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Ma X, Huang T, Song Y, Pan H, Du A, Zhou X, Zeng Y, Yuan K. Bioinformatics and system biology approach to discover the common pathogenetic processes between COVID-19 and chronic hepatitis B. PLoS One 2025; 20:e0323708. [PMID: 40408617 PMCID: PMC12101853 DOI: 10.1371/journal.pone.0323708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/12/2025] [Indexed: 05/25/2025] Open
Abstract
INTRODUCTION The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents a significant global public health threat. Concurrently, hepatitis B virus (HBV) remains a significant public health challenge. While previous studies have indicated an association between COVID-19 and chronic hepatitis B, the common underlying pathogenesis of these diseases remains incompletely understood. METHODS To investigate the shared molecular mechanisms between chronic HBV infection and COVID-19, a comprehensive investigation was conducted using bioinformatics and systems biology. Specifically, we utilized RNA-seq datasets (GSE196822 and GSE83148) to identify differentially expressed genes (DEGs) associated with both SARS-CoV-2 and HBV infection. Subsequently, these common DEGs were utilized to identify shared pathways, hub genes, transcriptional regulatory networks, and potential drugs. The differential expression of hub genes in both COVID-19 and HBV was verified using the GSE171110 and GSE94660 datasets, respectively. RESULTS From the 106 shared DEGs identified, immune-related pathways were found to play a role in the development and progression of chronic hepatitis B and COVID-19. Protein-protein interaction (PPI) network analysis revealed 8 hub genes: CDK1, E2F7, E2F8, TYMS, KIF20A, CENPE, TPX2, HMMR, CD8A, GZMA. In the validation set, the expression of hub genes was statistically significant in both the COVID-19 group and the HBV group compared with the healthy control group. Transcriptional regulatory network analysis identified 155 microRNAs (miRNAs) and 43 transcription factors (TFs) as potential regulatory signals. Notably, we identified potential therapeutic drugs for HBV chronic infection and COVID-19, including progesterone, estradiol, dasatinib, aspirin, etoposide, irinotecan hydrochloride, phorbol 12-myristate 13-acetate, lucanthone, calcitriol. CONCLUSION This research elucidates potential molecular targets, signaling pathways, and promising small molecule compounds that could aid in the treatment of chronic HBV infection and COVID-19.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yujia Song
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongyuan Pan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ao Du
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Zhou
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Petrea (Cliveți) CL, Ciortea DA, Gurău G, Matei NM, Dinu CA, Bergheș (Oprea) SE, Verga (Răuță) GI, Berbece SI. Vitamin D Imbalance and Hydro-Electrolyte Disturbances in Hospitalized Children: A Comparation Between Post-COVID-19 Status and SARS-CoV-2/EBV Coinfection. Biomedicines 2025; 13:1233. [PMID: 40427060 PMCID: PMC12109002 DOI: 10.3390/biomedicines13051233] [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: 03/30/2025] [Revised: 05/14/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: SARS-CoV-2 infection has the potential to cause multi-organ involvement and, when associated with Epstein-Barr virus (EBV) coinfection, may worsen the course of disease in pediatric patients by influencing the immune response. Methods: Our retrospective-observational study included 406 hospitalized children with post-COVID-19 status or SARS-CoV-2/EBV coinfection. Results: Hypovitaminosis D was more common in the coinfected sublot (59.18%) than in the COVID-19 one (50.74%), with a higher frequency of severe vitamin D deficiency (16.33% vs. 7.35%). Hypovitaminosis D was significantly associated with female sex (p = 0.033) only in the COVID-19 subgroup. Hypervitaminosis D, although rare, was only associated with severe forms of the disease (7.69%). Between clinical severity and vitamin D level, a statistically significant association of moderate intensity was identified only in the COVID-19 subgroup (χ2 = 11.708, φ = 0.293, p = 0.020). In the same subgroup, a significant correlation was found between vitamin D levels and serum potassium values (χ2 = 10.527, p = 0.032). Moreover, in the COVID-19 subgroup, an association between abnormal sodium levels and increased D-dimer levels was found (χ2 = 7.074, p = 0.029). Conclusions: These results underline the importance of monitoring immunologic, vitamin, and electrolyte imbalance in the management of these cases and highlight the need for personalized therapeutic strategies to prevent long-term complications.
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Affiliation(s)
- Carmen Loredana Petrea (Cliveți)
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Diana-Andreea Ciortea
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
- Emergency Clinical Hospital for Children “Maria Sklodowska Curie”, 041451 Bucharest, Romania
| | - Gabriela Gurău
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Nicoleta Mădălina Matei
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Ciprian Adrian Dinu
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
| | - Simona-Elena Bergheș (Oprea)
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Gabriela Isabela Verga (Răuță)
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Sorin Ion Berbece
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (N.M.M.); (C.A.D.); (S.-E.B.); (G.I.V.); (S.I.B.)
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Mataix RP, Morillo JSG, Martín JMS. Hepatic phenomena associated with SARS-CoV-2: Acute liver injury, autoimmune hepatitis and post-vaccination. Med Clin (Barc) 2025; 164:491-498. [PMID: 39909769 DOI: 10.1016/j.medcli.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 02/07/2025]
Abstract
The infection with SARS-CoV-2, primarily recognized for its respiratory effects, reveals itself as a multifaceted clinical phenomenon, extending beyond the pulmonary realm. Accompanied by gastrointestinal, neurological, thromboembolic, cardiovascular, and immune-related manifestations, the complexity of the systemic repercussions of the disease becomes apparent. Genetic predisposition is a significant factor in the development of autoimmune hepatitis, as both viruses, such as SARS-CoV-2, and drugs, including vaccines, can act as triggers in genetically susceptible individuals. A profound understanding of these mechanisms is essential to effectively address the clinical complexity of SARS-CoV-2 infection.
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Affiliation(s)
- Roberto Pertusa Mataix
- Unit of Systemic and Rare Autoimmune Diseases in Adults, Internal Medicine Service, Virgen del Rocío University Hospital, Manuel Siurot Avenue, S/n, 41013 Sevilla, Spain.
| | - José Salvador García Morillo
- Unit of Systemic and Rare Autoimmune Diseases in Adults, Internal Medicine Service, Virgen del Rocío University Hospital, Manuel Siurot Avenue, S/n, 41013 Sevilla, Spain
| | - José Manuel Sousa Martín
- Digestive Department, Virgen del Rocío University Hospital, Manuel Siurot Avenue, S/n, 41013 Sevilla, Spain
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Wang Z, Zhao L, Xie K. Development and validation of a nomogram to assess the occurrence of liver dysfunction in patients with COVID-19 pneumonia in the ICU. BMC Infect Dis 2025; 25:332. [PMID: 40065225 PMCID: PMC11892215 DOI: 10.1186/s12879-025-10684-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
The global pandemic of novel coronavirus pneumonia (COVID-19) has resulted in millions of deaths over the past three years. As one of the most commonly affected extra-pulmonary organs, numerous studies have reported varying degrees of liver injury in a significant proportion of patients with COVID-19, particularly in severe and critically ill patients. Early prediction of liver dysfunction in hospitalized patients would facilitate the clinical management of COVID-19 and improve clinical prognosis, but reliable and valid predictive models are still lacking.MethodsWe collected data from 286 patients with RT-PCR confirmed COVID-19 admitted to various ICUs from the case system. These patients were randomly divided into a training cohort (50%) and a validation cohort (50%). In the training cohort, we first used ROC curves to measure the predictive efficiency of each of the variables for the development of liver damage during hospitalization in patients with COVID-19, followed by LASSO regression analysis to screen the variables for predictive models and logistic regression analysis to identify relevant risk factors. A nomogram based on these variables was created following the above model. Finally, the efficiency of the prediction models in the training and validation cohorts was assessed using AUC, consistency index (C index), calibration curves and Decision Curve Analysis.ResultsOut of a total of 80 parameters for COVID-19 patients admitted to the ICUs, 10 were determined to be significantly associated with the occurrence of liver dysfunction during hospitalization. Based on these predictors, further prediction models were used to construct and develop a nomogram that was offered for practical clinical application. The C-index of the column line graphs for the training and validation cohorts was 0.956 and 0.844 respectively. in addition, the calibration curves for the model showed a high degree of agreement between the predicted and actual incidence of liver dysfunction in patients with COVID-19.ConclusionBy developing a predictive model and associated nomogram, we predicted the incidence of liver dysfunction during hospitalization in patients with COVID-19 in the ICU. The model's predictive performance was determined in both the training and validation cohorts, contributing to the clinical management of COVID-19.
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Affiliation(s)
- Zhiwei Wang
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Lina Zhao
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Keliang Xie
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China.
- Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province, School of Anesthesiology, Shandong Second Medical University, Weifangaq, Weifang, Shandong, 261053, China.
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5
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Stasi C. Post-COVID-19 Pandemic Sequelae in Liver Diseases. Life (Basel) 2025; 15:403. [PMID: 40141748 PMCID: PMC11943493 DOI: 10.3390/life15030403] [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: 02/08/2025] [Revised: 02/27/2025] [Accepted: 03/03/2025] [Indexed: 03/28/2025] Open
Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, several studies highlighted a worse prognosis for patients with alterations in liver function tests, especially those with pre-existing liver diseases. However, further studies are needed to define the long-term impact of the COVID-19 pandemic on liver diseases. Long COVID-19 encompasses a wide range of signs and symptoms, including exacerbations of pre-existing chronic conditions or new onset conditions developed after the COVID-19 acute phase. Therefore, the long-term effects of COVID-19 extensively include hepatic manifestations. The co-expression of angiotensin-converting receptor 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) has been demonstrated also in enterocytes, cholangiocytes, and hepatocytes. Studies on the post-COVID-19 sequelae have shown the presence of steatosis and necroinflammation in the liver, concomitantly with an alteration of inflammation, cytolysis and cholestasis indices. Some studies also demonstrated an increased risk for hepatobiliary pathologies, including secondary biliary cholangitis and worsening of the severity of metabolic-associated fatty liver disease (MASLD). Based on these premises, this review aims to provide an overview of the pathophysiological mechanisms contributing to COVID-19-related liver and hepatobiliary damage; explore its implications for liver inflammation and fibrosis, with a particular focus on MASLD and metabolic dysfunction-associated steatohepatitis (MASH); and analyze the short- and long-term COVID-19 sequelae. A literature search was conducted using the PubMed database for relevant studies published in English.
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Affiliation(s)
- Cristina Stasi
- Department of Life Science, Health and Health Professions, Link Campus University, 00165 Roma, Italy; or
- Epidemiology Unit, Regional Health Agency of Tuscany, 50141 Florence, Italy
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6
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Ghare S, Warner D, Warner J, Chilton PM, Lee J, Zhang J, Wang M, Hardesty J, Treves R, Gabbard J, Anderson C, Batra L, Sreenivasan C, Kraenzle J, McCulley M, McCoy S, Zhang L, Feng W, Gondim DD, Barve S, Zheng J, Palmer K, McClain C, Kirpich I. Impact of chronic ethanol consumption and SARS-COV-2 on the liver and intestine: A pilot dose-response study in mice. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2025; 49:587-598. [PMID: 39757351 PMCID: PMC11928281 DOI: 10.1111/acer.15528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD). METHODS After 4 weeks of ethanol (EtOH) feeding, C57BL/6 male mice received SARS-CoV-2 (SARS2-N501YMA30) intranasally at 3 × 102, 1 × 103, 3 × 103, and 1 × 104 plaque-forming units (PFU). Mice were then weighed/monitored daily for morbidity/mortality for 10 days while continuing EtOH consumption. Markers of liver inflammation, injury, and intestinal barrier integrity were evaluated. RESULTS A similar gradual weight loss was observed in all inoculated mice (slightly less in the 3 × 102 group) up to post-infection day 4. Greater mortality was observed in mice receiving the highest viral dose at days 3 and 4 post-infection. The majority of the surviving mice subjected to EtOH and inoculated with 3 × 103 or 1 × 104 PFU rapidly lost 25% of their body weight and were euthanized on post-infection day 4. Analysis of liver health in animals that survived to the end of the experiment exhibited no significant changes in hepatic steatosis but had a limited increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at all viral doses versus EtOH alone. However, the 1 × 104 PFU viral dose exacerbated EtOH-induced hepatic inflammation characterized by elevated levels of several pro-inflammatory cytokines, including Il-6 and Tnf-α. There was limited effect of viral infection on the intestine. CONCLUSIONS SARS-CoV-2 infection caused a dose-dependent negative impact on body weight and survival in mice fed EtOH. This pilot study suggests that early mortality observed after high-dose SARS-CoV-2 challenge could be due, in part, to hepatic dysfunction following chronic EtOH feeding.
