT2R. Therefore, this review focused on liver fibrosis, HCC cell proliferation, metastasis, tumor angiogenesis, and corresponding protective measures. ACE-Ang II-AT1 axis and ACE2-Ang-(1-7)-MasR axis were taken as the main lines to introduce the mechanism of RAS in the occurrence and development of HCC, so as to provide references for future clinical work and scientific research.
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Affiliation(s)
- Hai-Feng Zhang
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui 230032, China
| | - Xiang Gao
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui 230032, China
| | - Xuan Wang
- Department of Clinical Medical, the Second Clinical Medical College of Anhui Medical University, Hefei, Anhui 230032, China
| | - Xin Chen
- Department of Clinical Medical, the Second Clinical Medical College of Anhui Medical University, Hefei, Anhui 230032, China
| | - Yu Huang
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui 230032, China
| | - Lang Wang
- Department of Clinical Medical, the First Clinical Medical College of Anhui Medical University, Hefei, Anhui 230032, China
| | - Zhou-Wei Xu
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, China.
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13
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Sabet N, Soltani Z, Khaksari M. Multipotential and systemic effects of traumatic brain injury. J Neuroimmunol 2021; 357:577619. [PMID: 34058510 DOI: 10.1016/j.jneuroim.2021.577619] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/07/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023]
Abstract
Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.
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Affiliation(s)
- Nazanin Sabet
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Khaksari
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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14
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S-adenosylmethionine upregulates the angiotensin receptor-binding protein ATRAP via the methylation of HuR in NAFLD. Cell Death Dis 2021; 12:306. [PMID: 33753727 PMCID: PMC7985363 DOI: 10.1038/s41419-021-03591-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged globally and is associated with inflammatory signaling. The underlying mechanisms remain poorly delineated, although NAFLD has attracted considerable attention and been extensively investigated. Recent publications have determined that angiotensin II (Ang II) plays an important role in stimulating NAFLD progression by causing lipid metabolism disorder and insulin resistance through its main receptor, Ang II type 1 receptor (AT1R). Herein, we explored the effect of supplementary S-adenosylmethionine (SAM), which is the main biological methyl donor in mammalian cells, in regulating AT1R-associated protein (ATRAP), which is the negative regulator of AT1R. We found that SAM was depleted in NAFLD and that SAM supplementation ameliorated steatosis. In addition, in both high-fat diet-fed C57BL/6 rats and L02 cells treated with oleic acid (OA), ATRAP expression was downregulated at lower SAM concentrations. Mechanistically, we found that the subcellular localization of human antigen R (HuR) was determined by the SAM concentration due to protein methylation modification. Moreover, HuR was demonstrated to directly bind ATRAP mRNA and control its nucleocytoplasmic shuttling. Thus, SAM was suggested to upregulate ATRAP protein expression by maintaining the export of its mRNA from the nucleus. Taken together, our findings suggest that SAM can positively regulate ATRAP in NAFLD and may have various potential benefits for the treatment of NAFLD.
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15
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Papatsirou M, Artemaki PI, Scorilas A, Kontos CK. The role of circular RNAs in therapy resistance of patients with solid tumors. Per Med 2020; 17:469-490. [PMID: 33052780 DOI: 10.2217/pme-2020-0103] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Circular RNAs (circRNAs) are a type of single-stranded RNA molecules forming a covalently closed, continuous structure, lacking 5'-3' polarity and polyadenylated tails. Recent advances in high-throughput sequencing technologies have revealed that these molecules are abundant, resistant to degradation and often expressed in a tissue- or developmental stage-specific manner. circRNAs are produced by back-splicing circularization of primary transcripts and exhibit a variety of functions, including regulation of transcription, translation and cellular localization. This review focuses on differentially expressed circRNAs conferring therapy resistance or sensitivity of solid tumors, such as carcinomas, sarcomas and lymphomas. Deregulated circRNAs can participate in the development of resistance to treatment by modulating regulatory pathways and cellular processes, including the mitogen-activated protein kinase pathway, epithelial-mesenchymal transition, apoptosis and autophagy.
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Affiliation(s)
- Maria Papatsirou
- Department of Biochemistry & Molecular Biology, Faculty of Biology, National & Kapodistrian University of Athens, Athens 15701, Greece
| | - Pinelopi I Artemaki
- Department of Biochemistry & Molecular Biology, Faculty of Biology, National & Kapodistrian University of Athens, Athens 15701, Greece
| | - Andreas Scorilas
- Department of Biochemistry & Molecular Biology, Faculty of Biology, National & Kapodistrian University of Athens, Athens 15701, Greece
| | - Christos K Kontos
- Department of Biochemistry & Molecular Biology, Faculty of Biology, National & Kapodistrian University of Athens, Athens 15701, Greece
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16
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Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS. Clin Sci (Lond) 2020; 134:853-869. [PMID: 32227122 DOI: 10.1042/cs20191235] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/10/2020] [Accepted: 03/27/2020] [Indexed: 12/20/2022]
Abstract
Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Alamandine (ALA) protects against fibrosis by counteracting Ang II via the MAS-related G-protein coupled (MrgD) receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II-induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced CCl4-induced hepatic fibrosis, hydrogen peroxide (H2O2) content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with up-regulation of the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs). Treatment with NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine (NAC), and NOX4 small interfering RNA (siRNA) inhibited Ang II-induced autophagy and collagen synthesis. Alamandine shifted the balance of renin-angiotensin system (RAS) toward the angiotensin converting enzyme 2 (ACE2)/alamandine/MrgD axis, and inhibited both Ang II-induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4-dependent ROS.
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17
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Thylur RP, Roy SK, Shrivastava A, LaVeist TA, Shankar S, Srivastava RK. Assessment of risk factors, and racial and ethnic differences in hepatocellular carcinoma. JGH OPEN 2020; 4:351-359. [PMID: 32514436 PMCID: PMC7273694 DOI: 10.1002/jgh3.12336] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/05/2020] [Accepted: 03/24/2020] [Indexed: 12/24/2022]
Abstract
Despite improved screening and surveillance guidelines, significant race/ethnicity‐specific disparities in hepatocellular carcinoma (HCC) continue to exist and disproportionately affect minority and disadvantaged populations. This trend indicates that social determinants, genetic, and environmental factors are driving the epidemic at the population level. Race and geography had independent associations with risk of mortality among patients with HCC. The present review discusses the risk factors and issues related to disparities in HCC. The underlying etiologies for these disparities are complex and multifactorial. Some of the risk factors for developing HCC include hepatitis B (HBV) and hepatitis C (HCV) viral infection, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, smoking and alcohol consumption. In addition, population genetics; socioeconomic and health care access; treatment and prevention differences; and genetic, behavioral, and biological influences can contribute to HCC. Acculturation of ethnic minorities, insurance status, and access to health care may further contribute to the observed disparities in HCC. By increasing awareness, better modalities for screening and surveillance, improving access to health care, and adapting targeted preventive and therapeutic interventions, disparities in HCC outcomes can be reduced or eliminated.
