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Ojha U, Kim S, Rhee CY, You J, Choi YH, Yoon SH, Park SY, Lee YR, Kim JK, Bae SC, Lee YM. Endothelial RUNX3 controls LSEC dysfunction and angiocrine LRG1 signaling to prevent liver fibrosis. Hepatology 2025; 81:1228-1243. [PMID: 39042837 PMCID: PMC11902585 DOI: 10.1097/hep.0000000000001018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 06/23/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND AND AIMS Liver fibrosis represents a global health burden, given the paucity of approved antifibrotic therapies. Liver sinusoidal endothelial cells (LSECs) play a major gatekeeping role in hepatic homeostasis and liver disease pathophysiology. In early tumorigenesis, runt-related transcription factor 3 (RUNX3) functions as a sentinel; however, its function in liver fibrosis in LSECs remains unclear. This study aimed to investigate the role of RUNX3 as an important regulator of the gatekeeping functions of LSECs and explore novel angiocrine regulators of liver fibrosis. APPROACH AND RESULTS Mice with endothelial Runx3 deficiency develop gradual and spontaneous liver fibrosis secondary to LSEC dysfunction, thereby more prone to liver injury. Mechanistic studies in human immortalized LSECs and mouse primary LSECs revealed that IL-6/JAK/STAT3 pathway activation was associated with LSEC dysfunction in the absence of RUNX3. Single-cell RNA sequencing and quantitative RT-PCR revealed that leucine-rich alpha-2-glycoprotein 1 ( LRG1 ) was highly expressed in RUNX3-deficient and dysfunctional LSECs. In in vitro and coculture experiments, RUNX3-depleted LSECs secreted LRG1, which activated HSCs throughTGFBR1-SMAD2/3 signaling in a paracrine manner. Furthermore, circulating LRG1 levels were elevated in mouse models of liver fibrosis and in patients with fatty liver and cirrhosis. CONCLUSIONS RUNX3 deficiency in the endothelium induces LSEC dysfunction, LRG1 secretion, and liver fibrosis progression. Therefore, endothelial RUNX3 is a crucial gatekeeping factor in LSECs, and profibrotic angiocrine LRG1 may be a novel target for combating liver fibrosis.
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Affiliation(s)
- Uttam Ojha
- Vessel-Organ Interaction Research Center, VOICE (MRC), Research Institute of Pharmaceutical Sciences, Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Somi Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea
| | - Chang Yun Rhee
- Vessel-Organ Interaction Research Center, VOICE (MRC), Research Institute of Pharmaceutical Sciences, Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Jihye You
- Vessel-Organ Interaction Research Center, VOICE (MRC), Research Institute of Pharmaceutical Sciences, Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Yoon Ha Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea
| | - Soo-Hyun Yoon
- Vessel-Organ Interaction Research Center, VOICE (MRC), Research Institute of Pharmaceutical Sciences, Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jong Kyoung Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea
| | - Suk-Chul Bae
- Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju, Republic of Korea
| | - You Mie Lee
- Vessel-Organ Interaction Research Center, VOICE (MRC), Research Institute of Pharmaceutical Sciences, Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
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Yan P, Yu X, Chen Z, Lan L, Kang J, Zhao B, Liu D. Assessing the consistency of FIB-4, APRI, and GPR in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with concurrent liver diseases. BMC Gastroenterol 2025; 25:191. [PMID: 40114058 PMCID: PMC11927168 DOI: 10.1186/s12876-025-03770-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
OBJECTIVE This study investigated the consistency of the FIB-4, APRI, and GPR indices in assessing significant liver fibrosis and cirrhosis in patients with Coronavirus Disease 2019(COVID-19) who also suffer from various liver diseases, providing references for the clinical selection and application for non-invasive assessment methods. METHODS The study evaluated 744 COVID-19 patients with coexisting liver diseases: 508 cases with non-alcoholic fatty liver disease (NAFLD), 158 cases with chronic hepatitis B (CHB), and 78 cases with a combination of both ailments. FIB-4, APRI, and GPR were employed to assess significant liver fibrosis and cirrhosis. Concordance among the methods was determined using Kappa analysis, and receiver operating characteristic (ROC) curves helped identify the optimal cutoff values for each index. RESULTS For COVID-19 patients with NAFLD, Kappa values for significant liver fibrosis were 0.81, 0.90, 0.80, and 0.79, and for cirrhosis, they were 0.88, 0.97,0.88, and 0.88, respectively (all p < 0.05). Among those with CHB, Kappa values were 0.81, 0.81, 0.83, and 0.75 for fibrosis, and0.87, 0.91, 0.88, and 0.92 for cirrhosis (all p < 0.05). In patients with coexisting liver diseases, the values were 0.87, 0.86, 0.86, and 0.78 for fibrosis, and 0.67, 0.69, 0.54, and 0.81for cirrhosis (all p < 0.05). Linear trend analysis revealed significant relationships between FIB-4 values, APRI values, GPR values, and the severity of COVID-19 (χ2 trend: 15.205,35.114, and 13.973, respectively, all p < 0.001), between FIB-4 values and APRI values and the coronavirus negative conversion time (all p < 0.05) in COVID-19 with NAFLD, and between FIB-4 values and GPR values and the coronavirus negative conversion time in patients with COVID-19 with CHB(all p < 0.05). CONCLUSION Using the current cutoff values, the non-invasive assessments demonstrated almost perfect consistency in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with liver diseases, though FIB-4 and GPR showed moderate consistency in cirrhosis evaluation in patients with coexisting liver conditions. Moreover, it also indicated that increased liver fibrosis correlates with more severe COVID-19 and prolonged coronavirus negative conversion time.
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Affiliation(s)
- Pan Yan
- School of Public Health, Chengdu Medical College, Chengdu, Sichuan Province, 610500, China
| | - Xiaoping Yu
- School of Preclinical Medicine, Chengdu University, Chengdu, Sichuan Province, 610106, China
| | - Zhu Chen
- Department of Drug Clinical Trial Center, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Lijuan Lan
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Jun Kang
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Bennan Zhao
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Dafeng Liu
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China.
- , No.377 Jingming Road, Jinjiang District, Chengdu City, Sichuan Province Chengdu, 610060, China.
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Luo YW, Huang AL, Tang KF. Angiotensin-converting enzyme 2 and hepatic SARS-CoV-2 infection: Regulation, association, and therapeutic implications. World J Gastroenterol 2025; 31:100864. [PMID: 39958440 PMCID: PMC11752700 DOI: 10.3748/wjg.v31.i6.100864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/07/2024] [Accepted: 12/20/2024] [Indexed: 01/10/2025] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19-related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.
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Affiliation(s)
- Yu-Wei Luo
- Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Kai-Fu Tang
- Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing 400016, China
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Subramaniam S, Jose A, Kenney D, O’Connell AK, Bosmann M, Douam F, Crossland N. Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence. Front Immunol 2025; 16:1443932. [PMID: 39967675 PMCID: PMC11832389 DOI: 10.3389/fimmu.2025.1443932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 01/14/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
- Saravanan Subramaniam
- Department of Pharmacology and Toxicology, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, United States
- Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Asha Jose
- Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Devin Kenney
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Aoife K. O’Connell
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Markus Bosmann
- Department of Medicine, Pulmonary Center, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
- Department of Pathology and Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Florian Douam
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Nicholas Crossland
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
- Department of Pathology and Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
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Gupta P, Dev K, Kaur G. Phytoconstituents as modulator of inflammatory pathways for COVID-19: A comprehensive review and recommendations. Phytother Res 2024; 38:5389-5416. [PMID: 39246209 DOI: 10.1002/ptr.8302] [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: 01/18/2024] [Revised: 07/04/2024] [Accepted: 07/12/2024] [Indexed: 09/10/2024]
Abstract
SARS-CoV-2 infection causes disruptions in inflammatory pathways, which fundamentally contribute to COVID-19 pathophysiology. The present review critically evaluates the gaps in scientific literature and presents the current status regarding the inflammatory signaling pathways in COVID-19. We propose that phytoconstituents can be used to treat COVID-19 associated inflammation, several already formulated in traditional medications. For this purpose, extensive literature analysis was conducted in the PubMed database to collect relevant in vitro, in vivo, and human patient studies where inflammation pathways were shown to be upregulated in COVID-19. Parallelly, scientific literature was screened for phytoconstituents with known cellular mechanisms implicated for inflammation or COVID-19 associated inflammation. Studies with insufficient evidence on cellular pathways for autophagy and mitophagy were considered out of scope and excluded from the study. The final analysis was visualized in figures and evaluated for accuracy. Our findings demonstrate the frequent participation of NF-κB, a transcription factor, in inflammatory signaling pathways linked to COVID-19. Moreover, the MAPK signaling pathway is also implicated in producing inflammatory molecules. Furthermore, it was also analyzed that the phytoconstituents with flavonoid and phenolic backbones could inhibit either the TLR4 receptor or its consecutive signaling molecules, thereby, decreasing NF-κB activity and suppressing cytokine production. Although, allopathy has treated the early phase of COVID-19, anti-inflammatory phytoconstituents and existing ayurvedic formulations may act on the COVID-19 associated inflammatory pathways and provide an additional treatment strategy. Therefore, we recommend the usage of flavonoids and phenolic phytoconstituents for the treatment of inflammation associated with COVID-19 infection and similar viral ailments.
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Affiliation(s)
- Pragati Gupta
- School of Biotechnology, Shoolini University, Solan, Himachal Pradesh, India
| | - Kamal Dev
- School of Biotechnology, Shoolini University, Solan, Himachal Pradesh, India
- Department of Pharmacology & Toxicology, Wright State University, Dayton, Ohio, USA
| | - Gurjot Kaur
- School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, India
- National Center cum Department of Human Genome Research Center and Studies, Panjab University, Chandigarh, Punjab, India
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Yu J, Zhang Y, Ye Z, Tang K, Ma Y, Fu L, Cui T, Kang H, Yuan Y, Pan W. A Multi-Machine Learning Consensus Model Based on Clinical Features Reveals That Interleukin-10 Derived from Monocytes Leads to a Poor Prognosis in Patients with Coronavirus Disease-2019. J Inflamm Res 2024; 17:5923-5942. [PMID: 39247837 PMCID: PMC11378990 DOI: 10.2147/jir.s472099] [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: 06/03/2024] [Accepted: 08/27/2024] [Indexed: 09/10/2024] Open
Abstract
Background Despite ongoing interventions, SARS-CoV-2 continues to cause significant global morbidity and mortality. Early diagnosis and intervention are crucial for effective clinical management. However, prognostic features based on transcriptional data have shown limited effectiveness, highlighting the need for more precise biomarkers to improve COVID-19 treatment outcomes. Methods We retrospectively analyzed 149 clinical features from 189 COVID-19 patients, identifying prognostic features via univariate Cox regression. The cohort was split into training and validation sets, and 77 prognostic models were developed using seven machine learning algorithms. Among these, the least absolute shrinkage and selection operator (Lasso) method was employed to refine the selection of prognostic variables by ten-fold cross-validation strategy, which were then integrated with random survival forests (RSF) to build a robust COVID-19-related prognostic model (CRM). Model accuracy was evaluated across training, validation, and entire cohorts. The diagnostic relevance of interleukin-10 (IL-10) was confirmed in bulk transcriptional data and validated at the single-cell level, where we also examined changes in cellular communication between mononuclear cells with differing IL-10 expression and other immune cells. Results Univariate Cox regression identified 43 prognostic features. Among the 77 machine learning models, the combination of Lasso and RSF produced the most robust CRM. This model consistently performed well across training, validation, and entire cohorts. IL-10 emerged as a key prognostic feature within the CRM, validated by single-cell transcriptional data. Transcriptome analysis confirmed the stable diagnostic value of IL-10, with mononuclear cells identified as the primary IL-10 source. Moreover, differential IL-10 expression in these cells was linked to altered cellular communication in the COVID-19 immune microenvironment. Conclusion The CRM provides accurate prognostic predictions for COVID-19 patients. Additionally, the study underscores the importance of early IL-10 level testing upon hospital admission, which could inform therapeutic strategies.