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Affiliation(s)
- Smita Ghare
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Dennis Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Jeffrey Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Paula M. Chilton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Jiyeon Lee
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - JingWen Zhang
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Min Wang
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Josiah Hardesty
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Rui Treves
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Jon Gabbard
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Charles Anderson
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Lalit Batra
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Chithra Sreenivasan
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Jennifer Kraenzle
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Matthew McCulley
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Stephanie McCoy
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Lihua Zhang
- Department of Structural & Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, United States
| | - Wenke Feng
- Department of Structural & Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, United States
| | - Dibson Dibe Gondim
- Department of Pathology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Shirish Barve
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Alcohol Research Center, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Hepatobiology and Toxicology Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Jian Zheng
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Kenneth Palmer
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
| | - Craig McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Alcohol Research Center, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Hepatobiology and Toxicology Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Robley Rex Veterans Affairs Medical Center, 800 Zorn Avenue, Louisville, KY 40206, United States
| | - Irina Kirpich
- Alcohol Research Center, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Hepatobiology and Toxicology Center, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
- Department of Microbiology and Immunology, School of Medicine, University of Louisville, 505 South Hancock Street, Louisville KY, 40202, United States
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Khan S, Hussain Timraz J, Al Ghamdi NA, Metwali NY, Yaseen FA, Alshaqha AM, Alamri SH, Turkistani H, Dwaima A, Ali Algarni I. COVID-19 and Its Effects on the Hepatobiliary System: A Literature Review. Cureus 2025; 17:e80231. [PMID: 40190856 PMCID: PMC11972666 DOI: 10.7759/cureus.80231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2025] [Indexed: 04/09/2025] Open
Abstract
COVID-19 encompasses a wide clinical spectrum, from mild influenza-like illness to severe pneumonia and systemic complications. There is emerging literature on hepatobiliary involvement in COVID-19, especially elevation in liver enzymes as surrogate markers of liver injury. Angiotensin-converting enzyme 2 receptors within the hepatobiliary system are a portal of entry for SARS-CoV-2, after which injury may be perpetuated through hypoxia and cytokine storms. This literature review covers studies published before 2024 from databases such as PubMed, Google Scholar, Springer, and BMC Library. The keywords used were "COVID-19", "liver", "SARS-CoV-2", "chronic liver disease", and other relevant terms to ensure a wide scope of investigation. The most common liver enzymes elevated among COVID-19 patients include aspartate transaminase, alanine transaminase, and alkaline phosphatase, all of which are associated with the severity of the disease. Chronic liver disease (CLD) and hepatocellular carcinoma (HCC) patients have worse outcomes with increased ICU admission rates and increased mortality. COVID-19 vaccination in CLD and liver transplant recipients is very often associated with suboptimal antibody responses, adding to the risks. SARS-CoV-2 causes liver involvement through direct viral cytopathic effects, immune-mediated injury, and systemic hypoxia. Individuals with CLD are particularly vulnerable to severe illness.
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Affiliation(s)
- Sariya Khan
- General Medicine and Surgery, Batterjee Medical College, Jeddah, SAU
| | | | | | - Nada Y Metwali
- Obstetrics and Gynecology, Batterjee Medical College, Jeddah, SAU
| | - Faten A Yaseen
- Medicine and Surgery, Batterjee Medical College, Jeddah, SAU
| | | | - Sarah H Alamri
- Internal Medicine, Batterjee Medical College, Jeddah, SAU
| | | | - Anas Dwaima
- Internal Medicine, International Medical Center Hospital, Jeddah, SAU
| | - Ibraheem Ali Algarni
- Family Medicine, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, SAU
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Pan Y, Jia Z, Yu X, Lv H, Zhang Y, Wu Y, Jiang J. Study on SARS-CoV-2 infection in middle-aged and elderly population infected with hepatitis virus: a cohort study in a rural area of northeast China. PeerJ 2025; 13:e19021. [PMID: 39995984 PMCID: PMC11849502 DOI: 10.7717/peerj.19021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Background To investigate the symptoms, the level of antibody, the progression of liver disease after SARS-CoV-2 infection in middle-aged and elderly population infected with hepatitis virus. Methods The study was based on a cohort of high-risk liver cancer and the participants was recruited in April 2023. Blood sample were collected and information was obtained through questionnaires. Data on reinfection was obtained by follow-up until July 31, 2023. The SARS-CoV-2-specific neutralizing antibody and IgG were measured. Results A total of 599 participants infected with hepatitis virus were included and the mean age was 61.3 ± 7.4 years. The SARS-CoV-2 infection rate was 94.7%. Among the infected, 132 were asymptomatic, 435 were symptomatic, no severe cases occurred. Four months after infection, no difference was in liver function and aMAP score between the infected and uninfected. The infected had higher seropositivity rates of both antibodies than the uninfected (neutralizing antibody: uninfected: 93.7%, infected: 99.6%; IgG: uninfected: 59.4%, infected: 98.9%). The levels of both antibodies in the symptomatic were higher than those the asymptomatic and the uninfected (neutralizing antibody: uninfected: 0.75 AU/mL, asymptomatic: 15.46 AU/mL, symptomatic: 24.76 AU/mL; IgG: uninfected: 15.10 AU/mL, asymptomatic: 263.84 AU/mL, symptomatic: 291.83 AU/mL). By July 31, 2023, the incidence of reinfection was 17.5%. Conclusions Although the infection rate of SARS-CoV-2 was high, no severe cases occurred. Omicron infection may not aggravate progression of hepatitis. Four months after infection, the population showed high positivity rate in neutralizing antibody and IgG. Monitoring of virus mutations and targeted prevention and care strategies is crucial for vulnerable populations.
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Affiliation(s)
- Yuchen Pan
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
- Department of Epidemiology and Biostatistics, School of Public Health Jilin University, Changchun, China
| | - Zhifang Jia
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Xinyi Yu
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Haiyong Lv
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Yangyu Zhang
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Yanhua Wu
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Jing Jiang
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
- Department of Epidemiology and Biostatistics, School of Public Health Jilin University, Changchun, China
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Kupriyanova Y, Yurchenko I, Bobrov P, Bartels F, Wierichs S, Jonuscheit M, Korzekwa B, Prystupa K, Schön M, Mendez D, Trenkamp S, Burkart V, Wagner R, Schrauwen-Hinderling V, Roden M. Alterations of hepatic lipid content following COVID-19 in persons with type 2 diabetes. BMJ Open Diabetes Res Care 2025; 13:e004727. [PMID: 39965871 PMCID: PMC11836859 DOI: 10.1136/bmjdrc-2024-004727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
INTRODUCTION The study aimed to assess the effect of COVID-19 on hepatic lipid (HL) content, fibrosis risk, and adiposity in persons with type 2 diabetes. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes with a history of mild COVID-19 (n=15, age 58±12 years, body mass index 30.9±5.2 kg/m2) were examined before (baseline) and 1 year (12±2 months) after (follow-up) recovery from COVID-19. Investigations for changes in metabolic risk comprised clinical examination, fasting blood sampling and MR-based measurements. Potential changes were corrected with the time course of the respective parameters in a group of participants who did not contract COVID-19 over the same time course (n=14, 61±6 years, 30.0±4.6 kg/m2). RESULTS COVID-19 resulted in a relative increase in HL content of 56% (95% CI 18%, 106%; p=0.04) measured as proton density fat fraction (HL-PDFF), corrected for the time course in the absence of COVID-19. While no changes in hepatic stiffness and volume, intramyocellular lipids, whole-body, subcutaneous and visceral adipose tissue volumes as well as homeostatic model assessment of insulin resistance and beta-cell function were observed. CONCLUSIONS History of COVID-19 in persons with type 2 diabetes is associated with higher HL-PDFF after 1 year following recovery from infection. TRIAL REGISTRATION NUMBER NCT01055093.
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Affiliation(s)
- Yuliya Kupriyanova
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Iryna Yurchenko
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Pavel Bobrov
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frederik Bartels
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Stefan Wierichs
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Marc Jonuscheit
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Benedict Korzekwa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Katsiaryna Prystupa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Martin Schön
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Dania Mendez
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Sandra Trenkamp
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Volker Burkart
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Robert Wagner
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Vera Schrauwen-Hinderling
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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10
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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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11
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Li L, Zhang H, Dai T, Liu D, Xiao S, Xiao Y, Huang L. Development of a Preoperative Screening Tool to Reduce Morbidity and Mortality of COVID-19-positive Hepatobiliary Patients. J Perianesth Nurs 2025; 40:120-125.e2. [PMID: 39001741 DOI: 10.1016/j.jopan.2024.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/17/2024] [Accepted: 03/29/2024] [Indexed: 07/15/2024]
Abstract
PURPOSE This study aimed to create a preoperative risk assessment form for COVID-19-positive hepatobiliary patients to guide further prevention of complications after surgery and reduce morbidity and mortality. DESIGN Based on the literature, focus groups, and case studies, a multidisciplinary panel of 15 experts conducted three rounds of a Delphi study that resulted in the development of a preoperative risk assessment form to be used by healthcare professionals in the treatment of COVID-19-positive hepatobiliary patients. METHODS A preoperative risk assessment form for health professionals to use among COVID-19-positive hepatobiliary patients was developed based on literature, focus groups, and case studies. A 3-round Delphi study was conducted to validate and revise the risk assessment form using a multidisciplinary panel of 15 experts involved in hepatobiliary surgery. FINDINGS The experts demonstrated high cooperation and familiarity with the research topic, with positive coefficients ranging from 93.33% to 100% and authority coefficients ranging from 0.83 to 0.86. The coordination coefficients were 0.33, 0.26, and 0.22, respectively, indicating good coordination among expert opinions. The final risk assessment form included 9 primary (first-level) indicators, 38 secondary (second-level) indicators, and 122 tertiary (third-level) indicators. CONCLUSIONS The preoperative risk assessment form for hepatobiliary surgery patients infected with COVID-19 is scientifically rigorous, reliable, and valid. This screening tool may be used by health providers to identify high-risk patients, prevent postoperative complications, and reduce morbidity and mortality.
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Affiliation(s)
- Lihui Li
- Hunan Provincial People's Hospital (The First Hospital Affiliated to Hunan Normal University), Changsha, Hunan, China
| | - Honghui Zhang
- Hunan Provincial People's Hospital (The First Hospital Affiliated to Hunan Normal University), Changsha, Hunan, China.
| | - Ting Dai
- Hunan Provincial People's Hospital (The First Hospital Affiliated to Hunan Normal University), Changsha, Hunan, China
| | - Dan Liu
- Hunan Provincial People's Hospital (The First Hospital Affiliated to Hunan Normal University), Changsha, Hunan, China
| | - Shan Xiao
- Hunan Provincial People's Hospital (The First Hospital Affiliated to Hunan Normal University), Changsha, Hunan, China
| | - Yuting Xiao
- Hunan Provincial People's Hospital (The First Hospital Affiliated to Hunan Normal University), Changsha, Hunan, China
| | - Ling Huang
- Tibet Autonomous Region Blood Center, Lhasa, Tibet Autonomous Region, China
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12
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Pastor F, Delphin M, Lucifora J, Verrier ER. [Non-alphabetic viral hepatitis]. Med Sci (Paris) 2025; 41:145-153. [PMID: 40028952 DOI: 10.1051/medsci/2025010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025] Open
Abstract
The liver is the target of various viruses that can cause significant damage, impair function and potentially threaten a patient's life. While the "alphabetic" hepatitis viruses A, B, C, D, and E are well-characterized, and their impact on liver function well-documented, many emerging and re-emerging viruses, some of which are considered by the WHO to be potential pandemic threats, also infect the liver. In this review, we describe the current state of knowledge regarding liver infections caused by major non-alphabetic hepatotropic viruses and their effects on liver functions.
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Affiliation(s)
- Florentin Pastor
- CIRI, Centre international de recherche en infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | | | - Julie Lucifora
- CIRI, Centre international de recherche en infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Eloi R Verrier
- Université de Strasbourg, Inserm, ITM UMR_S1110, Strasbourg, France
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13
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Li H, Lin H, Fan T, Huang L, Zhou L, Tian X, Zhao R, Zhang Y, Yang X, Wan L, Zhong H, Jiang N, Wei C, Chen W, Hou L. Exosomes derived from syncytia induced by SARS-2-S promote the proliferation and metastasis of hepatocellular carcinoma cells. Front Cell Infect Microbiol 2025; 14:1415356. [PMID: 39844837 PMCID: PMC11750861 DOI: 10.3389/fcimb.2024.1415356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 10/29/2024] [Indexed: 01/24/2025] Open
Abstract
Introduction Coronavirus disease 2019 (COVID-19) is characterized by fever, fatigue, dry cough, dyspnea, mild pneumonia and acute lung injury (ALI), which can lead to acute respiratory distress syndrome (ARDS), and SARS-CoV-2 can accelerate tumor progression. However, the molecular mechanism for the increased mortality in cancer patients infected with COVID-19 is unclear. Methods Colony formation and wound healing assays were performed on Huh-7 cells cocultured with syncytia. Exosomes were purified from the cell supernatant and verified by nanoparticle tracking analysis (NTA), Western blot (WB) analysis and scanning electron microscopy (SEM). Differentially expressed proteins in syncytia-derived exosomes (Syn-Exos) and their functions was analyzed by Proteomic sequencing. Syn-Exo-mediated promotion of hepatocellular carcinoma cells was measured by CCK-8 and Transwell migration assays. The mechanism by which Syn-Exos promote tumor growth was analyzed by Western blotting. A patient-derived xenotransplantation (PDX) mouse model was constructed to evaluate the pathological role of the SARS-CoV-2 spike protein (SARS-2-S). The number of syncytia in the tumor tissue sections was determined by immunofluorescence analysis. Results Syncytium formation promoted the proliferation and migration of hepatocellular carcinoma cells. Proteomic sequencing revealed that proteins that regulate cell proliferation and metastasis in Syn-Exos were significantly upregulated. Syn-Exos promote the proliferation and migration of hepatocellular carcinoma cells. Animal experiments showed that a pseudotyped lentivirus bearing SARS-2-S (SARS-2-Spp) promoted tumor development in PDX mice. More syncytia were found in tumor tissue from SARS-2-Spp mice than from VSV-Gpp mice. Conclusions Syn-Exos induced by SARS-2-S can promote the proliferation and metastasis of hepatocellular carcinoma cells.
