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Adamopoulos PG, Bartzoka N, Tsiakanikas P, Scorilas A. Characterization of novel ACE2 mRNA transcripts: The potential role of alternative splicing in SARS-CoV-2 infection. Gene 2025; 936:149092. [PMID: 39549777 DOI: 10.1016/j.gene.2024.149092] [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: 08/20/2024] [Revised: 10/25/2024] [Accepted: 11/11/2024] [Indexed: 11/18/2024]
Abstract
The human angiotensin converting enzyme 2 (ACE2) gene encodes a type I transmembrane protein, which is homologous to angiotensin I-converting enzyme (ACE) and belongs to the angiotensin-converting enzyme family of dipeptidyl carboxypeptidases. As highlighted by the COVID-19 pandemic, ACE2 is not only crucial for the renin-angiotensin-aldosterone system (RAAS), but also displays great affinity with the SARS-CoV-2 spike protein, representing the major receptor of the virus. Given the significance of ACE2 in COVID-19, especially among cancer patients, the present study aims to explore the transcriptional landscape of ACE2 in human cancer and non-cancerous cell lines through the design and implementation of a custom targeted long-read sequencing approach. Bioinformatics analysis of the massive parallel sequencing data led to the identification of novel ACE2 mRNA splice variants (ACE2 sv.7-sv.12) that demonstrate previously uncharacterized exon-skipping events as well as 5' and/or 3' alternative splice sites. Demultiplexing of the sequencing data elucidated the differential expression profile of the identified splice variants in multiple human cell types, whereas in silico analysis suggests that some of the novel splice variants could produce truncated ACE2 isoforms with altered functionalities, potentially influencing their interaction with the SARS-CoV-2 spike protein. In summary, our study sheds light on the complex alternative splicing landscape of the ACE2 gene in cancer cell lines, revealing novel splice variants that could have significant implications for SARS-CoV-2 susceptibility in cancer patients. These findings contribute to the increased understanding of ACE2's role in COVID-19 and highlight the importance of considering alternative splicing as a key factor in viral pathogenesis. Undoubtably, further research is needed to explore the functional roles of these variants and their potential as therapeutic targets in the ongoing fight against COVID-19.
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Affiliation(s)
- Panagiotis G Adamopoulos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Natalia Bartzoka
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Tsiakanikas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece.
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Houghton MJ, Balland E, Gartner MJ, Thomas BJ, Subbarao K, Williamson G. The flavonoid quercetin decreases ACE2 and TMPRSS2 expression but not SARS-CoV-2 infection in cultured human lung cells. Biofactors 2024; 50:1268-1286. [PMID: 38886986 PMCID: PMC11627474 DOI: 10.1002/biof.2084] [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: 02/12/2024] [Accepted: 05/11/2024] [Indexed: 06/20/2024]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) on host cells, via its spike protein, and transmembrane protease, serine 2 (TMPRSS2) cleaves the spike-ACE2 complex to facilitate virus entry. As rate-limiting steps for virus entry, modulation of ACE2 and/or TMPRSS2 may decrease SARS-CoV-2 infectivity and COVID-19 severity. In silico modeling suggested the natural bioactive flavonoid quercetin can bind to ACE2 and a recent randomized clinical trial demonstrated that oral supplementation with quercetin increased COVID-19 recovery. A range of cultured human cells were assessed for co-expression of ACE2 and TMPRSS2. Immortalized Calu-3 lung cells, cultured and matured at an air-liquid interface (Calu-3-ALIs), were established as the most appropriate. Primary bronchial epithelial cells (PBECs) were obtained from healthy adult males (N = 6) and cultured under submerged conditions to corroborate the outcomes. Upon maturation or reaching 80% confluence, respectively, the Calu-3-ALIs and PBECs were treated with quercetin, and mRNA and protein expression were assessed by droplet digital PCR and ELISA, respectively. SARS-CoV-2 infectivity, and the effects of pre- and co-treatment with quercetin, was assessed by median tissue culture infectious dose assay. Quercetin dose-dependently decreased ACE2 and TMPRSS2 mRNA and protein in both Calu-3-ALIs and PBECs after 4 h, while TMPRSS2 remained suppressed in response to prolonged treatment with lower doses (twice daily for 3 days). Quercetin also acutely decreased ADAM17 mRNA, but not ACE, in Calu-3-ALIs, and this warrants further investigation. Calu-3-ALIs, but not PBECs, were successfully infected with SARS-CoV-2; however, quercetin had no antiviral effect, neither directly nor indirectly through downregulation of ACE2 and TMPRSS2. Calu-3-ALIs were reaffirmed to be an optimal cell model for research into the regulation of ACE2 and TMPRSS2, without the need for prior genetic modification, and will prove valuable in future coronavirus and respiratory infectious disease work. However, our data demonstrate that a significant decrease in the expression of ACE2 and TMPRSS2 by a promising prophylactic candidate may not translate to infection prevention.
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Affiliation(s)
- Michael James Houghton
- Department of Nutrition, Dietetics and FoodMonash University, BASE FacilityNotting HillVICAustralia
- Victorian Heart InstituteMonash University, Victorian Heart HospitalClaytonVICAustralia
| | - Eglantine Balland
- Department of Nutrition, Dietetics and FoodMonash University, BASE FacilityNotting HillVICAustralia
- Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental BiologyMonash UniversityClaytonVICAustralia
| | - Matthew James Gartner
- Department of Microbiology and ImmunologyUniversity of Melbourne at The Peter Doherty Institute for Infection and ImmunityMelbourneVICAustralia
| | - Belinda Jane Thomas
- Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonVICAustralia
- Monash Lung and Sleep, Monash Health, Monash Medical CentreClaytonVICAustralia
| | - Kanta Subbarao
- Department of Microbiology and ImmunologyUniversity of Melbourne at The Peter Doherty Institute for Infection and ImmunityMelbourneVICAustralia
- WHO Collaborating Centre for Reference and Research on InfluenzaThe Peter Doherty Institute for Infection and ImmunityMelbourneVICAustralia
| | - Gary Williamson
- Department of Nutrition, Dietetics and FoodMonash University, BASE FacilityNotting HillVICAustralia
- Victorian Heart InstituteMonash University, Victorian Heart HospitalClaytonVICAustralia
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Filip F, Terteliu-Baitan M, Avramia R, Filip R, Cocuz ME. Clinical management and complications of acute appendicitis in 3 children with SARS-CoV-2 infection: Case report. Medicine (Baltimore) 2024; 103:e40105. [PMID: 39470524 PMCID: PMC11521089 DOI: 10.1097/md.0000000000040105] [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: 06/24/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/30/2024] Open
Abstract
RATIONALE Sporadic cases of acute appendicitis (AA) in children with SARS-CoV-2 infection were still recorded at the end of COVID-19 pandemics. We consider that analyses of clinical courses and outcomes is useful to improve the clinical management of such cases in the setting of a general hospital. PATIENT CONCERNS Patient #1 was a 14-year-old girl who presented with nausea, right lower quadrant (RLQ) pain, myalgia, ad low-grade fever for 24 hours. Patient #2 was a 7-year-old boy with a 3-day history of abdominal pain, nausea and vomiting, and fever lasting for 4 days. Patient # 3 was a 16-year-old girl RLQ pain, nausea and vomiting, and fever lasting for 7 days. DIAGNOSES The patients were diagnosed with acute appendicitis (AA) based on the clinical picture, labs and abdominal ultrasound (US) findings. SARS-CoV- 2 infection was diagnosed using rapid antigen test performed at admission. INTERVENTIONS The patients were started on i.v. Ceftriaxone and Metronidazole, antalgics and i.v. fluids at admission. Appendectomy was performed the day after admission in patients # 1 and #2, and after 48 hours in patient #3. OUTCOMES Patient #1 had no complications and was discharged on postoperative day (POD) #5. Patient #2 developed a cecal fistula on POD #4 which was treated conservatively with Ertapenem, i.v. fluids, and local placement of colostomy bag. The fistula closed spontaneously on POD #12. He was discharged on POD #17. Patient #3 developed a postoperative abscess on POD # 6 and required laparoscopic surgical drainage of the abscess. She was discharged after another 6 days (POD #12). No patient required ICU admission, steroids, or supplemental O2 use during their hospitalization. There were no late complications or readmissions in these patients. LESSONS We consider that AA in these SARS-CoV-2 positive children had a similar course with SARS-CoV-2 negative cases. Compliance to previously established COVID-19 protocols was useful to improve the outcome. The parents should bring the sick child early to the hospital in order to avoid complications related to delayed presentation and not to SARS-CoV-2 infection itself.