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Affiliation(s)
- Jing Yu
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yike Zhang
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Zhixiong Ye
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Kun Tang
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yiming Ma
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Linlin Fu
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Tongtong Cui
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Hening Kang
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yadong Yuan
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Wensen Pan
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
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de Souza AJS, de Souza AF, Zimpel CK, Ayupe MC, de Araújo MV, Machado RRG, Salles E, Salgado CL, Tavares MS, Silva-Pereira TT, de Souza PC, Durigon EL, Heinemann MB, Brandão PE, da Fonseca DM, Guimarães AMDS, de Sá LRM. Hepatic endotheliitis in Golden Syrian hamsters (Mesocricetus auratus) experimentally infected with SARS-CoV-2. Rev Inst Med Trop Sao Paulo 2024; 66:e44. [PMID: 39082483 PMCID: PMC11295288 DOI: 10.1590/s1678-9946202466044] [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: 03/05/2024] [Accepted: 06/03/2024] [Indexed: 08/04/2024] Open
Abstract
Hepatic injuries in COVID-19 are not yet fully understood and indirect pathways (without viral replication in the liver) have been associated with the activation of vascular mechanisms of liver injury in humans infected with SARS-CoV-2. Golden Syrian hamsters are an effective model for experimental reproduction of moderate and self-limiting lung disease during SARS-CoV-2 infection. As observed in humans, this experimental model reproduces lesions of bronchointerstitial pneumonia and pulmonary vascular lesions, including endotheliitis (attachment of lymphoid cells to the luminal surface of endothelium). Extrapulmonary vascular lesions are well documented in COVID-19, but such extrapulmonary vascular lesions have not yet been described in the Golden Syrian hamster model of SARS-CoV-2 infection. The study aimed to evaluate microscopic liver lesions in Golden Syrian hamsters experimentally infected with SARS-CoV-2. In total, 38 conventional Golden Syrian hamsters, divided into infected group (n=24) and mock-infected group (n=14), were euthanized at 2-, 3-, 4-, 5-, 7-, 14-, and 15-days post infection with SARS-CoV-2. Liver fragments were evaluated by histopathology and immunohistochemical detection of SARS-CoV-2 Spike S2 antigens. The frequencies of portal vein endotheliitis, lobular activity, hepatocellular degeneration, and lobular vascular changes were higher among SARS-CoV-2-infected animals. Spike S2 antigen was not detected in liver. The main results indicate that SARS-CoV-2 infection exacerbated vascular and inflammatory lesions in the liver of hamsters with pre-existing hepatitis of unknown origin. A potential application of this animal model in studies of the pathogenesis and evolution of liver lesions associated with SARS-CoV-2 infection still needs further evaluation.
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Affiliation(s)
- Alex Junior Souza de Souza
- Universidade de São Paulo, Faculdade de Medicina Veterinária e Zootecnia, Departamento de Patologia, São Paulo, São Paulo, Brazil
| | - Antônio Francisco de Souza
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
| | - Cristina Kraemer Zimpel
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
- Universidade de São Paulo, Faculdade de Medicina Veterinária e Zootecnia, Departamento de Medicina Veterinária Preventiva e Saúde Animal, São Paulo, São Paulo, Brazil
| | - Marina Caçador Ayupe
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, São Paulo, Brazil
| | - Marcelo Valdemir de Araújo
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, São Paulo, Brazil
- Instituto Butantan, Centro de Desenvolvimento e Inovação, Laboratório de Virologia, São Paulo, São Paulo, Brazil
| | - Rafael Rahal Guaragna Machado
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
| | - Erika Salles
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, São Paulo, Brazil
| | - Caio Loureiro Salgado
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, São Paulo, Brazil
| | - Mariana Silva Tavares
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
| | - Taiana Tainá Silva-Pereira
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
| | - Paula Carolina de Souza
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, São Paulo, Brazil
| | - Edison Luiz Durigon
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
| | - Marcos Bryan Heinemann
- Universidade de São Paulo, Faculdade de Medicina Veterinária e Zootecnia, Departamento de Medicina Veterinária Preventiva e Saúde Animal, São Paulo, São Paulo, Brazil
| | - Paulo Eduardo Brandão
- Universidade de São Paulo, Faculdade de Medicina Veterinária e Zootecnia, Departamento de Medicina Veterinária Preventiva e Saúde Animal, São Paulo, São Paulo, Brazil
| | - Denise Morais da Fonseca
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, São Paulo, Brazil
| | - Ana Marcia de Sá Guimarães
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, São Paulo, Brazil
| | - Lilian Rose Marques de Sá
- Universidade de São Paulo, Faculdade de Medicina Veterinária e Zootecnia, Departamento de Patologia, São Paulo, São Paulo, Brazil
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He S, Luo Y, Ma W, Wang X, Yan C, Hao W, Fang Y, Su H, Lai B, Liu J, Xiong Y, Bai T, Ren X, Liu E, Han H, Wu Y, Yuan Z, Wang Y. Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis. J Hepatol 2024; 81:135-148. [PMID: 38460791 DOI: 10.1016/j.jhep.2024.02.032] [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: 07/20/2023] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 03/11/2024]
Abstract
BACKGROUND & AIMS NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. CONCLUSIONS Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen, which functions as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases. IMPACT AND IMPLICATIONS Paracrine signals produced by liver vasculature play a major role in the development of liver fibrosis, which is a pathological hallmark of most liver diseases. Identifying those paracrine signals is clinically relevant in that they may serve as therapeutic targets. In this study, we discovered that genetic deletion of Pofut1 aggravated experimental liver fibrosis in mouse models. Moreover, fibrinogen was identified as a downstream target repressed by Pofut1 in liver endothelial cells and functioned as a novel paracrine signal that drove liver fibrosis. In addition, fibrinogen was found to be relevant to cirrhosis and may serve as a potential therapeutic target for this devastating human disease.
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Affiliation(s)
- Shan He
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Stomatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuru Luo
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wangge Ma
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoke Wang
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Chengrong Yan
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wenyang Hao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuan Fang
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hongyu Su
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Baochang Lai
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Junhui Liu
- Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ying Xiong
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ting Bai
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoyong Ren
- Department of Stomatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Enqi Liu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hua Han
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancer and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yue Wu
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Zuyi Yuan
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Yidong Wang
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Cardiology, Wenling First People's Hospital, The Affiliated Hospital of Wenzhou Medical University, Wenling, Zhejiang, China.
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9
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Wang MJ, Zhang HL, Chen F, Guo XJ, Liu QG, Hou J. The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases. Exp Hematol Oncol 2024; 13:62. [PMID: 38890694 PMCID: PMC11184755 DOI: 10.1186/s40164-024-00527-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 05/23/2024] [Indexed: 06/20/2024] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine and exerts its complex biological functions mainly through three different signal modes, called cis-, trans-, and cluster signaling. When IL-6 binds to its membrane or soluble receptors, the co-receptor gp130 is activated to initiate downstream signaling and induce the expression of target genes. In the liver, IL-6 can perform its anti-inflammatory activities to promote hepatocyte reprogramming and liver regeneration. On the contrary, IL-6 also exerts the pro-inflammatory functions to induce liver aging, fibrosis, steatosis, and carcinogenesis. However, understanding the roles and underlying mechanisms of IL-6 in liver physiological and pathological processes is still an ongoing process. So far, therapeutic agents against IL‑6, IL‑6 receptor (IL‑6R), IL-6-sIL-6R complex, or IL-6 downstream signal transducers have been developed, and determined to be effective in the intervention of inflammatory diseases and cancers. In this review, we summarized and highlighted the understanding of the double-edged effects of IL-6 in liver homeostasis, aging, inflammation, and chronic diseases, for better shifting the "negative" functions of IL-6 to the "beneficial" actions, and further discussed the potential therapeutic effects of targeting IL-6 signaling in the clinics.
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Affiliation(s)
- Min-Jun Wang
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University (Naval Medical University), Shanghai, China.
| | - Hai-Ling Zhang
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Second Military Medical University (Naval Medical University), Shanghai, China
- Department of Neurology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Fei Chen
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xiao-Jing Guo
- Department of Health Statistics, Faculty of Health Service, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Qing-Gui Liu
- Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jin Hou
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Second Military Medical University (Naval Medical University), Shanghai, China.
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10
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Heinen N, Klöhn M, Westhoven S, Brown RJ, Pfaender S. Host determinants and responses underlying SARS-CoV-2 liver tropism. Curr Opin Microbiol 2024; 79:102455. [PMID: 38522265 DOI: 10.1016/j.mib.2024.102455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/01/2024] [Accepted: 03/01/2024] [Indexed: 03/26/2024]
Abstract
Hepatic sequelae are frequently reported in coronavirus disease 2019 cases and are correlated with increased disease severity. Therefore, a detailed exploration of host factors contributing to hepatic impairment and ultimately infection outcomes in patients is essential for improved clinical management. The causes of hepatic injury are not limited to drug-mediated toxicity or aberrant host inflammatory responses. Indeed, multiple studies report the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in liver autopsies and the susceptibility of explanted human hepatocytes to infection. In this review, we confirm that hepatic cells express an extensive range of factors implicated in SARS-CoV-2 entry. We also provide an overview of studies reporting evidence for direct infection of liver cell types and the infection-induced cell-intrinsic processes that likely contribute to hepatic impairment.
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Affiliation(s)
- Natalie Heinen
- Department of Molecular and Medical Virology, Ruhr University Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Germany
| | - Saskia Westhoven
- Department of Molecular and Medical Virology, Ruhr University Bochum, Germany; Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
| | - Richard Jp Brown
- Department of Molecular and Medical Virology, Ruhr University Bochum, Germany.
| | - Stephanie Pfaender
- Department of Molecular and Medical Virology, Ruhr University Bochum, Germany; Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany; University of Lübeck, Lübeck, Germany.
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11
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Rodríguez-Hernández MÁ, Baena-Bustos M, Carneros D, Zurita-Palomo C, Muñoz-Pinillos P, Millán J, Padillo FJ, Smerdou C, von Kobbe C, Rose-John S, Bustos M. Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy. EBioMedicine 2024; 103:105132. [PMID: 38677182 PMCID: PMC11061249 DOI: 10.1016/j.ebiom.2024.105132] [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: 09/06/2023] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. METHODS To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. FINDINGS We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. INTERPRETATION IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19. FUNDING The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.
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Affiliation(s)
- María Ángeles Rodríguez-Hernández
- Area of Liver, Digestive and Inflammatory Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital (HUVR), Spanish National Research Council (CSIC), University of Seville (US), Seville, Spain.
| | - Mercedes Baena-Bustos
- Pneumology Unit, Institute of Biomedicine of Seville (IBiS), Virgen Macarena University Hospital (HUVM), Spanish National Research Council (CSIC), University of Seville (US), Seville, Spain
| | - David Carneros
- Area of Liver, Digestive and Inflammatory Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital (HUVR), Spanish National Research Council (CSIC), University of Seville (US), Seville, Spain
| | - Carola Zurita-Palomo
- Area of Liver, Digestive and Inflammatory Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital (HUVR), Spanish National Research Council (CSIC), University of Seville (US), Seville, Spain
| | - Pablo Muñoz-Pinillos
- Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Cantoblanco, Madrid, Spain
| | - Jaime Millán
- Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Cantoblanco, Madrid, Spain
| | - Francisco Javier Padillo
- Area of Liver, Digestive and Inflammatory Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital (HUVR), Spanish National Research Council (CSIC), University of Seville (US), Seville, Spain
| | - Cristian Smerdou
- Division of DNA and RNA Medicine, Cima Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdISNA), and CCUN, Pamplona, Spain
| | - Cayetano von Kobbe
- Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Cantoblanco, Madrid, Spain
| | | | - Matilde Bustos
- Area of Liver, Digestive and Inflammatory Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital (HUVR), Spanish National Research Council (CSIC), University of Seville (US), Seville, Spain.
