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Elrashidy RA, Zakaria EM, Hasan RA, Elmaghraby AM, Hassan DA, Abdelgalil RM, Abdelmohsen SR, Negm AM, Khalil AS, Eraque AMS, Ahmed RM, Sabbah WS, Ahmed AA, Ibrahim SE. Implication of endoplasmic reticulum stress and mitochondrial perturbations in remote liver injury after renal ischemia/reperfusion in rats: potential protective role of azilsartan. Redox Rep 2024; 29:2319963. [PMID: 38411133 PMCID: PMC10903753 DOI: 10.1080/13510002.2024.2319963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024] Open
Abstract
Objectives: Distant liver injury is a complication of renal ischemia-reperfusion (I/R) injury, which imposes mortality and economic burden. This study aimed to elucidate the cross-talk of endoplasmic reticulum (ER) stress and mitochondrial perturbations in renal I/R-induced liver injury, and the potential hepatoprotective effect of azilsartan (AZL).Methods: Male albino Wister rats were pre-treated with AZL (3 mg/kg/day, PO) for 7 days then a bilateral renal I/R or sham procedure was performed. Activities of liver enzymes were assessed in plasma. The structure and ultra-structure of hepatocytes were assessed by light and electron microscopy. Markers of ER stress, mitochondrial biogenesis and apoptosis were analyzed in livers of rats.Results: Renal ischemic rats showed higher plasma levels of liver enzymes than sham-operated rats, coupled with histological and ultra-structural alterations in hepatocytes. Mechanistically, there was up-regulation of ER stress markers and suppression of mitochondrial biogenesis-related proteins and enhanced apoptosis in livers of renal ischemic rats. These abnormalities were almost abrogated by AZL pretreatment.Discussion: Our findings uncovered the involvement of mitochondrial perturbations, ER stress and apoptosis in liver injury following renal I/R, and suggested AZL as a preconditioning strategy to ameliorate remote liver injury in patients susceptible to renal I/R after adequate clinical testing.
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Affiliation(s)
- Rania A. Elrashidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Esraa M. Zakaria
- Pharmacology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Rehab A. Hasan
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Asmaa M. Elmaghraby
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Dina A. Hassan
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ranya M. Abdelgalil
- Anatomy and Embryology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Shaimaa R. Abdelmohsen
- Anatomy and Embryology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Amira M. Negm
- Medical Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Azza S. Khalil
- Medical Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ayat M. S. Eraque
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Reem M. Ahmed
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Walaa S. Sabbah
- Anatomy and Embryology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ahmed A. Ahmed
- Medical Student, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt
| | - Samah E. Ibrahim
- Medical Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
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Gish R, Fan JG, Dossaji Z, Fichez J, Laeeq T, Chun M, Boursier J. Review of current and new drugs for the treatment of metabolic-associated fatty liver disease. Hepatol Int 2024; 18:977-989. [PMID: 38850496 DOI: 10.1007/s12072-024-10698-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 05/03/2024] [Indexed: 06/10/2024]
Abstract
In the past 3 decades, metabolic-associated fatty liver disease (MAFLD) has emerged as a widespread liver condition, with its global prevalence on the rise. It ranks as a leading contributor to hepatocellular carcinoma (HCC) and necessitates liver transplantation. Under the multiple parallel hits model, the pathogenesis of MAFLD stems from various liver stressors, notably nutrient overload and sedentary lifestyles. While medical management for MAFLD is well-established, encompassing non-pharmaceutical and pharmaceutical interventions, determining the most effective pharmaceutical therapy has remained elusive. This review discusses diabetic medications for MAFLD treatment, emphasizing recent studies and emerging drugs while reviewing other nondiabetic agents. Emerging evidence suggests that combination therapies hold promise for resolving MAFLD and metabolic steatohepatitis (MASH) while managing side effects. Ongoing trials play a pivotal role in elucidating the effects of mono, dual, and triple receptor agonists in individuals with MASH. With the rising burden of MAFLD/MASH and its severe consequences, the need for effective treatments is more pressing than ever. This review provides a comprehensive overview of the current landscape of pharmaceutical interventions for MAFLD and MASH, shedding light on the potential of newer drugs especially diabetic medications and the importance of ongoing research in this field.
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Affiliation(s)
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China
| | - Zahra Dossaji
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, 1800 W Charleston Blvd, Las Vegas, NV, 89102, USA.
| | - Jeanne Fichez
- Department of Hepato-Gastroenterology and Digestive Oncology, Angers University Hospital, Angers, France
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
| | - Tooba Laeeq
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, 1800 W Charleston Blvd, Las Vegas, NV, 89102, USA
| | - Magnus Chun
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, 1800 W Charleston Blvd, Las Vegas, NV, 89102, USA
| | - Jerome Boursier
- Department of Hepato-Gastroenterology and Digestive Oncology, Angers University Hospital, Angers, France
- HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France
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Liao P, Liu H, Sun X, Zhang X, Zhang M, Wang X, Chen J. A novel ACE inhibitory peptide from Pelodiscus sinensis Wiegmann meat water-soluble protein hydrolysate. Amino Acids 2024; 56:40. [PMID: 38847939 PMCID: PMC11585513 DOI: 10.1007/s00726-024-03399-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/28/2024] [Indexed: 11/01/2024]
Abstract
Pelodiscus sinensis meat is a nutritional food and tonic with angiotensin-converting enzyme (ACE) inhibitory activities. To identify the bioactive substances responsible, several bioinformatics methods were integrated to enable a virtual screening for bioactive peptides in proteins identified within a water-soluble protein fraction of Pelodiscus sinensis meat by Shotgun proteomics. The peptides were generated from the identified proteins by in silico proteolysis using six proteases. A comparison of the numbers of proteins suitable for digestion with each enzyme and the iBAQ (intensity-based absolute quantification) values for these proteins revealed that bromelain and papain were the most suitable proteases for this sample. Next, the water solubility, toxicity, and ADMET (absorption/distribution/metabolism/excretion/toxicity) properties of these peptides were evaluated in silico. Finally, a novel ACE inhibitory peptide IEWEF with an IC50 value of 41.33 µM was identified. The activity of the synthesized peptide was verified in vitro, and it was shown to be a non-competitive ACE inhibitor. Molecular docking revealed that IEWEF could tightly bind to C-ACE, and N-ACE with energies less than 0 kJ mol-1, and the peptide IEWEF can form hydrogen bonds with C-ACE and N-ACE respectively. These results provide evidence that bioactive peptides in the water-soluble protein fraction account for (at least) some of the ACE inhibitory activities observed in Pelodiscus sinensis meat. Furthermore, our research provides a workflow for the efficient identification of novel ACE inhibitory peptides from complex protein mixtures.
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Affiliation(s)
- Pengying Liao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
- Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
| | - Huayu Liu
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
| | - Xueqin Sun
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
| | - Xinrui Zhang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
| | - Miao Zhang
- Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, Guangxi, China
| | - Xianyou Wang
- School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China.
| | - Jun Chen
- Teaching Experiment and Training Centre, Guangxi University of Chinese Medicine, Nanning, 530200, China.
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McGrath MS, Wentworth BJ. The Renin-Angiotensin System in Liver Disease. Int J Mol Sci 2024; 25:5807. [PMID: 38891995 PMCID: PMC11172481 DOI: 10.3390/ijms25115807] [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: 05/04/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.
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Affiliation(s)
- Mary S. McGrath
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA;
| | - Brian J. Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
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Linero PL, Castilla-Guerra L. Management of Cardiovascular Risk in the Non-alcoholic Fatty Liver Disease Setting. Eur Cardiol 2024; 19:e02. [PMID: 38807854 PMCID: PMC11131151 DOI: 10.15420/ecr.2023.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/02/2023] [Indexed: 05/30/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an overlooked and undetected pathology, which affects more than 32% of adults worldwide. NAFLD is becoming more common in Western industrialised countries, particularly in patients with central obesity, type 2 diabetes, dyslipidaemia and metabolic syndrome. Although NAFLD has traditionally been interpreted as a liver disease with a high risk of liver-related complications, NAFLD is an underappreciated and independent risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Treatment options to counteract both the progression and development of cardiovascular disease and NAFLD include lifestyle interventions, such as weight loss, increased physical activity and dietary modification, and optimal medical therapy of comorbid conditions; nevertheless, further studies are needed to define optimal treatment strategies for the prevention of both hepatic and cardiovascular complications of NAFLD.
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Affiliation(s)
- Paula Luque Linero
- Vascular Risk Unit, Department of Internal Medicine, Hospital Virgen MacarenaSeville, Spain
| | - Luis Castilla-Guerra
- Vascular Risk Unit, Department of Internal Medicine, Hospital Virgen MacarenaSeville, Spain
- Department of Medicine, University of SevilleSeville, Spain
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Ren Y, Feng Y, Qing J, Zhang P, Xiao L, Liang X. The correlation between nuts and algae-less diet and children's blood pressure: from a cross-sectional study in Chongqing. Clin Exp Hypertens 2023; 45:2180024. [PMID: 36823777 DOI: 10.1080/10641963.2023.2180024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
BACKGROUND Nuts and algae have been shown to improve BP levels, but their effectiveness is controversial. AIMS This study aims to illustrate the effect of dietary pattern with nuts and algae-less on BP levels in children and adolescents from a cross-sectional study. METHODS A total of 5645 children from the Chongqing Children's Health Cohort, aged 9.34 ± 1.74 years with 52.05% males, were analyzed. Stratified analysis was conducted to explore the differences between the two dietary patterns in urban or rural areas, as well as the differences in different gender. Logistic regression was used to analyze the influence factors of increased BP. And a GLM was used to analyze the influence of the two dietary patterns on systolic blood pressure (SBP, mmHg), diastolic blood pressure (DBP, mmHg), and mean arterial pressure (MAP, mmHg). RESULTS Children with nuts and algae-less dietary patterns had higher SBP (104.68 ± 10.31 vs 103.81 ± 9.74, P = .006), DBP (64.27 ± 7.53 vs 63.55 ± 7.52, P = .002), and MAP (77.74 ± 7.75 vs 76.97 ± 7.52, P = .001) compared with those children with a balanced diet. After adjusting for covariates, the nuts and algae-less diet was a risk factor for hypertension in children when compared with the balanced diet(OR(95%CI):1.455(1.097,1.930), P = .009). The nuts and algae-less diet has a significant influence on SBP (104.68 ± 10.31 mmHg vs.103.81 ± 9.74 mmHg, P = .006). Stratified analysis by sex showed that nuts and algae-less dietary patterns had a more significant impact on females than males. CONCLUSION Nuts and algae-less dietary pattern correlated with increased BP levels in children, and a greater impact on SBP levels was found in females, suggesting that a balanced diet with appropriate nuts and algae should be proposed for children in China.