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Affiliation(s)
- Ramesh P Thylur
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA
| | - Sanjit K Roy
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA
| | | | - Thomas A LaVeist
- Department of Health Policy and Management Tulane University School of Public Health and Tropical Medicine New Orleans Louisiana USA
| | - Sharmila Shankar
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA.,Department of Genetics Louisiana State University Health Sciences Center-New Orleans New Orleans Louisiana USA
| | - Rakesh K Srivastava
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA.,Department of Genetics Louisiana State University Health Sciences Center-New Orleans New Orleans Louisiana USA
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18
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Lafoz E, Ruart M, Anton A, Oncins A, Hernández-Gea V. The Endothelium as a Driver of Liver Fibrosis and Regeneration. Cells 2020; 9:E929. [PMID: 32290100 PMCID: PMC7226820 DOI: 10.3390/cells9040929] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.
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Affiliation(s)
- Erica Lafoz
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Maria Ruart
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Aina Anton
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Anna Oncins
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Virginia Hernández-Gea
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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19
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Zhang T, Hao H, Zhou ZQ, Zeng T, Zhang JM, Zhou XY. Lipoxin A4 inhibited the activation of hepatic stellate cells -T6 cells by modulating profibrotic cytokines and NF-κB signaling pathway. Prostaglandins Other Lipid Mediat 2020; 146:106380. [DOI: 10.1016/j.prostaglandins.2019.106380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 07/17/2019] [Accepted: 08/06/2019] [Indexed: 12/11/2022]
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20
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Adel N, Mantawy EM, El-Sherbiny DA, El-Demerdash E. Iron chelation by deferasirox confers protection against concanavalin A-induced liver fibrosis: A mechanistic approach. Toxicol Appl Pharmacol 2019; 382:114748. [PMID: 31499193 DOI: 10.1016/j.taap.2019.114748] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/04/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023]
Abstract
Hepatic iron overload is one of the causative factors for chronic liver injury and fibrosis. The present study aimed to investigate the potential antifibrotic effect of the iron chelator; deferasirox (DFX) in experimentally-induced liver fibrosis in rats. Male Sprague-Dawley rats were administered concanavalin A (Con A) and/or DFX for 6 consecutive weeks. Con A injection induced significant hepatotoxicity as was evident by the elevated transaminases activity, and decreased albumin level. Also, it disturbed the iron homeostasis through increasing C/EBP homologous protein (CHOP), decreasing phosphorylated cAMP responsive element binding protein(P-CREB) and hepcidin levels leading to significant serum and hepatic iron overload. In addition, it induced an imbalance in the oxidative status of the liver via upregulating NADPH oxidase 4 (NOX4), together with a marked decrease in anti-oxidant enzymes' activities. As a consequence, upregulation of nuclear factor-kappa b (NF-κB) and the downstream inflammatory mediators was observed. Those events all together precipitated in initiation of liver fibrosis as confirmed by the elevation of alpha-smooth muscle actin (α-SMA) and liver collagen content. Co-treatment with DFX protected against experimentally-induced liver fibrosis in rats via its iron chelating, anti-oxidant, and anti-inflammatory properties. These findings imply that DFX can attenuate the progression of liver fibrosis.
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Affiliation(s)
- Nada Adel
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Eman M Mantawy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Doaa A El-Sherbiny
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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21
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Liu M, Ai W, Sun L, Fang F, Wang X, Chen S, Wang H. Triclosan-induced liver injury in zebrafish (Danio rerio) via regulating MAPK/p53 signaling pathway. Comp Biochem Physiol C Toxicol Pharmacol 2019; 222:108-117. [PMID: 31048017 DOI: 10.1016/j.cbpc.2019.04.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 04/26/2019] [Accepted: 04/26/2019] [Indexed: 12/13/2022]
Abstract
Long-term exposure of triclosan (TCS), an important antimicrobial agent, can lead to deleterious effects on liver growth and development. However, the related mechanisms on TCS-induced hepatocyte injury remain unclear. Herein, we found that after long-time TCS exposure to adult zebrafish (Danio rerio) from 6 hpf (hours post-fertilization) to 90 dpf (days post-fertilization), the body weight and hepatic weight were significantly increased in concomitant with a large amount of lipid droplet accumulation in liver. Also, TCS exposure resulted in occurrence of oxidative stress by increasing the concentrations of malondialdehyde and reducing the activity of superoxide dismutase both in zebrafish larvae (120 hpf) and adult liver. By H&E staining, we observed a series of abnormal phenomena such as severely hepatocellular atrophy and necrosis, as well as prominently increased hepatic plate gap in TCS-exposure treatment groups. Through AO staining, TCS induced obvious apoptosis in larval heart and liver; through TUNEL assay, a concentration-dependent apoptosis was found to mainly occur in adult liver and its surrounding tissues. The mRNA and protein expression of anti-apoptotic protein Bcl-2 decreased, while that of pro-apoptosis protein Bax significantly increased, identifying that liver injury was closely related to hepatocyte apoptosis. The significant up-regulation of MAPK and p53 at both mRNA and protein levels proved that TCS-induced hepatocyte apoptosis was closely related to activating the MAPK/p53 signaling pathway. These results strongly suggest that long-term TCS-exposure may pose a great injury to zebrafish liver development by means of activating MAPK/p53 apoptotic signaling pathway, also lay theoretical foundation for further assessing TCS-induced ecological healthy risk.
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Affiliation(s)
- Mi Liu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Weiming Ai
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
| | - Limei Sun
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Fang Fang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Xuedong Wang
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Shaobo Chen
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Zhejiang Mariculture Research Institute, Wenzhou 325005, China.
| | - Huili Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
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22
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Ng HH, Shen M, Samuel CS, Schlossmann J, Bennett RG. Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways. Mol Cell Endocrinol 2019; 487:59-65. [PMID: 30660699 PMCID: PMC7384500 DOI: 10.1016/j.mce.2019.01.015] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 02/07/2023]
Abstract
Fibrosis is associated with accumulation of excess fibrillar collagen, leading to tissue dysfunction. Numerous processes, including inflammation, myofibroblast activation, and endothelial-to-mesenchymal transition, play a role in the establishment and progression of fibrosis. Relaxin is a peptide hormone with well-known antifibrotic properties that result from its action on numerous cellular targets to reduce fibrosis. Relaxin activates multiple signal transduction pathways as a mechanism to suppress inflammation and myofibroblast activation in fibrosis. In this review, the general mechanisms underlying fibrotic diseases are described, along with the current state of knowledge regarding cellular targets of relaxin. Finally, an overview is presented summarizing the signaling pathways activated by relaxin and other relaxin family peptide receptor agonists to suppress fibrosis.