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12
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Zhang Z, Tang L, Guo Y, Guo X, Pan Z, Ji X, Gao C. Development of Biomarkers and Prognosis Model of Mortality Risk in Patients with COVID-19. J Inflamm Res 2024; 17:2445-2457. [PMID: 38681069 PMCID: PMC11048291 DOI: 10.2147/jir.s449497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 04/04/2024] [Indexed: 05/01/2024] Open
Abstract
Background As of 30 April 2023, the COVID-19 pandemic has resulted in over 6.9 million deaths worldwide. The virus continues to spread and mutate, leading to continuously evolving pathological and physiological processes. It is imperative to reevaluate predictive factors for identifying the risk of early disease progression. Methods A retrospective study was conducted on a cohort of 1379 COVID-19 patients who were discharged from Xin Hua Hospital affiliated with Shanghai Jiao Tong University School of Medicine between 15 December 2022 and 15 February 2023. Patient symptoms, comorbidities, demographics, vital signs, and laboratory test results were systematically documented. The dataset was split into testing and training sets, and 15 different machine learning algorithms were employed to construct prediction models. These models were assessed for accuracy and area under the receiver operating characteristic curve (AUROC), and the best-performing model was selected for further analysis. Results AUROC for models generated by 15 machine learning algorithms all exceeded 90%, and the accuracy of 10 of them also surpassed 90%. Light Gradient Boosting model emerged as the optimal choice, with accuracy of 0.928 ± 0.0006 and an AUROC of 0.976 ± 0.0028. Notably, the factors with the greatest impact on in-hospital mortality were growth stimulation expressed gene 2 (ST2,19.3%), interleukin-8 (IL-8,17.2%), interleukin-6 (IL-6,6.4%), age (6.1%), NT-proBNP (5.1%), interleukin-2 receptor (IL-2R, 5%), troponin I (TNI,4.6%), congestive heart failure (3.3%) in Light Gradient Boosting model. Conclusion ST-2, IL-8, IL-6, NT-proBNP, IL-2R, TNI, age and congestive heart failure were significant predictors of in-hospital mortality among COVID-19 patients.
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Affiliation(s)
- Zhishuo Zhang
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Lujia Tang
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Yiran Guo
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Xin Guo
- School of Information Science and Technology, Sanda University, Shanghai, Pudong District, 201209, China
| | - Zhiying Pan
- School of Information Science and Technology, Sanda University, Shanghai, Pudong District, 201209, China
| | - Xiaojing Ji
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Chengjin Gao
- Department of Emergency, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
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13
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Kutlutürk I, Tokuç EÖ, Karabaş L, Rückert R, Kaya M, Karagöz A, Munk MR. How the immune response to the structural proteins of SARS-CoV-2 affects the retinal vascular endothelial cells: an immune thrombotic and/or endotheliopathy process with in silico modeling. Immunol Res 2024; 72:50-71. [PMID: 37642808 DOI: 10.1007/s12026-023-09412-1] [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: 04/14/2023] [Accepted: 07/28/2023] [Indexed: 08/31/2023]
Abstract
Thrombotic events associated with SARS-CoV-2 at the vascular endothelium still remains unclear. The aim of the current study is to determine the relationship between cellular proteins on the (ocular) vascular endothelial surface and the immune thrombotic and/or endotheliopathy process elicited by SARS-CoV-2 using an in-silico modeling. The structural S (spike glycoprotein), N (nucleocapsid protein), M (membrane protein), and E (envelope protein) proteins, an accessory protein (ORF1ab) of SARS-CoV-2 and 158 cellular proteins associated with retinal vascular endothelial cell surface or structure were included in this study for comparison of three-dimensional (3D) structure and sequence. Sixty-nine of the retinal proteins were obtained from the Uniprot database. Remaining proteins not included in the database were included in the study after they were converted into 3D structures using the RaptorX web tool. Sequence and three-dimensional structure of SARS-COV-2 S, N, M, E, ORF1ab proteins and retinal vascular endothelial proteins were compared with mTM-align server. Proteins with significant similarity (score above 0.5) were validated with the TM-align web server. Immune and thrombosis-related protein-receptor interactions of similar proteins was checked with CABS-dock. We detected a high level of structural similarity between E protein and ACE, ACE2, LAT1, and TM9SF4 endothelial proteins. In addition, PECAM-1 was found to be structurally similar to ORF1ab and S protein. When we evaluated the likelihood/potential to stimulate an immune responses/a cytokine release, TLR-2 and TLR-3, which are highly susceptible to SARS-CoV2, showed a potential receptor-protein interaction with retinal vascular endothelial proteins. Our study demonstrates that SARS-CoV-2 proteins may have structural similarities with vascular endothelial proteins, and therefore, as immunological target sites, the counterpart proteins on the endothelial surface of many organs may also be secondarily affected by any immune response against SARS-CoV-2 structural proteins.
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Affiliation(s)
- Işıl Kutlutürk
- Division of Ophthalmology, Ümraniye Trn. And Rch. Hospital, Istanbul, Turkey.
| | - Ecem Önder Tokuç
- Ophthalmology Department, University of Health Science, Derince Training and Research Hospital, Izmit-Kocaeli, Turkey
| | - Levent Karabaş
- Ophthalmology Department, Kocaeli University School of Medicine, Izmit-Kocaeli, Turkey
| | | | | | - Ali Karagöz
- Koşuyolu High Specialization Education and Research Hospital, Istanbul, Turkey
| | - Marion R Munk
- Inselspital, University Hospital Bern, Bern, Switzerland
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Augenarzt-Praxisgemeinschaft Gutblick AG, Bern, Switzerland
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14
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Maimunah U, Maharani ARK, Soegiarto G, Rahniayu A, Gunawan VA, Wiratama PA, Djuanda SN, Supriadi S, Marhana IA, Semedi BP, Lefi A, Kusumastuti EH, Suyanto E, Lilihata JG, Anggoro A, Rinjani LGP, Rosyid AN, Wahyu D, Fauziah D, Rahaju AS, Kurniasari N, Ariani G, Nugroho GMS, Yandi IKR, Nugraha RA. Correlation between interleukin-6 expression in post-mortem core liver biopsy and degree of liver injury in patients with fatal COVID-19. NARRA J 2023; 3:e463. [PMID: 38455630 PMCID: PMC10919438 DOI: 10.52225/narra.v3i3.463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/04/2023] [Indexed: 03/09/2024]
Abstract
Excessive release of interleukin-6 (IL-6) during the progression of coronavirus disease 2019 (COVID-19) induces cytokine storms, resulting in multi-organ damages including liver injury, similar in nature with mechanism of viral hepatitis. Systemic IL-6 has been associated with the incidence of liver injury among COVID-19 patients; however, studies on IL-6 expression in the liver tissue are completely lacking. The aim of this study was to measure the IL-6 expression in the liver tissues and to determine its correlation with the degree of liver injury in fatal COVID-19 patients. Through this first cross-sectional study, IL-6 expression was measured through immunohistochemical staining and the degree of liver injury was identified based on level of serum alanine aminotransferase (ALT). The Spearman correlation test was used to identify the correlation between IL-6 expression and the degree of liver injury. A total of 47 deceased COVID-19 patients were included and IL-6 expression was observed in all post-mortem liver specimens, ranging from mild to strong expression. Liver injury at various degrees (mild to severe) was found in more than half (59.5%) of the cases. The Spearman correlation analysis suggested a statistically insignificant correlation between liver IL-6 expression and the degree of liver injury (r=0.152; p=0.309). In conclusion, even IL-6 expression was observed in all post-mortem liver specimens, there was an insignificant correlation between IL-6 expression in the liver tissue with the degree of liver injury among fatal COVID-19 patients, suggesting that IL-6 was not the only main factor contributing to liver damage in COVID-19 patients.
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Affiliation(s)
- Ummi Maimunah
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Andi RK. Maharani
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Gatot Soegiarto
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Alphania Rahniayu
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Vania A. Gunawan
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Priangga A. Wiratama
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Stephanie N. Djuanda
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Supriadi Supriadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Isnin A. Marhana
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Bambang P. Semedi
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Anesthesiology and Reanimation, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia;
| | - Achmad Lefi
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Cardiology and Vascular Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Etty H. Kusumastuti
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Edi Suyanto
- Department of Forensics and Medicolegal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Forensics and Medicolegal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Jilientasia G. Lilihata
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Anesthesiology and Reanimation, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia;
| | - Adhitri Anggoro
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Lalu GP. Rinjani
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Cardiology and Vascular Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Alfian N. Rosyid
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Dwi Wahyu
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Dyah Fauziah
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Anny S. Rahaju
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Nila Kurniasari
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Grace Ariani
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Gilang MS. Nugroho
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - I KR. Yandi
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ricardo A. Nugraha
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Cardiology and Vascular Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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15
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Taylor-Robinson SD, Morgan MY. COVID-19 and the Liver: A Complex and Evolving Picture. Hepat Med 2023; 15:209-220. [PMID: 37965296 PMCID: PMC10641025 DOI: 10.2147/hmer.s384172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/28/2023] [Indexed: 11/16/2023] Open
Abstract
Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system, other organs, such as the liver, are also affected. In this overview, the effects of SARS-CoV-2 infection on the liver in both healthy people and in those with pre-existing liver disease are documented; the relationship between coronavirus disease 19 (COVID-19) vaccination and liver injury is examined; the mechanism of SARS-CoV-2-associated liver injury is explored; and the long-term consequences of COVID-19 are delineated, both in people with and without pre-existing liver disease.
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Affiliation(s)
- Simon D Taylor-Robinson
- Department of Surgery and Cancer, Imperial College London, London, UK
- Department of Public Health, Busitema University and Mbale Clinical Research Institute, Mbale, Uganda
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
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16
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Pepe-Mooney BJ, Smith CJ, Sherman MS, North TE, Padera RF, Goessling W. SARS-CoV-2 viral liver aggregates and scarce parenchymal infection implicate systemic disease as a driver of abnormal liver function. Hepatol Commun 2023; 7:e0290. [PMID: 37889528 PMCID: PMC10615432 DOI: 10.1097/hc9.0000000000000290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/22/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Liver function tests (LFTs) are elevated in >50% of hospitalized individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), with increased enzyme levels correlating with a more severe COVID-19 course. Despite these observations, evaluations of viral presence within liver parenchyma and viral impact on liver function remain controversial. METHODS AND RESULTS Our work is a comprehensive immunopathological evaluation of liver tissue from 33 patients with severe, and ultimately fatal, cases of SARS-CoV-2 infection. Coupled with clinical data, we reveal the absence of SARS-CoV-2 infection in cholangiocytes and hepatocytes despite dramatic systemic viral presence. Critically, we identify significant focal viral sinusoidal aggregates in 2/33 patients and single viral RNA molecules circulating in the hepatic sinusoids of 15/33 patients. Utilizing co-immunofluorescence, focal viral liver aggregates in patients with COVID-19 were colocalized to platelet and fibrin clots, indicating the presence of virus-containing sinusoidal microthrombi. Furthermore, this patient cohort, from the initial months of the COVID-19 pandemic, demonstrates a general downtrend of LFTs over the course of the study timeline and serves as a remarkable historical time point of unattenuated viral replication within patients. CONCLUSIONS Together, our findings indicate that elevated LFTs found in our patient cohort are not due to direct viral parenchymal infection with SARS-CoV-2 but rather likely a consequence of systemic complications of COVID-19. This work aids in the clinical treatment considerations of patients with SARS-CoV-2 as therapies for these patients may be considered in terms of their direct drug hepatotoxity rather than worsening hepatic function due to direct infection.