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Affiliation(s)
- Yanling Ren
- Clinical Epidemiology and Biostatistics Department, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Key Laboratory of Pediatrics in Chongqing, China International Science and Technology Cooperation Center of Child Development and Critical Disorders, Chongqing, China
| | - Ye Feng
- Clinical Epidemiology and Biostatistics Department, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Key Laboratory of Pediatrics in Chongqing, China International Science and Technology Cooperation Center of Child Development and Critical Disorders, Chongqing, China
| | - Jun Qing
- Center for Disease Control and Prevention of Jiulongpo District, Chongqing, China
| | - Ping Zhang
- Clinical Epidemiology and Biostatistics Department, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Key Laboratory of Pediatrics in Chongqing, China International Science and Technology Cooperation Center of Child Development and Critical Disorders, Chongqing, China
| | - Lun Xiao
- Center for Disease Control and Prevention of Jiulongpo District, Chongqing, China
| | - Xiaohua Liang
- Clinical Epidemiology and Biostatistics Department, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Key Laboratory of Pediatrics in Chongqing, China International Science and Technology Cooperation Center of Child Development and Critical Disorders, Chongqing, China
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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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Mohater S, Qahtan S, Alrefaie Z, Alahmadi A. Vitamin D improves hepatic alterations in ACE1 and ACE2 expression in experimentally induced metabolic syndrome. Saudi Pharm J 2023; 31:101709. [PMID: 37559868 PMCID: PMC10407910 DOI: 10.1016/j.jsps.2023.101709] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 07/20/2023] [Indexed: 08/11/2023] Open
Abstract
Metabolic Syndrome (MetS) is a term used to describe a cluster of pathophysiological, biochemical, and metabolic criteria; including high Blood Pressure (BP), high cholesterol, dyslipidaemia, central obesity and Insulin Resistance (IR). The Renin Angiotensin System (RAS) has a regulatory function in BP, hydroelectrolyte balance, and cardiovascular function. RAS is composed of angiotensinogen (AGT), (Ang I), (Ang II), (ACE1), (ACE2), (AT1R), (AT2R), and (Ang 1-7). Vitamin D had been proved to act as a protective factor against MetS. Therefore, the study is pursued to explore vitamin D supplementation roles on hepatic RAS in MetS experimental model. At first, 36 males Albino rats were separated into 4 groups and induced to MetS under controlled circumstances for 3 months. Then, data were collected from blood samples, whereas RNA extracted from liver were analyzed using biochemical and statistical analysis tests. As a result, the major finding was proving that vitamin D can balance the expression of ACE1 and ACE2. Also, confirming that it can improve MetS components by elevating HDL and insulin levels while reducing the levels of BP, cholesterol, LDL, TG, GLU, ALT, AST, and IR. These outcomes may give a new insight into the RAS pathways associated with MetS.
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Affiliation(s)
- Sara Mohater
- Department of Biological Sciences, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Samar Qahtan
- Department of Biological Sciences, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Zienab Alrefaie
- Medical Physiology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Physiology Department, Faculty of Medicine, Cairo University, Egypt
| | - Ahlam Alahmadi
- Department of Biological Sciences, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia
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9
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Singh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, Singal AK, Saraya A, Sharma BC, Eapen CE, Rao PN, Shukla A, Shalimar, Choudhary NS, Alcantara-Payawal D, Arora V, Aithal G, Kulkarni A, Roy A, Shrestha A, Mamun Al Mahtab, Niriella MA, Siam TS, Zhang CQ, Huei LG, Yu ML, Roberts SK, Peng CY, Chen T, George J, Wong V, Yilmaz Y, Treeprasertsuk S, Kurniawan J, Kim SU, Younossi ZM, Sarin SK. Asia-Pacific association for study of liver guidelines on management of ascites in liver disease. Hepatol Int 2023; 17:792-826. [PMID: 37237088 DOI: 10.1007/s12072-023-10536-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/08/2023] [Indexed: 05/28/2023]
Affiliation(s)
- Virendra Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India.
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rohit Mehtani
- Department of Hepatology, Amrita Institute of Medical Sciences and Research, Faridabad, India
| | - Paolo Angeli
- Department of Internal Medicine and Hepatology, University of Padova, Padua, Italy
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sanjaya Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
| | - Ashwini K Singal
- University of South Dakota Sanford School of Medicine, Sioux Falls, USA
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, Delhi, India
| | - C E Eapen
- Department of Hepatology, Christian Medical College, Vellore, India
| | - P N Rao
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Akash Shukla
- Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guru Aithal
- Biomedical Research Unit, NIHR Nottingham Digestive Diseases, Nottingham, UK
| | - Anand Kulkarni
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Akash Roy
- Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, India
| | - Ananta Shrestha
- Department of Hepatology, The Liver Clinic, Liver Foundation, Kathmandu, Nepal
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Madunil A Niriella
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
| | - Tan Soek Siam
- Department of Hepatology, Hospital Selayang, Selangor Darul Ehsan, Malaysia
| | - Chun-Qing Zhang
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Lee Guan Huei
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Ming-Lung Yu
- School of Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | | | - Cheng-Yuan Peng
- Centre for Digestive Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Tao Chen
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jacob George
- University of Sydney School of Medicine, Sydney, Australia
| | - Vincent Wong
- Mok Hing Yiu Professor of Medicine, Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Yusuf Yilmaz
- Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | | | - Juferdy Kurniawan
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital Jakarta, Jakarta, Indonesia
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Meng C, Song Z, Zhang L, Geng Y, Sun J, Miao G, Liu P. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial. Open Life Sci 2023; 18:20220583. [PMID: 36970603 PMCID: PMC10031500 DOI: 10.1515/biol-2022-0583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/18/2023] [Accepted: 02/19/2023] [Indexed: 03/24/2023] Open
Abstract
Losartan has become a hot spot in the treatment of non-alcoholic fatty liver disease (NAFLD) among angiotensin receptor blocker drugs. We sought to conduct a systematic examination and meta-analysis to examine the effects of losartan on patients with NAFLD. We searched for potentially randomized controlled trials in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database up to October 09, 2022. We used the Cochrane risk of bias tool to evaluate the study quality. Analysis of subgroups, sensitivity analysis, and publishing bias were explored. The quality of the included studies was moderate to high. Six trials involving 408 patients were included. The meta-analysis demonstrated that aspartate transaminase was significantly affected by losartan therapy (mean difference [MD] = −5.34, 95% confidence interval [CI] [−6.54, −4.13], Z = 8.70, P < 0.01). The meta-analysis subgroup showed that losartan 50 mg once daily could lower the level of alanine aminotransferase (MD = −18.92, 95% CI [−21.18, −16.66], Z = 16.41, P < 0.01). There was no statistically significant difference in serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein.
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Affiliation(s)
- Chang Meng
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Zejun Song
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, PR China
| | - Lingnan Zhang
- Department of Cardiology, Affiliated Hospital of Hebei University, Hebei University, 212 Yuhua East Road, Lianchi District, Baoding City, 071000, PR China
| | - Yu Geng
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, NO. 168 Litang Road, Changping District, Beijing102218, P. R. China
| | - Jing Sun
- Department of Critical Care Medicine, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Guobin Miao
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Peng Liu
- Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, 23 Yijinhuoluo West Street, Dongsheng District, Inner Mongolia, 017000, PR China
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Ortiz C, Klein S, Reul WH, Magdaleno F, Gröschl S, Dietrich P, Schierwagen R, Uschner FE, Torres S, Hieber C, Meier C, Kraus N, Tyc O, Brol M, Zeuzem S, Welsch C, Poglitsch M, Hellerbrand C, Alfonso-Prieto M, Mira F, Keller UAD, Tetzner A, Moore A, Walther T, Trebicka J. Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1. Cell Rep 2023; 42:112059. [PMID: 36729833 PMCID: PMC9989826 DOI: 10.1016/j.celrep.2023.112059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 11/17/2022] [Accepted: 01/18/2023] [Indexed: 02/03/2023] Open
Abstract
Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.
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Affiliation(s)
- Cristina Ortiz
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sabine Klein
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany
| | - Winfried H Reul
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | - Stefanie Gröschl
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Department of Internal Medicine 1, FAU Erlangen-Nuremberg and Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
| | - Robert Schierwagen
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Frank E Uschner
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sandra Torres
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christoph Hieber
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Caroline Meier
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Nico Kraus
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Olaf Tyc
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Maximilian Brol
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christoph Welsch
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
| | | | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Mercedes Alfonso-Prieto
- Institute for Neuroscience and Medicine INM-9 and Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, Jülich, Germany; Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Fabio Mira
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
| | - Anja Tetzner
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Andrew Moore
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Thomas Walther
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland; Department of Pediatric Surgery, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany; Department of Obstetrics, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany; Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Institute for Bioengineering of Catalonia, Barcelona, Spain; Department of Internal Medicine B, University of Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany.
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12
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Badr AM, Sherif IO, Mahran YF, Attia HA. Role of Renin-Angiotensin System in the Pathogenesis and Progression of Non-alcoholic Fatty Liver. THE RENIN ANGIOTENSIN SYSTEM IN CANCER, LUNG, LIVER AND INFECTIOUS DISEASES 2023:179-197. [DOI: 10.1007/978-3-031-23621-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
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13
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Borém LMA, Freitas DF, Machado AS, Paraíso AF, Caldas BV, Neto JFR, Lima JP, Guimarães ALS, de Paula AMB, Santos SHS. Angiotensin II type 1 receptor (AT1) blockade by Telmisartan attenuates hepatic steatosis in high-fat fed mice reducing Resistin, TRL4, and Myd88 expression. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00216-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Abstract
Background
Telmisartan is a non-peptide angiotensin II receptor antagonist which acts by ACE/AngII/AT1 axis blockade (ARB). In the last years increasing evidence of its metabolic benefits pointed out this drug as the most promising ARB for nonalcoholic fatty liver disease (NAFLD) treatment. The aim of the present study was to investigate the Telmisartan effect on treating NAFLD in mice fed with a high-fat diet evaluating liver gene modulation. Twenty-four male mice were divided into four groups and fed for 60 days with a standard diet (ST), standard diet plus TEL (ST+TEL 5 mg/kg/day by gavage for 4 weeks), high-fat diet (HFD), or high-fat diet plus TEL (HFD+TEL 5 mg/kg/day by gavage for 4 weeks). Body weight, lipid profile, insulin, alanine transaminase, and aspartate aminotransferase were evaluated. Liver histology was analyzed. US imaging was performed to access liver dimension and echogenicity and also epididymal fat pad thickness. The expression of proinflammatory resistin/TRL4/MYD88 pathway was analyzed.