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Affiliation(s)
- Florin Filip
- College of Medicine and Biological Sciences, Stefan Cel Mare University of Suceava, Suceava, Romania
- Suceava Emergency County Hospital, Suceava, Romania
| | - Monica Terteliu-Baitan
- College of Medicine and Biological Sciences, Stefan Cel Mare University of Suceava, Suceava, Romania
- Suceava Emergency County Hospital, Suceava, Romania
| | - Ramona Avramia
- College of Medicine and Biological Sciences, Stefan Cel Mare University of Suceava, Suceava, Romania
- Suceava Emergency County Hospital, Suceava, Romania
| | - Roxana Filip
- College of Medicine and Biological Sciences, Stefan Cel Mare University of Suceava, Suceava, Romania
- Suceava Emergency County Hospital, Suceava, Romania
| | - Maria Elena Cocuz
- Fundamental Prophylactic and Clinical Disciplines Department, Faculty of Medicine, Transilvania University of Brasov, Brașov, Romania
- Clinical Infectious Diseases Hospital of Brasov, Brasov, Romania
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Effah W, Khalil M, Hwang DJ, Miller DD, Narayanan R. Advances in the understanding of androgen receptor structure and function and in the development of next-generation AR-targeted therapeutics. Steroids 2024; 210:109486. [PMID: 39111362 PMCID: PMC11380798 DOI: 10.1016/j.steroids.2024.109486] [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: 05/23/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024]
Abstract
Androgen receptor (AR) and its ligand androgens are important for development and physiology of various tissues. AR and its ligands also play critical role in the development of various diseases, making it a valuable therapeutic target. AR ligands, both agonists and antagonists, are being widely used to treat pathological conditions, including prostate cancer and hypogonadism. Despite AR being studied widely over the last five decades, the last decade has seen striking advances in the knowledge on AR and discoveries that have the potential to translate to the clinic. This review provides an overview of the advances in AR biology, AR molecular mechanisms of action, and next generation molecules that are currently in development. Several of the areas described in the review are just unraveling and the next decade will bring more clarity on these developments that will put AR at the forefront of both basic biology and drug development.
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Affiliation(s)
- Wendy Effah
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Marjana Khalil
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Dong-Jin Hwang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Duane D Miller
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ramesh Narayanan
- Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States; UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States.
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Raheem MA, Rahim MA, Gul I, Reyad-Ul-Ferdous M, Zhang CY, Yu D, Pandey V, Du K, Wang R, Han S, Han Y, Qin P. COVID-19: Post infection implications in different age groups, mechanism, diagnosis, effective prevention, treatment, and recommendations. Life Sci 2024:122861. [PMID: 38925222 DOI: 10.1016/j.lfs.2024.122861] [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: 11/22/2023] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
SARS-CoV-2 is a highly contagious pathogen that predominantly caused the COVID-19 pandemic. The persistent effects of COVID-19 are defined as an inflammatory or host response to the virus that begins four weeks after initial infection and persists for an undetermined length of time. Chronic effects are more harmful than acute ones thus, this review explored the long-term effects of the virus on various human organs, including the pulmonary, cardiovascular, and neurological, reproductive, gastrointestinal, musculoskeletal, endocrine, and lymphoid systems and found that SARS-CoV-2 adversely affects these organs of older adults. Regarding diagnosis, the RT-PCR is a gold standard method of diagnosing COVID-19; however, it requires specialized equipment and personnel for performing assays and a long time for results production. Therefore, to overcome these limitations, artificial intelligence employed in imaging and microfluidics technologies is the most promising in diagnosing COVID-19. Pharmacological and non-pharmacological strategies are the most effective treatment for reducing the persistent impacts of COVID-19 by providing immunity to post-COVID-19 patients by reducing cytokine release syndrome, improving the T cell response, and increasing the circulation of activated natural killer and CD8 T cells in blood and tissues, which ultimately reduces fever, nausea, fatigue, and muscle weakness and pain. Vaccines such as inactivated viral, live attenuated viral, protein subunit, viral vectored, mRNA, DNA, or nanoparticle vaccines significantly reduce the adverse long-term virus effects in post-COVID-19 patients; however, no vaccine was reported to provide lifetime protection against COVID-19; consequently, protective measures such as physical separation, mask use, and hand cleansing are promising strategies. This review provides a comprehensive knowledge of the persistent effects of COVID-19 on people of varying ages, as well as diagnosis, treatment, vaccination, and future preventative measures against the spread of SARS-CoV-2.
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Affiliation(s)
- Muhammad Akmal Raheem
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Muhammad Ajwad Rahim
- College of Animal Science and Technology, Ahnui Agricultural University, Hefei, PR China
| | - Ijaz Gul
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Md Reyad-Ul-Ferdous
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Can Yang Zhang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Dongmei Yu
- School of Mechanical, Electrical & Information Engineering, Shandong University
| | - Vijay Pandey
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Ke Du
- Department of Chemical and Environmental Engineering, University of California, Riverside, CA, USA
| | - Runming Wang
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Sanyang Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Yuxing Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China
| | - Peiwu Qin
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Center of Precision Medicine and Healthcare, Tsinghua-Berkeley Shenzhen Institute, Shenzhen, Guangdong Province 518055, PR China.