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Affiliation(s)
- Brian J. Pepe-Mooney
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard–MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Colton J. Smith
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Marc S. Sherman
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Trista E. North
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Developmental and Regenerative Biology Program, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
| | - Robert F. Padera
- Harvard–MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston Massachusetts, USA
| | - Wolfram Goessling
- Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard–MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Developmental and Regenerative Biology Program, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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17
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Nasr P, Jönsson C, Ekstedt M, Kechagias S. Non-metabolic causes of steatotic liver disease. METABOLISM AND TARGET ORGAN DAMAGE 2023; 3. [DOI: 10.20517/mtod.2023.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Hepatic steatosis is caused by exaggerated hepatic lipid accumulation and is a common histological and radiological finding. Non-alcoholic fatty liver disease (NAFLD), or metabolic dysfunction associated steatotic liver disease (MASLD), is highly associated with metabolic syndrome and represents the most common cause of hepatic steatosis. However, since several comorbidities, lifestyle factors, and drugs can cause hepatic steatosis, MASLD is, to some extent, a diagnosis of exclusion. Nevertheless, initiatives have been taken to encompass positive (instead of negative) criteria for diagnosis - such as the presence of cardiometabolic risk factors together with hepatic steatosis. Nonetheless, before confirming a patient with MASLD, it is essential to map and evaluate other causes of fatty liver disease or steatotic liver disease. Several causes of hepatic steatosis have been identified in studies; however, the study cohorts are scarce and often anecdotal. Additionally, many studies have shown correlation without proving causation, and many are retrospective without reporting relevant patient characteristics and comorbidities - making it difficult to draw conclusions regarding the underlying etiology or present comorbidity of hepatic steatosis. In this narrative review, we aimed to identify and summarize present studies evaluating the impact of the most common and often suggested causes of hepatic steatosis.
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18
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Granados AA, Bucher S, Song H, Agrawal A, Chen AT, Peng T, Neff N, Pisco AO, Huang F, Wang B. Single-nuclei characterization of pervasive transcriptional signatures across organs in response to COVID-19. eLife 2023; 12:e81090. [PMID: 37830426 PMCID: PMC10575628 DOI: 10.7554/elife.81090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/16/2023] [Indexed: 10/14/2023] Open
Abstract
Background Infection by coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about the impact COVID-19 has across other organs. Methods Here, we contribute a single-nuclei RNA-sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. The integration of data from multiple organs enabled the identification of systemic transcriptional changes. Results Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of gene modules showed enrichment of specific signaling pathways across multiple organs in COVID-19 autopsies. Conclusions Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development. Funding The Chan-Zuckerberg Initiative, The Chan-Zuckerberg Biohub.
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Affiliation(s)
| | - Simon Bucher
- Division of Gastroenterology, Department of Medicine, University of California, San FranciscoSan FranciscoUnited States
| | - Hanbing Song
- Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California San FranciscoSan FranciscoUnited States
| | | | | | - Tien Peng
- Yale UniversityNew HavenUnited States
| | - Norma Neff
- Chan-Zuckerberg BiohubSan FranciscoUnited States
| | | | - Franklin Huang
- Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California San FranciscoSan FranciscoUnited States
| | - Bruce Wang
- Division of Gastroenterology, Department of Medicine, University of California, San FranciscoSan FranciscoUnited States
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19
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Chen X, Yang JB, Cao HH, Fang XC, Liu SH, Zou LF, Yu JH, Zuo JP, Zhao W, Lu ZB, Liu JS, Yu LZ. Liang-Ge-San inhibits dengue virus serotype 2 infection by reducing caveolin1-induced cytoplasmic heat shock protein 70 translocation into the plasma membrane. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 119:154977. [PMID: 37506573 DOI: 10.1016/j.phymed.2023.154977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/05/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023]
Abstract
BACKGROUND Dengue virus (DENV) is a major public health threat. However, there are no specific therapeutic drugs for DENV. Many Chinese heat-cleaning formulas, such as Liang-Ge-San (LGS), have been frequently used in the virus-induced diseases. The antiviral effect of LGS has not been reported yet. PURPOSE In this study, the effect of LGS on the inhibition of dengue virus serotype 2 (DENV-2) was investigated and the relevant mechanism was explored. METHODS High-performance liquid chromatography was applied to analyze the chemical characterization of LGS. The in vitro antiviral activities of LGS against DENV-2 were evaluated by time-of-drug-addition assay. The binding of heat shock protein 70 (Hsp70) and envelope (E) protein or caveolin1 (Cav1) were analyzed by immunofluorescence and immunoprecipitation assays. Then the role of Cav1 in the anti-DENV-2 effects of LGS was further examined. DENV-2 infected Institute of Cancer Research suckling mice (n = 10) and AG129 mice (n = 8) were used to examine the protective effects of LGS. RESULTS It was found that geniposide, liquiritin, forsythenside A, forsythin, baicalin, baicalein, rhein, and emodin maybe the characteristic components of LGS. LGS inhibited the early stage of DENV-2 infection, decreased the expression levels of viral E and non-structural protein 1 (NS1) proteins. LGS also reduced E protein and Hsp70 binding and attenuated the translocation of Hsp70 from cytoplasm to the cell membrane. Moreover, LGS decreased the binding of Hsp70 to Cav1. Further study showed that the overexpression of Cav1 reversed LGS-mediated E protein and Hsp70 inhibition in the plasma membrane. In the in vivo study, LGS was highly effective in prolonging the survival time, reducing viral loads. CONCLUSION This work demonstrates for the first time that LGS exerts anti-DENV-2 activity in vitro and in vivo. LGS decreases DENV-2-stimulated cytoplasmic Hsp70 translocation into the plasma membrane by Cav1 inhibition, thereby inhibiting the early stage of virus infection. These findings indicate that LGS may be a candidate for the treatment of DENV.
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Affiliation(s)
- Xi Chen
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Jia-Bin Yang
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Hui-Hui Cao
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Xiao-Chuan Fang
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Shan-Hong Liu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Li-Fang Zou
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Jian-Hai Yu
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, PR China
| | - Jian-Ping Zuo
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Wei Zhao
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, PR China
| | - Zi-Bin Lu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China.
| | - Jun-Shan Liu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, China, 510280, PR China.
| | - Lin-Zhong Yu
- Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China.
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20
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Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol 2023; 23:666-681. [PMID: 37069261 PMCID: PMC10108826 DOI: 10.1038/s41577-023-00856-y] [Citation(s) in RCA: 168] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2023] [Indexed: 04/19/2023]
Abstract
Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling - known as cluster signalling - involves preformed complexes of membrane-bound IL-6-mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.
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Affiliation(s)
- Stefan Rose-John
- Biochemical Institute, Medical Faculty, Christian-Albrechts-University, Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Christoph Garbers
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GC:I3), Otto-von-Guericke-University, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
| | - Jens M Moll
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
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21
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Kondo R, Iwakiri Y, Kage M, Yano H. Endotheliopathy of liver sinusoidal endothelial cells in liver disease. Pathol Int 2023; 73:381-393. [PMID: 37589433 DOI: 10.1111/pin.13361] [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: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 08/18/2023]
Abstract
Liver is the largest solid organ in the abdominal cavity, with sinusoid occupying about half of its volume. Under liver disease, hemodynamics in the liver tissue dynamically change, resulting in injury to liver sinusoidal endothelial cells (LSECs). We discuss the injury of LSECs in liver diseases in this article. Generally, in noninflamed tissues, vascular endothelial cells maintain quiescence of circulating leukocytes, and unnecessary blood clotting is inhibited by multiple antithrombotic factors produced by the endothelial cells. In the setting of inflammation, injured endothelial cells lose these functions, defined as inflammatory endotheliopathy. In chronic hepatitis C, inflammatory endotheliopathy in LSECs contributes to platelet accumulation in the liver tissue, and the improvement of thrombocytopenia by splenectomy is attenuated in cases with severe hepatic inflammation. In COVID-19, LSEC endotheliopathy induced by interleukin (IL)-6 trans-signaling promotes neutrophil accumulation and platelet microthrombosis in the liver sinusoids, resulting in liver injury. IL-6 trans-signaling promotes the expression of intercellular adhesion molecule-1, chemokine (C-X-C motif) ligand (CXCL1), and CXCL2, which are the neutrophil chemotactic mediators, and P-selectin, E-selectin, and von Willebrand factor, which are involved in platelet adhesion to endothelial cells, in LSECs. Restoring LSECs function is important for ameliorating liver injury. Prevention of endotheliopathy is a potential therapeutic strategy in liver disease.
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Affiliation(s)
- Reiichiro Kondo
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Masayoshi Kage
- Department of Medical Engineering, Junshin Gakuen University, Fukuoka, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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22
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Fiel MI, Schiano TD. Systemic Disease and the Liver-Part 1: Systemic Lupus Erythematosus, Celiac Disease, Rheumatoid Arthritis, and COVID-19. Surg Pathol Clin 2023; 16:473-484. [PMID: 37536883 DOI: 10.1016/j.path.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
The development of liver dysfunction in patients having various systemic diseases is common and has a broad differential diagnosis, at times being the initial manifestation of the disorder. Liver injury associated with systemic lupus erythematosus is heterogeneous and may present with nonspecific histology. Differentiating autoimmune hepatitis from lupus hepatitis is challenging on histologic grounds alone. Other systemic diseases that may present mostly with nonspecific findings are rheumatoid arthritis and celiac disease. More recently COVID-19 cholangiopathy and secondary sclerosing cholangitis have become increasingly recognized as distinct liver conditions. Many patients may also have intrinsic liver disease or may develop drug-induced liver injury from the treatment of the systemic disease. Timely identification of the cause of the liver dysfunction is essential and liver biopsy may help the clinician in diagnosis and management.
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Affiliation(s)
- Maria Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029, USA
| | - Thomas D Schiano
- Division of Liver Diseases, Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place-Box 1104, New York, NY 10029, USA.
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23
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McConnell MJ, Kostallari E, Ibrahim SH, Iwakiri Y. The evolving role of liver sinusoidal endothelial cells in liver health and disease. Hepatology 2023; 78:649-669. [PMID: 36626620 PMCID: PMC10315420 DOI: 10.1097/hep.0000000000000207] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/25/2022] [Indexed: 01/12/2023]
Abstract
LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.
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Affiliation(s)
- Matthew J. McConnell
- Section of Digestive Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| | | | - Samar H. Ibrahim
- Division of Gastroenterology, Mayo Clinic, Rochester, MN
- Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN
| | - Yasuko Iwakiri
- Section of Digestive Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
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24
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Zhu K, Tsai O, Chahal D, Hussaini T, Yoshida EM. COVID-19 and Liver Disease: An Evolving Landscape. Semin Liver Dis 2023; 43:351-366. [PMID: 37604206 DOI: 10.1055/a-2157-3318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
The COVID-19 pandemic has resulted in significant worldwide morbidity and mortality. In this review, we examine the intricate relationships between COVID-19 and liver diseases. While respiratory manifestations of COVID-19 are well known, its impact and consequences in patients with liver diseases remain an area of ongoing investigation. COVID-19 can induce liver injury through various mechanisms and is associated with higher mortality in individuals with preexisting chronic liver disease. Mortality increases with the severity of chronic liver disease and the level of care required. The outcomes in patients with autoimmune hepatitis remain unclear, whereas liver transplant recipients are more likely to experience symptomatic COVID-19 but have comparable outcomes to the general population. Despite suboptimal immunological response, COVID-19 vaccinations are safe and effective in liver disease, although cases of autoimmune hepatitis-like syndrome have been reported. In conclusion, COVID-19 has significant implications in liver diseases; early recognition and treatments are important for improving patient outcomes.