Results
The main findings showed that TEL reduced the resistin, TRL4, and Myd88 liver expression in the HFD + TEL group when compared to the obese control group (HFD). Decreased hepatic steatosis in the HFD + TEL group demonstrated by US measurements of the liver longitudinal axis and echogenicity were observed. In addition, TEL reduced epididymal adipose pad thickness, body weight, transaminases, and improved glucose tolerance test and HDL cholesterol.
Conclusions
We observed that Telmisartan treatment improved metabolism, decreasing NAFLD.
Graphical Abstract
Telmisartan improves metabolic and lipid profile and liver steatosis of obese mice
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Chen P, Liu C, Zhang Z, Li Z, Chen S, Lu Y. Protocol for high-throughput screening of ACE2 enzymatic activators to treat COVID-19-induced metabolic complications. STAR Protoc 2022; 3:101641. [PMID: 36035796 PMCID: PMC9350712 DOI: 10.1016/j.xpro.2022.101641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Drug repositioning represents a cost- and time-efficient strategy for drug development. Here, we present a workflow of in silico screening of ACE2 enzymatic activators to treat COVID-19-induced metabolic complications. By using structure-based virtual screening and signature-based off-target effect identification via the Connectivity Map database, we provide a ranked list of the repositioning candidates as potential ACE2 enzymatic activators to ameliorate COVID-19-induced metabolic complications. The workflow can also be applied to other diseases with ACE2 as a potential target. For complete details on the use and execution of this protocol, please refer to Li et al. (2022).
Structure-based high-throughput virtual screening for ACE2 enzymatic activators Signature-based drug repositioning for COVID-19-induced metabolic complications Workflow applicable for other diseases with ACE2 as a potential target Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
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Affiliation(s)
- Pin Chen
- National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Chenshu Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Zhongyu Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
| | - Yutong Lu
- National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
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15
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Renin–Angiotensin System in Liver Metabolism: Gender Differences and Role of Incretins. Metabolites 2022; 12:metabo12050411. [PMID: 35629915 PMCID: PMC9143858 DOI: 10.3390/metabo12050411] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/12/2022] [Accepted: 04/27/2022] [Indexed: 02/04/2023] Open
Abstract
The impaired hepatic lipids and carbohydrates metabolism result in various metabolic disorders, including obesity, diabetes, insulin resistance, hyperlipidemia and metabolic syndrome. The renin–angiotensin system (RAS) has been identified in the liver and it is now recognized as an important modulator of body metabolic processes. This review is intended to provide an update of the impact of the renin–angiotensin system on lipid and carbohydrate metabolism, regarding gender difference and prenatal undernutrition, specifically focused on the role of the liver. The discovery of angiotensin-converting enzyme 2 (ACE2) has renewed interest in the potential therapeutic role of RAS modulation. RAS is over activated in non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma. Glucagon-like peptide-1 (GLP-1) has been shown to modulate RAS. The GLP-I analogue liraglutide antagonizes hepatocellular steatosis and exhibits liver protection. Liraglutide has a negative effect on the ACE/AngII/AT1R axis and a positive impact on the ACE2/Ang(1-7)/Mas axis. Activation of the ACE2/Ang(1-7)/Mas counter-regulatory axis is able to prevent liver injuries. Angiotensin(1-7) and ACE2 shows more favorable effects on lipid homeostasis in males but there is a need to do more investigation in female models. Prenatal undernutrition exerts long-term effects in the liver of offspring and is associated with a number of metabolic and endocrine alterations. These findings provide a novel therapeutic regimen to prevent and treat many chronic diseases by accelerating the effect of the ACE2/Ang1-7/Mas axis and inhibiting the ACE/AngII/AT1R axis.
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Khurana V, Goswami B. Angiotensin converting enzyme (ACE). Clin Chim Acta 2022; 524:113-122. [PMID: 34728179 DOI: 10.1016/j.cca.2021.10.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/16/2021] [Accepted: 10/26/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Angiotensin converting enzyme (ACE) was isolated as a 'hypertensinconverting enzyme'. There have been considerable advances in understanding the metabolic role of ACE in the body. This review attempts to highlight the role of ACE enzyme in the physiological and pathological processes occurring in the organs in which it is localized. METHODS The literature was searched from the websites of the National Library of Medicine (http://www.ncbi.nlm.nih.gov/) and Pub Med Central, the U.S. National Library of Medicine's digital archive of life sciences journal literature. RESULTS The involvement of ACE in regulation of blood pressure forms its central action but it has a role to play in a variety of physiological processes occurring in the organs in which it is localized like the lungs, macrophages, brain, pancreas, liver etc. It has also been implicated in the pathogenesis of a number of diseases including COVID-19. CONCLUSIONS More studies need to be carried out in order to validate the use of ACE levels in the diagnosis and monitoring of the diseases associated, and facilitate the use of ACE inhibitors and Angiotensin Receptor Blockers in the management of the same, so this wonder molecule can be utilized to its full potential.
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Affiliation(s)
- Vatsala Khurana
- Department of Biochemistry, Maulana Azad Medical College, New Delhi, India.
| | - Binita Goswami
- Department of Biochemistry, Maulana Azad Medical College, New Delhi, India
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Lin SY, Sung FC, Lin CL, Lin CC, Hsu WH, Liao WC, Ho MW, Lin PC, Hsu CY, Kao CH. Association of antihypertensives during hospitalisation with acute respiratory failure in patients with viral pneumonia: A population-based case-control study. Int J Clin Pract 2021; 75:e14776. [PMID: 34510649 DOI: 10.1111/ijcp.14776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/03/2021] [Accepted: 08/30/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND We aimed to identify associations between the risk of acute respiratory failure (ARF) and types of antihypertensive agents in patients with viral pneumonia. METHODS In this case-control study, data extracted from the Taiwan National Health Insurance Research Database were analysed. The base population comprised patients with viral pneumonia treated from 2000 to 2013. The case group comprised patients with ARF and the control group comprised participants without ARF. Adjusted odds ratios (ORs) were calculated using a multivariable logistic regression model. RESULTS In total, 4427 viral pneumonia patients with ARF and 4427 matched control participants without ARF were recruited. Patients with diabetes, alcohol-related disease, asthma, chronic kidney disease or end-stage renal disease, chronic obstructive pulmonary disease, cancer, congestive heart failure, stroke, acute pulmonary oedema and shock had increased odds of developing ARF, especially shock (adjusted OR = 49.3; 95% CI = 27.4, 88.7), cancer (12.6; 8.67, 18.2) and stroke (7.51; 5.32, 10.6). Increasing odds of developing ARF were noted in patients using potassium-sparing diuretics (2.95; 1.54, 5.64), loop diuretics (68.2; 48.1, 96.6), calcium channel blockers (1.64; 1.26, 2.13) and angiotensin-converting enzyme inhibitors (1.70; 1.15, 2.53). Patients with prescriptions of α-blockers (0.44; 0.26, 0.74), β-blockers (0.37; 0.26, 0.52), thiazides (0.38; 0.25, 0.59) and angiotensin receptor blockers (0.65; 0.51, 0.83) had lower odds of having ARF. CONCLUSION Patients with viral pneumonia who received α-blockers, β-blockers, thiazides or angiotensin receptor blockers during hospitalisation had a lower risk of developing ARF.
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Affiliation(s)
- Shih-Yi Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan
| | - Fung-Chang Sung
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Chieh Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wu-Huei Hsu
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Chest Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wei-Chih Liao
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Chest Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Mao-Wang Ho
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Infection, China Medical University Hospital, Taichung, Taiwan
| | - Po-Chang Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Infection, China Medical University Hospital, Taichung, Taiwan
| | - Chung-Y Hsu
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
- Center of Augmented Intelligence in Healthcare, China Medical University Hospital, Taichung, Taiwan
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18
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Wang C, Ren L, Chen S, Zheng H, Yang Y, Gu T, Li Y, Wang C. Longdan Xiegan Tang attenuates liver injury and hepatic insulin resistance by regulating the angiotensin-converting enzyme 2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 274:114072. [PMID: 33781876 DOI: 10.1016/j.jep.2021.114072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/14/2021] [Accepted: 03/22/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The ancient Chinese herbal formula Longdan Xiegan Tang (LXT, also called Gentiana Longdancao Decoction to Drain the Liver) treats insulin resistance- and inflammation-associated liver injuries in clinical practice. AIM OF THE STUDY To investigate the molecular mechanisms underlying LXT-elicited improvement of the liver injuries. MATERIALS AND METHODS Male rats were co-treated with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) for eight weeks. Blood parameters were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. RESULTS LXT attenuated olanzapine-induced liver injury manifested by hyperactivities of plasma alanine aminotransferase and aspartate aminostransferase, hyperbilirubinemia and hypoalbuminemia. Furthermore, LXT improved hepatic insulin resistance that was indicated by hyperinsulinemia, the increased HOMA-IR index, and hepatic over-phosphorylation of Ser307 in insulin receptor substrate (IRS)1, Ser731 in IRS2, Tyr607 in phosphoinositide 3-kinase p85α and Ser473 in AKT at baseline. Mechanistically, LXT inhibited olanzapine-triggered hepatic over-phosphorylation of both IκB kinase (IKK)α/β and nuclear factor (NF)κB p65 proteins, and mRNA overexpression of tumor necrosis factor α, interleukin 6, interleukin 1β and CD68. More importantly, LXT restored the decreases in angiotensin-converting enzyme 2 (ACE2) protein level, and its downstream targets Ang (1-7) content and Mas receptor expression. CONCLUSIONS The present results demonstrate that LXT attenuates liver injury and hepatic insulin resistance by regulating the ACE2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats. Our findings provide a better understanding of LXT for treatment of insulin resistance- and inflammation-associated liver injuries.