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Asadipooya K, Asadipooya A, Adatorwovor R. Combination of spironolactone and DPP-4 inhibitors for treatment of SARS-CoV-2 infection: a literature review. Arch Virol 2024; 169:122. [PMID: 38753071 DOI: 10.1007/s00705-024-06043-1] [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: 04/27/2023] [Accepted: 03/23/2024] [Indexed: 05/21/2024]
Abstract
Coronavirus disease 2019 (COVID-19) is still causing hospitalization and death, and vaccination appears to become less effective with each emerging variant. Spike, non-spike, and other possible unrecognized mutations have reduced the efficacy of recommended therapeutic approaches, including monoclonal antibodies, plasma transfusion, and antivirals. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) and probably dipeptidyl peptidase 4 (DPP-4) to initiate the process of endocytosis by employing host proteases such as transmembrane serine protease-2 (TMPRSS-2) and ADAM metallopeptidase domain 17 (ADAM17). Spironolactone reduces the amount of soluble ACE2 and antagonizes TMPRSS-2 and ADAM17. DPP-4 inhibitors play immunomodulatory roles and may block viral entry. The efficacy of treatment with a combination of spironolactone and DPP-4 inhibitors does not appear to be affected by viral mutations. Therefore, the combination of spironolactone and DPP-4 inhibitors might improve the clinical outcome for COVID-19 patients by decreasing the efficiency of SARS-CoV-2 entry into cells and providing better anti-inflammatory, antiproliferative, and antifibrotic effects than those achieved using current therapeutic approaches such as antivirals and monoclonal antibodies.
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Affiliation(s)
- Kamyar Asadipooya
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Barnstable Brown Diabetes and Obesity Center, University of Kentucky, 2195 Harrodsburg Rd, Suite 125, Lexington, KY, 40504, USA.
| | - Artin Asadipooya
- Department of Neuroscience, University of Kentucky, Lexington, KY, USA
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7
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Baldelli A, Jerry Wong CY, Oguzlu H, Gholizadeh H, Guo Y, Ong HX, Singh A, Traini D, Pratap-Singh A. Nasal delivery of encapsulated recombinant ACE2 as a prophylactic drug for SARS-CoV-2. Int J Pharm 2024; 655:124009. [PMID: 38493838 DOI: 10.1016/j.ijpharm.2024.124009] [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: 01/26/2024] [Revised: 03/10/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is responsible for cell fusion with SARS-CoV viruses. ACE2 is contained in different areas of the human body, including the nasal cavity, which is considered the main entrance for different types of airborne viruses. We took advantage of the roles of ACE2 and the nasal cavity in SARS-CoV-2 replication and transmission to develop a nasal dry powder. Recombinant ACE2 (rhACE2), after a proper encapsulation achieved via spray freeze drying, shows a binding efficiency with spike proteins of SARS-CoV-2 higher than 77 % at quantities lower than 5 µg/ml. Once delivered to the nose, encapsulated rhACE2 led to viability and permeability of RPMI 2650 cells of at least 90.20 ± 0.67 % and 47.96 ± 4.46 %, respectively, for concentrations lower than 1 mg/ml. These results were validated using nasal dry powder containing rhACE2 to prevent or treat infections derived from SARS-CoV-2.
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Affiliation(s)
- Alberto Baldelli
- Faculty of Land and Food Systems, The University of British Columbia, Canada; School of Agriculture and Food Sustainability, The University of Queensland, Australia.
| | - Chun Yuen Jerry Wong
- Respiratory Technology, Woolcock Institute of Medical Research, Sydney, Australia
| | - Hale Oguzlu
- Faculty of Dentistry, Department of Oral Biological and Medical Sciences, University of British Columbia, Canada
| | - Hanieh Gholizadeh
- Respiratory Technology, Woolcock Institute of Medical Research, Sydney, Australia
| | - Yigong Guo
- Faculty of Land and Food Systems, The University of British Columbia, Canada
| | - Hui Xin Ong
- Respiratory Technology, Woolcock Institute of Medical Research, Sydney, Australia; Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University Australia Sydney, Australia
| | - Anika Singh
- Natural Health and Food Products Research Group, Centre for Applied Research, and Innovation (CARI), British Columbia Institute of Technology, Canada
| | - Daniela Traini
- Respiratory Technology, Woolcock Institute of Medical Research, Sydney, Australia; Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University Australia Sydney, Australia
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Owens CD, Bonin Pinto C, Detwiler S, Olay L, Pinaffi-Langley ACDC, Mukli P, Peterfi A, Szarvas Z, James JA, Galvan V, Tarantini S, Csiszar A, Ungvari Z, Kirkpatrick AC, Prodan CI, Yabluchanskiy A. Neurovascular coupling impairment as a mechanism for cognitive deficits in COVID-19. Brain Commun 2024; 6:fcae080. [PMID: 38495306 PMCID: PMC10943572 DOI: 10.1093/braincomms/fcae080] [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: 10/10/2023] [Revised: 02/08/2024] [Accepted: 03/05/2024] [Indexed: 03/19/2024] Open
Abstract
Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population.
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Affiliation(s)
- Cameron D Owens
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Camila Bonin Pinto
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Sam Detwiler
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Lauren Olay
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Ana Clara da C Pinaffi-Langley
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Peter Mukli
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Anna Peterfi
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Zsofia Szarvas
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Judith A James
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Veronica Galvan
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Stefano Tarantini
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Anna Csiszar
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Zoltan Ungvari
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Angelia C Kirkpatrick
- Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- Cardiovascular Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Calin I Prodan
- Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Andriy Yabluchanskiy
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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9
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Demyashkin G, Gorokhov K, Shchekin V, Vadyukhin M, Matevosyan A, Rudavina A, Pilipchuk A, Pilipchuk A, Kochetkova S, Atiakshin D, Shegay P, Kaprin A. Features of Appendix and the Characteristics of Appendicitis Development in Children with COVID-19. Biomedicines 2024; 12:312. [PMID: 38397914 PMCID: PMC10886907 DOI: 10.3390/biomedicines12020312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Research on the subject of the influence of SARS-CoV-2 mechanisms on human homeostasis remains an actual problem. Particular interest is the study of pathomorphological changes in the appendix in children with COVID-19. OBJECTIVES Aim of this study: morphological and molecular biological evaluation of the appendix in children of different age groups with COVID-19. METHODS Groups were formed on the basis of anamnestic, clinical, and morphological data: I (n = 42; aged 2 to 18 years, average age-10.8 ± 4.79)-with an established clinical diagnosis: coronavirus infection (COVID-19; PCR+); II (n = 55; aged 2 to 18 years, average age-9.7 ± 4.77)-with a confirmed clinical diagnosis of acute appendicitis; collected before the onset of the COVID-19 pandemic in 2017-2019; and III (n = 38; aged 2 to 18 years, average age-10.3 ± 4.62)-the control group. Histological and immunohistochemical studies were conducted using primary antibodies to CD3, CD4, CD68, CD163, CD20, and CD138 and to pro-inflammatory (IL-1, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines. RESULTS In most samples of appendixes in children with COVID-19, signs of destructive phlegmonous-ulcerative and gangrenous appendicitis were discovered. An increase in CD3+, CD4+, CD68+, CD163+, and CD20+ CD138+ immunocompetent cells was found in the appendix of children with COVID-19. As well, there was an increase in pro-inflammatory (IL-1, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines. CONCLUSIONS The aforementioned pathological and immunohistochemical changes were more pronounced in the group of children aged 6-12 years (childhood).