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Affiliation(s)
- Huilong Li
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Haotian Lin
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Tinghui Fan
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Linfei Huang
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Li Zhou
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Xiaoyu Tian
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Ruzhou Zhao
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Yanhong Zhang
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Xiaopan Yang
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Luming Wan
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Hui Zhong
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Nan Jiang
- Department of Pharmacy, Medical Supplies Center of People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Congwen Wei
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Wei Chen
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Lihua Hou
- College of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Genetic engineering, Beijing Institute of Biotechnology, Beijing, China
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14
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Krasnenkova SF, Zayratyants OV, Midiber KY, Mikhaleva LM. [Liver pathology in COVID-19]. Arkh Patol 2025; 87:53-59. [PMID: 39943730 DOI: 10.17116/patol20258701153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
The literature review presents an analysis of the pathogenesis and pathological anatomy of liver damage in COVID-19. Liver damage with the steatosis, vascular disorders, mild portal and lobular inflammatory infiltration, cholestasis and clinically - liver failure is observed in majority of the patients with COVID-19. Chronic liver diseases with infection SARS-CoV-2 tend to decompensate, which significantly worsens the prognosis of the disease. Pathogenesis of liver damage in COVID19 is unclear. There was no convincing evidence for the hypothesis of cytotoxicity for hepatocytes or cholangiocytes by SARS-CoV-2. Similar liver morphological changes described by different authors suggest their nonspecific nature and multifactorial pathogenesis related to hypoxia, cytokin storm, systemic inflammatory response syndrome, sepsis and shock, Covid-associated angio- and coagulopathy, as well as drug-induced hepatotoxicity. Further research is needed to clarify the pathogenesis and pathological anatomy of the liver pathology in COVID-19.
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Affiliation(s)
- S F Krasnenkova
- Russian University of Medicine, Moscow, Russia
- Research Institute of Organization of Medicine and Medicine Management, Moscow, Russia
| | - O V Zayratyants
- Russian University of Medicine, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
| | - K Yu Midiber
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
- Peoples' Friendship University of Russia named after Patrice Lumumba, Moscow, Russia
| | - L M Mikhaleva
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
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15
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Ko C, Cheng CC, Mistretta D, Ambike S, Sacherl J, Velkov S, Liao BH, Bester R, Gültan M, Polezhaeva O, Herrmann A, Jakwerth CA, Schmidt-Weber CB, Bugert JJ, Wölfel R, Grass V, Essbauer S, Schnepf D, Keppler OT, Vondran FWR, Pichlmair A, Mogler C, Ebert G, Protzer U. SARS-CoV-2 Productively Infects Human Hepatocytes and Induces Cell Death. J Med Virol 2025; 97:e70156. [PMID: 39760326 DOI: 10.1002/jmv.70156] [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: 07/02/2024] [Revised: 11/25/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
SARS-CoV-2 infection is accompanied by elevated liver enzymes, and patients with pre-existing liver conditions experience more severe disease. While it was known that SARS-CoV-2 infects human hepatocytes, our study determines the mechanism of infection, demonstrates viral replication and spread, and highlights direct hepatocyte damage. Viral replication was readily detectable upon infection of primary human hepatocytes and hepatoma cells with the ancestral SARS-CoV-2, Delta, and Omicron variants. Hepatocytes express the SARS-CoV-2 receptor ACE2 and the host cell protease TMPRSS2, and knocking down ACE2 and TMPRSS2 impaired SARS-CoV-2 infection. Progeny viruses released from infected hepatocytes showed the typical coronavirus morphology by electron microscopy and proved infectious when transferred to fresh cells, indicating that hepatocytes can contribute to virus spread. Importantly, SARS-CoV-2 infection rapidly induced hepatocyte death in a replication-dependent fashion, with the Omicron variant showing faster onset but less extensive cell death. C57BL/6 wild-type mice infected with a mouse-adapted SARS-CoV-2 strain showed high levels of viral RNA in liver and lung tissues. ALT peaked when viral RNA was cleared from the liver. Liver histology revealed profound tissue damage and immune cell infiltration, indicating that direct cytopathic effects of SARS-CoV-2 and immune-mediated killing of infected hepatocytes contribute to liver pathology.
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Grants
- This study was supported by the German Research Foundation (DFG) via SFB-TRR179 (project 272983813 to U.P.), TRR22 (project 398577603 to C.S.W.) and TRR353 (project 471011418 to G.E.), by the State of Bavaria via research network FOR-COVID and Bay-VOC, by the project "Virological and immunological determinants of COVID-19 pathogenesis-lessons to get prepared for future pandemics" (KA1-Co-02 "COVIPA" to U.P.) and "Airborne Transmission of SARS Coronavirus - From Fundamental Science to Efficient Air Cleaning Systems" (KA1-Co-06 "CORAERO" to G.E.), grants from the Helmholtz Association's Initiative and Networking Fund, by the European Commission FET Open Grant VIROFIGHT (grant no. 899619), by the State of Bavaria and the European Union via a grant for regional infrastructure development (EFRE - REACT, to U.P. and G.E.), by the State of Bavaria via research networks FOR-COVID and Bay-VOC (to U.P. and O.T.K.) by the Federal Ministry of Education and Research (project ESCAPE; 01KI20169A to C.S.W.), and by the Medical Biological Defense Research Program of the Bundeswehr Medical Service (to J.J.B.). In addition, this research was supported by intramural funds from KRICT (project KK2432-10 and BSF24-111 to C.K.).
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Affiliation(s)
- Chunkyu Ko
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
- Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon, South Korea
| | - Cho-Chin Cheng
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Daniele Mistretta
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Shubhankar Ambike
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Julia Sacherl
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Stoyan Velkov
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Bo-Hung Liao
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Romina Bester
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Merve Gültan
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Olga Polezhaeva
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Alexander Herrmann
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Constanze A Jakwerth
- Center of Allergy & Environment (ZAUM), Technical University of Munich/Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
| | - Carsten B Schmidt-Weber
- Center of Allergy & Environment (ZAUM), Technical University of Munich/Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany
- German Center for Lung Research (DZL), Munich Partner Site, Munich, Germany
| | - Joachim J Bugert
- Department of Viruses and Intracellular Pathogens, Bundeswehr Institute of Microbiology, Munich, Germany
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
| | - Roman Wölfel
- Department of Viruses and Intracellular Pathogens, Bundeswehr Institute of Microbiology, Munich, Germany
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
| | - Vincent Grass
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Sandra Essbauer
- Department of Viruses and Intracellular Pathogens, Bundeswehr Institute of Microbiology, Munich, Germany
| | - Daniel Schnepf
- Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany
- Immunoregulation Laboratory, The Francis Crick Institute, London, UK
| | - Oliver T Keppler
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
- Max von Pettenkofer Institute & Gene Center, Faculty of Medicine, University of Munich, Munich, Germany
| | - Florian W R Vondran
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
- ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Andreas Pichlmair
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
| | - Carolin Mogler
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Gregor Ebert
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Partner Sites Munich and Hannover-Braunschweig, Munich, Germany
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16
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Wang Z, Yang T, Zhang L, Makamure J, Hong W, Liang B. Age and clinical spectrum of COVID-19 are associated with safety of transarterial chemoembolization in hepatocellular carcinoma: a retrospective cohort study. J Gastrointest Oncol 2024; 15:2642-2655. [PMID: 39816043 PMCID: PMC11732337 DOI: 10.21037/jgo-24-527] [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: 07/10/2024] [Accepted: 11/22/2024] [Indexed: 01/18/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) patients with coronavirus disease 2019 (COVID-19) undergoing open surgery show increased adverse events (AEs) and mortality, while the safety of transarterial chemoembolization (TACE) in coinfected patients remains understudied, limiting available evidence. This study aims to investigate the safety of TACE in HCC patients coinfected with COVID-19, and to explore the potential risk factors affecting the occurrence of serious AEs (SAEs), thus providing evidence for clinical treatment strategies in such patients. Methods This retrospective study involved HCC patients who underwent TACE with or without COVID-19 infection at our institution from November 2022 to February 2023. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for the diagnosis of COVID-19. Patients were divided into an infected group (diagnosed with COVID-19 within 2 weeks before or after the procedure) and an uninfected group (tested negative for COVID-19). SAEs were ascertained according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Logistic regression analysis of multiple clinical factors in preoperative baseline characteristics was performed to identify risk factors that might predict the occurrence of SAEs. Results A total of 118 patients (73 in the infected group, 45 in the uninfected group) were included, of whom 83.9% were male (86.3% in the infected group vs. 80.0% in the uninfected group) and the median age was 55.9±12.4 years (56.8±12.3 vs. 54.5±12.7 years). The clinical spectrum of COVID-19 in the infected group were 80.8% mild, 13.7% moderate, 1.4% severe and 4.1% critical. Sixteen of the 118 patients experienced SAEs (19.2% vs. 4.4%, P=0.046). The predominant SAEs were respiratory system diseases (9.6% vs. 0.0%) and liver damage (2.7% vs. 2.2%). In the univariate analysis, infection status [odds ratio (OR): 5.102, P=0.04, 95% confidence interval (CI): 1.102-23.627], gender (OR: 2.857, P=0.09, 95% CI: 0.862-9.468), age (OR: 1.061, P=0.03, 95% CI: 1.007-1.118) and clinical spectrum of COVID-19 (OR: 4.259, P<0.001, 1.943-9.336) were considered as the potential risk factors of grade ≥3 AEs. In multivariate analysis, younger age (OR: 1.064, P=0.044, 95% CI: 1.002-1.131) and a milder clinical spectrum of COVID-19 (OR: 5.736, P=0.004, 95% CI: 1.772-18.568) were independent factors associated with a lower occurrence of SAEs. Conclusions TACE in HCC patients co-infected with COVID-19 was considered relatively safe. Age and clinical spectrum of COVID-19 were associated with SAEs in HCC patients treated with TACE.
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Affiliation(s)
- Zizhuo Wang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Yang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lijie Zhang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Joyman Makamure
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Hong
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Liang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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17
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Nyarko JA, Dogbe PM, Ativi LAE, Wutsika J, Agyenim EB, Awere-Duodu A, Botaeng AT, Ntim NAA. Pathological Sequelae of SARS-CoV-2: A Review for Clinicians. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2024; 97:431-445. [PMID: 39703609 PMCID: PMC11650917 DOI: 10.59249/dqjh2274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
The Coronavirus Disease 2019 (COVID-19) pandemic, driven by the novel coronavirus and its variants, has caused over 518 million infections and 6.25 million deaths globally, leading to a significant health crisis. Beyond its primary respiratory impact, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been implicated in various extra-pulmonary complications. Research studies reveal that the virus affects multiple organs, including the kidneys, liver, pancreas, and central nervous system (CNS), largely due to the widespread expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors. Clinical evidence shows that the virus can induce diabetes by disrupting pancreatic and liver functions as well as cause acute kidney injury. Additionally, neurological complications, including cognitive impairments and neuroinflammation, have been observed in a significant number of COVID-19 patients. This review discusses the mechanisms linking SARS-CoV-2 to acute kidney injury, Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM), emphasizing its effects on pancreatic beta cells, insulin resistance, and the regulation of gluconeogenesis. We also explore how SARS-CoV-2 induces neurological complications, detailing the intricate pathways of neuro-invasion and the potential to trigger conditions such as Alzheimer's disease (AD). By elucidating the metabolic and neurological manifestations of COVID-19 and the underlying pathogenic mechanisms, this review underscores the imperative for continued research and the development of effective therapeutic interventions to mitigate the long-term and short-term impacts of SARS-CoV-2 infection.
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Affiliation(s)
- Joseph Asuam Nyarko
- National Influenza Centre, Noguchi Memorial Institute
for Medical Research, Accra, Ghana
| | - Patience Mawuena Dogbe
- Department of Environmental Science, Kwame Nkrumah
University of Science and Technology, Kumasi, Ghana
| | | | - Jennifer Wutsika
- National Influenza Centre, Noguchi Memorial Institute
for Medical Research, Accra, Ghana
| | | | - Aaron Awere-Duodu
- Department of Medical Microbiology, University of Ghana
Medical School, Accra, Ghana
| | - Anthony Twumasi Botaeng
- Department of Environmental Science, Kwame Nkrumah
University of Science and Technology, Kumasi, Ghana
| | - Nana Afia Asante Ntim
- National Influenza Centre, Noguchi Memorial Institute
for Medical Research, Accra, Ghana
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18
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Balaji D, Balakrishnan R, Srinivasan D, Subbarayan R, Shrestha R, Srivastava N, Chauhan A. The Impact of SARS-CoV-2 on Liver Diseases and Potential Phytochemical Treatments. INFECTIOUS MICROBES AND DISEASES 2024; 6:177-188. [DOI: 10.1097/im9.0000000000000161] [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
Abstract
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has brought about numerous challenges. One of these challenges is the impact of SARS-CoV-2 on the liver. Although this virus primarily affects the lungs, it can induce elevated transaminase levels and the development of scar tissue in the liver, exacerbating preexisting liver conditions. Individuals with preexisting conditions, such as nonalcoholic fatty liver disease, alcohol-induced liver disease and hepatocellular carcinoma, face an increased risk of mortality from COVID-19. However, drugs currently used to treat COVID-19 have undesirable side effects, which make them unsuitable for patients with preexisting liver conditions. In this review, we explore the potential of phytochemicals, such as apigenin, berberine, curcumin, epigallocatechin-3-gallate, quercetin, resveratrol and silymarin, for treatment of the liver conditions, including nonalcoholic fatty liver disease, alcohol-induced liver disease and hepatocellular carcinoma. We also discuss significant associations between phytochemicals and COVID-19 by depicting their molecular interactions. Based on the discussed overlapping functions, it is important to assess the therapeutic efficacy of phytochemicals that possess hepatoprotective properties as potential alternative treatments for COVID-19.