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Affiliation(s)
- Hooi Hooi Ng
- Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
| | - Matthew Shen
- Cardiovascular Disease Theme, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC, Australia.
| | - Chrishan S Samuel
- Cardiovascular Disease Theme, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC, Australia.
| | - Jens Schlossmann
- Department of Pharmacology and Toxicology, Institute of Pharmacy, University Regensburg, Regensburg, Germany.
| | - Robert G Bennett
- Research Service, VA Nebraska-Western Iowa Health Care System, Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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Di Pascoli M, La Mura V. Renin-angiotensin-aldosterone system in cirrhosis: There's room to try! Dig Liver Dis 2019; 51:297-298. [PMID: 30220630 DOI: 10.1016/j.dld.2018.07.038] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 07/31/2018] [Accepted: 07/31/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Marco Di Pascoli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University of Padova, Padova, Italy.
| | - Vincenzo La Mura
- IRCCS Ca' Granda, Maggiore Hospital Foundation, Unit of General Medicine - Hemostasis and Thrombosis, Milan, Italy; CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
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Abstract
Oncostain M, a member of the IL-6 family of cytokines, is produced by immune cells in response to infections and tissue injury. OSM has a broad, often context-dependent effect on various cellular processes including differentiation, hematopoiesis, cell proliferation, and cell survival. OSM signaling is initiated by binding to type I (LIFRβ/gp130) or type II (OSMRβ/gp130) receptor complexes and involves activation of Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase, and phosphatidylinositol-3-kinase. High levels of OSM have been detected in many chronic inflammatory conditions characterized by fibrosis, giving a rationale to target OSM for the treatment of these diseases. Here we discuss the current knowledge on the role of OSM in various stages of the fibrotic process including inflammation, vascular dysfunction, and activation of fibroblasts.
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Affiliation(s)
| | - Maria Trojanowska
- Corresponding Author: Maria Trojanowska, Boston University School of Medicine, 72 East Concord St, E-5, Boston, MA 02118, Tel.: 617-638-4318; Fax: 617-638-5226
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Update in global trends and aetiology of hepatocellular carcinoma. Contemp Oncol (Pozn) 2018; 22:141-150. [PMID: 30455585 PMCID: PMC6238087 DOI: 10.5114/wo.2018.78941] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/25/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver responsible for an increasing number of cancer-related deaths, especially in developing economies of Asia and Africa. A plethora of risk factors have been described in the literature. Some of the important ones include chronic viral hepatitis, liver cirrhosis, environmental toxins such as aflatoxin, non-alcoholic fatty liver disease, lifestyle factors like alcohol consumption, smoking, and dietary factors, metabolic diseases like diabetes mellitus and obesity, and genetic and hereditary disorders. The development of HCC is complex involving sustained inflammatory damage leading to hepatocyte necrosis, regeneration, and fibrotic deposition. It also poses multiple challenges in diagnosis and treatment despite advances in diagnostic, surgical, and other therapeutic advancements. This is a narrative review of findings of multiple studies that were retrieved from electronic databases like PubMed, MEDLINE, Embase, Google Scholar, Scopus, and Cochrane. We summarise the current knowledge regarding the epidemiology and various risk factors for the development of HCC with a brief note on various prevention strategies.
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Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med 2018; 65:37-55. [PMID: 30213667 DOI: 10.1016/j.mam.2018.09.002] [Citation(s) in RCA: 746] [Impact Index Per Article: 106.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 02/06/2023]
Abstract
The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as sustained activation of liver fibrogenesis and wound healing response. Liver fibrogenesis, is a dynamic, highly integrated molecular, cellular and tissue process responsible for driving the excess accumulation of extracellular matrix (ECM) components (i.e., liver fibrosis) sustained by an eterogeneous population of hepatic myofibroblasts (MFs). The process of liver fibrogenesis recognizes a number of common and etiology-independent mechanisms and events but it is also significantly influenced by the specific etiology, as also reflected by peculiar morphological patterns of liver fibrosis development. In this review we will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets, to finally analyze selected and relevant clinical issues.
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Mortezaee K. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and liver fibrosis: A review. Cell Biochem Funct 2018; 36:292-302. [PMID: 30028028 DOI: 10.1002/cbf.3351] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/11/2018] [Accepted: 06/26/2018] [Indexed: 12/21/2022]
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are key producer of reactive oxygen species in liver cells. Hepatic stellate cells (HSCs) and Kupffer cells (KCs) are the two key cells for expression of NOX in liver. KCs produce only NOX2, while HSCs produce NOX1, 2, and 4, all of which play essential roles in the process of fibrogenesis within liver. These NOX subtypes are contributed to induction of liver fibrosis by acting through multiple pathways including induction of HSC activation, proliferation, survival and migration, stimulation of hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both KCs and HSCs. SIGNIFICANCE KCs and HSCs are two key cells for production of NOX in liver in relation to the pathology of liver fibrosis. NOX subtypes 1, 2, and 4 are inducers of fibrogenesis in liver. NOX activation favors hepatocyte apoptosis, HSC activation, and KC-mediated inflammatory cascade in liver, all of which are responsible for generation of liver fibrosis.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Schreier B, Wolf A, Hammer S, Pohl S, Mildenberger S, Rabe S, Gekle M, Zipprich A. The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis. Br J Pharmacol 2018; 175:2956-2967. [PMID: 29682743 DOI: 10.1111/bph.14341] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/27/2018] [Accepted: 03/08/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE The mineralocorticoid receptor (MR) contributes to fibrosis in various tissues, and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists in hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MRs and eplerenone in cirrhosis development. EXPERIMENTAL APPROACH Liver fibrosis (5 weeks) and cirrhosis, without (8 weeks) and with ascites (12 weeks), were induced by CCl4 in rats and comprehensively analysed. The effect of eplerenone on the development of cirrhosis with ascites was assessed. MR expression, cellular and subcellular distribution and impact of hypoxia were investigated in vivo and ex vivo. Primary rat hepatocytes and cell lines were used to investigate MR trafficking and transcriptional activity mechanistically. KEY RESULTS In cirrhosis with ascites, MR mRNA and protein expressions were reduced in hepatocytes of hypoxic areas. While in normoxic areas MRs were mainly cytosolic, the remaining MRs in hypoxic areas were mainly localized in the nuclei, indicating activation followed by translocation and degradation. Accordingly, eplerenone treatment prevented nuclear MR translocation and the worsening of cirrhosis. Exposing hepatocytes ex vivo to hypoxia induced nuclear MR translocation and enhanced transcriptional MR activity at response elements of the NF-κB pathway. CONCLUSIONS AND IMPLICATIONS We showed for the first time that hypoxia leads to a pathogenetic ligand-independent activation of hepatic MRs during cirrhosis resulting in their nuclear translocation and transcriptional activation of the NF-κB pathway. Treatment with eplerenone prevented the worsening of cirrhosis by blocking this ligand-independent activation of the MR.