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Affiliation(s)
- Grigory Demyashkin
- Department of Pathomorphology, National Medical Research Centre of Radiology, Ministry of Health of Russia, 249036 Obninsk, Russia; (K.G.); (P.S.); (A.K.)
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Konstantin Gorokhov
- Department of Pathomorphology, National Medical Research Centre of Radiology, Ministry of Health of Russia, 249036 Obninsk, Russia; (K.G.); (P.S.); (A.K.)
| | - Vladimir Shchekin
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Matvey Vadyukhin
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Artem Matevosyan
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Arina Rudavina
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Anna Pilipchuk
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Alina Pilipchuk
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Svetlana Kochetkova
- Laboratory of Histology and Immunohistochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (G.D.); (M.V.); (A.M.); (A.R.); (A.P.); (A.P.); (S.K.)
| | - Dmitrii Atiakshin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia;
| | - Petr Shegay
- Department of Pathomorphology, National Medical Research Centre of Radiology, Ministry of Health of Russia, 249036 Obninsk, Russia; (K.G.); (P.S.); (A.K.)
| | - Andrey Kaprin
- Department of Pathomorphology, National Medical Research Centre of Radiology, Ministry of Health of Russia, 249036 Obninsk, Russia; (K.G.); (P.S.); (A.K.)
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia;
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10
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Woods B, Mehta P, Jagirdhar GSK, Kashyap R, Bansal V. Upper and lower gastrointestinal symptoms and manifestations of COVID-19. MANAGEMENT, BODY SYSTEMS, AND CASE STUDIES IN COVID-19 2024:523-537. [DOI: 10.1016/b978-0-443-18703-2.00008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Siratavičiūtė V, Pangonytė D, Utkienė L, Jusienė L, Marcinkevičienė J, Stanionienė Z, Radikė R. Myocardial Angiotensin-Converting Enzyme 2 Protein Expression in Ischemic Heart Failure. Int J Mol Sci 2023; 24:17145. [PMID: 38138974 PMCID: PMC10743033 DOI: 10.3390/ijms242417145] [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: 11/06/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis plays a significant role in regulating myocardial remodeling and the development of heart failure (HF), with ACE2 being the primary focus. However, contemporary understanding of the membrane-bound form of the human ACE2 protein remains insufficient. The purpose of this study was to determine the expression of ACE2 protein in different cells of the left ventricular myocardium in non-diseased hearts and at various stages of ischemic HF. A total of 103 myocardial tissue samples from the left ventricle underwent quantitative and semi-quantitative immunohistochemical analysis. Upon assessing ACE2 immunostaining in all myocardial cells through unselective digital image analysis, there was no change in the stage A HF group. Nevertheless, the expression of ACE2 membrane protein in cardiomyocytes showed a tendency to increase, while non-cardiomyocyte ACE2 expression decreased significantly (p < 0.001). In the stage B HF group, the intensity of ACE2 immunostaining continued to increase with rising cardiomyocyte ACE2 expression (p < 0.001). Non-cardiomyocyte expression, in contrast, remained similar to that observed in the stage A HF group. In the stages C/D HF group, ACE2 expression reached its highest level in cardiomyocytes (p < 0.001), while ACE2 expression in non-cardiomyocytes was the lowest (p < 0.001). These changes in ACE2 protein levels are associated with left ventricular remodeling in ischemic HF.
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Affiliation(s)
| | - Dalia Pangonytė
- Laboratory of Cardiac Pathology, Institute of Cardiology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (V.S.); (L.U.); (L.J.); (J.M.); (Z.S.); (R.R.)
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12
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Xia T, Fu X, Fulham M, Wang Y, Feng D, Kim J. CT-based Radiogenomics Framework for COVID-19 Using ACE2 Imaging Representations. J Digit Imaging 2023; 36:2356-2366. [PMID: 37553526 PMCID: PMC10584804 DOI: 10.1007/s10278-023-00895-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 08/01/2023] [Accepted: 08/01/2023] [Indexed: 08/10/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 which enters the body via the angiotensin-converting enzyme 2 (ACE2) and altering its gene expression. Altered ACE2 plays a crucial role in the pathogenesis of COVID-19. Gene expression profiling, however, is invasive and costly, and is not routinely performed. In contrast, medical imaging such as computed tomography (CT) captures imaging features that depict abnormalities, and it is widely available. Computerized quantification of image features has enabled 'radiogenomics', a research discipline that identifies image features that are associated with molecular characteristics. Radiogenomics between ACE2 and COVID-19 has yet to be done primarily due to the lack of ACE2 expression data among COVID-19 patients. Similar to COVID-19, patients with lung adenocarcinoma (LUAD) exhibit altered ACE2 expression and, LUAD data are abundant. We present a radiogenomics framework to derive image features (ACE2-RGF) associated with ACE2 expression data from LUAD. The ACE2-RGF was then used as a surrogate biomarker for ACE2 expression. We adopted conventional feature selection techniques including ElasticNet and LASSO. Our results show that: i) the ACE2-RGF encoded a distinct collection of image features when compared to conventional techniques, ii) the ACE2-RGF can classify COVID-19 from normal subjects with a comparable performance to conventional feature selection techniques with an AUC of 0.92, iii) ACE2-RGF can effectively identify patients with critical illness with an AUC of 0.85. These findings provide unique insights for automated COVID-19 analysis and future research.