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Affiliation(s)
- Dhanvee Balaji
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Ranjith Balakrishnan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | | | | | | | - Ankush Chauhan
- Centre for Herbal Pharmacology and Environmental Sustainability, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
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19
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Wang Q, Wei J, He J, Ming S, Li X, Huang X, Hong Z, Wu Y. HSP70 contributes to pathogenesis of fulminant hepatitis induced by coronavirus. Int Immunopharmacol 2024; 141:112963. [PMID: 39159560 DOI: 10.1016/j.intimp.2024.112963] [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: 07/03/2024] [Revised: 08/07/2024] [Accepted: 08/15/2024] [Indexed: 08/21/2024]
Abstract
Fulminant viral hepatitis (FH) represents a significant clinical challenge, with its pathogenesis not yet fully elucidated. Heat shock protein (HSP)70, a molecular chaperone protein with a broad range of cytoprotective functions, is upregulated in response to stress. However, the role of HSP70 in FH remains to be investigated. Notably, HSP70 expression is upregulated in the livers of coronavirus-infected mice and patients. Therefore, we investigated the mechanistic role of HSP70 in coronavirus-associated FH pathogenesis. FH was induced in HSP70-deficient (HSP70 KO) mice or in WT mice treated with the HSP70 inhibitor VER155008 when infected with the mouse hepatitis virus strain A59 (MHV-A59). MHV-A59-infected HSP70 KO mice exhibited significantly reduced liver damage and mortality. This effect was attributed to decreased infiltration of monocyte-macrophages and neutrophils in the liver of HSP70 KO mice, resulting in lower levels of inflammatory cytokines such as IL-1β, TNFα, and IL-6, and a reduced viral load. Moreover, treatment with the HSP70 inhibitor VER155008 protected mice from MHV-A59-induced liver damage and FH mortality. In summary, HSP70 promotes coronavirus-induced FH pathogenesis by enhancing the infiltration of monocyte-macrophages and neutrophils and promoting the secretion of inflammatory cytokines. Therefore, HSP70 is a potential therapeutic target in viral FH intervention.
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Affiliation(s)
- Qiaohua Wang
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Jiayou Wei
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Jianzhong He
- Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Siqi Ming
- Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai, Guangdong Province 519015, China
| | - Xingyu Li
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Xi Huang
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Zhongsi Hong
- Center of Infectious Disease, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
| | - Yongjian Wu
- Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
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20
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Khanal R, Heinen N, Bogomolova A, Meister TL, Herrmann ST, Westhoven S, Nocke MK, Todt D, Jockenhövel F, Klein IM, Hartmann L, Vondran FWR, Steinmann E, Zimmer G, Ott M, Brown RJP, Sharma AD, Pfaender S. MicroRNAs modulate SARS-CoV-2 infection of primary human hepatocytes by regulating the entry factors ACE2 and TMPRSS2. Liver Int 2024; 44:2983-2995. [PMID: 39175256 DOI: 10.1111/liv.16079] [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: 08/07/2024] [Accepted: 08/10/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND AND AIMS Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection. METHODS We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed. RESULTS We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome. CONCLUSION We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.
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Affiliation(s)
- Rajendra Khanal
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group Liver Regeneration & RNA Therapeutics, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Natalie Heinen
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Alexandra Bogomolova
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group Liver Regeneration & RNA Therapeutics, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Toni L Meister
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Institute for Infection Research and Vaccine Development (IIRVD), Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Simon T Herrmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
| | - Saskia Westhoven
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
| | - Maximilian K Nocke
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Daniel Todt
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Freya Jockenhövel
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Isabel M Klein
- Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Laura Hartmann
- Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian W R Vondran
- Department of General, Visceral, Pediatric and Transplant Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Eike Steinmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Gert Zimmer
- Institute of Virology and Immunology, Bern, Switzerland
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Michael Ott
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard J P Brown
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Amar Deep Sharma
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group Liver Regeneration & RNA Therapeutics, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Stephanie Pfaender
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Research Unit Emerging Viruses, Leibniz Institute of Virology (LIV), Hamburg, Germany
- University of Lübeck, Lübeck, Germany
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21
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Badary HA, Hashem MB, El-Kassas M. Drug-induced liver injury during the era of COVID-19 polypharmacy: a statement of account, lessons learned, and a proposed approach. EGYPTIAN LIVER JOURNAL 2024; 14:75. [DOI: 10.1186/s43066-024-00381-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 10/07/2024] [Indexed: 01/03/2025] Open
Abstract
AbstractThe coronavirus disease 2019 (COVID-19) causes a systemic illness that can result in various manifestations. In addition to severe acute respiratory syndrome, patients often exhibit complications unrelated to the respiratory system. Potential liver damage can occur in 14.8 to 53.0% of the affected patients. Liver impairment in COVID-19 can also occur because of the use of polypharmacy during disease management. It is essential to be aware of drug-induced liver injury (DILI) in patients diagnosed with COVID-19, especially when considering the off-label usage of medications in both preventative and therapeutic regimens used on a wide scale. This review aims to give pertinent information regarding drugs utilized thus far in COVID-19 patients and their potential toxicity to the liver. We also present a suggested management approach to DILI in COVID-19 patients and lessons learned from the pharmacological management of this pandemic.
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22
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Petrea (Cliveți) CL, Ciortea DA, Candussi IL, Gurău G, Matei NM, Bergheș SE, Chirila SI, Berbece SI. A Study of Hydroelectrolytic and Acid-Base Disturbances in MIS-C Patients: A Perspective on Antidiuretic Hormone Secretion. Curr Issues Mol Biol 2024; 46:11438-11459. [PMID: 39451561 PMCID: PMC11505753 DOI: 10.3390/cimb46100681] [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: 09/11/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024] Open
Abstract
COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) is a rare autoimmune disorder characterized by a range of polymorphic manifestations, similar to but distinct from other well-known inflammatory syndromes in children. We conducted a retrospective-descriptive study in which we summarized the clinical presentation of, biomarker variations in, and complications occurring in patients diagnosed with MIS-C, admitted to the Emergency Clinical Hospital for Children "Sf. Ioan", Galati, between July 2020 and June 2024. A total of 36 children met the MIS-C classification criteria according to the WHO-approved case definitions. A total of 41.7% (n = 15) were male and 58.3% (n = 21) were female. The median age of the study group was 4 years (IQR: 1.75-9.25 years). Surgical involvement was suspected in 16.7% (n = 6) of the patients, while 52.8% (n = 19) required intensive care. Clinically, fever was the most common symptom present in 89% (n = 32) of the cases. Gastrointestinal disorders were also common, with 50% (n = 18) presenting with inappetence, 42% (n = 15) with vomiting, and 39% (n = 14) with abdominal pain from admission, which worsened over time. Paraclinically, all patients exhibited signs of inflammation, and 86.1% (n = 31) had hydroelectrolytic and acid-base imbalances. The median hospital stay was 10 days (IQR: 7-12 days), with a stagnant clinical course in most cases. The inflammatory mechanisms in MIS-C, which can affect the secretion of antidiuretic hormone (ADH), were correlated with hydroelectrolytic disturbances and may lead to severe complications. For this reason, it is imperative to evaluate hydroelectrolytic disorders in the context of MIS-C and use diagnostic and prognostic biomarkers to develop effective therapeutic management strategies, ultimately improving the quality of life of affected children.
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Affiliation(s)
- Carmen Loredana Petrea (Cliveți)
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Diana-Andreea Ciortea
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
- Emergency Clinical Hospital for Children “Maria Sklodowska Curie”, 041451 Bucharest, Romania
| | - Iuliana-Laura Candussi
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Gabriela Gurău
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Nicoleta Mădălina Matei
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
- Emergency Clinical Hospital for Children “Sf. Ioan”, 800487 Galati, Romania
| | - Simona-Elena Bergheș
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
| | | | - Sorin Ion Berbece
- Faculty of Medicine and Pharmacy, University “Dunarea de Jos” of Galati, 800008 Galati, Romania; (C.L.P.); (G.G.); (S.-E.B.)
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23
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Schneeweiss-Gleixner M, Krenn K, Petter M, Haselwanter P, Kraft F, Adam L, Semmler G, Hartl L, Halilbasic E, Buchtele N, Krall C, Staudinger T, Zauner C, Trauner M, Stättermayer AF. Presence of cholestasis and its impact on survival in SARS-CoV-2 associated acute respiratory distress syndrome. Sci Rep 2024; 14:23377. [PMID: 39379494 PMCID: PMC11461911 DOI: 10.1038/s41598-024-73948-x] [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: 04/16/2024] [Accepted: 09/23/2024] [Indexed: 10/10/2024] Open
Abstract
Data on cholestasis and biliary injury in patients with COVID-19 are scarce. The primary aim of this study was to evaluate the prevalence of cholestasis and factors associated with its development and outcome in critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS). In this retrospective exploratory study, COVID-19 patients with ARDS admitted to an intensive care unit (ICU) at the Medical University of Vienna were evaluated for the development of cholestasis defined as an alkaline phosphatase level of 1.67x upper limit of normal for at least three consecutive days. Simple and multiple logistic regression analysis was used to evaluate parameters associated with development of cholestasis and survival. Of 225 included patients 119 (53%) developed cholestasis during ICU stay. Patients with cholestasis had higher peak levels of alkaline phosphatase, gamma-glutamyl transferase, bilirubin and inflammation parameters. Factors independently associated with cholestasis were extracorporeal membrane oxygenation support, ketamine use, high levels of inflammation parameters and disease severity. Presence of cholestasis and peak ALP levels were independently associated with worse ICU and 6-month survival. Development of cholestasis is a common complication in critically ill COVID-19 patients and represents a negative prognostic marker for survival. It is associated with disease severity and specific treatment modalities of intensive care.
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Affiliation(s)
- Mathias Schneeweiss-Gleixner
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Katharina Krenn
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Mathias Petter
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Patrick Haselwanter
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Felix Kraft
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Lukas Adam
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Nina Buchtele
- Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, Vienna, Austria
| | - Christoph Krall
- Department of Medical Statistics, Medical University of Vienna, Vienna, Austria
| | - Thomas Staudinger
- Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, Vienna, Austria
| | - Christian Zauner
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria.
| | - Albert Friedrich Stättermayer
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria.
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24
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Tan X, Gao X, Zheng H, Yuan H, Liu H, Ran Q, Luo M. Platelet dysfunction caused by differentially expressed genes as key pathogenic mechanisms in COVID-19. Minerva Cardiol Angiol 2024; 72:517-534. [PMID: 38804627 DOI: 10.23736/s2724-5683.24.06501-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
At the end of 2019, the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became prevalent worldwide, which brought a heavy medical burden and tremendous economic losses to the world population. In addition to the common clinical respiratory symptoms such as fever, cough and headache, patients with COVID-19 often have hematological diseases, especially platelet dysfunction. Platelet dysfunction usually leads to multiple organ dysfunction, which is closely related to patient severity or mortality. In addition, studies have confirmed significant changes in the gene expression profile of circulating platelets under SARS-CoV-2 infection, which will further lead to changes in platelet function. At the same time, studies have shown that platelets may absorb SARS-COV-2 mRNA independently of ACE2, which further emphasizes the importance of the stability of platelet function in defense against SARS-CoV-2 infection. This study reviewed the relationship between COVID-19 and platelet and SARS-CoV-2 damage to the circulatory system, and further analyzed the significantly differentially expressed mRNA in platelets after infection with SARS-CoV-2 on the basis of previous studies. The top eight hub genes were identified as NLRP3, MT-CO1, CD86, ICAM1, MT-CYB, CASP8, CXCL8 and CXCR4. Subsequently, the effects of SARS-CoV-2 infection on platelet transcript abnormalities and platelet dysfunction were further explored on the basis of 8 hub genes. Finally, the treatment measures of complications caused by platelet dysfunction in patients with COVID-19 were discussed in detail, so as to provide reference for the prevention, diagnosis and treatment of COVID-19.