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Affiliation(s)
- Barbara Schreier
- Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Anja Wolf
- Laboratory of Molecular Hepatology, Clinic of Internal Medicine I, Martin Luther University of Halle-Wittenberg, Halle, Germany.,Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Stefanie Hammer
- Laboratory of Molecular Hepatology, Clinic of Internal Medicine I, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Sabine Pohl
- Laboratory of Molecular Hepatology, Clinic of Internal Medicine I, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Sigrid Mildenberger
- Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Sindy Rabe
- Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Michael Gekle
- Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Alexander Zipprich
- Laboratory of Molecular Hepatology, Clinic of Internal Medicine I, Martin Luther University of Halle-Wittenberg, Halle, Germany
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Hypertension and hepatic triglycerides content: a two (multi)-faceted clinical challenge? J Hypertens 2018; 35:715-717. [PMID: 28248900 DOI: 10.1097/hjh.0000000000001290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Li Y, Xu H, Wu W, Ye J, Fang D, Shi D, Li L. Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Oncotarget 2018; 9:24155-24167. [PMID: 29844879 PMCID: PMC5963622 DOI: 10.18632/oncotarget.23816] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/27/2017] [Indexed: 02/07/2023] Open
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management. Results Accounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment (standardized mean difference 0.20; 95% confidence interval (CI) [−0.04, 0.44]; P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment (MD 5.21; 95% CI [3.01, 7.40]; P < 0.00001), and total cholesterol also decreased in response to ARBs (MD 2.10; 95% CI [−0.37, 4.57]; P = 0.10). However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment (MD 0.10; 95% CI [−0.58, 0.78]; P = 0.77) (MD −0.25; 95% CI [−1.05, 0.55]; P = 0.53). Materials and Methods Keywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3). Conclusions Although ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients.
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Affiliation(s)
- Yating Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Hong Xu
- Department of Orthopaedics, Tianjin Medical University General Hospital, Heping District, Tianjin 300052, People's Republic of China
| | - Wenrui Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Jianzhong Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Daiqiong Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
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Yao J, Dai Q, Liu Z, Zhou L, Xu J. Circular RNAs in Organ Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1087:259-273. [DOI: 10.1007/978-981-13-1426-1_21] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Cannito S, Novo E, Parola M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv Drug Deliv Rev 2017; 121:57-84. [PMID: 28578015 DOI: 10.1016/j.addr.2017.05.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/28/2017] [Accepted: 05/26/2017] [Indexed: 02/07/2023]
Abstract
Myofibroblasts (MFs) play a critical role in the progression of chronic inflammatory and fibroproliferative diseases in different tissues/organs, whatever the etiology. Fibrosis is preceded and sustained by persistent injury and inflammatory response in a profibrogenic scenario involving mutual interactions, operated by several mediators and pathways, of MFs and related precursor cells with innate immunity cells and virtually any cell type in a defined tissue. These interactions, mediators and related signaling pathways are critical in initiating and perpetuating the differentiation of precursor cells into MFs that in different tissues share peculiar traits and phenotypic responses, including the ability to proliferate, produce ECM components, migrate and contribute to the modulation of inflammatory response and tissue angiogenesis. Literature studies related to liver, lung and kidney fibrosis have outlined a number of MF-related core regulatory fibrogenic signaling pathways conserved across these different organs and potentially targetable in order to develop effective antifibrotic therapeutic strategies.
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Hu Q, Hu Z, Chen Q, Huang Y, Mao Z, Xu F, Zhou X. BML-111 equilibrated ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis to protect hepatic fibrosis in rats. Prostaglandins Other Lipid Mediat 2017; 131:75-82. [PMID: 28822808 DOI: 10.1016/j.prostaglandins.2017.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/10/2017] [Accepted: 08/10/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND It was recently reported Lipoxins (LXs) had protective effects on fibrous diseases, and renin-angiotensin-aldosterone system (RAAS) had played vital and bidirectional roles in hepatic fibrosis. In this paper, a hepatic fibrosis model, induced by carbon tetrachloride (CCL4) in rats, was used to observe the relations between RAAS and LXs, as well as to further explore the alternative anti-fibrosis mechanisms of LXs. METHODS The model was evaluated by morphological observations and biochemical assays. The activities and contents of angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2) were examined through assay kits and ELISA. The expression levels of angiotensinII (AngII), Angiotensin II type 1 receptor (AT1R), angiotensin-(1-7) (Ang-1-7), and Mas were all measured using real time PCR, ELISA, and Western blot. RESULTS The model was established successfully and BML-111 significantly ameliorated CCL4-induced hepatic fibrosis, including reduction inflammation injury, decrease extracellular matrix deposition, and improvement hepatic functions. Furthermore, BML-111 could obviously decrease not only the activities of ACE but also the expression levels of ACE, AngII,and AT1R, which were induced by CCL4. On the other hand, BML-111 could markedly increase the activities of ACE2, besides the expression levels of ACE2, Ang-(1-7) and Mas. More importantly, BOC-2, a lipoxin A4 receptor blocker, could reverse all these phenomena. CONCLUSIONS Equilibrating ACE-AngII-AT1R axis and ACE2-Ang-(1-7)-Mas axis mediated the protective effect of BML-111 on hepatic fibrosis in rats.
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Affiliation(s)
- Quandong Hu
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Zhenzhen Hu
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Qiongfeng Chen
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yonghong Huang
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Jiangxi Province Key Laboratory of Tumor pathogenesis and Molecular Pathology, Nanchang, Jiangxi 330006, PR China
| | - Zi Mao
- The First Clinical Medical College, Nanchang University, Jiangxi 330006, PR China
| | - Fangyun Xu
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Xiaoyan Zhou
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Jiangxi Province Key Laboratory of Tumor pathogenesis and Molecular Pathology, Nanchang, Jiangxi 330006, PR China.