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Affiliation(s)
- Kai Zhu
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Olivia Tsai
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Daljeet Chahal
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
- BC Liver Transplant Program, Vancouver, British Columbia, Canada
| | - Trana Hussaini
- BC Liver Transplant Program, Vancouver, British Columbia, Canada
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
- BC Liver Transplant Program, Vancouver, British Columbia, Canada
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25
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Bartoli A, Cursaro C, Seferi H, Andreone P. Secondary Sclerosing Cholangitis After SARS-CoV2: ICU Ketamine Use or Virus-Specific Biliary Tropism and Injury in the Context of Biliary Ischemia in Critically Ill Patients? Hepat Med 2023; 15:93-112. [PMID: 37547355 PMCID: PMC10404108 DOI: 10.2147/hmer.s384220] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 07/12/2023] [Indexed: 08/08/2023] Open
Abstract
Purpose From the beginning of the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV2) pandemic, different cases of a cholangiopathy with features of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) have been reported. Patients developing it are generally recovering from severe Coronavirus disease 19 (COVID-19) and required intensive care unit (ICU) admission and mechanical ventilation. Many of them have been administered with ketamine during their ICU stay. The pathogenesis of this novel disease is still debated, and, since prognosis is poor, efforts are needed in order to better understand it. Patients and Methods In this review, we focused our attention on COVID-19 SSC clinical, imaging, and histology findings in order to clarify the different pathogenetic options, particularly in regard of the ischemic-direct viral damage and ketamine-related theories, beginning with a recapitulation of SSC-CIP and ketamine-induced cholangiopathy in abusers. The research has been conducted using PubMed and Google Scholar databases. Key-words were "Secondary Sclerosing Cholangiopathy", "SSC-CIP", "Secondary Sclerosing Cholangiopathy in critically ill patients", "Ketamine and cholangiopathy", "Ketamine abusers and liver disease", "Ketamine-related cholangiopathy", "SARS-CoV2 infection and liver disease", "post Covid-19 secondary sclerosing cholangitis", "Covid-19 cholangiopathy". Results Many authors, based on the clinical, histological, imaging, and prognostic features of the disease, have pointed out the similarities between post COVID-19 SSC and SSC-CIP; however, peculiar features in the former were not previously observed. Therefore, a direct viral cytopathic action and SARS-CoV2-related coagulopathy are considered the most likely causes. On the other hand, ketamine, with the available data, cannot be surely linked as the main determinant cause of cholangiopathy. Moreover, ketamine-induced cholangitis (KIC) presentation is different from post COVID-19 SSC. Its role as a cofactor precipitating the disease cannot be ruled out. Conclusion Post COVID-19 SSC is a rare clinical entity following severe COVID-19 disease. The most accepted theory is that a sum of different insults determines the disease: biliary ischemia, direct viral damage, toxic bile, possibly worsened by ketamine and hyperinflammation due to the cytokine storm. Given the severe prognosis of the disease, with persistent cholangiopathy, organ failure, and orthotopic liver transplantation (OLT), further study on this novel clinical entity is needed.
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Affiliation(s)
- Alessandra Bartoli
- Division of Internal Medicine and Metabolism, Department of Internal Medicine, Ospedale Civile di Baggiovara, University of Modena and Reggio Emilia, Modena, Italy
- Post Graduate School of Allergy and Clinical Immunology, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Carmela Cursaro
- Division of Internal Medicine and Metabolism, Department of Internal Medicine, Ospedale Civile di Baggiovara, University of Modena and Reggio Emilia, Modena, Italy
| | - Hajrie Seferi
- Division of Internal Medicine and Metabolism, Department of Internal Medicine, Ospedale Civile di Baggiovara, University of Modena and Reggio Emilia, Modena, Italy
| | - Pietro Andreone
- Chief of Division of Internal Medicine and metabolism, Department of Internal Medicine, University Hospital of Modena, Modena, Italy
- Chief of Post Graduate School of Allergy and Clinical Immunology, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
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26
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Duan M, Liu X, Yang Y, Zhang Y, Wu R, Lv Y, Lei H. Orchestrated regulation of immune inflammation with cell therapy in pediatric acute liver injury. Front Immunol 2023; 14:1194588. [PMID: 37426664 PMCID: PMC10323196 DOI: 10.3389/fimmu.2023.1194588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 05/26/2023] [Indexed: 07/11/2023] Open
Abstract
Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury.
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Affiliation(s)
- Mingyue Duan
- Department of Clinical Laboratory, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoguai Liu
- Department of Infectious Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ying Yang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yanmin Zhang
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hong Lei
- Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Shaanxi Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, China
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Oobo H, Inada H, Setoyama H, Narahara S, Tanaka K, Kurano S, Tokunaga T, Iio E, Yoshimaru Y, Nagaoka K, Watanabe T, Tanaka M, Tateyama M, Tanaka Y. Two cases of acute liver failure complicated by COVID-19 remarkably responded to anticoagulant therapy. KANZO 2023; 64:270-279. [DOI: 10.2957/kanzo.64.270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Affiliation(s)
- Hiromitsu Oobo
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Hiroki Inada
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Hiroko Setoyama
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Satoshi Narahara
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Kentaro Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Soutaro Kurano
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Takayuki Tokunaga
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Etsuko Iio
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Yoko Yoshimaru
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Katsuya Nagaoka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | | | - Masakuni Tateyama
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University
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28
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Akkiz H. Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury. Viruses 2023; 15:1287. [PMID: 37376587 DOI: 10.3390/v15061287] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 06/29/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage.
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Affiliation(s)
- Hikmet Akkiz
- Department of Gastroenterology and Hepatology, Medical Faculty, Bahçeşehir University, Istanbul 34349, Turkey
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29
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Barbalho SM, Minniti G, Miola VFB, Haber JFDS, Bueno PCDS, de Argollo Haber LS, Girio RSJ, Detregiachi CRP, Dall'Antonia CT, Rodrigues VD, Nicolau CCT, Catharin VMCS, Araújo AC, Laurindo LF. Organokines in COVID-19: A Systematic Review. Cells 2023; 12:1349. [PMID: 37408184 DOI: 10.3390/cells12101349] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/03/2023] [Accepted: 05/06/2023] [Indexed: 07/07/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a viral infection caused by SARS-CoV-2 that induces a generalized inflammatory state. Organokines (adipokines, osteokines, myokines, hepatokines, and cardiokines) can produce beneficial or harmful effects in this condition. This study aimed to systematically review the role of organokines on COVID-19. PubMed, Embase, Google Scholar, and Cochrane databases were searched, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and 37 studies were selected, comprising more than 2700 individuals infected with the virus. Among COVID-19 patients, organokines have been associated with endothelial dysfunction and multiple organ failure due to augmented cytokines and increased SARS-CoV-2 viremia. Changes in the pattern of organokines secretion can directly or indirectly contribute to aggravating the infection, promoting immune response alterations, and predicting the disease progression. These molecules have the potential to be used as adjuvant biomarkers to predict the severity of the illness and severe outcomes.
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Affiliation(s)
- Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília 17500-000, SP, Brazil
| | - Giulia Minniti
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Vitor Fernando Bordin Miola
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Jesselina Francisco Dos Santos Haber
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Centro Interdisciplinar em Diabetes (CENID), School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Patrícia Cincotto Dos Santos Bueno
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Department of Animal Sciences, School of Veterinary Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Luiza Santos de Argollo Haber
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Raul S J Girio
- Department of Animal Sciences, School of Veterinary Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Cláudia Rucco Penteado Detregiachi
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Pharmacology, Faculdade de Medicina de Marília (FAMEMA), School of Medicine, Avenida Monte Carmelo, 800, Marília 17519-030, SP, Brazil
| | - Camila Tiveron Dall'Antonia
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Victória Dogani Rodrigues
- Department of Biochemistry and Pharmacology, Faculdade de Medicina de Marília (FAMEMA), School of Medicine, Avenida Monte Carmelo, 800, Marília 17519-030, SP, Brazil
| | - Claudia C T Nicolau
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília 17500-000, SP, Brazil
| | - Virginia Maria Cavallari Strozze Catharin
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Pharmacology, Faculdade de Medicina de Marília (FAMEMA), School of Medicine, Avenida Monte Carmelo, 800, Marília 17519-030, SP, Brazil
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30
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Ni R, Jiang L, Zhang C, Liu M, Luo Y, Hu Z, Mou X, Zhu Y. Biologic Mechanisms of Macrophage Phenotypes Responding to Infection and the Novel Therapies to Moderate Inflammation. Int J Mol Sci 2023; 24:ijms24098358. [PMID: 37176064 PMCID: PMC10179618 DOI: 10.3390/ijms24098358] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Pro-inflammatory and anti-inflammatory types are the main phenotypes of the macrophage, which are commonly notified as M1 and M2, respectively. The alteration of macrophage phenotypes and the progression of inflammation are intimately associated; both phenotypes usually coexist throughout the whole inflammation stage, involving the transduction of intracellular signals and the secretion of extracellular cytokines. This paper aims to address the interaction of macrophages and surrounding cells and tissues with inflammation-related diseases and clarify the crosstalk of signal pathways relevant to the phenotypic metamorphosis of macrophages. On these bases, some novel therapeutic methods are proposed for regulating inflammation through monitoring the transition of macrophage phenotypes so as to prevent the negative effects of antibiotic drugs utilized in the long term in the clinic. This information will be quite beneficial for the diagnosis and treatment of inflammation-related diseases like pneumonia and other disorders involving macrophages.
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Affiliation(s)
- Renhao Ni
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Lingjing Jiang
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Chaohai Zhang
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Mujie Liu
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Yang Luo
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Zeming Hu
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Xianbo Mou
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Yabin Zhu
- Health Science Center, Ningbo University, Ningbo 315211, China
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31
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Ma X, Liang J, Zhu G, Bhoria P, Shoara AA, MacKeigan DT, Khoury CJ, Slavkovic S, Lin L, Karakas D, Chen Z, Prifti V, Liu Z, Shen C, Li Y, Zhang C, Dou J, Rousseau Z, Zhang J, Ni T, Lei X, Chen P, Wu X, Shaykhalishahi H, Mubareka S, Connelly KA, Zhang H, Rotstein O, Ni H. SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance: Implications for Antibody Therapy and Vaccinations against COVID-19. RESEARCH (WASHINGTON, D.C.) 2023; 6:0124. [PMID: 37223472 PMCID: PMC10202384 DOI: 10.34133/research.0124] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/28/2023] [Indexed: 10/10/2023]
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden. Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia (VITT) are both associated with thrombosis and thrombocytopenia; however, the underlying mechanisms remain inadequately understood. Both infection and vaccination utilize the spike protein receptor-binding domain (RBD) of SARS-CoV-2. We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice. Further investigation revealed the RBD could bind platelets, cause platelet activation, and potentiate platelet aggregation, which was exacerbated in the Delta and Kappa variants. The RBD-platelet interaction was partially dependent on the β3 integrin as binding was significantly reduced in β3-/- mice. Furthermore, RBD binding to human and mouse platelets was significantly reduced with related αIIbβ3 antagonists and mutation of the RGD (arginine-glycine-aspartate) integrin binding motif to RGE (arginine-glycine-glutamate). We developed anti-RBD polyclonal and several monoclonal antibodies (mAbs) and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation, aggregation, and clearance in vivo, and SARS-CoV-2 infection and replication in Vero E6 cells. Our data show that the RBD can bind platelets partially though αIIbβ3 and induce platelet activation and clearance, which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT. Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.
