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Effects of Yinchenhao Decoction on Self-regulation of Renin-angiotensin System by Targeting Angiotensin converting enzyme 2 in Bile Duct-ligated Rat Liver

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2015年第4期35卷 519-524页

作者：吴琳周丕琪谢纪文朱锐周顺长汪赓吴中旭郝莎 Department of Integrated Traditional Chinese and Western Medicine Union HospitalTongji Medical CollegeHuazhong University of Science and Technology Animal Experiment Center Tongji Medical CollegeHuazhong University of Science and Technology Department of Gastrointestinal Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Gastroenterology Xianning Central Hospital

Summary： In order to investigate whether Yinchenhao decoction （YCHD） attenuates hepatic fibro- genesis in the bile duct ligation （BDL） model via recovering and restoring the self-regulation and bal- ance of the renin-angiotensin system （RAS）, 33 specific-pathogen-free （SPF） male Sprague-Dawley rats with common BDL and scission were randomly divided into five groups as follows： G1, the sham group （n=4）; G2, BDL 7-day group （n=5）; G3, BDL＋YCHD 430 mg/mL （n=8）; G4, BDL＋losartan 0.65 mg/mL （ARB group, n=8）; G5, model group （BDL without any treatment, n=8）. YCHD and losartan （10 mL.kgl.day-1） were given by gastric gavage for 16 days following BDL in G3 and G4 groups, respec- tively. The effect of YCHD on liver fibrosis and the detailed molecular mechanisms were assessed by liver function including total bilirubin （TBIL）, direct bilirubin （DBIL）, indirect bilirubin （IDBIL）, alanine aminotransferase （ALT）, and aspartate aminotransferase （AST）. Histological changes were ob-. served by transmission electron microscopy （TEM） and Masson trichrome staining. Western blotting was used to detect the protein expression level of the renin-angiotensin system （RAS） components in- cluding angiotensin converting enzyme （ACE）, angiotensin II type 1 receptor （AT1R）, ACE2, angio- tensin II （Ang II） as well as transforming growth factor 131 （TGF131）. The experimental data were ana- lyzed by principle component analytical method of pattern recognition. The results showed that bio- chemically, serum TBIL, DBIL, IDBIL, ALT and AST levels were markedly increased following BDL as compared with the sham group （P〈0.05）. Serum TBIL, IDBIL and DBIL levels in G3 group were dramatically decreased as compared with G5 and G4 groups （P〈0.05）. Serum AST level in G3 was sig- nificantly lowered than in G5 group （P〈0.05）, but there was no significant difference in ALT among G3, G4 and G5 groups （P〉0.05）. Histologically, livers in G3 group showed less hepatocytes necrosis, less bile duct hyperplasia and less collagen formation than in G4 and G5 groups. The

关键词： Yinchenhao decoction liver fibrosis Angiotensin converting enzyme 2 rein-angiotensin system transforming growth factorβ1 bile duct ligation

angiotensin-converting enzyme 2 receptors,chronic liver diseases,common medications,and clinical outcomes in coronavirus disease 2019 patients

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World Journal of Virology 2021年第3期10卷 86-96页

作者： Wattana Leowattana Clinical Tropical Medicine Faculty of Tropical MedicineMahidol UniversityBangkok 10400Thailand

The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the virus responsible for coronavirus disease 2019(COVID-19),enters affected cells through the angiotensin-converting enzyme 2(ACE2)receptor,which is highly expressed in type II alveolar cells,enterocytes,and cholangiocytes.SARS-CoV-2 infection causes fever,dry cough,and breathing difficulty,which can progress to respiratory distress due to interstitial pneumonia,and hepatobiliary injury due to COVID-19 is increasingly recognized.The hepatobiliary injury may be evident at presentation of the disease or develop during the disease progression.The development of more severe clinical outcomes in patients with chronic liver diseases(CLD)with or without cirrhosis infected with SARS-CoV-2 has not been elucidated.Moreover,there is limited data related to common medications that affect the disease severity of COVID-19 patients.Additionally,ACE2 receptor expression of hepatobiliary tissue related to the disease severity also have not been clarified.This review summarized the current situation regarding the clinical outcomes of COVID-19 patients with chronic liver diseases who were treated with common medications.Furthermore,the association between ACE2 receptor expression and disease severity in these patients is discussed.