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Affiliation(s)
- Xiaoyong Tan
- Department of Pharmacy, Xuanhan County People's Hospital, Dazhou, China
| | - Xiaojun Gao
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Huanhuan Zheng
- School of Public Health, Southwest Medical University, Luzhou, China
| | - Hui Yuan
- Department of Clinical Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hong Liu
- Department of Pharmacy, Xuanhan County People's Hospital, Dazhou, China
| | - Qijun Ran
- Department of Pharmacy, Xuanhan County People's Hospital, Dazhou, China
| | - Mao Luo
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, China -
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Drug Discovery Research Center, Southwest Medical University, Luzhou, China
- Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
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25
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Eisenreich W, Leberfing J, Rudel T, Heesemann J, Goebel W. Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View. Int J Mol Sci 2024; 25:9977. [PMID: 39337465 PMCID: PMC11432161 DOI: 10.3390/ijms25189977] [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: 08/15/2024] [Revised: 09/13/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Viruses are obligate intracellular parasites, and they exploit the cellular pathways and resources of their respective host cells to survive and successfully multiply. The strategies of viruses concerning how to take advantage of the metabolic capabilities of host cells for their own replication can vary considerably. The most common metabolic alterations triggered by viruses affect the central carbon metabolism of infected host cells, in particular glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. The upregulation of these processes is aimed to increase the supply of nucleotides, amino acids, and lipids since these metabolic products are crucial for efficient viral proliferation. In detail, however, this manipulation may affect multiple sites and regulatory mechanisms of host-cell metabolism, depending not only on the specific viruses but also on the type of infected host cells. In this review, we report metabolic situations and reprogramming in different human host cells, tissues, and organs that are favorable for acute and persistent SARS-CoV-2 infection. This knowledge may be fundamental for the development of host-directed therapies.
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Affiliation(s)
- Wolfgang Eisenreich
- Structural Membrane Biochemistry, Bavarian NMR Center (BNMRZ), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Lichtenbergstr. 4, 85747 Garching, Germany;
| | - Julian Leberfing
- Structural Membrane Biochemistry, Bavarian NMR Center (BNMRZ), Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Lichtenbergstr. 4, 85747 Garching, Germany;
| | - Thomas Rudel
- Chair of Microbiology, Biocenter, University of Würzburg, 97074 Würzburg, Germany;
| | - Jürgen Heesemann
- Max von Pettenkofer Institute, Ludwig Maximilian University of Munich, 80336 München, Germany; (J.H.); (W.G.)
| | - Werner Goebel
- Max von Pettenkofer Institute, Ludwig Maximilian University of Munich, 80336 München, Germany; (J.H.); (W.G.)
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Mekuanint A, Ambachew S, Worede A, Asrie F, Sinishaw MA, Gelaw Y, Dagnew M, Gelaw A, Negash M, Kassa E, Bizuneh S, Wudineh D, Dimah B, Abebe W, Chane E, Fetene G. Assessment of abnormal liver function tests and associated factors among COVID-19-infected patients in Addis Ababa, Ethiopia, 2022: a facility-based comparative cross-sectional study. BMJ Open 2024; 14:e076647. [PMID: 39260868 PMCID: PMC11409313 DOI: 10.1136/bmjopen-2023-076647] [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: 06/16/2023] [Accepted: 07/19/2024] [Indexed: 09/13/2024] Open
Abstract
OBJECTIVE Liver function test (LFT) abnormalities are higher in patients with severe COVID-19. Most of the studies on this theme were conducted in foreign nations, and the association with LFT abnormalities was not sufficiently addressed in the study areas. Therefore, the current study aimed to investigate the effects of COVID-19 infection on liver function of patients. SETTING A facility-based comparative cross-sectional study was carried out from 10 April to 15 June 2022, among COVID-19 infected individuals admitted in Eka Kotebe General Hospital and Saint Petrous Specialized Hospitals, Addis Ababa, 2022. PARTICIPANTS A total of 284 confirmed COVID-19-positive and COVID-19-negative controls matched by gender and age were included in the present study. RESULTS Among SARS-COV-2 positive groups, 63 (44.4%) had one or more LFT abnormalities. The most common elevated level of the LFTs among patients with COVID-19 were gamma-glutamyl transferase (GGT) 50 (35.2%), while the most common lowered level was albumin 58 (40.8%). The mean values of aspartate aminotransferase (AST) (35.4±26.9 vs 22.9±12.6, p<0.001) were significantly different between patients with COVID-19 and the COVID-19-free groups. Being COVID-19-positive was significantly associated with an elevated level of AST (AOR=3.0, 95% CI 1.2 to 7.4) and GGT (AOR=4.55, 95% CI 2.02 to 10.3). Being male was significantly associated with an elevated level of total bilirubin (BILT, AOR=2.41, 95% CI 1.2 to 4.9) and direct bilirubin (BILD, AOR=3.7, 95% CI 1.72 to 8.2), and also severe stage of COVID-19 was associated with hypoalbuminaemia (AOR=3.3, 95% CI 1.4 to 7.9). SARS-COV-2 infection was independently associated with LFT abnormality. CONCLUSION Patients with COVID-19 had decreased albumin levels, and elevated AST, GGT, BILT and BILD levels.
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Affiliation(s)
- Amare Mekuanint
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Sintayehu Ambachew
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Abebaw Worede
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Fikir Asrie
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Mulusew Alemneh Sinishaw
- Department of Clinical Chemistry, College of Medicine and Health Science, Bahir Dar University, Bahir Dar, Ethiopia
| | - Yemataw Gelaw
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Mulat Dagnew
- Department of Medical Microbiology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Aschalew Gelaw
- Department of Medical Microbiology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Markos Negash
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Eyuel Kassa
- University of Gondar Comprehensive Specialized Hospital Laboratory, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Segenet Bizuneh
- Department of Internal Medicine, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Dessalew Wudineh
- Department of Medical Laboratory Sciences, Institute of Health Sciences, Mizan Tepi University, Mizan Tepi, Ethiopia
| | - Belayneh Dimah
- Department of Microbiology, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Wagaw Abebe
- Department of Medical Laboratory Sciences, College of Health Sciences, Woldia University, Woldia, Ethiopia
| | - Elias Chane
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Getnet Fetene
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Heinen N, Khanal R, Westhoven S, Klöhn M, Herrmann ST, Herrmann M, Tuoc T, Ulmke PA, Nguyen HD, Nguyen HP, Steinmann E, Todt D, Brown RJP, Sharma AD, Pfaender S. Productive infection of primary human hepatocytes with SARS-CoV-2 induces antiviral and proinflammatory responses. Gut 2024; 73:e14. [PMID: 38123990 PMCID: PMC11420759 DOI: 10.1136/gutjnl-2023-330961] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023]
Affiliation(s)
- Natalie Heinen
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Rajendra Khanal
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group RNA Therapeutics & Liver Regeneration, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany, Hannover Medical School, Hannover, Germany
| | - Saskia Westhoven
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Simon T Herrmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Maike Herrmann
- Division of Veterinary Medicine, Paul-Ehrlich-Institute, Langen, Germany
| | - Tran Tuoc
- Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
| | | | - Hoang Duy Nguyen
- Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
| | - Huu Phuc Nguyen
- Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
| | - Eike Steinmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany, Bochum, Germany
| | - Daniel Todt
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Richard J P Brown
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Division of Veterinary Medicine, Paul-Ehrlich-Institute, Langen, Germany
| | - Amar Deep Sharma
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Research Group RNA Therapeutics & Liver Regeneration, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany, Hannover Medical School, Hannover, Germany
| | - Stephanie Pfaender
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
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Antar SA, Ashour NA, Hamouda AO, Noreddin AM, Al-Karmalawy AA. Recent advances in COVID-19-induced liver injury: causes, diagnosis, and management. Inflammopharmacology 2024:10.1007/s10787-024-01535-7. [PMID: 39126569 DOI: 10.1007/s10787-024-01535-7] [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: 10/14/2023] [Accepted: 03/29/2024] [Indexed: 08/12/2024]
Abstract
Since the start of the pandemic, considerable advancements have been made in our understanding of the effects of SARS-CoV-2 infection and the associated COVID-19 on the hepatic system. There is a broad range of clinical symptoms for COVID-19. It affects multiple systems and has a dominant lung illness depending on complications. The progression of COVID-19 in people with pre-existing chronic liver disease (CLD) has also been studied in large multinational groups. Notably, SARS-CoV-2 infection is associated with a higher risk of hepatic decompensation and death in patients with cirrhosis. In this review, the source, composition, mechanisms, transmission characteristics, clinical characteristics, therapy, and prevention of SARS-CoV-2 were clarified and discussed, as well as the evolution and variations of the virus. This review briefly discusses the causes and effects of SARS-CoV-2 infection in patients with CLD. As part of COVID-19, In addition, we assess the potential of liver biochemistry as a diagnostic tool examine the data on direct viral infection of liver cells, and investigate potential pathways driving SARS-CoV-2-related liver damage. Finally, we explore how the pandemic has had a significant impact on patient behaviors and hepatology services, which may increase the prevalence and severity of liver disease in the future. The topics encompassed in this review encompass the intricate relationships between SARS-CoV-2, liver health, and broader health management strategies, providing valuable insights for both current clinical practice and future research directions.
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Affiliation(s)
- Samar A Antar
- Center for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA, 24016, USA
- Department of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Nada A Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Amir O Hamouda
- Department of Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Ayman M Noreddin
- Department of Clinical Pharmacy, Faculty of Pharmacy, Ahram Canadian University, 6Th of October City, Giza, 12566, Egypt
- Department of Internal Medicine, School of Medicine, University of California -Irvine, Irvine, USA
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, New Damietta, 34518, Egypt.
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6Th of October City, Giza, 12566, Egypt.
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29
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Gheban-Roşca IA, Gheban BA, Pop B, Mironescu DC, Siserman VC, Jianu EM, Drugan T, Bolboacă SD. A histopathological analysis of extrapulmonary lesions in fatal coronavirus disease (COVID-19). Pathol Res Pract 2024; 260:155373. [PMID: 38901140 DOI: 10.1016/j.prp.2024.155373] [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: 02/06/2024] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 06/22/2024]
Abstract
INTRODUCTION The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents diverse clinical manifestations and multi-organ involvement. This study aimed to evaluate the extra-pulmonary histopathological patterns underpinning COVID-19-induced lesions in cardiac, hepatic, renal, brainstem, and splenic tissues. MATERIALS AND METHODS The research involved conventional forensic autopsies conducted between April 2020 and April 2021 on individuals with confirmed SARS-CoV-2 infection in Cluj-Napoca, Romania. Tissues were processed and stained for histological examination. Differences in patients with and without diffuse alveolar damage (DAD) were evaluated. RESULTS In our study of 79 COVID-19 autopsies conducted on unvaccinated patients besides lung involvement, the patients had histological changes in at least two out of five (brain, heart, liver, kidney, and spleen) organs. Notable findings include hepatitis observed in 46.8 % of cases, 21.5 % with lobular hepatitis, and 41.8 % with liver steatosis. Additionally, 69.6 % exhibited acute tubular necrosis, and 55.7 % had varying degrees of splenic lymphocyte depletion. Almost 41 % of cases had pericardial effusion, 36.7 % myocarditis, 24.1 % myocardial infarction, and 12.7 % of cases had encephalitis. Acute tubular necrosis (78.6 %) was the most frequent histopathological finding observed in patients with DAD. Myocarditis was described in 45.9 % of the patients without DAD. DISCUSSION The autopsy findings in our cohort of COVID-19 victims align with international scientific literature. Distinguishing viral-induced myocarditis, encephalitis, hepatitis, or systemic inflammatory syndrome remains challenging. CONCLUSION Post-mortem analysis identified lesions associated with SARS-CoV-2 in multiple organs, highlighting the systemic nature of the virus and emphasizing the need for continued research into organ-specific damage and long-term sequelae of COVID-19.
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Affiliation(s)
- Ioana-Andreea Gheban-Roşca
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania; Clinical Hospital for Infectious Diseases, Cluj-Napoca 400003, Romania
| | - Bogdan-Alexandru Gheban
- County Emergency Clinical Hospital, Cluj-Napoca 400347, Romania; Department of Histology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania.
| | - Bogdan Pop
- The Oncology Institute " Prof. Dr. Ion Chiricuță", Cluj-Napoca 400015, Romania; Department of Anatomic Pathology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Daniela-Cristina Mironescu
- Forensic Institute, Cluj-Napoca 400006, Romania; Department of Forensic Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Vasile Costel Siserman
- Forensic Institute, Cluj-Napoca 400006, Romania; Department of Forensic Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Elena Mihaela Jianu
- Department of Histology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Tudor Drugan
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
| | - Sorana D Bolboacă
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca 400347, Romania
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30
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Wu Q, Lu M, Ouyang H, Zhou T, Lei J, Wang P, Wang W. CDKL3 is a promising biomarker for diagnosis and prognosis prediction in patients with hepatocellular carcinoma. Exp Biol Med (Maywood) 2024; 249:10106. [PMID: 38993199 PMCID: PMC11237920 DOI: 10.3389/ebm.2024.10106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/02/2023] [Indexed: 07/13/2024] Open
Abstract
Cyclin-dependent kinase-like 3 (CDKL3) has been identified as an oncogene in certain types of tumors. Nonetheless, its function in hepatocellular carcinoma (HCC) is poorly understood. In this study, we conducted a comprehensive analysis of CDKL3 based on data from the HCC cohort of The Cancer Genome Atlas (TCGA). Our analysis included gene expression, diagnosis, prognosis, functional enrichment, tumor microenvironment and metabolic characteristics, tumor burden, mRNA expression-based stemness, alternative splicing, and prediction of therapy response. Additionally, we performed a cell counting kit-8 assay, TdT-mediated dUTP nick-end Labeling staining, migration assay, wound healing assay, colony formation assay, and nude mouse experiments to confirm the functional relevance of CDKL3 in HCC. Our findings showed that CDKL3 was significantly upregulated in HCC patients compared to controls. Various bioinformatic analyses suggested that CDKL3 could serve as a potential marker for HCC diagnosis and prognosis. Furthermore, CDKL3 was found to be involved in various mechanisms linked to the development of HCC, including copy number variation, tumor burden, genomic heterogeneity, cancer stemness, and alternative splicing of CDKL3. Notably, CDKL3 was also closely correlated with tumor immune cell infiltration and the expression of immune checkpoint markers. Additionally, CDKL3 was shown to independently function as a risk predictor for overall survival in HCC patients by multivariate Cox regression analysis. Furthermore, the knockdown of CDKL3 significantly inhibited cell proliferation in vitro and in vivo, indicating its role as an oncogene in HCC. Taken together, our findings suggest that CDKL3 shows promise as a biomarker for the detection and treatment outcome prediction of HCC patients.