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Affiliation(s)
- Xiaoying Ma
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Jady Liang
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Department of Physiology,
University of Toronto, Toronto, ON, Canada
| | - Guangheng Zhu
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- CCOA Therapeutics Inc., Toronto, ON, Canada
| | - Preeti Bhoria
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- CCOA Therapeutics Inc., Toronto, ON, Canada
| | - Aron A. Shoara
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Department of Physiology,
University of Toronto, Toronto, ON, Canada
| | - Daniel T. MacKeigan
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Department of Physiology,
University of Toronto, Toronto, ON, Canada
| | - Christopher J. Khoury
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Sladjana Slavkovic
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- CCOA Therapeutics Inc., Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
| | - Lisha Lin
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Danielle Karakas
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Ziyan Chen
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
| | - Viktor Prifti
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Zhenze Liu
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Chuanbin Shen
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Yuchong Li
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease,
The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Cheng Zhang
- CCOA Therapeutics Inc., Toronto, ON, Canada
- Department of Laboratory Medicine,
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiayu Dou
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Zack Rousseau
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Jiamin Zhang
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Tiffany Ni
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
| | - Xi Lei
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- CCOA Therapeutics Inc., Toronto, ON, Canada
| | - Pingguo Chen
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
| | - Xiaoyu Wu
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy,
University of Toronto, Toronto, ON, Canada
| | - Hamed Shaykhalishahi
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- CCOA Therapeutics Inc., Toronto, ON, Canada
| | - Samira Mubareka
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Medical Microbiology and Infectious Disease,
Sunnybrook Health Science Centre, Toronto, ON, Canada
| | - Kim A. Connelly
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Department of Medicine,
University of Toronto, Toronto, ON, Canada
- Division of Cardiology,
St. Michael's Hospital, Toronto, ON, Canada
| | - Haibo Zhang
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease,
The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Medical Microbiology and Infectious Disease,
Sunnybrook Health Science Centre, Toronto, ON, Canada
- Department of Anesthesiology and Pain Medicine and Division of Critical Care Medicine,
University of Toronto, Toronto, ON, Canada
- Interdepartmental Division of Critical Care Medicine,
University of Toronto, Toronto, ON, Canada
| | - Ori Rotstein
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Department of Surgery,
University of Toronto, Toronto, ON, Canada
| | - Heyu Ni
- Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine,
Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON, Canada
- Toronto Platelet Immunobiology Group, Toronto, ON, Canada
- Department of Physiology,
University of Toronto, Toronto, ON, Canada
- CCOA Therapeutics Inc., Toronto, ON, Canada
- Canadian Blood Services Centre for Innovation, Toronto, ON, Canada
- Department of Medicine,
University of Toronto, Toronto, ON, Canada
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32
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McConnell MJ, Iwakiri Y. Portal Hypertension in Alcohol-Associated Hepatitis. CURRENT HEPATOLOGY REPORTS 2023; 22:67-73. [PMCID: PMC10075503 DOI: 10.1007/s11901-023-00601-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/23/2023] [Indexed: 04/08/2023]
Abstract
Purpose of Review This review article will examine portal hypertension in alcoholic hepatitis (AH) from both a basic mechanistic and a clinical perspective. Recent Findings Alcoholic hepatitis is a major public health problem in the USA, accounting for over 300,000 hospital admissions in a recent year of data (Jinjuvadia et al. J Clin Gastroenterol. 60;49:506–511). Portal hypertension is a key consequence of AH and a driver of liver-related morbidity and mortality. Alcohol may directly mediate portal hypertension via multiple possible mechanisms, including increased portal inflow, increased intrahepatic vasoconstriction, inflammation, and changes in the liver vasculature such as perisinusoidal fibrosis and phlebosclerosis. Summary Portal hypertension is a key consequence of AH and a critical area for future research.
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Affiliation(s)
- Matthew J. McConnell
- grid.47100.320000000419368710Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520 USA
| | - Yasuko Iwakiri
- grid.47100.320000000419368710Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520 USA
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33
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Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin 2023; 44:695-709. [PMID: 36253560 PMCID: PMC9574180 DOI: 10.1038/s41401-022-00998-0] [Citation(s) in RCA: 175] [Impact Index Per Article: 87.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 09/11/2022] [Indexed: 12/15/2022]
Abstract
The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.
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Affiliation(s)
- Suo-Wen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
| | - Iqra Ilyas
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China
| | - Jian-Ping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
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Wilson AD, Forse LB. Potential for Early Noninvasive COVID-19 Detection Using Electronic-Nose Technologies and Disease-Specific VOC Metabolic Biomarkers. SENSORS (BASEL, SWITZERLAND) 2023; 23:2887. [PMID: 36991597 PMCID: PMC10054641 DOI: 10.3390/s23062887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/19/2023] [Accepted: 03/03/2023] [Indexed: 06/12/2023]
Abstract
The established efficacy of electronic volatile organic compound (VOC) detection technologies as diagnostic tools for noninvasive early detection of COVID-19 and related coronaviruses has been demonstrated from multiple studies using a variety of experimental and commercial electronic devices capable of detecting precise mixtures of VOC emissions in human breath. The activities of numerous global research teams, developing novel electronic-nose (e-nose) devices and diagnostic methods, have generated empirical laboratory and clinical trial test results based on the detection of different types of host VOC-biomarker metabolites from specific chemical classes. COVID-19-specific volatile biomarkers are derived from disease-induced changes in host metabolic pathways by SARS-CoV-2 viral pathogenesis. The unique mechanisms proposed from recent researchers to explain how COVID-19 causes damage to multiple organ systems throughout the body are associated with unique symptom combinations, cytokine storms and physiological cascades that disrupt normal biochemical processes through gene dysregulation to generate disease-specific VOC metabolites targeted for e-nose detection. This paper reviewed recent methods and applications of e-nose and related VOC-detection devices for early, noninvasive diagnosis of SARS-CoV-2 infections. In addition, metabolomic (quantitative) COVID-19 disease-specific chemical biomarkers, consisting of host-derived VOCs identified from exhaled breath of patients, were summarized as possible sources of volatile metabolic biomarkers useful for confirming and supporting e-nose diagnoses.
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Affiliation(s)
- Alphus Dan Wilson
- Pathology Department, Center for Forest Health & Disturbance, Forest Genetics and Ecosystems Biology, Southern Research Station, USDA Forest Service, Stoneville, MS 38776, USA
| | - Lisa Beth Forse
- Southern Hardwoods Laboratory, Southern Research Station, USDA Forest Service, Stoneville, MS 38776, USA
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35
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Yang C, Cai L, Xiao SY. Pathologic Characteristics of Digestive Tract and Liver in Patients with Coronavirus Disease 2019. Gastroenterol Clin North Am 2023; 52:201-214. [PMID: 36813426 PMCID: PMC9531645 DOI: 10.1016/j.gtc.2022.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
With the high prevalence of coronavirus disease-2019 (COVID-19), there has been increasing understanding of the pathologic changes associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review summarizes the pathologic changes in the digestive system and liver associated with COVID-19, including the injuries induced by SARS-CoV2 infection of GI epithelial cells and the systemic immune responses. The common digestive manifestations associated with COVID-19 include anorexia, nausea, vomiting, and diarrhea; the clearance of the viruses in COVID-19 patients with digestive symptoms is usually delayed. COVID-19-associated gastrointestinal histopathology is characterized by mucosal damage and lymphocytic infiltration. The most common hepatic changes are steatosis, mild lobular and portal inflammation, congestion/sinusoidal dilatation, lobular necrosis, and cholestasis.
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Affiliation(s)
- Chunxiu Yang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lijun Cai
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shu-Yuan Xiao
- Department of Pathology, University of Chicago Medicine, University of Chicago Medicine, MC6101, Anatomic Pathology, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
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36
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Farias JP, Codes L, Vinhaes D, Amorim AP, D’Oliveira RC, Farias AQ, Bittencourt PL. Impact of baseline abnormal liver enzymes in the outcome of COVID-19 infection. Transl Gastroenterol Hepatol 2023; 8:5. [PMID: 36704646 PMCID: PMC9813650 DOI: 10.21037/tgh-22-41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022] Open
Abstract
Background Little is known about the significance of liver function tests (LFT) abnormalities in COVID-19 and their impact on disease outcomes. The aims of the study were to evaluate abnormalities of LFT in patients with COVID-19 and their impact on disease severity, mortality, and correlation with leukocyte markers of inflammation. Methods All patients with COVID-19 admitted to the emergency department (ED) of a single reference center were retrospectively evaluated. Data were collected using an electronic medical database covering the following variables: demographics, baseline complete blood count (CBC) and ratios, neutrophil-lymphocyte (NLR) and monocyte-lymphocyte ratios (MLR), systemic immune-inflammation index (SII), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Disease severity was defined by the presence of organ failure (OF) or requirement for intensive care unit (ICU) support. Mortality was considered as patient death during hospitalization. Results A total of 1,539 subjects (799 women, mean age 57±18 years) with COVID-19 were evaluated. Abnormal AST and/or ALT were seen in 50% of them, with a frequency and magnitude that significantly correlated with leukocyte count and ratios. Both LFT were significantly associated with requirement for hospital and ICU admission and mortality. High AST levels were significantly associated with the presence, number, and types of OFs and in-hospital length of stay (LOS). Elevated ALT was also significantly associated with the aforementioned variables, with the exception of OFs presence, circulatory failure and LOS. Conclusions LFT abnormalities are frequently seen in COVID-19 patients, reflect SARS-CoV-2 associated inflammation and may predict adverse outcomes. LFT may be useful to aid decision-making in the ED for hospital admission or scheduled outpatient reevaluation.
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Affiliation(s)
| | - Liana Codes
- Portuguese Hospital of Bahia, Salvador, Bahia, Brazil;,Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil
| | - Diana Vinhaes
- Portuguese Hospital of Bahia, Salvador, Bahia, Brazil
| | | | - Ricardo Cruz D’Oliveira
- Portuguese Hospital of Bahia, Salvador, Bahia, Brazil;,Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil
| | | | - Paulo Lisboa Bittencourt
- Portuguese Hospital of Bahia, Salvador, Bahia, Brazil;,Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil
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Ali FEM, Abd El-Aziz MK, Ali MM, Ghogar OM, Bakr AG. COVID-19 and hepatic injury: cellular and molecular mechanisms in diverse liver cells. World J Gastroenterol 2023; 29:425-449. [PMID: 36688024 PMCID: PMC9850933 DOI: 10.3748/wjg.v29.i3.425] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/15/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) represents a global health and economic challenge. Hepatic injuries have been approved to be associated with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. The viral tropism pattern of SARS-CoV-2 can induce hepatic injuries either by itself or by worsening the conditions of patients with hepatic diseases. Besides, other factors have been reported to play a crucial role in the pathological forms of hepatic injuries induced by SARS-CoV-2, including cytokine storm, hypoxia, endothelial cells, and even some treatments for COVID-19. On the other hand, several groups of people could be at risk of hepatic COVID-19 complications, such as pregnant women and neonates. The present review outlines and discusses the interplay between SARS-CoV-2 infection and hepatic injury, hepatic illness comorbidity, and risk factors. Besides, it is focused on the vaccination process and the role of developed vaccines in preventing hepatic injuries due to SARS-CoV-2 infection.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| | | | - Mahmoud M Ali
- Department of Pharmacology, Al-Azhar University, Assiut 71524, Egypt
| | - Osama M Ghogar
- Department of Biochemistry Faculty of Pharmacy, Badr University in Assiut, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
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38
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Zhao SW, Li YM, Li YL, Su C. Liver injury in COVID-19: Clinical features, potential mechanisms, risk factors and clinical treatments. World J Gastroenterol 2023; 29:241-256. [PMID: 36687127 PMCID: PMC9846943 DOI: 10.3748/wjg.v29.i2.241] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/11/2022] [Accepted: 12/08/2022] [Indexed: 01/06/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has been a serious threat to global health for nearly 3 years. In addition to pulmonary complications, liver injury is not uncommon in patients with novel COVID-19. Although the prevalence of liver injury varies widely among COVID-19 patients, its incidence is significantly increased in severe cases. Hence, there is an urgent need to understand liver injury caused by COVID-19. Clinical features of liver injury include detectable liver function abnormalities and liver imaging changes. Liver function tests, computed tomography scans, and ultrasound can help evaluate liver injury. Risk factors for liver injury in patients with COVID-19 include male sex, preexisting liver disease including liver transplantation and chronic liver disease, diabetes, obesity, and hypertension. To date, the mechanism of COVID-19-related liver injury is not fully understood. Its pathophysiological basis can generally be explained by systemic inflammatory response, hypoxic damage, ischemia-reperfusion injury, and drug side effects. In this review, we systematically summarize the existing literature on liver injury caused by COVID-19, including clinical features, underlying mechanisms, and potential risk factors. Finally, we discuss clinical management and provide recommendations for the care of patients with liver injury.