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Chen Y, Yuan B, Wu Z, Dong Y, Zhang L, Zeng Z. Microarray profiling of circular RNAs and the potential regulatory role of hsa_circ_0071410 in the activated human hepatic stellate cell induced by irradiation. Gene 2017; 629:35-42. [PMID: 28774651 DOI: 10.1016/j.gene.2017.07.078] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 07/04/2017] [Accepted: 07/30/2017] [Indexed: 12/14/2022]
Abstract
Radiation-induced liver fibrosis (RILF) is considered as a major complication of radiation therapy for liver cancer. Circular RNA (circRNA) has been recently identified as a functional noncoding RNA involving in various biological processes. However, the expression pattern and regulatory capacity of circRNA in the irradiated hepatic stellate cell (HSC), the main fibrogenic cell type, still remain unclear. A circRNA microarray was used to identify circRNA expression profiles in irradiated and normal HSC. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm the dysregulated circRNAs. Bioinformatic analyses including gene ontology (GO), KEGG pathway and circRNA/microRNA interaction network analysis were applied to predict the potential functions of circRNAs. Compared with the normal HSC, 179 circRNAs were found to be up-regulated and 630 circRNAs were down-regulated in irradiated HSC (fold change ≥2.0 and P<0.05). Six dysregulated circRNAs selected randomly were successfully verified by qRT-PCR. Bioinformatic analyses indicated that dysregulated circRNA might be involved in the cell response to irradiation and biological processes of hepatic fibrosis. Furthermore, inhibition of hsa_circ_0071410 increased the expression of miR-9-5p, resulting in the attenuation of irradiation induced HSC activation. In summary, this study revealed the expression profile and potential function of differentially expressed circRNAs in irradiated HSC, which provides novel clues for RILF study.
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Affiliation(s)
- Yuhan Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, Shanghai 200032, PR China
| | - Baoying Yuan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, Shanghai 200032, PR China
| | - Zhifeng Wu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, Shanghai 200032, PR China
| | - Yinying Dong
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, Shanghai 200032, PR China
| | - Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, Shanghai 200032, PR China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 180# Fenglin Road, Shanghai 200032, PR China.
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Souza-Mello V. Hepatic structural enhancement and insulin resistance amelioration due to AT1 receptor blockade. World J Hepatol 2017; 9:74-79. [PMID: 28144388 PMCID: PMC5241531 DOI: 10.4254/wjh.v9.i2.74] [Citation(s) in RCA: 12] [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: 08/27/2016] [Revised: 10/27/2016] [Accepted: 11/21/2016] [Indexed: 02/06/2023] Open
Abstract
Over the last decade, the role of renin-angiotensin system (RAS) on the development of obesity and its comorbidities has been extensively addressed. Both circulating and local RAS components are up-regulated in obesity and involved in non-alcoholic fatty liver disease onset. Pharmacological manipulations of RAS are viable strategies to tackle metabolic impairments caused by the excessive body fat mass. Renin inhibitors rescue insulin resistance, but do not have marked effects on hepatic steatosis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) yield beneficial hepatic remodeling. ARBs elicit body mass loss and normalize insulin levels, tackling insulin resistance. Also, this drug class increases adiponectin levels, besides countering interleukin-6, tumoral necrosis factor-alpha, and transforming growth factor-beta 1. The latter is essential to prevent from liver fibrosis. When conjugated with peroxisome proliferator-activated receptor (PPAR)-alpha activation, ARB fully rescues fatty liver. These effects might be orchestrated by an indirect up-regulation of MAS receptor due to angiotensin II receptor type 1 (AT1R) blockade. These associations of ARB with PPAR activation and ACE2-angiotensin (ANG) (1-7)-MAS receptor axis deserve a better understanding. This editorial provides a brief overview of the current knowledge regarding AT1R blockade effects on sensitivity to insulin and hepatic structural alterations as well as the intersections of AT1R blockade with peroxisome proliferator-activated receptor activation and ACE2-ANG (1-7) - MAS receptor axis.
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Affiliation(s)
- Vanessa Souza-Mello
- Vanessa Souza-Mello, Biomedical Centre, Institute of Biology, Department of Anatomy, State University of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
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Incidence and Predictors of Advanced Liver Fibrosis by a Validated Serum Biomarker in Liver Transplant Recipients. Can J Gastroenterol Hepatol 2017; 2017:4381864. [PMID: 28409147 PMCID: PMC5376470 DOI: 10.1155/2017/4381864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 06/13/2015] [Indexed: 12/29/2022] Open
Abstract
Background and Aims. Serum fibrosis biomarkers have shown good accuracy in the liver transplant (LT) population. We employed a simple serum biomarker to elucidate incidence and predictors of advanced fibrosis after LT over a long follow-up period. Methods. We included 440 consecutive patients who underwent LT between 1991 and 2013. Advanced liver fibrosis was defined as FIB-4 > 3.25 beyond 12 months after LT. Results. Over 2030.5 person-years (PY) of follow-up, 189 (43%) developed FIB-4 > 3.25, accounting for an incidence of 9.3/100 PY (95% confidence interval [CI], 8.1-10.7). Advanced fibrosis was predicted by chronic HCV infection (adjusted hazard ratio (aHR) = 3.96, 95% CI 2.92-5.36, p < 0.001), hypoalbuminemia (aHR = 2.31, 95% CI 1.72-3.09; p < 0.001), and hyponatremia (aHR = 1.48, 95% CI 1.09-2.01; p = 0.01). LT recipients with more than 1 predictor had a higher incidence of advanced fibrosis, the highest being when all 3 predictors coexisted (log-rank: p < 0.001). Conclusions. Chronic HCV infection, hypoalbuminemia, and hyponatremia predict progression to advanced liver fibrosis following LT. Patients with these risk factors should be serially monitored using noninvasive fibrosis biomarkers and prioritized for interventions.
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Ahmadian E, Pennefather PS, Eftekhari A, Heidari R, Eghbal MA. Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention. Expert Rev Gastroenterol Hepatol 2016; 10:1279-1288. [PMID: 27352778 DOI: 10.1080/17474124.2016.1207523] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The current review aimed to outline the functions of the renin angiotensin system (RAS) in the context of the oxidative stress-associated liver disease. Areas covered: Angiotensin II (Ang II) as the major effector peptide of the RAS is a pro-oxidant and fibrogenic cytokine. Mechanistically, NADPH oxidase (NOX) is a multicomponent enzyme complex that is able to generate reactive oxygen species (ROS) as a downstream signaling pathway of Ang II which is expressed in liver. Ang II has a detrimental role in the pathogenesis of chronic liver disease through possessing pro-oxidant, fibrogenic, and pro-inflammatory impact in the liver. The alternative axis (ACE2/Ang(1-7)/mas) of the RAS serves as an anti-inflammatory, antioxidant and anti-fibrotic component of the RAS. Expert commentary: In summary, the use of alternative axis inhibitors accompanying with ACE2/ Ang(1-7)/mas axis activation is a promising new strategy serving as a novel therapeutic option to prevent and treat chronic liver diseases.