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Affiliation(s)
- Qingsi Wu
- Department of Blood Transfusion, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Provincial Key Laboratory of Microbiology and Parasitology, Hefei, Anhui, China
| | - Mengran Lu
- School of Public Health, Department of Hygiene Inspection and Quarantine, Anhui Medical University, Hefei, Anhui, China
| | - Huijuan Ouyang
- School of Public Health, Department of Hygiene Inspection and Quarantine, Anhui Medical University, Hefei, Anhui, China
| | - Tingting Zhou
- School of Public Health, Department of Hygiene Inspection and Quarantine, Anhui Medical University, Hefei, Anhui, China
| | - Jingyuan Lei
- School of Public Health, Department of Hygiene Inspection and Quarantine, Anhui Medical University, Hefei, Anhui, China
| | - Panpan Wang
- School of Public Health, Department of Hygiene Inspection and Quarantine, Anhui Medical University, Hefei, Anhui, China
| | - Wei Wang
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
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31
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Guarnieri JW, Haltom JA, Albrecht YES, Lie T, Olali AZ, Widjaja GA, Ranshing SS, Angelin A, Murdock D, Wallace DC. SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19. Pharmacol Res 2024; 204:107170. [PMID: 38614374 DOI: 10.1016/j.phrs.2024.107170] [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: 02/06/2024] [Revised: 03/29/2024] [Accepted: 04/02/2024] [Indexed: 04/15/2024]
Abstract
To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.
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Affiliation(s)
- Joseph W Guarnieri
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Jeffrey A Haltom
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Yentli E Soto Albrecht
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Timothy Lie
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Arnold Z Olali
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Gabrielle A Widjaja
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Sujata S Ranshing
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Alessia Angelin
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Deborah Murdock
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Douglas C Wallace
- Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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32
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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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33
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Ariza D, Castellar-Visbal L, Marquina M, Rivera-Porras D, Galbán N, Santeliz R, Gutiérrez-Rey M, Parra H, Vargas-Manotas J, Torres W, Quintana-Espinosa L, Manzano A, Cudris-Torres L, Bermúdez V. COVID-19: Unveiling the Neuropsychiatric Maze-From Acute to Long-Term Manifestations. Biomedicines 2024; 12:1147. [PMID: 38927354 PMCID: PMC11200893 DOI: 10.3390/biomedicines12061147] [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: 04/17/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 06/28/2024] Open
Abstract
The SARS-CoV-2 virus has spread rapidly despite implementing strategies to reduce its transmission. The disease caused by this virus has been associated with a diverse range of symptoms, including common neurological manifestations such as dysgeusia, anosmia, and myalgias. Additionally, numerous cases of severe neurological complications associated with this disease have been reported, including encephalitis, stroke, seizures, and Guillain-Barré syndrome, among others. Given the high prevalence of neurological manifestations in this disease, the objective of this review is to analyze the mechanisms by which this virus can affect the nervous system, from its direct invasion to aberrant activation of the immune system and other mechanisms involved in the symptoms, including neuropsychiatric manifestations, to gain a better understanding of the disease and thus facilitate the search for effective therapeutic strategies.
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Affiliation(s)
- Daniela Ariza
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - Lily Castellar-Visbal
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia; (L.C.-V.); (M.G.-R.); (J.V.-M.); (L.Q.-E.)
| | - Maria Marquina
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - Diego Rivera-Porras
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Centro de Investigación en Estudios Fronterizos, Cúcuta 540001, Colombia;
| | - Nestor Galbán
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - Raquel Santeliz
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - Melissa Gutiérrez-Rey
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia; (L.C.-V.); (M.G.-R.); (J.V.-M.); (L.Q.-E.)
| | - Heliana Parra
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - José Vargas-Manotas
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia; (L.C.-V.); (M.G.-R.); (J.V.-M.); (L.Q.-E.)
| | - Wheeler Torres
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - Laura Quintana-Espinosa
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia; (L.C.-V.); (M.G.-R.); (J.V.-M.); (L.Q.-E.)
| | - Alexander Manzano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (D.A.); (M.M.); (N.G.); (R.S.); (H.P.); (W.T.); (A.M.)
| | - Lorena Cudris-Torres
- Departamento de Ciencias Sociales, Universidad de la Costa, Barranquilla 080001, Colombia;
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia; (L.C.-V.); (M.G.-R.); (J.V.-M.); (L.Q.-E.)
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Centro de Investigaciones en Ciencias de la Vida, Barranquilla 080001, Colombia
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Holden MG, Schmiech KV, Martinez Telleria M, Sun X, Bender WR, Karjane NW. COVID-stasis of Pregnancy: An Increased Prevalence of COVID-19 in Patients with Cholestasis. Am J Perinatol 2024; 41:e3286-e3292. [PMID: 38006876 DOI: 10.1055/a-2217-8313] [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: 11/27/2023]
Abstract
OBJECTIVE To evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and coronavirus disease 2019 (COVID-19). STUDY DESIGN We performed a retrospective cohort study of pregnant women undergoing induction of labor (IOL) at a single institution between May 2020 to January 2021. Primary exposure was diagnosis of intrahepatic cholestasis of pregnancy (ICP). The primary outcome was the prevalence of COVID-19 as determined by reverse-transcriptase polymerase chain reaction testing on nasopharyngeal swabs for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) on routine admission testing. Secondary outcomes were abnormal laboratory values and adverse fetal outcomes. Logistic regression with log link analysis was performed comparing patients undergoing IOL for ICP compared with IOL for all other indications. The moderating effect of ethnicity was assessed by the interaction between ethnicity and ICP in a logistic regression model. The Wilcoxon rank-sum test and Fisher's exact test were performed for the secondary outcome analyses. RESULTS Over the course of the study, 596 patients underwent IOL: 24 for ICP and 572 for other indications. The overall prevalence of COVID-19 positivity in the cohort was 5.5% (33 of 596). Those with ICP were more likely to test positive for COVID-19 compared with those with other IOL indications (29.2 vs. 4.5%, RR = 6.4, 95% CI: 2.8-12.5, p < 0.001). All patients with ICP who tested positive for COVID-19 were Hispanic. To analyze the moderating effect of ethnicity, the results of the logistic model found the interaction between ethnicity and ICP to not be significant (p = 0.991). In patients with ICP, the median AST (aspartate aminotransferase) was higher than those with COVID-19 (p = 0.0182). There were no adverse fetal outcomes in the ICP group. CONCLUSION In this single-site retrospective cohort study, we demonstrated an increased prevalence of COVID-19 in those with ICP in general and among Hispanic patients specifically. Despite this difference, there was no increased risk of adverse fetal outcomes. KEY POINTS · There is an increased prevalence of COVID-19 among Hispanic patients with ICP.. · The median AST of COVID-19-positive patients was significantly higher than COVID-19-negative patients.. · There was no increased risk of adverse fetal outcomes in with COVID-19 and ICP..
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Affiliation(s)
- Marissa G Holden
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia
| | - Kathryn V Schmiech
- Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, Maryland
| | | | - Xinxin Sun
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia
| | - Whitney R Bender
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia
| | - Nicole W Karjane
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia
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Tahoun M, Sadaka AS. Deregulated expression of autophagy genes; PIK3C3 and RAB7A in COVID-19 patients. Hum Immunol 2024; 85:110801. [PMID: 38609772 DOI: 10.1016/j.humimm.2024.110801] [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: 01/05/2024] [Revised: 03/20/2024] [Accepted: 04/08/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND The role of autophagy in coronaviruses infection and replication has a lot of debate. Autophagy involves the catalytic breakdown of intracellular components to be subsequently recycled by the lysosome. The aim of the study was to evaluate autophagy genes; PIK3C3 and RAB7A expressions in COVID-19 patients, and identify if PIK3C3 and RAB7A can be used as markers for monitoring COVID-19 patients. METHODS A case-control study was carried out on 50 patients and 50 healthy controls. Genes expression was performed using quantitative real-time polymerase chain reaction. RESULTS Compared to controls, PIK3C3 and RAB7A gene expression levels were significantly lower in patients (p < 0.001) with approximately with 9.4 and 2.3 decreased fold in PIK3C3 and RAB7A respectively. The ROC curve of PIK3C3 and RAB7A expressions showed sensitivity of 84 % and 74 % and specificity of 98 % and 78 % respectively. There was a positive correlation between PIK3C3 expression and WBCs, absolute neutrophil count, interleukin-6, D-dimer, and ALT among patients and between RAB7A expression and WBCs, CRP, IL-6, D-dimer and ALT in patients. CONCLUSIONS The study showed reduction of PIK3C3 and RAB7A expressions in COVID-19 patients. However, further studies are recommended to clarify their roles in the disease pathogenies as autophagy genes.
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Affiliation(s)
- Mona Tahoun
- Clinical and Chemical Pathology Department, Faculty of Medicine, Alexandria University, Egypt.
| | - Ahmed S Sadaka
- Chest Diseases Department, Faculty of Medicine, Alexandria University, Egypt
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Singh L, Kumar A, Rai M, Basnet B, Rai N, Khanal P, Lai KS, Cheng WH, Asaad AM, Ansari S. Spectrum of COVID-19 induced liver injury: A review report. World J Hepatol 2024; 16:517-536. [PMID: 38689748 PMCID: PMC11056898 DOI: 10.4254/wjh.v16.i4.517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/20/2024] [Accepted: 02/28/2024] [Indexed: 04/24/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused changes in the global health system, causing significant setbacks in healthcare systems worldwide. This pandemic has also shown resilience, flexibility, and creativity in reacting to the tragedy. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection targets most of the respiratory tract, resulting in a severe sickness called acute respiratory distress syndrome that may be fatal in some individuals. Although the lung is the primary organ targeted by COVID-19 viruses, the clinical aspect of the disease is varied and ranges from asymptomatic to respiratory failure. However, due to an unorganized immune response and several affected mechanisms, the liver may also experience liver cell injury, ischemic liver dysfunction, and drug-induced liver injury, which can result in respiratory failure because of the immune system's disordered response and other compromised processes that can end in multisystem organ failure. Patients with liver cirrhosis or those who have impaired immune systems may be more likely than other groups to experience worse results from the SARS-CoV-2 infection. We thus intend to examine the pathogenesis, current therapy, and consequences of liver damage concerning COVID-19.
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Affiliation(s)
- Lokjan Singh
- Department of Microbiology, Karnali Academy of Health Science, Teaching Hospital, Jumla 21200, Karnali, Nepal
| | - Anil Kumar
- Department of Microbiology, Karnali Academy of Health Science, Teaching Hospital, Jumla 21200, Karnali, Nepal
| | - Maya Rai
- Department of Microbiology, Karnali Academy of Health Science, Teaching Hospital, Jumla 21200, Karnali, Nepal
| | - Bibek Basnet
- Health Sciences, Asian College of Advance Studies, Purbanchal University, Satdobato 24122, Lalitpur, Nepal
| | - Nishant Rai
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun 248002, Uttarakhand, India
| | - Pukar Khanal
- Department of Pharmacology & Toxicology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, Karnataka, India
| | - Kok-Song Lai
- Division of Health Sciences, Abu Dhabi Women's College, Higher Colleges of Technology, Abu Dhabi 41012, United Arab Emirates
| | - Wan-Hee Cheng
- Health and Life Sciences, INTI International University, Nilai 71800, Malaysia
| | - Ahmed Morad Asaad
- Department of Microbiology, College of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Shamshul Ansari
- Division of Health Sciences, Abu Dhabi Women's College, Higher Colleges of Technology, Abu Dhabi 41012, United Arab Emirates.
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Malarkiewicz P, Nowacka U, Januszaniec A, Mankiewicz A, Kozłowski S, Issat T. Intrahepatic Cholestasis of Pregnancy during COVID-19 Pandemic. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:676. [PMID: 38674322 PMCID: PMC11052128 DOI: 10.3390/medicina60040676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024]
Abstract
Background and Objectives: Intrahepatic cholestasis of pregnancy (ICP) stands as one of the most prevalent concerns in maternal-fetal medicine, presenting a significant risk to fetal health and often associated with liver dysfunction. Concurrently, the coronavirus-19 (COVID-19) infection can lead to hepatic cell injury through both direct and indirect pathways. Hypothetically, these two conditions may coincide, influencing each other. This study aimed to comparatively assess the incidence and severity of ICP before and during the COVID-19 pandemic. Methods: A retrospective cohort study was conducted, comparing the incidence and severity of ICP between January 2018 and February 2020 (pre-COVID-19 period) and March 2020 to March 2022 (COVID-19 period) across two hospitals, encompassing 7799 deliveries. The diagnosis of ICP was established using the ICD-10 code and defined as total bile acids (BA) levels ≥ 10 μmol/L. Statistical analysis included descriptive statistics, Chi-square and Mann-Whitney U tests, as well as multiple or logistic regression analysis. Results: A total of 226 cases of ICP were identified. The incidence of mild cholestasis (BA < 40 μmol/L) was lower during the pandemic compared to before (3% before versus 2%, p < 0.05), while the incidence of moderate and severe ICP remained unchanged (0.6% before vs. 0.4%, p = 0.2). Overall, the total incidence of ICP was lower during the pandemic (3.6% before versus 2.4%, p = 0.01). No significant differences were observed in severity (as defined by BA and liver function test levels), rates of caesarean section, or neonatal birth weights. Conclusions: During the COVID-19 pandemic, the total incidence of ICP appeared to be lower. However, this reduction was primarily observed in cases of mild ICP, potentially indicating challenges in detection or reduced access to medical services during this period. The incidence of moderate and severe ICP remained unchanged, suggesting that these forms of the condition were unaffected by the pandemic's circumstances.