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Affiliation(s)
- Tian Xia
- School of Computer Science, Faculty of Engineering, The University of Sydney, Sydney, NSW, 2006, Australia.
| | - Xiaohang Fu
- School of Computer Science, Faculty of Engineering, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Michael Fulham
- School of Computer Science, Faculty of Engineering, The University of Sydney, Sydney, NSW, 2006, Australia
- Department of Molecular Imaging, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia
| | - Yue Wang
- Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA, 22203, USA
| | - Dagan Feng
- School of Computer Science, Faculty of Engineering, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Jinman Kim
- School of Computer Science, Faculty of Engineering, The University of Sydney, Sydney, NSW, 2006, Australia
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13
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Reveret L, Leclerc M, Emond V, Tremblay C, Loiselle A, Bourassa P, Bennett DA, Hébert SS, Calon F. Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease. Acta Neuropathol Commun 2023; 11:159. [PMID: 37784209 PMCID: PMC10544218 DOI: 10.1186/s40478-023-01647-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 10/04/2023] Open
Abstract
Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population, which has been disproportionately affected by the COVID-19 pandemic. In this study, we investigated the levels of angiotensin-converting enzyme 2 (ACE2), a regulator of the renin-angiotensin system and the main entry receptor of SARS-CoV-2 in host cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein (p < 0.01) and mRNA (p < 0.01) were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02) and markers of pericytes (PDGFRβ, p = 0.02 and ANPEP, p = 0.007), but positively correlated with concentrations of soluble amyloid-β peptides (Aβ) (p = 0.01) and insoluble phospho-tau (S396/404, p = 0.002). However, no significant differences in ACE2 were observed in the 3xTg-AD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is predominantly localized in microvessels in the mouse brain whereas it is more frequently found in neurons in the human brain. The present data suggest that higher levels of soluble ACE2 in the human brain may contribute to AD, but their role in CNS infection by SARS-CoV-2 remains unclear.
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Affiliation(s)
- Louise Reveret
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
| | - Manon Leclerc
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
| | - Vincent Emond
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
| | - Cyntia Tremblay
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
| | - Andréanne Loiselle
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
| | - Philippe Bourassa
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
| | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Sébastien S Hébert
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada
- Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Frédéric Calon
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada.
- CHU de Quebec Research Center, 2705, Boulevard Laurier, Room T2-05, Québec, QC, G1V 4G2, Canada.
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14
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Potokar M, Zorec R, Jorgačevski J. Astrocytes Are a Key Target for Neurotropic Viral Infection. Cells 2023; 12:2307. [PMID: 37759529 PMCID: PMC10528686 DOI: 10.3390/cells12182307] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 08/28/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Astrocytes are increasingly recognized as important viral host cells in the central nervous system. These cells can produce relatively high quantities of new virions. In part, this can be attributed to the characteristics of astrocyte metabolism and its abundant and dynamic cytoskeleton network. Astrocytes are anatomically localized adjacent to interfaces between blood capillaries and brain parenchyma and between blood capillaries and brain ventricles. Moreover, astrocytes exhibit a larger membrane interface with the extracellular space than neurons. These properties, together with the expression of various and numerous viral entry receptors, a relatively high rate of endocytosis, and morphological plasticity of intracellular organelles, render astrocytes important target cells in neurotropic infections. In this review, we describe factors that mediate the high susceptibility of astrocytes to viral infection and replication, including the anatomic localization of astrocytes, morphology, expression of viral entry receptors, and various forms of autophagy.
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Affiliation(s)
- Maja Potokar
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
- Celica Biomedical, Tehnološki Park 24, 1000 Ljubljana, Slovenia
| | - Robert Zorec
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
- Celica Biomedical, Tehnološki Park 24, 1000 Ljubljana, Slovenia
| | - Jernej Jorgačevski
- Laboratory of Neuroendocrinology–Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
- Celica Biomedical, Tehnološki Park 24, 1000 Ljubljana, Slovenia
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15
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Peka M, Balatsky V. Analysis of RBD-ACE2 interactions in livestock species as a factor in the spread of SARS-CoV-2 among animals. Vet Anim Sci 2023; 21:100303. [PMID: 37521409 PMCID: PMC10372456 DOI: 10.1016/j.vas.2023.100303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023] Open
Abstract
The high mutation rate of SARS-CoV-2, which has led to the emergence of a number of virus variants, creates risks of transmission from humans to animal species and the emergence of new animal reservoirs of COVID-19. This study aimed to identify animal species among livestock susceptible to infection and develop an approach that would be possible to use for assessing the hazards caused by new SARS-CoV-2 variants for animals. Bioinformatic analysis was used to evaluate the ability of receptor-binding domains (RBDs) of different SARS-CoV-2 variants to interact with ACE2 receptors of livestock species. The results indicated that the stability of RBD-ACE2 complexes depends on both amino acid residues in the ACE2 sequences of animal species and on mutations in the RBDs of SARS-CoV-2 variants, with the residues in the interface of the RBD-ACE2 complex being the most important. All studied SARS-CoV-2 variants had high affinity for ferret and American mink receptors, while the affinity for horse, donkey, and bird species' receptors significantly increased in the highly mutated Omicron variant. Hazards that future SARS-CoV-2 variants may acquire specificity to new animal species remain high given the mutability of the virus. The continued use and expansion of the bioinformatic approach presented in this study may be relevant for monitoring transmission risks and preventing the emergence of new reservoirs of COVID-19 among animals.
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Affiliation(s)
- Mykyta Peka
- V. N. Karazin Kharkiv National University, 4 Svobody Sq, Kharkiv, 61022, Ukraine
- Institute of Pig Breeding and Agroindustrial Production, National Academy of Agrarian Sciences of Ukraine, 1 Shvedska Mohyla St, Poltava, 36013, Ukraine
| | - Viktor Balatsky
- V. N. Karazin Kharkiv National University, 4 Svobody Sq, Kharkiv, 61022, Ukraine
- Institute of Pig Breeding and Agroindustrial Production, National Academy of Agrarian Sciences of Ukraine, 1 Shvedska Mohyla St, Poltava, 36013, Ukraine
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16
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Huynh TTX, Pham TX, Lee GH, Lee JB, Lee SG, Tark D, Lim YS, Hwang SB. Amuvatinib Blocks SARS-CoV-2 Infection at the Entry Step of the Viral Life Cycle. Microbiol Spectr 2023; 11:e0510522. [PMID: 36995225 PMCID: PMC10269473 DOI: 10.1128/spectrum.05105-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 03/14/2023] [Indexed: 03/31/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 propagation is mediated by the protein interaction between viral proteins and host cells. Tyrosine kinase has been implicated in viral replication, and hence, it has become a target for developing antiviral drugs. We have previously reported that receptor tyrosine kinase inhibitor blocks the replication of hepatitis C virus (HCV). In the present study, we investigated two receptor tyrosine kinase-specific inhibitors, amuvatinib and imatinib, for their potential antiviral efficacies against SARS-CoV-2. Treatment with either amuvatinib or imatinib displays an effective inhibitory activity against SARS-CoV-2 propagation without an obvious cytopathic effect in Vero E6 cells. Notably, amuvatinib exerts a stronger antiviral activity than imatinib against SARS-CoV-2 infection. Amuvatinib blocks SARS-CoV-2 infection with a 50% effective concentration (EC50) value ranging from ~0.36 to 0.45 μM in Vero E6 cells. We further demonstrate that amuvatinib inhibits SARS-CoV-2 propagation in human lung Calu-3 cells. Using pseudoparticle infection assay, we verify that amuvatinib blocks SARS-CoV-2 at the entry step of the viral life cycle. More specifically, amuvatinib inhibits SARS-CoV-2 infection at the binding-attachment step. Moreover, amuvatinib exhibits highly efficient antiviral activity against emerging SARS-CoV-2 variants. Importantly, we demonstrate that amuvatinib inhibits SARS-CoV-2 infection by blocking ACE2 cleavage. Taken together, our data suggest that amuvatinib may provide a potential therapeutic agent for the treatment of COVID-19. IMPORTANCE Tyrosine kinase has been implicated in viral replication and has become an antiviral drug target. Here, we chose two well-known receptor tyrosine kinase inhibitors, amuvatinib and imatinib, and evaluated their drug potencies against SARS-CoV-2. Surprisingly, amuvatinib displays a stronger antiviral activity than imatinib against SARS-CoV-2. Amuvatinib blocks SARS-CoV-2 infection by inhibiting ACE2 cleavage and the subsequent soluble ACE2 receptor. All these data suggest that amuvatinib may be a potential therapeutic agent in SARS-CoV-2 prevention for those experiencing vaccine breakthroughs.