关键词： SARS-CoV-2 COVID-19 Hepatobiliary tissue Angiotensin converting enzyme 2 Chronic liver disease Common medications Clinical outcome

COVID-19 and Alzheimer’s disease:how one crisis worsens the other

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Translational Neurodegeneration 2021年第2期10卷 178-194页

作者： Xiaohuan Xia Yi Wang Jialin Zheng Center for Translational Neurodegeneration and Regenerative Therapy Tenth People’s Hospital of Tongji UniversityShanghai 200072China Translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People’s Hospital Affiliated to Tongji University School of MedicineShanghai 200434China Collaborative Innovation Center for Brain Science Tongji UniversityShanghai 200092China Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical CenterOmahaNE 68198-5930USA

Alzheimer’s disease(AD)has emerged as a key comorbidity of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).The morbidity and mortality of COVID-19 are elevated in AD due to multiple pathological changes in AD patients such as the excessive expression of viral receptor Angiotensin converting enzyme 2 and pro-inflammatory molecules,various AD complications including diabetes,lifestyle alterations in AD,and drug-drug interactions.Meanwhile,COVID-19 has also been reported to cause various neurologic symptoms including cognitive impairment that may ultimately result in AD,probably through the invasion of SARS-CoV-2 into the central nervous system,COVID-19-induced inflammation,long-term hospitalization and delirium,and post-COVID-19 syndrome.In addition,the COVID-19 crisis also worsens behavioral symptoms in uninfected AD patients and poses new challenges for AD prevention.In this review,we first introduce the symptoms and pathogenesis of COVID-19 and AD.Next,we provide a comprehensive discussion on the aggravating effects of AD on COVID-19 and the underlying mechanisms from molecular to social levels.We also highlight the influence of COVID-19 on cognitive function,and propose possible routes of viral invasion into the brain and potential mechanisms underlying the COVID-19-induced cognitive impairment.Last,we summarize the negative impacts of COVID-19 pandemic on uninfected AD patients and dementia prevention.

关键词： COVID-19 SARS-CoV-2 Alzheimer’s disease Central nervous system Inflammation Cognitive impairment Angiotensin converting enzyme 2

2019 novel-coronavirus: Cardiovascular insights about risk factors, myocardial injury, therapy and clinical implications

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Chronic Diseases and Translational Medicine 2020年第4期6卷 246-250页

作者： Luigi Cappannoli Roberto Scacciavillani Giulia Iannaccone Gianluca Anastasia Federico Di Giusto Valentina Loria Nadia Aspromonte Department of Cardiovascular and Thoracic Sciences Fondazione Policlinico Universitario A.Gemelli IRCCSRome 00168Italy

From December 31st,2019,a novel highly pathogenic coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide,reaching at present the dimension of a pandemic.In addition to damaging the lungs,SARS-CoV-2 may also damage the heart and this is corroborated by the evidence that cardiovascular comorbidities are associated with a higher mortality and poor clinical outcomes in patient infected by the virus.During the infection myocardial injury,myocarditis and arrhythmias have also been reported,but the pathophysiological mechanisms of these complications are yet to be understood.Great attention is also being posed on the potential beneficial/harmful role of angiotensin converting enzyme(ACE)inhibitors,as far as the virus binds to ACE2 to infect cells,but evidences lack.Furthermore,SARS-CoV-2 can also affect the aspect of acute coronary syndromes,not only because these two distinct pathological entities share pathogenic aspects(such as the systemic inflammatory state and cytokine release),but also and above all for the consequences that the need to contain the infection has on the management of cardiological urgencies.The aim of this review was therefore to summarize the relationship between the virus and the cardiovascular system.

关键词： COVID-19 Cardiovascular Angiotensin converting enzyme 2 angiotensin converting enzyme inhibitors angiotensin-II receptor blockers

Clinical implications of COVID-19 in patients with metabolicassociated fatty liver disease

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World Journal of Gastroenterology 2023年第3期29卷 487-502页

作者： Mohammad Sadiq Jeeyavudeen Rahul Chaudhari Joseph M Pappachan Sherouk Fouda Department of Endocrinology and Metabolism University Hospitals of EdinburghEdinburgh EH42XUUnited Kingdom Department of Gastroenterology Hepatology and NutritionVirginia Commonwealth UniversityRichmondVA 23298United States Department of Endocrinology and Metabolism Lancashire Teaching Hospitals NHS TrustPreston PR29HTUnited Kingdom Faculty of Science Manchester Metropolitan UniversityManchester M156BHUnited Kingdom Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PLUnited Kingdom School of Health and Biomedical Sciences RMIT UniversityMelbourne VICAustralia