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Affiliation(s)
- Shu-Wu Zhao
- Department of Anesthesiology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha 410013, Hunan Province, China
| | - Yi-Ming Li
- School of Basic Medical Science, Naval Medical University/Second Military University, Shanghai 200433, China
| | - Yi-Lin Li
- Department of Pathology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha 410013, Hunan Province, China
| | - Chen Su
- Department of Anesthesiology and Pain, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha 410013, Hunan Province, China
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Dietrich CG, Geier A, Merle U. Non-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier? World J Gastroenterol 2023; 29:367-377. [PMID: 36687116 PMCID: PMC9846932 DOI: 10.3748/wjg.v29.i2.367] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/09/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The pandemics of coronavirus disease 2019 (COVID-19) and non-alcoholic fatty liver disease (NAFLD) coexist. Elevated liver function tests are frequent in COVID-19 and may influence liver damage in NAFLD, while preexisting liver damage from NAFLD may influence the course of COVID-19. However, the prognostic relevance of this interaction, though, is unclear. Obesity is a risk factor for the presence of NAFLD as well as a severe course of COVID-19. Cohort studies reveal conflicting results regarding the influence of NAFLD presence on COVID-19 illness severity. Striking molecular similarities of cytokine pathways in both diseases, including postacute sequelae of COVID-19, suggest common pathways for chronic low-activity inflammation. This review will summarize existing data regarding the interaction of both diseases and discuss possible mechanisms of the influence of one disease on the other.
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Affiliation(s)
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg 97080, Germany
| | - Uta Merle
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany
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Gunji M, Sawa C, Akiyama M, Mukai S, Takaki T, Kang D, Honda K. Gemcitabine alters sialic acid binding of the glycocalyx and induces inflammatory cytokine production in cultured endothelial cells. Med Mol Morphol 2023; 56:128-137. [PMID: 36622466 PMCID: PMC9828377 DOI: 10.1007/s00795-022-00347-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/30/2022] [Indexed: 01/10/2023]
Abstract
Gemcitabine (GEM) is an anticancer drug inhibiting DNA synthesis. Glomerular thrombotic microangiopathy (TMA) has been reported as an adverse effect. However, the precise mechanism of GEM-induced endothelial injury remains unknown. Cultured human umbilical vein endothelial cells (HUVECs) in the confluent phase were exposed to GEM (5-100 μM) for 48 h and evaluated cell viability and morphology, lectin binding concerning sialic acid of endothelial glycocalyx (GCX), and immunofluorescent staining of platelet-endothelial cell adhesion molecule (PECAM) and vascular endothelial growth factor receptor 2 (VEGFR2). The mRNA expression of α2,6-sialyltransferase (ST6Gal1), sialidase (neuraminidase-1: NEU-1), and interleukin (IL)-1β and IL-6 was also evaluated. GEM exposure at 5 μM induced cellular shrinkage and intercellular dissociation, accompanied by slight attenuation of PECAM and VEGFR2 immunostaining, although cell viability was still preserved. At this concentration, lectin binding showed a reduction of terminal sialic acids in endothelial GCX, probably associated with reduced ST6Gal1 mRNA expression. IL-1β and IL-6 mRNA expression was significantly increased after GEM exposure. GEM reduced terminal sialic acids in endothelial GCX through mRNA suppression of ST6Gal1 and induced inflammatory cytokine production in HUVECs. This phenomenon could be associated with the mechanism of GEM-induced TMA.
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Affiliation(s)
- Mariko Gunji
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan
| | - Chika Sawa
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan
| | - Minako Akiyama
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan
| | - Shumpei Mukai
- Department of Pathology, Showa University School of Medicine, Tokyo, Japan
| | - Takashi Takaki
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan ,Center for Electron Microscopy, Showa University, Tokyo, Japan
| | - Dedong Kang
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555 Japan
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41
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Hu WS, Jiang FY, Shu W, Zhao R, Cao JM, Wang DP. Liver injury in COVID-19: A minireview. World J Gastroenterol 2022; 28:6716-6731. [PMID: 36620342 PMCID: PMC9813934 DOI: 10.3748/wjg.v28.i47.6716] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/02/2022] [Accepted: 11/23/2022] [Indexed: 12/19/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has escalated into a global tragedy afflicting human health, life, and social governance. Through the increasing depth of research and a better understanding of this disease, it has been ascertained that, in addition to the lungs, SARS-CoV-2 can also induce injuries to other organs including the liver. Liver injury is a common clinical manifestation of COVID-19, particularly in severe cases, and is often associated with a poorer prognosis and higher severity of COVID-19. This review focuses on the general existing information on liver injury caused by COVID-19, including risk factors and subpopulations of liver injury in COVID-19, the association between preexisting liver diseases and the severity of COVID-19, and the potential mechanisms by which SARS-CoV-2 affects the liver. This review may provide some useful information for the development of therapeutic and preventive strategies for COVID-19-associated liver injury.
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Affiliation(s)
- Wen-Shu Hu
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Fang-Ying Jiang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Wen Shu
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Rong Zhao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Ji-Min Cao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - De-Ping Wang
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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Charles J, Ploplis VA. COVID-19 Induces Cytokine Storm and Dysfunctional Hemostasis. Curr Drug Targets 2022; 23:1603-1610. [PMID: 36284376 DOI: 10.2174/1389450124666221025102929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 10/05/2022] [Accepted: 10/12/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Infection with SARS-CoV-2 leads to COVID-19 which can manifest in various ways from asymptomatic or mild disease to acute respiratory distress syndrome. The occurrence of dysregulated inflammatory responses in the form of a cytokine storm has been reported in patients with severe COVID-19. Infection can also lead to dysfunctional hemostasis reflected in elevated circulating D-dimer and fibrin degradation products. Components of hemostasis and the immune system during infection can result in a procoagulation and/or proinflammatory state. The interplay between coagulation and inflammation has been elucidated in a number of diseases. OBJECTIVE In this article, we discuss the occurrence of cytokine storms and dysfunctional hemostasis induced in COVID-19. METHODS This review was written using literature from the past two to three years investigating coagulation and inflammation in COVID-19. Additional literature, both clinical and basic research, related to pathogen infection and host responses were also considered in this review. RESULTS/CONCLUSIONS Infection with SARS-CoV-2 can lead to dysregulated inflammatory responses that may be detrimental to the host. The increased expression of various inflammatory factors can ultimately create an environment that promotes thrombosis.
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Affiliation(s)
- Jermilia Charles
- W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Victoria A Ploplis
- W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA
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43
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Subramaniam S, Kothari H, Bosmann M. Tissue factor in COVID-19-associated coagulopathy. Thromb Res 2022; 220:35-47. [PMID: 36265412 PMCID: PMC9525243 DOI: 10.1016/j.thromres.2022.09.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/24/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022]
Abstract
Evidence of micro- and macro-thrombi in the arteries and veins of critically ill COVID-19 patients and in autopsies highlight the occurrence of COVID-19-associated coagulopathy (CAC). Clinical findings of critically ill COVID-19 patients point to various mechanisms for CAC; however, the definitive underlying cause is unclear. Multiple factors may contribute to the prothrombotic state in patients with COVID-19. Aberrant expression of tissue factor (TF), an initiator of the extrinsic coagulation pathway, leads to thrombotic complications during injury, inflammation, and infections. Clinical evidence suggests that TF-dependent coagulation activation likely plays a role in CAC. Multiple factors could trigger abnormal TF expression and coagulation activation in patients with severe COVID-19 infection. Proinflammatory cytokines that are highly elevated in COVID-19 (IL-1β, IL-6 and TNF-α) are known induce TF expression on leukocytes (e.g. monocytes, macrophages) and non-immune cells (e.g. endothelium, epithelium) in other conditions. Antiphospholipid antibodies, TF-positive extracellular vesicles, pattern recognition receptor (PRR) pathways and complement activation are all candidate factors that could trigger TF-dependent procoagulant activity. In addition, coagulation factors, such as thrombin, may further potentiate the induction of TF via protease-activated receptors on cells. In this systematic review, with other viral infections, we discuss potential mechanisms and cell-type-specific expressions of TF during SARS-CoV-2 infection and its role in the development of CAC.
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Affiliation(s)
- Saravanan Subramaniam
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Hema Kothari
- Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA; Cardiovascular Division, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - Markus Bosmann
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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Yin G, Liang H, Sun W, Zhang S, Feng Y, Liang P, Chen S, Liu X, Pan W, Zhang F. Shuangyu Tiaozhi decoction alleviates non-alcoholic fatty liver disease by improving lipid deposition, insulin resistance, and inflammation in vitro and in vivo. Front Pharmacol 2022; 13:1016745. [PMID: 36506575 PMCID: PMC9727266 DOI: 10.3389/fphar.2022.1016745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Our previous studies have found that Shuangyu Tiaozhi Decoction (SYTZD) could produce an improvement in NAFLD-related indicators, but the underlying mechanism associated with this improvement remains unclear. The study aimed to investigate the potential mechanism of SYTZD against NAFLD through network pharmacology and experimental verification. The components of SYTZD and SYTZD drug containing serum were analyzed using ultra-performance liquid chromatography to quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS). Active components and targets of SYTZD were screened by the traditional Chinese medical systems pharmacology (TCMSP) and encyclopedia of traditional Chinese medicine (ETCM) databases. NAFLD-related targets were collected from the GeneCards and DisGeNET databases. The component-disease targets were mapped to identify the common targets of SYTZD against NAFLD. Protein-protein interaction (PPI) network of the common targets was constructed for selecting the core targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the core targets was performed using the database for annotation, visualization, and integrated discovery (DAVID) database. Furthermore, animal and cell models were constructed for validating the predictions of network pharmacology. Lipid accumulation, liver histopathology, insulin resistance, and core gene expression were measured by oil red O staining, hematoxylin and eosin staining, insulin tolerance test, real-time quantitative polymerase chain reaction, and Western blotting, respectively. Two components and 22 targets of SYTZD against NAFLD were identified by UPLC-Q/TOF-MS and relevant databases. PPI analysis found that ESR1, FASN, mTOR, HIF-1α, VEGFA, and GSK-3β might be the core targets of SYTZD against NAFLD, which were mainly enriched in the thyroid hormone pathway, insulin resistance pathway, HIF-1 pathway, mTOR pathway, and AMPK pathway. Experimental results revealed that SYTZD might exert multiple anti-NAFLD mechanisms, including improvements in lipid deposition, inflammation, and insulin resistance. SYTZD treatment led to decreases in the lipid profiles, hepatic enzyme levels, inflammatory cytokines, and homeostatic model assessment for insulin resistance (HOMA-IR). SYTZD treatment affected relative mRNA and protein levels associated with various pathways. Our findings reveal that SYTZD could alleviate NAFLD through a multi-component, multi-target, and multi-pathway mechanism of action.