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Affiliation(s)
- Chengliang Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Liying Ren
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Shankang Chen
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Huihui Zheng
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Yifan Yang
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, NSW 2000, Australia.
| | - Tieguang Gu
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, NSW 2000, Australia.
| | - Yuhao Li
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, NSW 2000, Australia.
| | - Chunxia Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
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Ginsenoside Rg 3 Attenuates Early Hepatic Injury via Inhibiting PPARγ- and Ang II-Related Inflammation and Fibrosis in Type II Diabetic Mice. Nat Prod Commun 2021. [DOI: 10.1177/1934578x211009691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Ginsenoside Rg3 (Rg3), a natural product abundantly present in Korean Red Ginseng, is widely known for its anti-tumor activity. In our previous studies, we had further demonstrated that Rg3 has protective effects on the hearts, kidneys, and aortas of animals with hypertension or hypercholesterolemia, and its main mechanisms include down-regulation of angiotensin II (Ang II) levels and activation of peroxisome proliferator-activated receptor gamma (PPARγ) pathway in those tissues. In this study, the protective effects of Rg3 on liver were determined in db/db mice, a most recognized type II diabetes (T2DM) animal model with nonalcoholic fatty liver disease (NAFLD). The results showed that Rg3 did not have obvious effects to the body weight, blood glucose, and lipids of db/db mice. According to the results of histology examination, Rg3 could not improve steatosis in the hepatic tissue, too. But Rg3 did attenuate alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation in serum and collagen deposition in hepatic tissue. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) showed that Rg3 upregulated PPARγ and downregulated Ang II in hepatic tissue in db/db mice, which resulted in reducing activities of transforming growth factor β (TGF-β)/connective tissue growth factor (CTGF) pathway, downregulating the levels of inflammatory cytokines and attenuating collagen accumulation. In conclusion, although it has no obvious effect on steatosis in the hepatic tissue, Rg3 indeed attenuates early hepatic injury from NAFLD via inhibiting PPARγ- and Ang II-related inflammation and fibrosis in T2DM db/db mice. These effects are independent of reducing blood glucose and lipids, and the mechanisms are similar to the protective effects of Rg3 in hypertension and hypercholesterolemia animals in our previous studies.
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The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis? Cells 2021; 10:cells10030650. [PMID: 33804069 PMCID: PMC7999456 DOI: 10.3390/cells10030650] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/13/2021] [Indexed: 01/18/2023] Open
Abstract
Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1–7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.
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Bobkova NV. The Balance between Two Branches of RAS Can Protect from Severe COVID-19 Course. BIOCHEMISTRY (MOSCOW) SUPPLEMENT. SERIES A, MEMBRANE AND CELL BIOLOGY 2021; 15:36-51. [PMID: 33643542 PMCID: PMC7897458 DOI: 10.1134/s1990747821010037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/09/2020] [Accepted: 09/22/2020] [Indexed: 12/23/2022]
Abstract
The COVID-19 pandemic has swept the world and required the mobilization of scientists and clinicians around the world to combat this serious disease. Along with SARS-CoV-2 virology research, understanding of the fundamental physiological processes, molecular and cellular mechanisms and intracellular signaling pathways underlying the clinical manifestations of COVID-19 is important for effective therapy of this disease. The review describes in detail the interaction of the components of the renin-angiotensin system (RAS) and receptors of end-glycosylated products (RAGE), which plays a special role in normal lung physiology and in pathological conditions in COVID-19, including the development of acute respiratory distress syndrome and "cytokine storm". A separate section is devoted to the latest developments aimed at correcting the dysfunction of the RAS caused by the binding of the virus to angiotensin converting enzyme 2 (ACE2)- the central element of this system. Analysis of published theoretical, clinical, and experimental data indicates the need for a complex treatment to prevent a severe course of COVID-19 using MasR agonists, blockers of the AT1R and NF-κB signaling pathway, as well as compounds with neuroprotective and neuroregenerative effects.
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Affiliation(s)
- N. V. Bobkova
- Institute of Cell Biophysics, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, Moscow oblast Russia
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22
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Update on New Aspects of the Renin-Angiotensin System in Hepatic Fibrosis and Portal Hypertension: Implications for Novel Therapeutic Options. J Clin Med 2021; 10:jcm10040702. [PMID: 33670126 PMCID: PMC7916881 DOI: 10.3390/jcm10040702] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/29/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023] Open
Abstract
There is considerable experimental evidence that the renin angiotensin system (RAS) plays a central role in both hepatic fibrogenesis and portal hypertension. Angiotensin converting enzyme (ACE), a key enzyme of the classical RAS, converts angiotensin I (Ang I) to angiotensin II (Ang II), which acts via the Ang II type 1 receptor (AT1R) to stimulate hepatic fibrosis and increase intrahepatic vascular tone and portal pressure. Inhibitors of the classical RAS, drugs which are widely used in clinical practice in patients with hypertension, have been shown to inhibit liver fibrosis in animal models but their efficacy in human liver disease is yet to be tested in adequately powered clinical trials. Small trials in cirrhotic patients have demonstrated that these drugs may lower portal pressure but produce off-target complications such as systemic hypotension and renal failure. More recently, the alternate RAS, comprising its key enzyme, ACE2, the effector peptide angiotensin-(1–7) (Ang-(1–7)) which mediates its effects via the putative receptor Mas (MasR), has also been implicated in the pathogenesis of liver fibrosis and portal hypertension. This system is activated in both preclinical animal models and human chronic liver disease and it is now well established that the alternate RAS counter-regulates many of the deleterious effects of the ACE-dependent classical RAS. Work from our laboratory has demonstrated that liver-specific ACE2 overexpression reduces hepatic fibrosis and liver perfusion pressure without producing off-target effects. In addition, recent studies suggest that the blockers of the receptors of alternate RAS, such as the MasR and Mas related G protein-coupled receptor type-D (MrgD), increase splanchnic vascular resistance in cirrhotic animals, and thus drugs targeting the alternate RAS may be useful in the treatment of portal hypertension. This review outlines the role of the RAS in liver fibrosis and portal hypertension with a special emphasis on the possible new therapeutic approaches targeting the ACE2-driven alternate RAS.
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Moraes DS, Lelis DDF, Andrade JMO, Meyer L, Guimarães ALS, De Paula AMB, Farias LC, Santos SHS. Enalapril improves obesity associated liver injury ameliorating systemic metabolic markers by modulating Angiotensin Converting Enzymes ACE/ACE2 expression in high-fat feed mice. Prostaglandins Other Lipid Mediat 2021; 152:106501. [PMID: 33049402 DOI: 10.1016/j.prostaglandins.2020.106501] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/24/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
Obesity is a chronic disease caused multiple associated factors that results in excessive body fat accumulation. The Renin-Angiotensin System (RAS) unbalance is now recognized as a key factor on regulating body energy and metabolism. AIM The aim of the present study was to evaluate the Enalapril (ACE inhibitor) effects on the metabolic function and hepatic steatosis of obese mice evaluating Angiotensin Converting Enzymes (ACEs) expression. METHODS The experiment was performed using 32 male Swiss mice (8 weeks old) equally and randomly divided into 4 groups (n = 8): standard diet (ST), standard diet plus Enalapril (ST + ENAL), hyperlipidic diet (HF) and hyperlipidic diet plus Enalapril (HF + ENAL). Weekly measurements of animal weight and feed consumption were performed. At the end of treatment period a glucose tolerance test (GTT) and insulin sensitivity test (IST) were performed. Ultrasonography was used to evaluate hepatic and epididymal fat pad. Liver samples were submitted to HE histology and gene expression analyses were performed using Real-Time PCR. RESULTS The main results showed a decrease in body weight after treatment with Enalapril, as well as a reduced size of epididymal fat pad (EFP). Hepatic echogenicity and steatosis measurement were lower in the obese groups treated with Enalapril also modulating ACE2/ACE expressions. CONCLUSIONS Enalapril use improved metabolism reducing hepatic steatosis, decreasing ACE expression and increasing ACE2 expression.
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Affiliation(s)
- Daniel Silva Moraes
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Deborah de Farias Lelis
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - João Marcus Oliveira Andrade
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Lara Meyer
- Department of Biomedical Sciences, McMurry University, Abilene, TX, USA
| | - André Luiz Sena Guimarães
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Alfredo Maurício Batista De Paula
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Lucyana Conceição Farias
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil
| | - Sérgio Henrique Sousa Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (UNIMONTES), Montes Claros, Minas Gerais, Brazil; Institute of Agricultural Sciences. Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
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Galanopoulos M, Doukatas A, Gazouli M. Origin and genomic characteristics of SARS-CoV-2 and its interaction with angiotensin converting enzyme type 2 receptors, focusing on the gastrointestinal tract. World J Gastroenterol 2020; 26:6335-6345. [PMID: 33244196 PMCID: PMC7656204 DOI: 10.3748/wjg.v26.i41.6335] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/10/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
The emergence of coronavirus disease-2019 induced by a newly identified b-coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2 (ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract (GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system (RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.
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Affiliation(s)
- Michail Galanopoulos
- Department of Gastroenterology, 401 General Military Hospital of Athens, Athens 11525, Attiki, Greece
| | - Aris Doukatas
- Medical Office of Hellenic Army General Staff, 401 General Military Hospital of Athens, Athens 11525, Attiki, Greece
| | - Maria Gazouli
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Attiki, Greece
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Zhou Y, Zheng KI, Wang X, Sun Q, Pan K, Wang T, Ma H, Chen Y, George J, Zheng M. Metabolic-associated fatty liver disease is associated with severity of COVID-19. Liver Int 2020; 40:2160-2163. [PMID: 32573883 PMCID: PMC7361853 DOI: 10.1111/liv.14575] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/07/2020] [Accepted: 06/14/2020] [Indexed: 02/06/2023]
Abstract
The Corona Virus Disease 2019 (COVID-19) pandemic has attracted increasing worldwide attention. While metabolic-associated fatty liver disease (MAFLD) affects a quarter of world population, its impact on COVID-19 severity has not been characterized. We identified 55 MAFLD patients with COVID-19, who were 1:1 matched by age, sex and obesity status to non-aged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients without MAFLD. Our results demonstrate that in patients aged less than 60 years with COVID-19, MAFLD is associated with an approximately fourfold increase (adjusted odds ratio 4.07, 95% confidence interval 1.20-13.79, P = .02) in the probability for severe disease, after adjusting for confounders. Healthcare professionals caring for patients with COVID-19 need to be aware that there is a positive association between MAFLD and severe illness with COVID-19.