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Affiliation(s)
- Elham Ahmadian
- a Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,b Biotechnology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,c Pharmacology and Toxicology Department, School of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.,d Students Research Committee , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Peter S Pennefather
- e Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , ON , Canada
| | - Aziz Eftekhari
- a Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,d Students Research Committee , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Reza Heidari
- f Pharmaceutical Sciences Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.,g Gerash School of Paramedical Sciences , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mohammad Ali Eghbal
- a Drug Applied Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,b Biotechnology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.,c Pharmacology and Toxicology Department, School of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran
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Zhang LL, Huang S, Ma XX, Zhang WY, Wang D, Jin SY, Zhang YP, Li Y, Li X. Angiotensin(1-7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1β/Smad circuit. Free Radic Biol Med 2016; 97:531-543. [PMID: 27445100 DOI: 10.1016/j.freeradbiomed.2016.07.014] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 07/14/2016] [Accepted: 07/17/2016] [Indexed: 02/07/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is correlated with NAPDH oxidase (NOX)-derived reactive oxygen species (ROS). The ROS-induced NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a novel mechanism of EMT. Angiotensin II (AngII) induces EMT by regulating intracellular ROS. Nevertheless, it has not been reported whether AngII could induce hepatocyte EMT. Angiotensin-(1-7) [Ang-(1-7)] can inhibit the effects of AngII via a counter-regulatory mechanism. However, whether Ang-(1-7) attenuated the effects of AngII on hepatocyte EMT remains unclear. The aim of this study was to determine whether Ang-(1-7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived ROS-mediated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, two animal models were established. In the first model, rats were infused AngII. In the second model, Ang-(1-7) was constantly infused into double bile duct ligated (BDL) rats. In vitro, hepatocytes were pretreated with antioxidant, NLRP3 siRNA, NOX4 siRNA, or Ang-(1-7) before exposure to AngII. In vitro, AngII induced hepatocyte EMT, which was inhibited by N-acetylcysteine (NAC), diphenylene iodonium (DPI), and NOX4 siRNA. NLRP3 inflammasome, which was activated by hydrogen peroxide (H2O2), mediated AngII-induced hepatocyte EMT. Ang-(1-7) suppressed AngII-induced EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, infusion of AngII induced activation of H2O2-correlated NLRP3 inflammasome in rat livers and accumulation of α-collagen I (Col1A1) in hepatocytes. Infusion of Ang-(1-7) alleviated BDL-induced liver fibrosis and inhibited the expression of Col1A1 and the activation of NLRP3 inflammasome in hepatocytes. Ang-(1-7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit.
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Affiliation(s)
- Li-Li Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shan Huang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Xin Ma
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wen-Yong Zhang
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Dan Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Si-Yi Jin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yan-Ping Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yang Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xu Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Salama ZA, Sadek A, Abdelhady AM, Darweesh SK, Morsy SA, Esmat G. Losartan may inhibit the progression of liver fibrosis in chronic HCV patients. Hepatobiliary Surg Nutr 2016; 5:249-55. [PMID: 27275467 DOI: 10.21037/hbsn.2016.02.06] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients. METHODS A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1(st) group (n=25) was given losartan 50 mg OD for 1 year and the 2(nd) group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study). RESULTS In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively). CONCLUSIONS Histopathological scores showed that losartan had an inhibitory effect on progression and even led to regression of fibrosis stage but had no effect on the grade of inflammation.
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Affiliation(s)
- Zakaria A Salama
- 1 Department of Tropical Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt ; 2 Department of Tropical Medicine, 3 Department of Pathology, Theodor Bilharz Research Institute, Gizah, Egypt
| | - Ahmed Sadek
- 1 Department of Tropical Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt ; 2 Department of Tropical Medicine, 3 Department of Pathology, Theodor Bilharz Research Institute, Gizah, Egypt
| | - Ahmed M Abdelhady
- 1 Department of Tropical Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt ; 2 Department of Tropical Medicine, 3 Department of Pathology, Theodor Bilharz Research Institute, Gizah, Egypt
| | - Samar Kamal Darweesh
- 1 Department of Tropical Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt ; 2 Department of Tropical Medicine, 3 Department of Pathology, Theodor Bilharz Research Institute, Gizah, Egypt
| | - Shereif Ahmed Morsy
- 1 Department of Tropical Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt ; 2 Department of Tropical Medicine, 3 Department of Pathology, Theodor Bilharz Research Institute, Gizah, Egypt
| | - Gamal Esmat
- 1 Department of Tropical Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt ; 2 Department of Tropical Medicine, 3 Department of Pathology, Theodor Bilharz Research Institute, Gizah, Egypt
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Targeting the renin-angiotensin system in liver fibrosis. Hepatol Int 2016; 10:730-2. [PMID: 27246697 DOI: 10.1007/s12072-016-9740-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 05/11/2016] [Indexed: 12/27/2022]
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Cai SM, Yang RQ, Li Y, Ning ZW, Zhang LL, Zhou GS, Luo W, Li DH, Chen Y, Pan MX, Li X. Angiotensin-(1-7) Improves Liver Fibrosis by Regulating the NLRP3 Inflammasome via Redox Balance Modulation. Antioxid Redox Signal 2016; 24:795-812. [PMID: 26728324 DOI: 10.1089/ars.2015.6498] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS Angiotensin II (Ang II) aggravates hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Angiotensin-(1-7) [Ang-(1-7)], which counter-regulates Ang II, has been evidenced to protect against hepatic fibrosis. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, being activated by reactive oxygen species (ROS), is identified as a novel mechanism of liver fibrosis. However, whether the NLRP3 inflammasome involves in regulation of Ang II-induced hepatic fibrosis remains unclear. This study investigates the different effects of the Ang II and Ang-(1-7) on collagen synthesis by regulating the NLRP3 inflammasome/Smad pathway via redox balance modulation. RESULTS In vivo, Ang-(1-7) improved bile duct ligation-induced hepatic fibrosis, reduced H2O2 content, protein levels of NOX4, and the NLRP3 inflammasome, whereas it increased glutathione (GSH) and nuclear erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE). In vitro, Ang II treatment elevated NOX4 protein expression and ROS production in hepatic stellate cells (HSCs), whereas it inhibited GSH and Nrf2-ARE, resulting in the activation of the NLRP3 inflammasome in the mitochondria of HSCs. NLRP3 depletion inhibited Ang II-induced collagen synthesis. Furthermore, Ang II increased NLRP3 and pro-IL-1β levels by activating the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway. Treatment with antioxidants, NOX4 small interference RNA (siRNA), or Nrf2 activator inhibited Ang II-induced NLRP3 inflammasome activation and collagen synthesis. In contrast, the action of Ang-(1-7) opposed the effects of Ang II. INNOVATION AND CONCLUSIONS Ang-(1-7) improved liver fibrosis by regulating NLRP3 inflammasome activation induced by Ang II-mediated ROS via redox balance modulation. Antioxid. Redox Signal. 24, 795-812.