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Affiliation(s)
- Guoliang Yin
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hongyi Liang
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenxiu Sun
- Department of Nursing, Taishan Vocational College of Nursing, Taian, China
| | - Shizhao Zhang
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yanan Feng
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Pengpeng Liang
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Suwen Chen
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiangyi Liu
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenchao Pan
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fengxia Zhang
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China,*Correspondence: Fengxia Zhang,
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Jiang ST, Liu YG, Zhang L, Sang XT, Xu YY, Lu X. Systems biology approach reveals a common molecular basis for COVID-19 and non-alcoholic fatty liver disease (NAFLD). Eur J Med Res 2022; 27:251. [PMCID: PMC9664052 DOI: 10.1186/s40001-022-00865-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
Abstract
Background
Patients with non-alcoholic fatty liver disease (NAFLD) may be more susceptible to coronavirus disease 2019 (COVID-19) and even more likely to suffer from severe COVID-19. Whether there is a common molecular pathological basis for COVID-19 and NAFLD remains to be identified. The present study aimed to elucidate the transcriptional alterations shared by COVID-19 and NAFLD and to identify potential compounds targeting both diseases.
Methods
Differentially expressed genes (DEGs) for COVID-19 and NAFLD were extracted from the GSE147507 and GSE89632 datasets, and common DEGs were identified using the Venn diagram. Subsequently, we constructed a protein–protein interaction (PPI) network based on the common DEGs and extracted hub genes. Then, we performed gene ontology (GO) and pathway analysis of common DEGs. In addition, transcription factors (TFs) and miRNAs regulatory networks were constructed, and drug candidates were identified.
Results
We identified a total of 62 common DEGs for COVID-19 and NAFLD. The 10 hub genes extracted based on the PPI network were IL6, IL1B, PTGS2, JUN, FOS, ATF3, SOCS3, CSF3, NFKB2, and HBEGF. In addition, we also constructed TFs–DEGs, miRNAs–DEGs, and protein–drug interaction networks, demonstrating the complex regulatory relationships of common DEGs.
Conclusion
We successfully extracted 10 hub genes that could be used as novel therapeutic targets for COVID-19 and NAFLD. In addition, based on common DEGs, we propose some potential drugs that may benefit patients with COVID-19 and NAFLD.
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Cooper KM, Colletta A, Asirwatham AM, Moore Simas TA, Devuni D. COVID-19 associated liver injury: A general review with special consideration of pregnancy and obstetric outcomes. World J Gastroenterol 2022; 28:6017-6033. [PMID: 36405386 PMCID: PMC9669825 DOI: 10.3748/wjg.v28.i42.6017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 11/15/2022] Open
Abstract
Liver injury is an increasingly recognized extra-pulmonary manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Coronavirus disease 2019 (COVID-19) associated liver injury (COVALI) is a clinical syndrome encompassing all patients with biochemical liver injury identified in the setting of SARS-CoV-2 infection. Despite profound clinical implications, its pathophysiology is poorly understood. Unfortunately, most information on COVALI is derived from the general population and may not be applicable to individuals under-represented in research, including pregnant individuals. This manuscript reviews: Clinical features of COVALI, leading theories of COVALI, and existing literature on COVALI during pregnancy, a topic not widely explored in the literature. Ultimately, we synthesized data from the general and perinatal populations that demonstrates COVALI to be a hepatocellular transaminitis that is likely induced by systemic inflammation and that is strongly associated with disease severity and poorer clinical outcome, and offered perspective on approaching transaminitis in the potentially COVID-19 positive patient in the obstetric setting.
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Affiliation(s)
- Katherine M. Cooper
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States
| | - Alessandro Colletta
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States
| | - Alison M. Asirwatham
- Department of Obstetrics and Gynecology, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States
| | - Tiffany A. Moore Simas
- Department of Obstetrics and Gynecology, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States
- Departments of Pediatrics, Psychiatry, and Population & Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States
| | - Deepika Devuni
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, United States
- Division of Gastroenterology and Hepatology, University of Massachusetts Chan Medical School, Worcester, MA 1605, United States
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dos Santos AAC, Rodrigues LE, Alecrim-Zeza AL, de Araújo Ferreira L, Trettel CDS, Gimenes GM, da Silva AF, Sousa-Filho CPB, Serdan TDA, Levada-Pires AC, Hatanaka E, Borges FT, de Barros MP, Cury-Boaventura MF, Bertolini GL, Cassolla P, Marzuca-Nassr GN, Vitzel KF, Pithon-Curi TC, Masi LN, Curi R, Gorjao R, Hirabara SM. Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2. Front Microbiol 2022; 13:1037467. [PMID: 36439786 PMCID: PMC9684198 DOI: 10.3389/fmicb.2022.1037467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/26/2022] [Indexed: 09/09/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is triggered by the SARS-CoV-2, which is able to infect and cause dysfunction not only in lungs, but also in multiple organs, including central nervous system, skeletal muscle, kidneys, heart, liver, and intestine. Several metabolic disturbances are associated with cell damage or tissue injury, but the mechanisms involved are not yet fully elucidated. Some potential mechanisms involved in the COVID-19-induced tissue dysfunction are proposed, such as: (a) High expression and levels of proinflammatory cytokines, including TNF-α IL-6, IL-1β, INF-α and INF-β, increasing the systemic and tissue inflammatory state; (b) Induction of oxidative stress due to redox imbalance, resulting in cell injury or death induced by elevated production of reactive oxygen species; and (c) Deregulation of the renin-angiotensin-aldosterone system, exacerbating the inflammatory and oxidative stress responses. In this review, we discuss the main metabolic disturbances observed in different target tissues of SARS-CoV-2 and the potential mechanisms involved in these changes associated with the tissue dysfunction.
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Affiliation(s)
| | - Luiz Eduardo Rodrigues
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Amanda Lins Alecrim-Zeza
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Liliane de Araújo Ferreira
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Caio dos Santos Trettel
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Gabriela Mandú Gimenes
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Adelson Fernandes da Silva
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | | | - Tamires Duarte Afonso Serdan
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Department of Molecular Pathobiology, University of New York, New York, NY, United States
| | - Adriana Cristina Levada-Pires
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Elaine Hatanaka
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Fernanda Teixeira Borges
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Divisão de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Marcelo Paes de Barros
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Maria Fernanda Cury-Boaventura
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Gisele Lopes Bertolini
- Department of Physiological Sciences, Biological Science Center, State University of Londrina, Londrina, PR, Brazil
| | - Priscila Cassolla
- Department of Physiological Sciences, Biological Science Center, State University of Londrina, Londrina, PR, Brazil
| | | | - Kaio Fernando Vitzel
- School of Health Sciences, College of Health, Massey University, Auckland, New Zealand
| | - Tania Cristina Pithon-Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Laureane Nunes Masi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Rui Curi
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
- Instituto Butantan, São Paulo, Brazil
| | - Renata Gorjao
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
| | - Sandro Massao Hirabara
- Programa de Pós-graduação Interdisciplinar em Ciências da Saúde, Universidade Cruzeiro do Sul, São Paulo, São Paulo, Brazil
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48
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Li P, Liu Y, Cheng Z, Yu X, Li Y. COVID-19-associated liver injury: Clinical characteristics, pathophysiological mechanisms and treatment management. Biomed Pharmacother 2022; 154:113568. [PMID: 36029543 PMCID: PMC9381432 DOI: 10.1016/j.biopha.2022.113568] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global epidemic and poses a major threat to public health. In addition to COVID-19 manifesting as a respiratory disease, patients with severe disease also have complications in extrapulmonary organs, including liver damage. Abnormal liver function is relatively common in COVID-19 patients; its clinical manifestations can range from an asymptomatic elevation of liver enzymes to decompensated hepatic function, and liver injury is more prevalent in severe and critical patients. Liver injury in COVID-19 patients is a comprehensive effect mediated by multiple factors, including liver damage directly caused by SARS-CoV-2, drug-induced liver damage, hypoxia reperfusion dysfunction, immune stress and inflammatory factor storms. Patients with chronic liver disease (especially alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma) are at increased risk of severe disease and death after infection with SARS-CoV-2, and COVID-19 aggravates liver damage in patients with chronic liver disease. This article reviews the latest SARS-CoV-2 reports, focusing on the liver damage caused by COVID-19 and the underlying mechanism, and expounds on the risk, treatment and vaccine safety of SARS-CoV-2 in patients with chronic liver disease and liver transplantation.
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Affiliation(s)
- Penghui Li
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Ying Liu
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Ziqi Cheng
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xiaorui Yu
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yinxiong Li
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; State Key Laboratory of Respiratory Disease, Guangzhou, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China.
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Gao Y, Wang L, Wang L, Lu F. Severe acute hepatitis in children with unknown aetiology, etiology analysis and the next action. Virol Sin 2022; 37:778-782. [PMID: 35817405 PMCID: PMC9583125 DOI: 10.1016/j.virs.2022.07.004] [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] [Received: 05/27/2022] [Accepted: 07/04/2022] [Indexed: 11/24/2022] Open
Abstract
•MIS-C and severe acute hepatitis might share the common pathogenic mechanism. •SARS-CoV-2 persistence throughout multiorgan and tissues. •Relationship between COVID-19 vaccines and severe acute hepatitis worth investigating.
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Affiliation(s)
- Yuan Gao
- The Fourth Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Leijie Wang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Lin Wang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China; Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Beijing, 100044, China.
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50
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Alnamshan MM. Potential histopathological and immunological effects of SARS-CoV-2 on the liver. BRAZ J BIOL 2022; 82:e262008. [PMID: 36074418 DOI: 10.1590/1519-6984.262008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/05/2022] [Indexed: 12/15/2022] Open
Abstract
The coronavirus disease outbreak of 2019 (COVID-19) poses a serious threat to public health worldwide. Lung injury is the most common complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, other organs, including the liver, can also be affected. Currently, there is limited evidence that liver impairment is associated with severe SARS-CoV-2 infection. Clinicians will need to determine whether liver injury is caused by an underlying liver condition, COVID-19 therapy, the virus directly, or immune-mediated inflammation or represents a complicated disease course in the context of COVID-19. To address the scarcity of data on histopathological changes and immunological effects on the liver with COVID-19 positivity, we analyze and summarize recent findings. We searched PubMed, Medline, Google Scholar, Science Direct, Scopus, and Web of Science databases up to December 1, 2021, identifying published studies with the search terms "Histopathology in COVID-19," "COVID-19," "Pathological changes in liver in COVID-19," "Liver pathology in COVID-19," "immunological effects in liver in COVID-19," and "SARS-CoV-2." This concise review will aid clinicians and researchers in better understanding the tissue histopathology and immunological consequences of SARS-CoV-2 on the liver, enabling improved care planning and avoiding future dangers.
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Affiliation(s)
- M M Alnamshan
- Imam Abdulrahman Bin Faisal University, College of Science, Department of Biology, Dammam, Saudi Arabia
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