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Affiliation(s)
- Yu‐Jie Zhou
- MAFLD Research Center, Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina,Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and HepatologyMinistry of HealthRenji HospitalSchool of Medicine, Shanghai Jiao Tong UniversityShanghai Institute of Digestive DiseaseShanghaiChina
| | - Kenneth I. Zheng
- MAFLD Research Center, Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Xiao‐Bo Wang
- Department of Critical Care MedicineWenzhou Central HospitalWenzhouChina
| | - Qing‐Feng Sun
- Department of Infectious DiseasesRuian People's HospitalWenzhouChina
| | - Ke‐Hua Pan
- Department of RadiologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ting‐Yao Wang
- Department of NephrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Hong‐Lei Ma
- MAFLD Research Center, Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Yong‐Ping Chen
- MAFLD Research Center, Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Jacob George
- Storr Liver CentreWestmead Institute for Medical ResearchWestmead Hospital and University of SydneySydneyAustralia
| | - Ming‐Hua Zheng
- MAFLD Research Center, Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina,Institute of HepatologyWenzhou Medical UniversityWenzhouChina,Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang ProvinceWenzhouChina
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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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Hu YY, Fang QQ, Wang XF, Zhao WY, Zheng B, Zhang DD, Tan WQ. Angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker: Potential agents to reduce post-surgical scar formation in humans. Basic Clin Pharmacol Toxicol 2020; 127:488-494. [PMID: 32564469 DOI: 10.1111/bcpt.13458] [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: 05/01/2020] [Revised: 06/13/2020] [Accepted: 06/15/2020] [Indexed: 12/01/2022]
Abstract
Studies on the effectiveness and mechanisms of reducing scar formation by interfering with the renin-angiotensin-aldosterone-system (RAAS) have been demonstrated in animals, but not in humans due to the lack of clinical support. Our aim was to investigate whether angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor blocker (ARB) could inhibit scar formation in humans. Thus, an observational and hypothesis-generating study using a designed questionnaire was carried out. A total of 347 patients with postoperative scars secondary to thyroid tumours were enrolled. They were divided into four groups: ACEI group, ARB group, other antihypertensive drugs control group and blank control group according to the administration of antihypertensive drugs. The width of scar was measured, and the Scar Cosmesis Assessment and Rating (SCAR) Scale was filled out. Results showed that patients of ACEI group (mean scar width 1.60 mm) and ARB group (mean scar width 1.57 mm) formed smaller scars than those of other antihypertensive drugs control group (mean scar width 2.09 mm) and blank control group (mean scar width 2.0 mm). Oral administration of ACEI and ARB may be associated with better post-surgical scar formation in humans. These two kinds of antihypertensive drugs may be active components of anti-scar medicine.
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Affiliation(s)
- Yan-Yan Hu
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qing-Qing Fang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao-Feng Wang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wan-Yi Zhao
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Zheng
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ding-Ding Zhang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei-Qiang Tan
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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AlQudah M, Hale TM, Czubryt MP. Targeting the renin-angiotensin-aldosterone system in fibrosis. Matrix Biol 2020; 91-92:92-108. [PMID: 32422329 DOI: 10.1016/j.matbio.2020.04.005] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
Abstract
Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.
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Affiliation(s)
- Mohammad AlQudah
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Canada; Department of Physiology and Biochemistry, College of Medicine, Jordan University of Science and Technology, Jordan
| | - Taben M Hale
- Department of Basic Medical Sciences, University of Arizona College of Medicine Phoenix, United States
| | - Michael P Czubryt
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Canada.
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The Role of High Fat Diets and Liver Peptidase Activity in the Development of Obesity and Insulin Resistance in Wistar Rats. Nutrients 2020; 12:nu12030636. [PMID: 32121057 PMCID: PMC7146256 DOI: 10.3390/nu12030636] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/13/2022] Open
Abstract
High-fat diets (HFD) have been widely associated with an increased risk of metabolic disorders and overweight. However, a high intake of sources that are rich in monounsaturated fatty acids has been suggested as a dietary agent that is able to positively influence energy metabolism and vascular function. The main objective of this study was to analyze the role of dietary fats on hepatic peptidases activities and metabolic disorders. Three diets: standard (S), HFD supplemented with virgin olive oil (VOO), and HFD supplemented with butter plus cholesterol (Bch), were administered over six months to male Wistar rats. Plasma and liver samples were collected for clinical biochemistry and aminopeptidase activities (AP) analysis. The expression of inducible nitric oxide synthase (iNOS) was also determined by Western blot in liver samples. The diet supplement with VOO did not induce obesity, in contrast to the Bch group. Though the VOO diet increased the time that was needed to return to the basal levels of plasma glucose, the fasting insulin/glucose ratio and HOMA2-%B index (a homeostasis model index of insulin secretion and valuation of β-cell usefulness (% β-cell secretion)) were improved. An increase of hepatic membrane-bound dipeptidyl-peptidase 4 (DPP4) activity was found only in VOO rats, even if no differences in fasting plasma glucagon-like peptide 1 (GLP-1) were obtained. Both HFDs induced changes in hepatic pyroglutamyl-AP in the soluble fraction, but only the Bch diet increased the soluble tyrosyl-AP. Angiotensinase activities that are implicated in the metabolism of angiotensin II (AngII) to AngIV increased in the VOO diet, which was in agreement with the higher activity of insulin-regulated-AP (IRAP) in this group. Otherwise, the diet that was enriched with butter increased soluble gamma-glutamyl transferase (GGT) and Leucyl-AP, iNOS expression in the liver, and plasma NO. In summary, VOO increased the hepatic activity of AP that were related to glucose metabolism (DPP4, angiotensinases, and IRAP). However, the Bch diet increased activities that are implicated in the control of food intake (Tyrosine-AP), the index of hepatic damage (Leucine-AP and GGT), and the expression of hepatic iNOS and plasma NO. Taken together, these results support that the source of fat in the diet affects several peptidases activities in the liver, which could be related to alterations in feeding behavior and glucose metabolism.
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Romão MH, de Bem GF, Santos IB, de Andrade Soares R, Ognibene DT, de Moura RS, da Costa CA, Resende ÂC. Açaí (Euterpe oleracea Mart.) seed extract protects against hepatic steatosis and fibrosis in high-fat diet-fed mice: Role of local renin-angiotensin system, oxidative stress and inflammation. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103726] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Zhang Y, Liu H, Jia W, Qi J, Zhang W, Zhang W, Liang G, Zhang Y, Chen H. Myeloid Differentiation Protein 2 Mediates Angiotensin II-Induced Liver Inflammation and Fibrosis in Mice. Molecules 2019; 25:molecules25010025. [PMID: 31861702 PMCID: PMC6983196 DOI: 10.3390/molecules25010025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 12/03/2019] [Accepted: 12/16/2019] [Indexed: 12/18/2022] Open
Abstract
Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.
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Affiliation(s)
- Yi Zhang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China; (Y.Z.); (G.L.)
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Hui Liu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Wenjing Jia
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Jiayu Qi
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Wentao Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Wenxin Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Guang Liang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China; (Y.Z.); (G.L.)
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Yali Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
| | - Hongjin Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; (H.L.); (W.J.); (J.Q.); (W.Z.); (W.Z.); (Y.Z.)
- Correspondence:
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Ranjbar G, Mikhailidis DP, Sahebkar A. Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box! Metabolism 2019; 101:154001. [PMID: 31672448 DOI: 10.1016/j.metabol.2019.154001] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/02/2019] [Accepted: 10/15/2019] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.
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Affiliation(s)
- Golnaz Ranjbar
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Shu Y, Cao XY, Chen J. Preparation and antagonistic effect of ACE inhibitory peptide from cashew. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2019; 99:6822-6832. [PMID: 31385307 DOI: 10.1002/jsfa.9967] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/18/2019] [Accepted: 08/02/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Angiotensin-converting enzyme (ACE) inhibitory peptides were found to alleviate acute hepatitis significantly. In this study, we purified and identified ACE inhibitory peptide from cashew to evaluate its protective role on alcohol-induced acute hepatitis in mice. RESULTS The ACE inhibitory peptides were purified by using consecutive chromatographic techniques. One of these peptides (FETISFK) exhibited the highest ACE inhibition rate (91.04 ± 0.31%). In vivo, the results showed that ACE inhibitory peptide decreased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by alcohol exposure. Moreover, it could increase the activities of superoxide dismutase (SOD) and glutathione (GSH), and decrease the level of malondialdehyde (MDA). It was also found to down-regulate markedly the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). It could also decrease the expression of ACE, angiotensin II (AngII) and angiotensin II type 1 receptor (AT1 R). CONCLUSION These findings support the view that the ACE inhibitory peptide alleviated acute hepatitis by down-regulating the ACE-AngII-AT1 R axis, broadening the research approach to prevent acute hepatitis, and providing experimental data for the development and utilization of cashews. © 2019 Society of Chemical Industry.