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Affiliation(s)
- Trang T. X. Huynh
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Thuy X. Pham
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Gun-Hee Lee
- Laboratory for Infectious Disease Prevention, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Jae-Bong Lee
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Sung-Geun Lee
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Dongseob Tark
- Laboratory for Infectious Disease Prevention, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Yun-Sook Lim
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
| | - Soon B. Hwang
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, South Korea
- Ilsong Institute of Life Science, Hallym University, Seoul, South Korea
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17
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Kiouri DP, Ntallis C, Kelaidonis K, Peana M, Tsiodras S, Mavromoustakos T, Giuliani A, Ridgway H, Moore GJ, Matsoukas JM, Chasapis CT. Network-Based Prediction of Side Effects of Repurposed Antihypertensive Sartans against COVID-19 via Proteome and Drug-Target Interactomes. Proteomes 2023; 11:21. [PMID: 37368467 PMCID: PMC10305495 DOI: 10.3390/proteomes11020021] [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: 04/10/2023] [Revised: 05/26/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
The potential of targeting the Renin-Angiotensin-Aldosterone System (RAAS) as a treatment for the coronavirus disease 2019 (COVID-19) is currently under investigation. One way to combat this disease involves the repurposing of angiotensin receptor blockers (ARBs), which are antihypertensive drugs, because they bind to angiotensin-converting enzyme 2 (ACE2), which in turn interacts with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. However, there has been no in silico analysis of the potential toxicity risks associated with the use of these drugs for the treatment of COVID-19. To address this, a network-based bioinformatics methodology was used to investigate the potential side effects of known Food and Drug Administration (FDA)-approved antihypertensive drugs, Sartans. This involved identifying the human proteins targeted by these drugs, their first neighbors, and any drugs that bind to them using publicly available experimentally supported data, and subsequently constructing proteomes and protein-drug interactomes. This methodology was also applied to Pfizer's Paxlovid, an antiviral drug approved by the FDA for emergency use in mild-to-moderate COVID-19 treatment. The study compares the results for both drug categories and examines the potential for off-target effects, undesirable involvement in various biological processes and diseases, possible drug interactions, and the potential reduction in drug efficiency resulting from proteoform identification.
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Affiliation(s)
- Despoina P. Kiouri
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (D.P.K.); (C.N.)
- Department of Chemistry, Laboratory of Organic Chemistry, National Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Charalampos Ntallis
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (D.P.K.); (C.N.)
| | | | - Massimiliano Peana
- Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;
| | - Sotirios Tsiodras
- 4th Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Thomas Mavromoustakos
- Department of Chemistry, Laboratory of Organic Chemistry, National Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Alessandro Giuliani
- Environment and Health Department, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Harry Ridgway
- Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne, VIC 8001, Australia
- AquaMem Consultants, Rodeo, NM 88056, USA
| | - Graham J. Moore
- Pepmetics Inc., 772 Murphy Place, Victoria, BC V6Y 3H4, Canada;
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - John M. Matsoukas
- NewDrug PC, Patras Science Park, 26504 Patras, Greece;
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
- Department of Chemistry, University of Patras, 26504 Patras, Greece
| | - Christos T. Chasapis
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (D.P.K.); (C.N.)
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18
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Tavakoli R, Rahimi P, Hamidi-Fard M, Eybpoosh S, Doroud D, Ahmadi I, Anvari E, Aghasadeghi M, Fateh A. Expression of TRIM56 gene in SARS-CoV-2 variants and its relationship with progression of COVID-19. Future Virol 2023; 18:563-574. [PMID: 38051999 PMCID: PMC10348059 DOI: 10.2217/fvl-2022-0210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 06/19/2023] [Indexed: 10/13/2023]
Abstract
AIM The present study aimed to determine a correlation between differential TRIM56 expression levels and severe infections of COVID-19 between the Alpha, Delta and Omicron BA.5 variants. MATERIALS & METHODS This study was performed on 330 COVID-19 patients, including 142 with severe and 188 with mild infections, as well as 160 healthy controls. The levels of TRIM56 gene expression were determined using a qPCR. RESULTS TRIM56 gene showed significantly lower mRNA expression in the severe and mild groups compared with healthy individuals. Our finding indicated the high and low reduction of TRIM56 mRNA expression in Delta and Omicron BA.5 variant, respectively. CONCLUSION Further research is needed to characterize the impact of TRIM proteins on the severity of COVID-19.