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Affiliation(s)
- Paulina Malarkiewicz
- Department of Obstetrics and Gynecology, School of Medicine, Collegium Medicum of the University of Warmia and Mazury, al. Warszawska 30, 10-082 Olsztyn, Poland
| | - Urszula Nowacka
- Department of Obstetrics and Gynecology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland
| | - Aleksandra Januszaniec
- Department of Obstetrics and Gynecology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland
| | - Alicja Mankiewicz
- Department of Obstetrics and Gynecology, Olsztyn Specialist Hospital, Żołnierska 18; 10-561 Olsztyn, Poland
| | - Szymon Kozłowski
- Department of Obstetrics and Gynecology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland
| | - Tadeusz Issat
- Department of Obstetrics and Gynecology, Institute of Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland
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Mironova M, Gopalakrishna H, Rodriguez Franco G, Holland SM, Koh C, Kleiner DE, Heller T. Granulomatous liver diseases. Hepatol Commun 2024; 8:e0392. [PMID: 38497932 PMCID: PMC10948139 DOI: 10.1097/hc9.0000000000000392] [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: 11/10/2023] [Accepted: 12/18/2023] [Indexed: 03/19/2024] Open
Abstract
A granuloma is a discrete collection of activated macrophages and other inflammatory cells. Hepatic granulomas can be a manifestation of localized liver disease or be a part of a systemic process, usually infectious or autoimmune. A liver biopsy is required for the detection and evaluation of granulomatous liver diseases. The prevalence of granulomas on liver biopsy varies from 1% to 15%. They may be an incidental finding in an asymptomatic individual, or they may represent granulomatous hepatitis with potential to progress to liver failure, or in chronic disease, to cirrhosis. This review focuses on pathogenesis, histological features of granulomatous liver diseases, and most common etiologies, knowledge that is essential for timely diagnosis and intervention.
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Affiliation(s)
- Maria Mironova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Harish Gopalakrishna
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Gian Rodriguez Franco
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Steven M. Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - David E. Kleiner
- Department of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
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Jalili S, Hashemi SMA, Sarvari J. SARS-COV-2 ORF9b Dysregulate Fibrinogen and Albumin Genes in a Liver Cell Line. Rep Biochem Mol Biol 2024; 13:51-58. [PMID: 39582820 PMCID: PMC11580134 DOI: 10.61186/rbmb.13.1.51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/02/2024] [Indexed: 11/26/2024]
Abstract
Background Individuals experiencing severe cases of Coronavirus Disease 2019 (COVID-19) exhibited elevated fibrinogen levels and decreased albumin levels, potentially linked to the presence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) proteins. Consequently, our study endeavors to examine the impact of SARS-CoV-2 ORF9b on the expression of fibrinogen and albumin genes within the Hep-G2 cell line. Methods In this study, the Hep-G2 liver cell line was utilized alongside the plasmid pcDNA3.1 hyg+ containing ORF9b from the SARS-CoV-2 strain originating in Wuhan. Transfection procedures were executed, and the transfected cells were selected utilizing hygromycin B. Validation of ORF9b expression was conducted through SYBR green-based real-time PCR, and the expression of the Fibrinogen α (FGA), Fibrinogen β (FGB), Fibrinogen γ (FGG), and Albumin (ALB) genes was quantified using the same method. Results The real-time PCR analysis revealed a significant upregulation of fibrinogen genes-α (P=0.03), β (P=0.02), and γ (P=0.029) in Hep-G2 cells containing ORF9b compared to control cells. Furthermore, the findings indicated a markedly lower expression level of albumin in Hep-G2 cells harboring ORF9b compared to the control cells (P=0.028). Conclusions The findings suggest that SARS-CoV-2 ORF9b could potentially influence the course of SARS-CoV-2 infection by triggering the expression of α, β, and γ fibrinogen gene chains while suppressing the albumin gene. Further investigations are warranted to validate these observations across various SARS-CoV-2 strains exhibiting differing levels of pathogenicity.
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Affiliation(s)
- Shirin Jalili
- Institute of police equipment and technologies, policing sciences and social studies research institute, Tehran, Iran.
| | - Seyed Mohammad Ali Hashemi
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Jamal Sarvari
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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40
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Carregari VC, Reis-de-Oliveira G, Crunfli F, Smith BJ, de Souza GF, Muraro SP, Saia-Cereda VM, Vendramini PH, Baldasso PA, Silva-Costa LC, Zuccoli GS, Brandão-Teles C, Antunes A, Valença AF, Davanzo GG, Virgillio-da-Silva JV, Dos Reis Araújo T, Guimarães RC, Chaim FDM, Chaim EA, Kawagosi Onodera CM, Ludwig RG, Saccon TD, Damásio ARL, Leiria LOS, Vinolo MAR, Farias AS, Moraes-Vieira PM, Mori MA, Módena JLP, Martins-de-Souza D. Diving into the proteomic atlas of SARS-CoV-2 infected cells. Sci Rep 2024; 14:7375. [PMID: 38548777 PMCID: PMC10978884 DOI: 10.1038/s41598-024-56328-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/05/2024] [Indexed: 04/01/2024] Open
Abstract
The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome_App/ ) to enrich and expand this knowledgebase.
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Affiliation(s)
- Victor C Carregari
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
| | - Guilherme Reis-de-Oliveira
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Fernanda Crunfli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Bradley J Smith
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Gabriela Fabiano de Souza
- Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Stéfanie Primon Muraro
- Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Veronica M Saia-Cereda
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Pedro H Vendramini
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Paulo A Baldasso
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Lícia C Silva-Costa
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Caroline Brandão-Teles
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - André Antunes
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Aline F Valença
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Gustavo G Davanzo
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - João Victor Virgillio-da-Silva
- Department of Pharmacology, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
- Center for Research in Inflammatory Diseases, Ribeirão Preto, SP, Brazil
| | | | - Raphael Campos Guimarães
- Center for Research in Inflammatory Diseases, Ribeirão Preto, SP, Brazil
- Obesity and Comorbidities Research Center (OCRC), Campinas, São Paulo, Brazil
| | | | - Elinton Adami Chaim
- Department of Surgery, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil
| | | | - Raissa Guimarães Ludwig
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Tatiana Dandolini Saccon
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - André R L Damásio
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Luiz Osório S Leiria
- Department of Pharmacology, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
- Center for Research in Inflammatory Diseases, Ribeirão Preto, SP, Brazil
| | - Marco Aurélio R Vinolo
- Obesity and Comorbidities Research Center (OCRC), Campinas, São Paulo, Brazil
- Hematology-Hemotherapy Center, University of Campinas, Campinas, SP, Brazil
- Laboratory of Immunoinflammation, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Alessandro S Farias
- Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, 05403-000, Brazil
- D'Or Institute for Research and Education (IDOR), São Paulo, 04501-000, Brazil
- Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Pedro M Moraes-Vieira
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
- Obesity and Comorbidities Research Center (OCRC), Campinas, São Paulo, Brazil
- Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Marcelo A Mori
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Pharmacology, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
- Laboratory of Immunoinflammation, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - José Luiz P Módena
- Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
- D'Or Institute for Research and Education (IDOR), São Paulo, 04501-000, Brazil.
- Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
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Hussein HAM, Thabet AA, Wardany AA, El-Adly AM, Ali M, Hassan MEA, Abdeldayem MAB, Mohamed ARMA, Sobhy A, El-Mokhtar MA, Afifi MM, Fathy SM, Sultan S. SARS-CoV-2 outbreak: role of viral proteins and genomic diversity in virus infection and COVID-19 progression. Virol J 2024; 21:75. [PMID: 38539202 PMCID: PMC10967059 DOI: 10.1186/s12985-024-02342-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 03/12/2024] [Indexed: 05/15/2024] Open
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is the cause of coronavirus disease 2019 (COVID-19); a severe respiratory distress that has emerged from the city of Wuhan, Hubei province, China during December 2019. COVID-19 is currently the major global health problem and the disease has now spread to most countries in the world. COVID-19 has profoundly impacted human health and activities worldwide. Genetic mutation is one of the essential characteristics of viruses. They do so to adapt to their host or to move to another one. Viral genetic mutations have a high potentiality to impact human health as these mutations grant viruses unique unpredicted characteristics. The difficulty in predicting viral genetic mutations is a significant obstacle in the field. Evidence indicates that SARS-CoV-2 has a variety of genetic mutations and genomic diversity with obvious clinical consequences and implications. In this review, we comprehensively summarized and discussed the currently available knowledge regarding SARS-CoV-2 outbreaks with a fundamental focus on the role of the viral proteins and their mutations in viral infection and COVID-19 progression. We also summarized the clinical implications of SARS-CoV-2 variants and how they affect the disease severity and hinder vaccine development. Finally, we provided a massive phylogenetic analysis of the spike gene of 214 SARS-CoV-2 isolates from different geographical regions all over the world and their associated clinical implications.
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Affiliation(s)
- Hosni A M Hussein
- Department of Microbiology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt.
| | - Ali A Thabet
- Department of Zoology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt
| | - Ahmed A Wardany
- Department of Microbiology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt
| | - Ahmed M El-Adly
- Department of Microbiology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt
| | - Mohamed Ali
- Department of Microbiology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt
| | - Mohamed E A Hassan
- Department of Microbiology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt
| | - Mohamed A B Abdeldayem
- Department of Microbiology, Faculty of Science, Al-Azhar University, 71524, Assiut, Egypt
| | | | - Ali Sobhy
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, 71524, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos Campus, Lebanon
| | - Magdy M Afifi
- Department of Botany and Microbiology, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt
| | - Samah M Fathy
- Department of Zoology, Faculty of Science, Fayoum University, Fayoum, Egypt.
| | - Serageldeen Sultan
- Department of Microbiology, Virology Division, Faculty of Veterinary medicine, South Valley University, 83523, Qena, Egypt.
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Brilakis L, Theofilogiannakou E, Lykoudis PM. Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19. World J Gastroenterol 2024; 30:1480-1487. [PMID: 38617460 PMCID: PMC11008415 DOI: 10.3748/wjg.v30.i11.1480] [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: 12/29/2023] [Revised: 01/30/2024] [Accepted: 03/04/2024] [Indexed: 03/21/2024] Open
Abstract
During the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, particular interest rose regarding the interaction between metabolic dysfunction-associated fatty liver disease (MAFLD) and the COVID-19 infection. Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes. One of the proposed mechanisms is the inflammatory response pathway, especially the one involving cytokines, such as interleukin 6, which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver. This should increase our vigilance in terms of early detection, close follow up and early treatment for individuals with MAFLD and COVID-19 infection. In the direction of early diagnosis, biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed. COVID-19 is a newly described entity, expected to be of concern for the years to come, and MAFLD is a condition with an ever-increasing impact. Delineating the interaction between these two entities should be brought into the focus of research. Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective, and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.
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Affiliation(s)
- Leonidas Brilakis
- School of Medicine, National & Kapodistrian University of Athens, Athens 11527, Greece
| | | | - Panagis M Lykoudis
- School of Medicine, National & Kapodistrian University of Athens, Athens 11527, Greece
- Division of Surgery & Interventional Science, University College London, London WC1E 6BT, United Kingdom
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Odintsova AK, Akberova DR, Sadykova LR, Cheremina NA, Minnullin MM, Kirshin AA, Gabitova EN, Khasanshina AY, Abdulganieva DI. Thirteen-Year Follow-Up of a Patient with Liver Cirrhosis Resulting from the Overlap Syndrome of Autoimmune Hepatitis and Primary Biliary Cholangitis: Severe COVID-19 and Liver Transplantation. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:76-84. [DOI: 10.22416/1382-4376-2024-34-1-76-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Aim: to present the difficulties of long-term management of a patient with liver cirrhosis in the outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis) who suffered from severe COVID-19 infection.Key points. The diagnosis of liver cirrhosis as an outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis) was established at the patient’s age of 33 years. At the age of 40, the patient became pregnant for the first time, the pregnancy proceeded well, and a cesarean section was performed at 36 weeks. At the age of 45, the patient suffered a severe new coronavirus infection, followed by decompensation of liver cirrhosis, which required liver transplantation 4 months after COVID-19, followed by a favorable postoperative course.Conclusion. This clinical case demonstrates the successful onset and outcome of pregnancy in a patient with liver cirrhosis in the outcome of overlap syndrome (autoimmune hepatitis and primary biliary cholangitis). The pronounced activity of the disease after severe new coronavirus infection required liver transplantation with successful outcome.