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Affiliation(s)
- Yang Shu
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, China
| | - Xian-Ying Cao
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, China
- College of Food Science and Technology, Hainan University, Haikou, China
| | - Jian Chen
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, China
- College of Food Science and Technology, Hainan University, Haikou, China
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Abd El-Rahman SS, Fayed HM. Targeting AngII/AT1R signaling pathway by perindopril inhibits ongoing liver fibrosis in rat. J Tissue Eng Regen Med 2019; 13:2131-2141. [PMID: 31348596 DOI: 10.1002/term.2940] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 07/09/2019] [Accepted: 07/18/2019] [Indexed: 12/14/2022]
Abstract
The renin-angiotensin system (RAS) has a substantial role in liver fibrosis, cirrhosis, and portal hypertension. Hence, targeting RAS through angiotensin-converting enzyme (ACE) inhibitors can mend hepatic fibrosis; the current study was designed to examine the potential fibrosis inhibition activity of perindopril using a rat model of liver fibrosis induced by thioacetamide (TAA). Four groups of rats were used throughout this study, Group I (control group); rats received the vehicle. TAA was used for inducing liver fibrosis in rats by intraperitoneal injection of 200-mg/kg body weight twice a week for 6 weeks. Group II served as (TAA group). Rats of Groups III and IV were given perindopril at doses of 2 and 8 mg/kg 2 weeks after TAA administration and continued concomitantly with TAA till the end of the experiment. Injection of TAA resulted in a significant increase in aminotransferases' activities and bilirubin with a significant decrease in serum albumin and total protein and a significant decrease in hepatic content of GSH and SOD. Additionally, TAA injection raised the hepatic content of TGF-β1, α-SMA, TNF-α, and level of MDA. Histological and immunohistochemical data presented marked fibrosis in liver sections of TAA-administrated rats with increased collagen deposition, elevated METAVIR scoring, and increased expression of α-SMA, caspase-3, and AT1R. Oral dosing of perindopril for 4 weeks concomitant with TAA could mend the altered parameters near to normal values and abolished the ongoing fibrosis extension. In conclusion, these results demonstrated that perindopril, as ACE inhibitor, could grant a superior remedial nominee in preventing liver fibrosis progression through targeting angiotensin II formation.
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Affiliation(s)
| | - Hany M Fayed
- Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
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Abstract
OBJECTIVE Epidemiological studies confirm that hypertensive patients respond differently to renin-angiotensin system (RAS) inhibition depending on their gender. The aim of present work is to focus on sex-dependent differences in RAS regulation under conditions of increased salt intake. METHOD To investigate RAS, we measured the expression of angiotensinogen (Agt) mRNA, angiotensin receptor type 1 (AT1) mRNA and mitochondria assembly receptor (MasR) in the liver of rats under control conditions and after feeding with a salt diet (2% NaCl). In parallel, vascular endothelial growth factor A (VEGF-A) mRNA was analyzed. RESULTS Regression analysis revealed sex-dependent differences in the correlation between mRNA expression of AT1 and that of Agt, MasR and VEGF-A in both groups. There was a significant negative correlation between AT1 and Agt mRNA expression in the male control group, but this correlation disappeared in males exposed to a salt diet. In females, AT1 and Agt expression correlated only in the group exposed to the salt diet. In control males, there was a borderline trend to correlation between AT1 and MasR mRNA expression. The correlation between AT1 and VEGF-A mRNA expression was significant only in the control females, however, after exposure to a salt diet, this correlation diminished. CONCLUSIONS We hypothesize that RAS components expression is compensated differently in males and females. The observed loss of compensatory relationships in RAS between AT1 and Agt and AT1 and MasR in male rats under a salt diet can contribute to the differences observed in human with hypertension associated with an unhealthy diet.
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Charni-Natan M, Aloni-Grinstein R, Osher E, Rotter V. Liver and Steroid Hormones-Can a Touch of p53 Make a Difference? Front Endocrinol (Lausanne) 2019; 10:374. [PMID: 31244779 PMCID: PMC6581675 DOI: 10.3389/fendo.2019.00374] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 05/28/2019] [Indexed: 12/12/2022] Open
Abstract
The liver is the main metabolic organ in the body, serving as a significant hormonal secretory gland and functioning to maintain hormone balance and homeostasis. Steroid hormones regulate various biological pathways, mainly in the reproductive system and in many metabolic processes. The liver, as well as steroid hormones, contribute significantly, through functional intertwine, to homeostasis maintenance, and proper responses during stress. Malfunction of either has a significant impact on the other and may lead to severe liver diseases as well as to several endocrine syndromes. Thus, the regulation on liver functions as on steroid hormones levels and activities is well-controlled. p53, the well-known tumor suppressor gene, was recently found to regulate metabolism and general homeostasis processes, particularly within the liver. Moreover, p53 was shown to be involved in steroid hormones regulation. In this review, we discuss the bi-directional regulation of the liver and the steroid hormones pointing to p53 as a novel regulator in this axis. A comprehensive understanding of the molecular mechanisms of this axis may help to prevent and treat related disease, especially with the increasing exposure of the population to environmental steroid hormones and steroid hormone-based medication.
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Affiliation(s)
- Meital Charni-Natan
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ronit Aloni-Grinstein
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Etty Osher
- Sackler Faculty of Medicine, Tel Aviv-Sourasky Medical Center, Institute of Endocrinology Metabolism and Hypertension, Tel Aviv University, Tel Aviv, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Mirabito Colafella KM, Bovée DM, Danser AHJ. The renin-angiotensin-aldosterone system and its therapeutic targets. Exp Eye Res 2019; 186:107680. [PMID: 31129252 DOI: 10.1016/j.exer.2019.05.020] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 05/16/2019] [Accepted: 05/22/2019] [Indexed: 12/22/2022]
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment of cardiovascular and renal diseases. Angiotensin II and aldosterone are the two most powerful biologically active products of the RAAS, inducing all of the classical actions of the RAAS including vasoconstriction, sodium retention, tissue remodeling and pro-inflammatory and pro-fibrotic effects. In recent years, new components of the RAAS have been discovered beyond the classical pathway that have led to the identification of depressor or so-called protective RAAS pathways and the development of novel therapies targeting this system. Moreover, dual inhibitors which block the RAAS and other systems involved in the regulation of blood pressure or targeting upstream of angiotensin II by selectively deleting liver-derived angiotensinogen, the precursor to all angiotensins, may provide superior treatment for cardiovascular and renal diseases and revolutionize RAAS-targeting therapy.
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Affiliation(s)
- Katrina M Mirabito Colafella
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia
| | - Dominique M Bovée
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
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Nehme A, Zouein FA, Zayeri ZD, Zibara K. An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology. J Cardiovasc Dev Dis 2019. [PMID: 30934934 DOI: 10.3390/jcdd6020014.pmid:30934934;pmcid:pmc6617132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
In its classical view, the renin angiotensin system (RAS) was defined as an endocrinesystem involved in blood pressure regulation and body electrolyte balance. However, the emergingconcept of tissue RAS, along with the discovery of new RAS components, increased thephysiological and clinical relevance of the system. Indeed, RAS has been shown to be expressed invarious tissues where alterations in its expression were shown to be involved in multiple diseasesincluding atherosclerosis, cardiac hypertrophy, type 2 diabetes (T2D) and renal fibrosis. In thischapter, we describe the new components of RAS, their tissue-specific expression, and theiralterations under pathological conditions, which will help achieve more tissue- and conditionspecifictreatments.
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Affiliation(s)
- Ali Nehme
- EA4173, Functional genomics of arterial hypertension, Univeristy Claude Bernard Lyon-1 (UCBL-1),69008 Lyon, France.
| | - Fouad A Zouein
- Department of Pharmacology and Toxicology, Heart Repair Division, Faculty of Medicine,American University of Beirut, Beirut 11-0236, Lebanon.
| | - Zeinab Deris Zayeri
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz JundishapurUniversity of Medical Sciences, Ahvaz, Iran.
| | - Kazem Zibara
- PRASE, Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
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Nehme A, Zouein FA, Zayeri ZD, Zibara K. An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology. J Cardiovasc Dev Dis 2019; 6:jcdd6020014. [PMID: 30934934 PMCID: PMC6617132 DOI: 10.3390/jcdd6020014] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 03/18/2019] [Accepted: 03/26/2019] [Indexed: 02/07/2023] Open
Abstract
In its classical view, the renin angiotensin system (RAS) was defined as an endocrine system involved in blood pressure regulation and body electrolyte balance. However, the emerging concept of tissue RAS, along with the discovery of new RAS components, increased the physiological and clinical relevance of the system. Indeed, RAS has been shown to be expressed in various tissues where alterations in its expression were shown to be involved in multiple diseases including atherosclerosis, cardiac hypertrophy, type 2 diabetes (T2D) and renal fibrosis. In this chapter, we describe the new components of RAS, their tissue-specific expression, and their alterations under pathological conditions, which will help achieve more tissue- and condition-specific treatments.
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Affiliation(s)
- Ali Nehme
- EA4173, Functional genomics of arterial hypertension, Univeristy Claude Bernard Lyon-1 (UCBL-1),69008 Lyon, France.
| | - Fouad A Zouein
- Department of Pharmacology and Toxicology, Heart Repair Division, Faculty of Medicine,American University of Beirut, Beirut 11-0236, Lebanon.
| | - Zeinab Deris Zayeri
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz JundishapurUniversity of Medical Sciences, Ahvaz, Iran.
| | - Kazem Zibara
- PRASE, Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
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Deng Z, Guo Q, Zhu Z. Dynamic Regulation of Level Set Parameters Using 3D Convolutional Neural Network for Liver Tumor Segmentation. JOURNAL OF HEALTHCARE ENGINEERING 2019; 2019:4321645. [PMID: 30918620 PMCID: PMC6409057 DOI: 10.1155/2019/4321645] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/06/2019] [Indexed: 02/07/2023]
Abstract
Segmentation of liver tumors plays an important role in the choice of therapeutic strategies for liver disease and treatment monitoring. In this paper, we generalize the process of a level set with a novel algorithm of dynamic regulation to energy functional parameters. The presented method is fully automatic once the tumor has been detected. First, a 3D convolutional neural network with dense layers for classification is used to estimate current contour location relative to the tumor boundary. Second, the output 3D CNN probabilities can dynamically regulate parameters of the level set functional over the process of segmentation. Finally, for full automation, appropriate initializations and local window size are generated based on the current contour position probabilities. We demonstrate the proposed method on the dataset of MICCAI 2017 LiTS Challenge and 3DIRCADb that include low contrast and heterogeneous tumors as well as noisy images. To illustrate the strength of our method, we evaluated it against the state-of-the-art methods. Compared with the level set framework with fixed parameters, our method performed better significantly with an average DICE improvement of 0.15. We also analyzed a challenging dataset 3DIRCADb of tumors and obtained a competitive DICE of 0.85 ± 0.06 with the proposed method.