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Affiliation(s)
- Shuang-Ming Cai
- 1 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .,2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Ren-Qiang Yang
- 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Yang Li
- 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Zuo-Wei Ning
- 3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Li-Li Zhang
- 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Gao-Su Zhou
- 4 Department of Emergency Medicine, the Military General Hospital of Beijing PLA , Beijing, China
| | - Wei Luo
- 3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Da-Huan Li
- 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Yan Chen
- 5 Department of Respiratory Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Miao-Xia Pan
- 5 Department of Respiratory Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China
| | - Xu Li
- 1 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .,3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, the Southern Medical University , Guangzhou, China
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Abuelezz SA, Hendawy N, Osman WM. Aliskiren attenuates bleomycin-induced pulmonary fibrosis in rats: focus on oxidative stress, advanced glycation end products, and matrix metalloproteinase-9. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:897-909. [PMID: 27154762 DOI: 10.1007/s00210-016-1253-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 04/25/2016] [Indexed: 01/15/2023]
Abstract
Pulmonary fibrosis is a progressive lung disorder with high mortality rate and limited successful treatment. This study was designed to assess the potential anti-oxidant and anti-fibrotic effects of aliskiren (Alsk) during bleomycin (BLM)-induced pulmonary fibrosis. Male Wistar rats were used as control untreated or treated with the following: a single dose of 2.5 mg/kg of BLM endotracheally and BLM and Alsk (either low dose 30 mg/kg/day or high dose 60 mg/kg/day), and another group was given Alsk 60 mg/kg/day alone. Alsk was given by gavage. Alsk anti-oxidant and anti-fibrotic effects were assessed. BLM significantly increased relative lung weight and the levels of lactate dehydrogenase and total and differential leucocytic count in bronchoalveolar lavage that was significantly ameliorated by high-dose Alsk treatment. As markers of oxidative stress, BLM caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease of superoxide dismutase and glutathione transferase enzymes. High-dose Alsk treatment restored these markers toward normal values. Alsk counteracted the overexpression of advanced glycation end products, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 in lung tissue induced by BLM. Fibrosis assessed by measuring hydroxyproline content, which markedly increased in the BLM group, was also significantly reduced by Alsk. These were confirmed by histopathological and immunohistochemical examination which revealed that Alsk attenuates signs of pulmonary fibrosis and decreased the overexpressed MMP-9 and transforming growth factor β1. Collectively, these findings indicate that Alsk has a potential anti-fibrotic effect beside its anti-oxidant activity.
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Affiliation(s)
- Sally A Abuelezz
- Pharmacology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
| | - Nevien Hendawy
- Pharmacology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Wesam M Osman
- Pathology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
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Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 185:2641-52. [PMID: 26435412 DOI: 10.1016/j.ajpath.2015.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 04/16/2015] [Accepted: 06/01/2015] [Indexed: 12/27/2022]
Abstract
Traumatic brain injury affects the whole body in addition to the direct impact on the brain. The systemic response to trauma is associated with the hepatic acute-phase response. To further characterize this response, we performed controlled cortical impact injury on male mice and determined the expression of serum amyloid A1 (SAA1), an apolipoprotein, induced at the early stages of the acute-phase response in liver and plasma. After cortical impact injury, induction of SAA1 was detectable in plasma at 6 hours post-injury and in liver at 1 day post-injury, followed by gradual diminution over time. In the liver, cortical impact injury increased neutrophil and macrophage infiltration, apoptosis, and expression of mRNA encoding the chemokines CXCL1 and CXCL10. An increase in angiotensin II AT1 receptor mRNA at 3 days post-injury was also observed. Administration of the AT1 receptor antagonist telmisartan 1 hour post-injury significantly decreased liver SAA1 levels and CXCL10 mRNA expression, but did not affect CXCL1 expression or the number of apoptotic cells or infiltrating leukocytes. To our knowledge, this is the first study to demonstrate that SAA1 is induced in the liver after traumatic brain injury and that telmisartan prevents this response. Elucidating the molecular pathogenesis of the liver after brain injury will assist in understanding the efficacy of therapeutic approaches to brain injury.
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Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis. Sci Rep 2016; 6:21592. [PMID: 26883384 PMCID: PMC4756304 DOI: 10.1038/srep21592] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 01/27/2016] [Indexed: 02/08/2023] Open
Abstract
The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1–7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2−/y) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2−/y mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1–7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what’s more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1–7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1–7)/Mas axis in prevention and treatment of hepatic lipid metabolism.
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Zhu Q, Li N, Li F, Zhou Z, Han Q, Lv Y, Sang J, Liu Z. Therapeutic effect of renin angiotensin system inhibitors on liver fibrosis. J Renin Angiotensin Aldosterone Syst 2016; 17:1470320316628717. [PMID: 27009285 PMCID: PMC5843853 DOI: 10.1177/1470320316628717] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Currently, there is no effective therapy available for liver fibrosis. This study aims to evaluate the efficacy of renin angiotensin system inhibitors on liver fibrosis. METHOD Full-text randomized controlled trials in patients with liver fibrosis were identified and included in the meta-analysis. The primary outcome measure was the histological fibrosis score of the liver. Secondary outcome measures included fibrosis area of the liver, serological levels of fibrosis markers, adverse events, and withdrawals. RESULTS From 6973 non-duplicated entries by systematic search, four randomized controlled trials with 210 patients were identified. The renin angiotensin system inhibitors therapy resulted in a marginally significant reduction in liver fibrosis score (MD = -0.30; 95% CI: -0.62-0.02, p = 0.05) and a significant reduction in liver fibrosis area (MD = -2.36%; 95% CI: -4.22%--0.50%, p = 0.01) as compared with control. The therapy was well tolerated and there was no significant difference in withdrawals between treatment and control groups (RD = 0.00; 95% CI: -0.06-0.06, p = 0.97). CONCLUSIONS Renin angiotensin system inhibitor therapy results in a reduction in liver fibrosis score and liver fibrosis area in patients with hepatic fibrosis with good safety profile. However, randomized controlled trials of high-quality will clarify the effectiveness of renin angiotensin system inhibitors on liver fibrosis.