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Affiliation(s)
- Rezvan Tavakoli
- Hepatitis & AIDS Department, Pasteur Institute of Iran, Tehran, Iran
| | - Pooneh Rahimi
- Hepatitis & AIDS Department, Pasteur Institute of Iran, Tehran, Iran
- Viral Vaccine Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mojtaba Hamidi-Fard
- Hepatitis & AIDS Department, Pasteur Institute of Iran, Tehran, Iran
- Viral Vaccine Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sana Eybpoosh
- Department of Epidemiology & Biostatistics, Research Centre for Emerging & Reemerging Infectious Diseases, Pasteur Institute of Iran, Tehran, Iran
| | - Delaram Doroud
- Quality Control Department, Production & Research Complex, Pasteur Institute of Iran, Tehran, Iran
| | - Iraj Ahmadi
- Department of Physiology, School of Medicine, Ilam University of Medical Science, Ilam, Iran
| | - Enayat Anvari
- Department of Physiology, School of Medicine, Ilam University of Medical Science, Ilam, Iran
| | - Mohammadreza Aghasadeghi
- Hepatitis & AIDS Department, Pasteur Institute of Iran, Tehran, Iran
- Viral Vaccine Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Department of Mycobacteriology & Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
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19
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Fopase R, Panda C, Rajendran AP, Uludag H, Pandey LM. Potential of siRNA in COVID-19 therapy: Emphasis on in silico design and nanoparticles based delivery. Front Bioeng Biotechnol 2023; 11:1112755. [PMID: 36814718 PMCID: PMC9939533 DOI: 10.3389/fbioe.2023.1112755] [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: 11/30/2022] [Accepted: 01/13/2023] [Indexed: 02/09/2023] Open
Abstract
Small interfering RNA (siRNA)-mediated mRNA degradation approach have imparted its eminence against several difficult-to-treat genetic disorders and other allied diseases. Viral outbreaks and resulting pandemics have repeatedly threatened public health and questioned human preparedness at the forefront of drug design and biomedical readiness. During the recent pandemic caused by the SARS-CoV-2, mRNA-based vaccination strategies have paved the way for a new era of RNA therapeutics. RNA Interference (RNAi) based approach using small interfering RNA may complement clinical management of the COVID-19. RNA Interference approach will primarily work by restricting the synthesis of the proteins required for viral replication, thereby hampering viral cellular entry and trafficking by targeting host as well as protein factors. Despite promising benefits, the stability of small interfering RNA in the physiological environment is of grave concern as well as site-directed targeted delivery and evasion of the immune system require immediate attention. In this regard, nanotechnology offers viable solutions for these challenges. The review highlights the potential of small interfering RNAs targeted toward specific regions of the viral genome and the features of nanoformulations necessary for the entrapment and delivery of small interfering RNAs. In silico design of small interfering RNA for different variants of SARS-CoV-2 has been discussed. Various nanoparticles as promising carriers of small interfering RNAs along with their salient properties, including surface functionalization, are summarized. This review will help tackle the real-world challenges encountered by the in vivo delivery of small interfering RNAs, ensuring a safe, stable, and readily available drug candidate for efficient management of SARS-CoV-2 in the future.
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Affiliation(s)
- Rushikesh Fopase
- Bio-Interface & Environmental Engineering Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, India
| | - Chinmaya Panda
- Bio-Interface & Environmental Engineering Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, India
| | - Amarnath P. Rajendran
- Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada
| | - Hasan Uludag
- Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Lalit M. Pandey
- Bio-Interface & Environmental Engineering Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam, India
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20
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Louise R, Manon L, Vincent E, Andréanne L, Philippe B, Cyntia T, Bennett DA, Sébastien H, Frédéric C. Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.17.524254. [PMID: 36711734 PMCID: PMC9882134 DOI: 10.1101/2023.01.17.524254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFRβ, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-β peptides (Aβ) concentrations (p = 0.01) and insoluble phospho- tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.
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Affiliation(s)
- Reveret Louise
- Faculty of pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, Quebec, QC, Canada
| | - Leclerc Manon
- Faculty of pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, Quebec, QC, Canada
| | | | | | - Bourassa Philippe
- Faculty of pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, Quebec, QC, Canada
| | | | - David A Bennett
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
| | - Hébert Sébastien
- CHU de Quebec Research Center, Quebec, QC, Canada
- Faculty of medicine, Laval University, Quebec, QC, Canada
| | - Calon Frédéric
- Faculty of pharmacy, Laval University, Quebec, QC, Canada
- CHU de Quebec Research Center, Quebec, QC, Canada
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21
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Ameer MA, Chaudhry H, Babar M, Patel N, Song M, Mathew M. The Rationale for Using Corticosteroids in COVID-19 Encephalopathy: Lessons From a Case Report With Evidence From Literature. Cureus 2023; 15:e33233. [PMID: 36733547 PMCID: PMC9889839 DOI: 10.7759/cureus.33233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2023] [Indexed: 01/04/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) virus primarily affects the pulmonary system, but neurological manifestations and complication of COVID-19 has been reported in abundance in the literature. We present a case of a middle-aged Caucasian male who was brought to the emergency department for altered mental status. His chief complaints were neurological rather than respiratory. A positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) nasal swab confirmed the diagnosis. Brain imaging showed mildly dilated ventricles with no other acute findings. As the patient did not require oxygen, he was treated with remdesivir alone without corticosteroids, which is also a precipitating factor of psychosis but, unfortunately, thickly used in practice. That led to remarkable results in full recovery without exposing the patient to steroid therapy. We strongly believe that remdesivir alone is sufficient in treating COVID-19-induced encephalopathy in a patient who does not require oxygen, and evidence supports this practice.
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Affiliation(s)
| | - Haroon Chaudhry
- Internal Medicine, Suburban Community Hospital, East Norriton, USA
| | - Maham Babar
- Department of Medicine, Khyber Medical University, Peshawar, PAK
| | - Nimi Patel
- Internal Medicine, Krupa Hospital, Ahmedabad, IND
| | - Monata Song
- Internal Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, USA
| | - Mathew Mathew
- Internal Medicine, Suburban Community Hospital, Philadelphia, USA
- Internal Medicine, Suburban Hospital, Norristown, USA
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22
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Bafadhel M, Faner R, Taillé C, Russell REK, Welte T, Barnes PJ, Agustí A. Inhaled corticosteroids for the treatment of COVID-19. Eur Respir Rev 2022; 31:220099. [PMID: 36450371 PMCID: PMC9724831 DOI: 10.1183/16000617.0099-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 10/09/2022] [Indexed: 12/02/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused severe illness and mortality for millions worldwide. Despite the development, approval and rollout of vaccination programmes globally to prevent infection by SARS-CoV-2 and the development of coronavirus disease 2019 (COVID-19), treatments are still urgently needed to improve outcomes. Early in the pandemic it was observed that patients with pre-existing asthma or COPD were underrepresented among those with COVID-19. Evidence from clinical studies indicates that the inhaled corticosteroids (ICS) routinely taken for asthma and COPD could have had a protective role in preventing severe COVID-19 and, therefore, may be a promising treatment for COVID-19. This review summarises the evidence supporting the beneficial effects of ICS on outcomes in patients with COVID-19 and explores the potential protective mechanisms.