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Affiliation(s)
- Zhuofu Deng
- College of Software, Northeastern University, Shenyang 110004, China
| | - Qingzhe Guo
- College of Software, Northeastern University, Shenyang 110004, China
| | - Zhiliang Zhu
- College of Software, Northeastern University, Shenyang 110004, China
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Gonçalves LR, de Oliveira da Silva B, Scarinci LD, Ramos LF, Moraes KC. MicroRNA-1254 contributes to the controlling of pro-fibrogenic environment in LX-2 cells by modulating SMAD3 and wound repair: new insights in hepatic fibrosis. Cell Biol Int 2019; 43:333-343. [DOI: 10.1002/cbin.11075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 11/15/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Letícia Rocha Gonçalves
- Laboratório de Biologia Molecular, Departamento de Biologia; Instituto de Biociências, Universidade Estadual Paulista “Júlio de Mesquita Filho” − Campus Rio Claro; Rio Claro SP 13506-900 Brazil
| | | | - Letícia Destefani Scarinci
- Laboratório de Biologia Molecular, Departamento de Biologia; Instituto de Biociências, Universidade Estadual Paulista “Júlio de Mesquita Filho” − Campus Rio Claro; Rio Claro SP 13506-900 Brazil
| | - Letícia Ferreira Ramos
- Laboratório de Biologia Molecular, Departamento de Biologia; Instituto de Biociências, Universidade Estadual Paulista “Júlio de Mesquita Filho” − Campus Rio Claro; Rio Claro SP 13506-900 Brazil
| | - Karen C.M. Moraes
- Laboratório de Biologia Molecular, Departamento de Biologia; Instituto de Biociências, Universidade Estadual Paulista “Júlio de Mesquita Filho” − Campus Rio Claro; Rio Claro SP 13506-900 Brazil
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de Miranda AS, Simões e Silva AC. Liver. ANGIOTENSIN-(1-7) 2019. [PMCID: PMC7121918 DOI: 10.1007/978-3-030-22696-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The discovery that renin–angiotensin system (RAS) components are locally expressed in the liver tissue, pointed out to a role for this system in the pathogenesis of hepatic fibrosis and cirrhosis. The RAS counter-regulatory axis composed by the angiotensin converting enzyme 2 (ACE2), angiotensin-(1-7) [Ang-(1-7)] and Mas receptor mediates pro-inflammatory, pro-thrombotic, and pro-fibrotic processes, frequently opposing the classical RAS arm (ACE-Ang II-AT1 receptor) actions. Therefore, the balance between both RAS axes most likely affects the clinical and histopathological expression of liver diseases. It is worth noticing that liver diseases are major causes of morbidity and mortality worldwide. Without proper treatment, all types of chronic hepatitis will progress to end-stage liver diseases, including cirrhosis, liver failure, and hepatocellular carcinoma, which ultimately lead to death. In this context, to better comprehend the role of RAS components in liver failure might pave the way for the search of potential predictive biomarkers as well as the development of novel therapeutic approaches. Valuable data have been generated from preclinical and clinical studies. Herein, we summarize the current evidence, mainly focusing in the ACE2-Ang-(1-7)-Mas receptor arm, regarding the role of RAS in liver diseases. The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.
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Hussain SA, Utba RM, Assumaidaee AM. Effects of Azilsartan, Aliskiren or their Combination on High Fat Diet-induced Non-alcoholic Liver Disease Model in Rats. Med Arch 2018; 71:251-255. [PMID: 28974844 PMCID: PMC5585811 DOI: 10.5455/medarh.2017.71.251-255] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION In addition to its role in regulation of blood pressure, fluid and electrolyte homeostasis, the renin-angiotensin system (RAS) components were expressed in many other tissues suggesting potential roles in their functions. AIM The present study aims to evaluate the protective effect aliskiren, when used alone or in combination with azilsartan against high fat diet-induced liver disease in rats. MATERIAL AND METHODS Thirty-two Wistar male rats, weighing 150-200 gm were allocated evenly into four groups and treated as follow: group I, rats were fed a specially formulated high-fat diet for 8 weeks to induce non-alcoholic liver disease and considered as control group; groups II, III and IV, the rats were administered azilsartan (0.5 mg/kg), aliskiren (25 mg/kg) or their combination orally via gavage tube once daily, and maintained on high fat diet for 8 weeks. The possible treatment outcome was evaluated through measuring serum levels of glucose, insulin, lipid profile, TNF-α, IL-1β and liver enzymes. Additionally, the liver tissue contents of glycogen and lipids and histological changes were also evaluated. RESULT The results showed that azilsartan significantly improves the studied markers greater than aliskiren, and their combination o has no additive or synergistic effects on the activity of each one of them. CONCLUSION Both azilsartan and aliskiren protects the rats against high-fat diet induced NAFLD with predominant effects for the former, and their combination showed no beneficial synergistic or additive effects.
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Affiliation(s)
| | - Rabab Mohammed Utba
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
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Karimi J, Mohammadalipour A, Sheikh N, Khodadadi I, Hashemnia M, Goudarzi F, Khanjarsim V, Solgi G, Hajilooi M, Bahabadi M, Kheiripour N, Hedayatyanfard K. Protective effects of combined Losartan and Nilotinib on carbon tetrachloride (CCl 4)-induced liver fibrosis in rats. Drug Chem Toxicol 2018; 43:468-478. [PMID: 30207194 DOI: 10.1080/01480545.2018.1504960] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tyrosine kinase inhibitors (TKIs) have been developed as therapeutic compounds for inhibiting the progression of liver fibrosis. In the present study, the simultaneous treatment of Nilotinib (TKIs) and Losartan was studied. Forty rats were divided into eight groups of fibrosis induced by carbon tetrachloride (CCl4) and therapeutics (Nilotinib, Losartan, and combination therapy). In the end, serum parameters of the liver and gene expression analysis of transforming growth factor-β1, its receptors (TβRII), platelet-derived growth factor, its receptors (PDGFRβ), matrix metalloproteinases (MMP-2 and MMP-9), tumor necrosis factor-α, cytochrome P450 2E1, and collagen1 type 1 were performed. The oxidant/antioxidant factors were also analyzed. Histopathology analysis along with α-SMA immunohistochemistry and hydroxyproline evaluation was also conducted for a more in-depth study. The overall results indicated a better therapeutic effect of co-treatment of Nilotinib-Losartan in comparison with the treatment of each of them alone. Interestingly, some gene and protein factors and fibrotic indices were reduced even to the normal levels of the control group. The results of this study suggest that co-administration of these two combinations, strengthens their anti-fibrotic properties and, due to the routine use of these compounds against AML and blood pressure, these compounds can be used with caution against human liver fibrosis.
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Affiliation(s)
- Jamshid Karimi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.,Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Adel Mohammadalipour
- Faculty of Pharmacy and Pharmaceutical Sciences, Department of Clinical Biochemistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasrin Sheikh
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Iraj Khodadadi
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Hashemnia
- Veterinary Medicine Faculty, Departments of Pathobiology, Razi University, Kermanshah, Iran
| | - Farjam Goudarzi
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Vahid Khanjarsim
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ghasem Solgi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mehrdad Hajilooi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Majid Bahabadi
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Nejat Kheiripour
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Keshvad Hedayatyanfard
- Faculty of Medicine, Department of Pharmacology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Tiao MM, Lin YJ, Yu HR, Sheen JM, Lin IC, Lai YJ, Tain YL, Huang LT, Tsai CC. Resveratrol ameliorates maternal and post-weaning high-fat diet-induced nonalcoholic fatty liver disease via renin-angiotensin system. Lipids Health Dis 2018; 17:178. [PMID: 30055626 PMCID: PMC6064630 DOI: 10.1186/s12944-018-0824-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/11/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD. METHODS Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120. RESULTS We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group. CONCLUSION Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.
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Affiliation(s)
- Mao-Meng Tiao
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Yu-Ju Lin
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 83301, Taiwan, Republic of China
| | - Hong-Ren Yu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - I-Chun Lin
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Yun-Ju Lai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 83301, Taiwan, Republic of China
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung, 83301, Taiwan
| | - Ching-Chou Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 83301, Taiwan, Republic of China.
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Borém LMA, Neto JFR, Brandi IV, Lelis DF, Santos SHS. The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease: a brief review. Hypertens Res 2018; 41:394-405. [PMID: 29636553 PMCID: PMC7091617 DOI: 10.1038/s41440-018-0040-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 10/31/2017] [Accepted: 11/17/2017] [Indexed: 01/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered an important component of metabolic syndrome (MetS). The spectrum of NAFLD includes conditions that range from simple hepatic steatosis to non-alcoholic steatohepatitis. NAFLD is correlated with liver-related death and is predicted to be the most frequent indication for liver transplantation by 2030. Insulin resistance is directly correlated to the central mechanisms of hepatic steatosis in NAFLD patients, which is strongly correlated to the imbalance of the renin–angiotensin system, that is involved in lipid and glucose metabolism. Among the emerging treatment approaches for NAFLD is the anti-hypertensive agent telmisartan, which has positive effects on liver, lipid, and glucose metabolism, especially through its action on the renin–angiotensin system, by blocking the ACE/AngII/AT1 axis and increasing ACE2/Ang(1–7)/Mas axis activation. However, treatment with this drug is only recommended for patients with an established indication for anti-hypertensive therapy. Thus, there is an increased need for large randomized controlled trials with the aim of elucidating the effects of telmisartan on liver disease, especially NAFLD. From this perspective, the present review aims to provide a brief examination of the pathogenesis of NAFLD/NASH and the role of telmisartan on preventing liver disorders and thus to improve the discussion on potential therapies.
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Affiliation(s)
- Luciana M A Borém
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil.,Medicine Department, Faculdades Integradas Pitágoras, Montes Claros, Minas Gerais, Brazil
| | - João F R Neto
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Igor V Brandi
- Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
| | - Deborah F Lelis
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Sergio H S Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil. .,Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
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47
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Eshraghian A, Iravani S, Azimzadeh P. The Association between Angiotensin II Type 1 Receptor Gene A1166C Polymorphism and Non-alcoholic Fatty Liver Disease and Its Severity. Middle East J Dig Dis 2018; 10:96-104. [PMID: 30013758 PMCID: PMC6040929 DOI: 10.15171/mejdd.2018.97] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 03/20/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Genetic predisposition may have important role in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Angiotensin II type I receptor (AGTR1) has been known to involve in the process of liver steatosis and fibrosis. This study aimed to investigate the association between AGTR1 A1166C polymorphism and NAFLD. METHODS A cross-sectional study was conducted during May 2014-May 2015 among healthy adults referring to our radiology clinic for abdominal sonography. AGTR1 A1166C polymorphism was evaluated in subjects with NAFLD and healthy individuals using allelic discrimination method. RESULTS 58 subjects with NAFLD were compared with 88 healthy individuals without NAFLD. The frequency of AA and CC genotypes of AGTR1 was significantly higher in patients with NAFLD compared with controls (p = 0.029 and 0.042, respectively). C allele was more detected in subjects with NAFLD compared with the healthy controls (OR: 2.1; 95% CI: 1.23-3.61, p = 0.006). CC genotype (OR: 10.62; 95% CI: 1.05-106.57, p = 0.045) and C allele (OR: 6.81; 95% CI: 1.42- 32.48, p = 0.016) were also predictors of severe fatty liver disease in our study population. CONCLUSION Our results provide the first evidence that AGTR1 gene A1166C polymorphism not only is associated with NAFLD and but also may predict its severity.