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Affiliation(s)
- Qianqian Zhu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Fang Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Zhihua Zhou
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, China Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, China
| | - Jiao Sang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, China Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, China
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Tsujino K, Sheppard D. Critical Appraisal of the Utility and Limitations of Animal Models of Scleroderma. Curr Rheumatol Rep 2015; 18:4. [DOI: 10.1007/s11926-015-0553-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Effectiveness of Losartan-Loaded Hyaluronic Acid (HA) Micelles for the Reduction of Advanced Hepatic Fibrosis in C3H/HeN Mice Model. PLoS One 2015; 10:e0145512. [PMID: 26714035 PMCID: PMC4699854 DOI: 10.1371/journal.pone.0145512] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 12/04/2015] [Indexed: 12/18/2022] Open
Abstract
Advanced hepatic fibrosis therapy using drug-delivering nanoparticles is a relatively unexplored area. Angiotensin type 1 (AT1) receptor blockers such as losartan can be delivered to hepatic stellate cells (HSC), blocking their activation and thereby reducing fibrosis progression in the liver. In our study, we analyzed the possibility of utilizing drug-loaded vehicles such as hyaluronic acid (HA) micelles carrying losartan to attenuate HSC activation. Losartan, which exhibits inherent lipophilicity, was loaded into the hydrophobic core of HA micelles with a 19.5% drug loading efficiency. An advanced liver fibrosis model was developed using C3H/HeN mice subjected to 20 weeks of prolonged TAA/ethanol weight-adapted treatment. The cytocompatibility and cell uptake profile of losartan-HA micelles were studied in murine fibroblast cells (NIH3T3), human hepatic stellate cells (hHSC) and FL83B cells (hepatocyte cell line). The ability of these nanoparticles to attenuate HSC activation was studied in activated HSC cells based on alpha smooth muscle actin (α-sma) expression. Mice treated with oral losartan or losartan-HA micelles were analyzed for serum enzyme levels (ALT/AST, CK and LDH) and collagen deposition (hydroxyproline levels) in the liver. The accumulation of HA micelles was observed in fibrotic livers, which suggests increased delivery of losartan compared to normal livers and specific uptake by HSC. Active reduction of α-sma was observed in hHSC and the liver sections of losartan-HA micelle-treated mice. The serum enzyme levels and collagen deposition of losartan-HA micelle-treated mice was reduced significantly compared to the oral losartan group. Losartan-HA micelles demonstrated significant attenuation of hepatic fibrosis via an HSC-targeting mechanism in our in vitro and in vivo studies. These nanoparticles can be considered as an alternative therapy for liver fibrosis.
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Cengiz M, Ozenirler S, Yılmaz G, Erkan G. Impact of hepatic immunoreactivity of angiotensin-converting enzyme 2 on liver fibrosis due to non-alcoholic steatohepatitis. Clin Res Hepatol Gastroenterol 2015; 39:692-698. [PMID: 25887687 DOI: 10.1016/j.clinre.2015.02.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 10/26/2014] [Accepted: 02/05/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND We aimed to evaluate the hepatic immunoreactivity of angiotensin-converting enzyme 2 (ACE2) in non-alcoholic steatohepatitis (NASH) patients, elucidate its association with the clinicopathological characteristics and also determine its role in fibrosis progression. METHODS The consecutive biopsy proven NASH patients were subdivided into two groups according to their fibrosis score. Fibrotic stages<3 in mild fibrosis group and fibrotic stages ≥ 3 in advanced fibrosis depending on the presence of bridging fibrosis. Liver biopsy specimens were immunohistochemically stained for ACE2 immunoreactivity. Demographics and clinical properties were compared between the groups. Univariate and multivariate analysis were also performed to evaluate the independent predicting factors for the presence of advanced liver fibrosis caused by NASH. RESULTS One hundred and eight patients were enrolled in the study. Out of this, ninety-four patients representing 87% were classified as mild fibrosis group, whilst fourteen representing 13% were in advanced fibrosis group. We compared high hepatic immunoreactivity of ACE2 between mild and advanced fibrosis groups and found a statistically significant difference 65.9% vs 28.5%, respectively and P=0.008. Hepatic ACE2 immunoreactivity was inversely correlated with the fibrosis score (r: -0.337; P<0.001). The significant variables in the univariate analysis were then evaluated in multivariate logistic regression analysis and hepatic ACE2 immunoreactivity was an independent predicting factor of liver fibrosis [odds ratio (OR): 0.194; 95% confidence interval (CI): 0.082-0.897, P=0.036]. CONCLUSION Hepatic immunoreactivity of ACE2 was inversely correlated with the liver fibrosis among biopsy proven NASH patients and it was also an independent predicting factor of advanced fibrosis.
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Affiliation(s)
- Mustafa Cengiz
- Dr. A.Y. Ankara Oncology Training and Research Hospital, Department of Gastroenterology, 06200 Ankara, Turkey.
| | - Seren Ozenirler
- Gazi University Faculty of Medicine, Department of Gastroenterology, Ankara, Turkey
| | - Guldal Yılmaz
- Gazi University Faculty of Medicine, Department of Pathology, Ankara, Turkey
| | - Gulbanu Erkan
- Ufuk University Faculty of Medicine, Department of Gastroenterology, Ankara, Turkey
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All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells. PLoS One 2015; 10:e0138655. [PMID: 26407160 PMCID: PMC4583235 DOI: 10.1371/journal.pone.0138655] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
Background & Aims Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen. Methods Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity. Results Cell preparation yielded the following cell counts per gram of liver tissue: 2.0±0.4×107 hepatocytes, 1.8±0.5×106 Kupffer cells, 4.3±1.9×105 liver sinusoidal endothelial cells, and 3.2±0.5×105 stellate cells. Hepatocytes were identified by albumin (95.5±1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5±1.2%) and exhibited phagocytic activity, as determined with 1μm latex beads. Endothelial cells were CD146+ (97.8±1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1±1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence. Conclusions Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease.
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Stefano J, Pereira I, Torres M, Bida P, Coelho A, Xerfan M, Cogliati B, Barbeiro D, Mazo D, Kubrusly M, D'Albuquerque L, Souza H, Carrilho F, Oliveira C. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model. Braz J Med Biol Res 2015; 48:408-414. [PMID: 25714891 PMCID: PMC4445663 DOI: 10.1590/1414-431x20143962] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 11/12/2014] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg(-1)·day(-1) by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.
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Affiliation(s)
- J.T. Stefano
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - I.V.A. Pereira
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - M.M. Torres
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - P.M. Bida
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - A.M.M. Coelho
- Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37),
Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP,
Brasil
| | - M.P. Xerfan
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - B. Cogliati
- Departamento de Patologia, Faculdade de Medicina Veterinária e
Zootecnia, Universidade de São Paulo, São Paulo, SP, Brasil
| | - D.F. Barbeiro
- Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina,
Universidade de São Paulo, São Paulo, SP, Brasil
| | - D.F.C. Mazo
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - M.S. Kubrusly
- Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37),
Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP,
Brasil
| | - L.A.C. D'Albuquerque
- Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37),
Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP,
Brasil
| | - H.P. Souza
- Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina,
Universidade de São Paulo, São Paulo, SP, Brasil
| | - F.J. Carrilho
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - C.P. Oliveira
- Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de
Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
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