People across the world are affected by the"coronavirus disease 2019(COVID-19)",brought on by the"SARS-CoV type-2 coronavirus".Due to its high incidence in individuals with diabetes,metabolic syndrome,and metabolic-associated fatty liver disease(MAFLD),COVID-19 has gained much attention.The metabolic syndrome's hepatic manifestation,MAFLD,carries a significant risk of type-2-diabetes.The link between the above two conditions has also drawn increasing consideration since MAFLD is intricately linked to the obesity epidemic.Independent of the metabolic syndrome,MAFLD may impact the severity of the viral infections,including COVID-19 or may even be a risk factor.An important question is whether the present COVID-19 pandemic has been fueled by the obesity and MAFLD epidemics.Many liver markers are seen elevated in COVID-19.MAFLD patients with associated comorbid conditions like obesity,cardiovascular disease,renal disease,malignancy,hypertension,and old age are prone to develop severe disease.There is an urgent need for more studies to determine the link between the two conditions and whether it might account for racial differences in the mortality and morbidity rates linked to COVID-19.The role of innate and adaptive immunity alterations in MAFLD patients may influence the severity of COVID-19.This review investigates the implications of COVID-19 on liver injury and disease severity and viceversa.We also addressed the severity of COVID-19 in patients with prior MAFLD and its potential implications and therapeutic administration in the clinical setting.

关键词： Metabolic-associated fatty liver disease COVID-19 Metabolic syndrome Non-alcoholic steatohepatitis Angiotensin converting enzyme 2

Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract

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World Journal of Gastroenterology 2021年第39期27卷 6590-6600页

作者： Izabela Berdowska Malgorzata Matusiewicz Department of Biochemistry and Immunochemistry Wroclaw Medical UniversityWroclaw 50-368Lower SilesiaPoland

Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)seems to employ two routes of entrance to the host cell;via membrane fusion(with the cells expressing both Angiotensin converting enzyme 2(ACE2)and transmembrane peptidase/serine subfamily member 2/4(TMPRSS2/4))or via receptor-mediated endocytosis(to the target cells expressing only ACE2).The second mode is associated with cysteine cathepsins(probably cathepsin L)involvement in the virus spike protein(S protein)proteolytic activation.Also furin might activate the virus S protein enabling it to enter cells.Gastrointestinal tract(GIT)involvement in SARS-CoV-2 infection is evident in a subset of coronavirus disease 2019(COVID-19)patients exhibiting GIT symptoms,such as diarrhea,and presenting viral-shedding in feces.Considering the abundance and co-localization of ACE2 and TMPRSS2 in the lower GIT(especially brush-border enterocytes),these two receptors seem to be mainly involved in SARS-CoV-2 invasion of the digestive tract.Additionally,in vitro studies have demonstrated the virions capability of infection and replication in the human epithelial cells lining GIT.However,also furin and cysteine cathepsins(cathepsin L)might participate in the activation of SARS-CoV-2 spike protein contributing to the virus invasiveness within GIT.Moreover,cathepsin L(due to its involvement in extracellular matrix components degradation and remodeling,the processes enhanced during SARS-CoV-2-induced inflammation)might be responsible for the dysregulation of absorption/digestion functions of GIT,thus adding to the observed in some COVID-19 patients symptoms such as diarrhea.

关键词： COVID-19 SARS-CoV-2 Angiotensin converting enzyme 2 Transmembrane peptidase/serine subfamily member 2/4 Cathepsin L Gastrointestinal tract

Ocular renin-angiotensin system with special reference in the anterior part of the eye

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World Journal of Ophthalmology 2015年第3期5卷 110-124页

作者： Mervi Holappa Heikki Vapaatalo Anu Vaajanen BioMediTech University of Tampere Institute of Biomedicine PharmacologyUniversity of Helsinki Department of Ophthalmology Tampere University Hospital SILK Department of OphthalmologySchool of MedicineUniversity of Tampere

The renin-angiotensin system(RAS) regulates blood pressure(BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin Ⅱ, angiotensin converting enzyme 1 and angiotensin Ⅱ type 1 receptor(AngⅡ-ACE1-AT1R) together with angiotensin(1-7), Angiotensin converting enzyme 2 and Mas receptor(Ang(1-7)-ACE2-Mas R) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory system accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngⅡ-ACE1-AT1 R and Ang(1-7)-ACE2-Mas R, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure(IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.

关键词： angiotensin converting enzyme 1 Angiotensin converting enzyme 2 angiotensin converting enzyme-inhibitors angiotensinⅡ angiotensin(1-9) angiotensin(1-7) Glaucoma Intraocular pressure Renin-angiotensin system