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Affiliation(s)
- Ahad Eshraghian
- Department of Gastroenterology and Hepatology, AJA University of Medical Sciences, Tehran, Iran.,Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahrokh Iravani
- Department of Gastroenterology and Hepatology, AJA University of Medical Sciences, Tehran, Iran
| | - Pedram Azimzadeh
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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48
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Xiao P, Long X, Zhang L, Ye Y, Guo J, Liu P, Zhang R, Ning J, Yu W, Wei F, Yu J. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. Oncoimmunology 2018; 7:e1440166. [PMID: 29900041 DOI: 10.1080/2162402x.2018.1440166] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 01/31/2018] [Accepted: 02/06/2018] [Indexed: 12/12/2022] Open
Abstract
We previously demonstrated that neurotensin (NTS) induces local inflammation and promotes tumor invasion in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms are not clear. In this study, positive correlations between NTS and interleukin (IL)-8 were identified at both the mRNA and protein levels in 71 fresh HCC tissues and 100 paraffin-embedded HCC tissues. Furthermore, significant correlations were determined among the co-expression of NTS and IL-8, infiltration of inflammatory cells and enhanced epithelial-mesenchymal transition (EMT) of HCC cells. NTS-induced IL-8 production was associated with activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways rather than the protein kinase C (PKC) and phosphoinositide-3 kinase (PI3K) pathways, whose specific antagonists significantly inhibited activation of the NTS/IL-8 pathway. IL-8, which promoted EMT and HCC invasion both in vitro and in vivo, was produced by NTS-induced HCC cells and was effectively attenuated by blocking IL-8 receptors in vitro. Moreover, HCC-derived IL-8 attracted more CD68+ tumor-associated macrophages (TAMs) and CD66b+ polymorphonuclear neutrophils (PMNs) to the local microenvironment, displaying enhanced cytokine secretion and phagocytosis. IL-8 stimulated the M2 polarization of TAMs, which promoted the EMT and invasive potential of HCC cells. Blockage of the IL-8 receptor, NTR1 receptor or both significantly reduced HCC metastases in tumor-bearing mouse models via inhibiting EMT. In summary, aberrant activation of the NTS/IL-8 pathway in HCC dramatically stimulated the invasive potential of HCC cells. HCC-derived IL-8 promoted a pro-oncogenic inflammatory microenvironment by inducing M2-type TAMs and indirectly promoting EMT, which might be a valuable therapeutic target to prevent tumor progression.
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Affiliation(s)
- Pei Xiao
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China.,Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, P. R. China
| | - Xinxin Long
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Shandong, P.R. China
| | - Lijie Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China.,Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, P. R. China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
| | - Jincheng Guo
- Bioinformatics Research Group & Health Big-Data, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
| | - Rui Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China
| | - Junya Ning
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China.,Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, P. R. China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, P. R. China
| | - Feng Wei
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, P. R. China
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P. R. China.,Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, P. R. China
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de Oliveira da Silva B, Alberici LC, Ramos LF, Silva CM, da Silveira MB, Dechant CRP, Friedman SL, Sakane KK, Gonçalves LR, Moraes KCM. Altered global microRNA expression in hepatic stellate cells LX-2 by angiotensin-(1-7) and miRNA-1914-5p identification as regulator of pro-fibrogenic elements and lipid metabolism. Int J Biochem Cell Biol 2018. [PMID: 29524604 DOI: 10.1016/j.biocel.2018.02.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of new therapeutic strategies to control or reverse hepatic fibrosis requires thorough knowledge about its molecular and cellular basis. It is known that the heptapeptide angiotensin-(1-7) [ang-(1-7)] can reduce hepatic fibrosis and steatosis in vivo; therefore, it is important to uncover the mechanisms regulating its activity and cellular model of investigation. Ang-(1-7) is a peptide of the renin-angiotensin system (RAS), and here we investigated its modulatory effect on the expression pattern of microRNAs (miRNAs) in hepatic stellate cells (HSCs) LX-2, which transdifferentiate into fibrogenic and proliferative cells. We compared the miRNA profiles between quiesced, activated and ang-(1-7)-treated activated HSCs to identify miRNAs that may regulate their transdifferentiation. Thirteen miRNAs were pointed, and cellular and molecular analyses identified miRNA-1914-5p as a molecule that contributes to the effects of ang-(1-7) on lipid metabolism and on the pro-fibrotic environment control. In our cellular model, we also analyzed the regulators of fatty acid metabolism. Specifically, miRNA-1914-5p regulates the expression of malonyl-CoA decarboxylase (MLYCD) and phosphatidic acid phosphohydrolase (PAP or Lipin-1). Additionally, Lipin-1 was closely correlated with mRNA expression of peroxisome proliferator-activated receptors (PPAR)-α and -γ, which also contribute to lipid homeostasis and to the reduction of TGF-β1 expression. These findings provide a novel link between RAS and lipid metabolism in controlling HSCs activation.
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Affiliation(s)
- Brenda de Oliveira da Silva
- Núcleo de Pesquisa em Biologia, Universidade Federal de Ouro Preto, UFOP, Ouro Preto, MG, Brazil; Molecular Biology Laboratory, Department of Biology, Bioscience Institute, Universidade Estadual Paulista "Júlio de Mesquita Filho", UNESP, Rio Claro, SP, Brazil
| | - Luciane Carla Alberici
- Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil
| | - Letícia Ferreira Ramos
- Molecular Biology Laboratory, Department of Biology, Bioscience Institute, Universidade Estadual Paulista "Júlio de Mesquita Filho", UNESP, Rio Claro, SP, Brazil
| | - Caio Mateus Silva
- Molecular Biology Laboratory, Department of Biology, Bioscience Institute, Universidade Estadual Paulista "Júlio de Mesquita Filho", UNESP, Rio Claro, SP, Brazil
| | - Marina Bonfogo da Silveira
- Molecular Biology Laboratory, Department of Biology, Bioscience Institute, Universidade Estadual Paulista "Júlio de Mesquita Filho", UNESP, Rio Claro, SP, Brazil
| | - Carlos R P Dechant
- Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA
| | - Kumiko Koibuchi Sakane
- Institute of Research and Development of Universidade do Vale do Paraíba, UNIVAP, São José dos Campos, SP, Brazil
| | - Letícia Rocha Gonçalves
- Molecular Biology Laboratory, Department of Biology, Bioscience Institute, Universidade Estadual Paulista "Júlio de Mesquita Filho", UNESP, Rio Claro, SP, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Department of Biology, Bioscience Institute, Universidade Estadual Paulista "Júlio de Mesquita Filho", UNESP, Rio Claro, SP, Brazil.
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Balancing Effect of Biejiajian Oral Liquid () on ACE-Ang II-AT1R Axis and ACE2-Ang-(1-7)-Mas Axis in Rats with CCl 4-Induced Hepatic Fibrosis. Chin J Integr Med 2018; 24:853-859. [PMID: 29335866 DOI: 10.1007/s11655-017-2909-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To explore the effect of Biejiajian Oral Liquid (, BOL) on CCl4-induced hepatic fibrosis in rats by detecting the changes in the levels of angiotensin II (Ang II), angiotensin-(1-7) [Ang-(1-7)], angiotensin-converting enzyme (ACE), ACE2, angiotensin II type 1 receptor (AT1R), Mas, etc. METHODS: A total of 180 Wistar rats were randomly divided into two groups by random digital table method: prevention experiment and treatment experiment. Each group was further subdivided into the following 6 subgroups: normal control group, model group, vitamin E [100 mg/(kg·d), VE] group, enalapril [10 mg/(kg·g), Ena] group, high-dosage [20 g/(kg·d)] BOL group, and low-dosage [10 g/(kg·d)] BOL group. The hepatic fibrosis rat model was established by subcutaneous injection of CCl4 for 6 weeks. Prevention experiment and treatment experiment were administered with specific drugs at different times. At the end of treatment experiment, the pathological changes of liver were observed after hematoxylin-eosin staining. The expressions of ingredients in renin-angiotensin-aldosterone system (RAAS) such as AngII, Ang-(1-7), ACE, ACE2, AT1R, Mas, renin, CYP11B2 and angen in liver were detected by enzyme linked immunosorbent assay, immunohistochemistry method or reverse transcription-polymerase chain reaction, respectively. RESULTS The levels of AngII and Ang-(1-7) at the 6th week increased by 496.10% and 73.64%, respectively, compared with those at the 2nd week in the model group (P<0.01). With prevention or treatment with high-dosage BOL, there was an evident reduction of AngII level but an improvement of Ang-(1-7) level. Specifically, AngII level of high-dosage group decreased by 77.50% in prevention experiment (P=0.000) and by 76.93% in treatment experiment (P=0.002) compared with that in the model group. Ang-(1-7) level increased by 91.69% in prevention experiment (P=0.006) and by 70.77% in the treatment experiment (P=0.010) compared with that in the model group. The expression levels of mRNA of renin, ACE, CYP11B2, angen and AT1R decreased by 58.15%, 99.90%, 99.84%, 99.99% and 99.99% (all P<0.01), respectively. CONCLUSIONS BOL could help resist liver fibrosis in rats by enhancing the level of each ingredient in ACE2-Ang-(1-7)-Mas axis, while decreasing the level of each ingredient in ACE-AngII-AT1R axis. To some extent, BOL could enhance the regulation of RAAS in rats with CCl4-induced hepatic fibrosis.
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