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Affiliation(s)
- A. Kh. Odintsova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | | | - L. R. Sadykova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - N. A. Cheremina
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | | | - A. A. Kirshin
- Republican Clinical Oncological Dispensary named after Professor M.Z. Sigal
| | - E. N. Gabitova
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - A. Yu. Khasanshina
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
| | - D. I. Abdulganieva
- Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan; Kazan State Medical University
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Conte C, Cipponeri E, Roden M. Diabetes Mellitus, Energy Metabolism, and COVID-19. Endocr Rev 2024; 45:281-308. [PMID: 37934800 PMCID: PMC10911957 DOI: 10.1210/endrev/bnad032] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/30/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.
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Affiliation(s)
- Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome 00166, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Elisa Cipponeri
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Neuherberg 85764, Germany
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Huang W, Chen X, Yin M, Li J, Luo M, Ai Y, Xie L, Li W, Liu Y, Xie X, Chen Y, Zhang X, He J. Protection effects of mice liver and lung injury induced by coronavirus infection of Qingfei Paidu decoction involve inhibition of the NLRP3 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117512. [PMID: 38040130 DOI: 10.1016/j.jep.2023.117512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 11/12/2023] [Accepted: 11/24/2023] [Indexed: 12/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Coronavirus Disease 2019 (COVID-19) is a grave and pervasive global infectious malady brought about by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), posing a significant menace to human well-being. Qingfei Paidu decoction (QFPD) represents a pioneering formulation derived from four classical Chinese medicine prescriptions. Substantiated evidence attests to its efficacy in alleviating clinical manifestations, mitigating the incidence of severe and critical conditions, and reducing mortality rates among COVID-19 patients. AIM OF THE STUDY This study aims to investigate the protection effects of QFPD in mice afflicted with a coronavirus infection, with a particular focus on determining whether its mechanism involves the NLRP3 signaling pathway. MATERIALS AND METHODS The coronavirus mice model was established through intranasal infection of Kunming mice with Hepatic Mouse Virus A59 (MHV-A59). In the dose-effect experiment, normal saline, ribavirin (80 mg/kg), or QFPD (5, 10, 20 g/kg) were administered to the mice 2 h following MHV-A59 infection. In the time-effect experiment, normal saline or QFPD (20 g/kg) was administered to mice 2 h post MHV-A59 infection. Following the assessment of mouse body weights, food consumption, and water intake, intragastric administration was conducted once daily at consistent intervals over a span of 5 days. The impact of QFPD on pathological alterations in the livers and lungs of MHV-A59-infected mice was evaluated through H&E staining. The viral loads of MHV-A59 in both the liver and lung were determined using qPCR. The expression levels of genes and proteins related to the NLRP3 pathway in the liver and lung were assessed through qPCR, Western Blot analysis, and immunofluorescence. RESULTS The administration of QFPD was shown to ameliorate the reduced weight gain, decline in food consumption, and diminished water intake, all of which were repercussions of MHV-A59 infection in mice. QFPD treatment exhibited notable efficacy in safeguarding tissue integrity. The extent of hepatic and pulmonary injury, when coupled with QFPD treatment, demonstrated not only a reduction with higher treatment dosages but also a decline with prolonged treatment duration. In the dose-effect experiment, there was a notable, dose-dependent reduction in the viral loads, as well as the expression levels of IL-1β, NLRP3, ASC, Caspase 1, Caspase-1 p20, GSDMD, GSDMD-N, and NF-κB within the liver of the QFPD-treated groups. Additionally, in the time-effects experiments, the viral loads and the expression levels of genes and proteins linked to the NLRP3 pathway were consistently lower in the QFPD-treated groups compared with the model control groups, particularly during the periods when their expressions reached their zenith in the model group. Notably, IL-18 showed only a modest elevation relative to the blank control group following QFPD treatment. CONCLUSIONS To sum up, our current study demonstrated that QFPD treatment has the capacity to alleviate infection-related symptoms, mitigate tissue damage in infected organs, and suppress viral replication in coronavirus-infected mice. The protective attributes of QFPD in coronavirus-infected mice are plausibly associated with its modulation of the NLRP3 signaling pathway. We further infer that QFPD holds substantial promise in the context of coronavirus infection therapy.
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Affiliation(s)
- Wenguan Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiuyun Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Mingyu Yin
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Junlin Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Minyi Luo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ying Ai
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Lei Xie
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wanxi Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yatian Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xinyuan Xie
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuan Chen
- Animal Experiment Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xinyu Zhang
- Clinical Medical College of Acupuncture Moxibustion and Rehabilitation. Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinyang He
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Pan B, Wang X, Lai H, Vernooij RWM, Deng X, Ma N, Li D, Huang J, Zhao W, Ning J, Liu J, Tian J, Ge L, Yang K. Risk of kidney and liver diseases after COVID-19 infection: A systematic review and meta-analysis. Rev Med Virol 2024; 34:e2523. [PMID: 38512106 DOI: 10.1002/rmv.2523] [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: 09/11/2023] [Revised: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 03/22/2024]
Abstract
COVID-19 is not only associated with substantial acute liver and kidney injuries, but also with an elevated risk of post-acute sequelae involving the kidney and liver system. We aimed to investigate whether COVID-19 exposure increases the long-term risk of kidney and liver disease, and what are the magnitudes of these associations. We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, and the Living Overview of the Evidence COVID-19 Repository for cohort studies estimating the association between COVID-19 and kidney and liver outcomes. Random-effects meta-analyses were performed to combine the results of the included studies. We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Fifteen cohort studies with more than 32 million participants were included in the systematic review COVID-19 was associated with a 35% greater risk of kidney diseases (10 more per 1000 persons; low certainty evidence) and 54% greater risk of liver disease (3 more per 1000 persons; low certainty evidence). The absolute increases due to COVID-19 for acute kidney injury, chronic kidney disease, and liver test abnormality were 3, 8, and 3 per 1000 persons, respectively. Subgroup analyses found no differences between different type of kidney and liver diseases. The findings provide further evidence for the association between COVID-19 and incident kidney and liver conditions. The absolute magnitude of the effect of COVID-19 on kidney and liver outcomes was, however, relatively small.
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Affiliation(s)
- Bei Pan
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Xiaoman Wang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Honghao Lai
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Robin W M Vernooij
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Xiyuan Deng
- Gansu Provincial Maternity and Child-care Hospital, Lanzhou, China
| | - Ning Ma
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Dan Li
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Jiajie Huang
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Weilong Zhao
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Jinling Ning
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Jianing Liu
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Jinhui Tian
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Long Ge
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
| | - Kehu Yang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
- Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
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Yang X, Zheng X, Zhu Y, Zhao X, Liu J, Xun J, Yuan S, Chen J, Pan H, Yang J, Wang J, Liang Z, Shen X, Liang Y, Lin Q, Liang H, Li M, Peng F, Lu D, Xu J, Lu H, Jiang S, Zhao P, Zhu H. Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes. Signal Transduct Target Ther 2024; 9:42. [PMID: 38355848 PMCID: PMC10866945 DOI: 10.1038/s41392-024-01754-y] [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: 08/29/2023] [Revised: 12/18/2023] [Accepted: 01/23/2024] [Indexed: 02/16/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage, which includes hepatic dysfunction, as observed in over 50% of COVID-19 patients. Angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into host cells, and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2, but at extremely low levels. Consequently, we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells. To address this question, we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1 (ASGR1) promoted SARS-CoV-2 pseudovirus infection of HeLa cells. In Huh-7 cells, simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells, both of which barely expressed ACE2, SARS-CoV-2 pseudovirus could successfully establish an infection. However, after treatment with ASGR1 antibody or siRNA targeting ASGR1, the infection rate significantly dropped, suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism. We confirmed that ASGR1 could interact with Spike protein, which depends on receptor binding domain (RBD) and N-terminal domain (NTD). Finally, we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells. After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA, the infection efficiency of the live virus decreased significantly. Collectively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.
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Affiliation(s)
- Xinyi Yang
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Xu Zheng
- Department of Microbiology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Yuqi Zhu
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Xiaying Zhao
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Jun Liu
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Jiangna Xun
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Songhua Yuan
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jun Chen
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Hanyu Pan
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Jinlong Yang
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Jing Wang
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Zhimin Liang
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Xiaoting Shen
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Yue Liang
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Qinru Lin
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Huitong Liang
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Min Li
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Fei Peng
- Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Daru Lu
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China
| | - Jianqing Xu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hongzhou Lu
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- Department of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Shibo Jiang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ping Zhao
- Department of Microbiology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Huanzhang Zhu
- State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute, Fudan University, Shanghai, China.
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Pradhan S, Rouster SD, Blackard JT, Dean GE, Sherman KE. Replication and Injury Associated With SARS-CoV-2 in Cultured Hepatocytes. Pathog Immun 2024; 8:59-73. [PMID: 38361525 PMCID: PMC10868721 DOI: 10.20411/pai.v8i2.648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 12/18/2023] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Liver dysfunction is one of the hallmarks of SARS-CoV-2 infection. The mechanism(s) of hepatic injury in SARS-CoV-2 infection remains controversial with some reporting viral replication and cellular injury and others suggesting lack of replication and injury due to non-cytopathogenic etiologies. To investigate this further, we evaluated SARS-CoV-2 replication in immortalized hepatic cell lines and primary hepatocytes, examined whether cell injury was associated with apoptotic pathways, and also determined the effect of the antiviral remdesivir on these processes. METHODS Immortalized hepatocyte cell lines (HepG2 and Huh7.5), as well as primary human hepatocytes, were exposed to SARS-CoV-2 at a multiplicity of infection of 0.1 PFU/mL. Viral replication was evaluated by plaque assays, immunohistochemical staining for the viral spike protein, and caspase-3 expression evaluated with and without exposure to remdesivir. RESULTS All hepatocyte cell lines and primary hepatocytes supported active replication of SARS-CoV-2. Significant cytopathic effect was observed by light microscopy, and caspase-3 staining supported activation of apoptotic pathways. Remdesivir abrogated infection in a dose-dependent fashion and was not independently associated with hepatocyte injury. CONCLUSION Hepatocytes appear to be highly permissive of SARS-CoV-2 replication which leads to rapid cell death associated with activation of apoptotic pathways. Viral replication and hepatocytes injury are abrogated with remdesivir. We conclude that active viral replication is most likely a key contributor to liver enzyme abnormalities observed in the setting of acute SARS-CoV-2 infection.
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Affiliation(s)
- Suman Pradhan
- Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Susan D. Rouster
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jason T. Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Gary E. Dean
- Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Kenneth E. Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts
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Michalak A, Lach T, Szczygieł K, Cichoż-Lach H. COVID-19, Possible Hepatic Pathways and Alcohol Abuse-What Do We Know up to 2023? Int J Mol Sci 2024; 25:2212. [PMID: 38396888 PMCID: PMC10888568 DOI: 10.3390/ijms25042212] [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: 01/01/2024] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
The pandemic period due to coronavirus disease 2019 (COVID-19) revolutionized all possible areas of global health. Significant consequences were also related to diverse extrapulmonary manifestations of this pathology. The liver was found to be a relatively common organ, beyond the respiratory tract, affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple studies revealed the essential role of chronic liver disease (CLD) in the general outcome of coronavirus infection. Present concerns in this field are related to the direct hepatic consequences caused by COVID-19 and pre-existing liver disorders as risk factors for the severe course of the infection. Which mechanism has a key role in this phenomenon-previously existing hepatic disorder or acute liver failure due to SARS-CoV-2-is still not fully clarified. Alcoholic liver disease (ALD) constitutes another not fully elucidated context of coronavirus infection. Should the toxic effects of ethanol or already developed liver cirrhosis and its consequences be perceived as a causative or triggering factor of hepatic impairment in COVID-19 patients? In the face of these discrepancies, we decided to summarize the role of the liver in the whole picture of coronavirus infection, paying special attention to ALD and focusing on the pathological pathways related to COVID-19, ethanol toxicity and liver cirrhosis.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
| | - Karolina Szczygieł
- Clinical Dietetics Unit, Department of Bioanalytics, Medical University of Lublin, Chodźki 7, 20-093 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
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Ruz-Maldonado I, Gonzalez JT, Zhang H, Sun J, Bort A, Kabir I, Kibbey RG, Suárez Y, Greif DM, Fernández-Hernando C. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage. Nat Commun 2024; 15:1247. [PMID: 38341404 PMCID: PMC10858916 DOI: 10.1038/s41467-024-45439-0] [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: 12/19/2022] [Accepted: 01/24/2024] [Indexed: 02/12/2024] Open
Abstract
Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution of other hepatocyte subpopulations to regeneration has been controversial. Thus, re-examining hepatocyte dynamics during regeneration is critical for cell therapy and treatment of liver diseases. Using a mouse model of hepatocyte- and non-hepatocyte- multicolor lineage tracing, we demonstrate that midlobular hepatocytes also undergo hypertrophy in response to chemical, physical, and viral insults. Our study shows that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocytes also expand in number and size during the repair process and Galectin-9-CD44 pathway may be critical for driving these processes. Notably, we also identified that transdifferentiation and cell fusion during regeneration after severe injury contribute to recover hepatic function.
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Affiliation(s)
- Inmaculada Ruz-Maldonado
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Departments of Internal Medicine (Endocrinology) and Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - John T Gonzalez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Hanming Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Jonathan Sun
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Alicia Bort
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Inamul Kabir
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Richard G Kibbey
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Departments of Internal Medicine (Endocrinology) and Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Daniel M Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA.
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