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Affiliation(s)
- Mona Bafadhel
- King's Centre for Lung Health, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Rosa Faner
- CIBER Enfermedades Respiratorias, IDIBAPS, Barcelona, Spain
| | - Camille Taillé
- Department of Pulmonary Diseases, University Hospital Bichat-Claude Bernard, AP-HP Nord, University of Paris, Paris, France
| | - Richard E K Russell
- King's Centre for Lung Health, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Tobias Welte
- Department of Pulmonary and Infectious Diseases, Hannover University School of Medicine, Hannover, Germany
| | - Peter J Barnes
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Alvar Agustí
- Cátedra de Salud Respiratoria (University of Barcelona), Respiratory Institute (Hospital Clinic Barcelona), IDIBAPS and CIBERES, Barcelona, Spain
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23
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Bravaccini S, Nicolini F, Zanoni M, Gaimari A, Cerchione C, Maltoni R, Pirini F, Mazzotti L, Cortesi M, Ravaioli S, Tumedei MM, Mazza M. Why the complications of COVID-19 patients differ in elderly and young cancer patients. Transl Oncol 2022; 26:101541. [PMID: 36119944 PMCID: PMC9464575 DOI: 10.1016/j.tranon.2022.101541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/07/2022] [Indexed: 10/31/2022] Open
Abstract
Zhang et al. reported the impact of different risk factors and comorbidities in COVID-19 lethality. The authors observed that the odds of dying by COVID-19 in cancer patients decrease with age and cancer becomes a non-significant factor above 80 years. We speculate on the possible causes for the different COVID-19 severity between elderly and young patients. Several factors that can have a different impact on young and elderly have to be taken into account such as inflammation, microbiota and anti-cancer therapies. Inflammaging is a complex process that characterizes elderly people and it is believed to contribute to the severity of COVID-19 associated with old age. Cancer and related therapies may alter the process of inflammaging both quantitatively and qualitatively and could impact on COVID-19 severity. Moreover, therapies used in elderly cancer patients are usually different from that used for young people where the presence of comorbidities and the mechanisms of action of the different drugs both on the susceptibility genes and on other factors have to be considered. Sex hormones and anti-estrogen therapies affect significantly gene expression in target cells thereby modulating the susceptibility of the tissues to SARS-CoV-2 infection and as a consequence the extent of the symptoms. The concentration of sex hormones varies with aging and among sexes. Interestingly, recent evidences, further corroborate the hypothesis that also sex hormones or anti-estrogen therapies impact the susceptibility to COVID-19 and its severity.
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Affiliation(s)
- Sara Bravaccini
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Fabio Nicolini
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michele Zanoni
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Anna Gaimari
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Claudio Cerchione
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Roberta Maltoni
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Francesca Pirini
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Lucia Mazzotti
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michela Cortesi
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Sara Ravaioli
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | | | - Massimiliano Mazza
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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24
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Pu Y, He X, Chen L, Wang H, Ma Y, Jiang W. Apple polyphenols attenuate the binding ability of angiotensin converting enzyme 2 to viral proteins: Computer simulation and in vitro experiments. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.102090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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25
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Soltani Rezaiezadeh J, Lord JS, Yekaninejad MS, Izadi P. The association of ACE I/D polymorphism with the severity of COVID-19 in Iranian patients: A case-control study. HUMAN GENE (AMSTERDAM, NETHERLANDS) 2022; 34:201099. [PMID: 37521445 PMCID: PMC9364667 DOI: 10.1016/j.humgen.2022.201099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/19/2022] [Accepted: 08/06/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND Since the beginning of the COVID-19 pandemic, researchers have tried to find the reason behind the variety of the symptoms and disease severity among patients. It seems that genetic background may contribute in severity of this infection. The renin-angiotensin system (RAS) is involved in the pathogenesis of COVID-19. An Insertion/Deletion (I/D) polymorphism in the ACE1 gene may explain the genetic risk for disease severity. METHODS We genotyped 251 COVID-19 patients: 151 patients with mild or asymptomatic disease compared with 100 patients with severe to critical illness (without any comorbidities for the disease severity). RESULTS There was a significant association between the ACE1 DD genotype and disease severity (p-value = 1 × 10-2; OR = 2.004, 95%CI = 1.147-3.499) and our results showed that it was inherited under recessive or codominant inheritance patterns. Also, the I allele showed a protective role against the severe form of COVID-19 disease (p-value = 1 × 10-4). CONCLUSION We concluded that ACE1 DD genotype can predict the risk of severe form of COVID-19 infection in the absence of known comorbidities as disease severity risk factors. Further studies with larger sample sizes in other populations are still needed to clarify the role of ACE I/D polymorphism in SARS-CoV-2 infection severity.
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Affiliation(s)
- Javad Soltani Rezaiezadeh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences and Health Services, Tehran, Islamic Republic of Iran
| | - Javad Safdari Lord
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences and Health Services, Tehran, Islamic Republic of Iran
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences and Health Services, Tehran, Islamic Republic of Iran
| | - Pantea Izadi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences and Health Services, Tehran, Islamic Republic of Iran
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26
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Ranjbar T, Oza PP, Kashfi K. The Renin-Angiotensin-Aldosterone System, Nitric Oxide, and Hydrogen Sulfide at the Crossroads of Hypertension and COVID-19: Racial Disparities and Outcomes. Int J Mol Sci 2022; 23:ijms232213895. [PMID: 36430371 PMCID: PMC9699619 DOI: 10.3390/ijms232213895] [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: 09/22/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin-angiotensin-aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19's symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus.
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Affiliation(s)
- Tara Ranjbar
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
| | - Palak P. Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10016, USA
- Correspondence:
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27
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Borczuk AC, Yantiss RK. The pathogenesis of coronavirus-19 disease. J Biomed Sci 2022; 29:87. [PMID: 36289507 PMCID: PMC9597981 DOI: 10.1186/s12929-022-00872-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/20/2022] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity. Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of “thrombo-inflammation”. These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. The purpose of this review is to discuss the pathogenesis underlying organ damage that can occur in patients with SARS-CoV-2 infection. Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.
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Affiliation(s)
- Alain C. Borczuk
- grid.512756.20000 0004 0370 4759Department of Pathology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Greenvale, NY USA
| | - Rhonda K. Yantiss
- grid.5386.8000000041936877XDepartment of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065 USA
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28
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Dehghani J, Movafeghi A, Mathieu-Rivet E, Mati-Baouche N, Calbo S, Lerouge P, Bardor M. Microalgae as an Efficient Vehicle for the Production and Targeted Delivery of Therapeutic Glycoproteins against SARS-CoV-2 Variants. Mar Drugs 2022; 20:md20110657. [PMID: 36354980 PMCID: PMC9698596 DOI: 10.3390/md20110657] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/27/2022] Open
Abstract
Severe acute respiratory syndrome–Coronavirus 2 (SARS-CoV-2) can infect various human organs, including the respiratory, circulatory, nervous, and gastrointestinal ones. The virus is internalized into human cells by binding to the human angiotensin-converting enzyme 2 (ACE2) receptor through its spike protein (S-glycoprotein). As S-glycoprotein is required for the attachment and entry into the human target cells, it is the primary mediator of SARS-CoV-2 infectivity. Currently, this glycoprotein has received considerable attention as a key component for the development of antiviral vaccines or biologics against SARS-CoV-2. Moreover, since the ACE2 receptor constitutes the main entry route for the SARS-CoV-2 virus, its soluble form could be considered as a promising approach for the treatment of coronavirus disease 2019 infection (COVID-19). Both S-glycoprotein and ACE2 are highly glycosylated molecules containing 22 and 7 consensus N-glycosylation sites, respectively. The N-glycan structures attached to these specific sites are required for the folding, conformation, recycling, and biological activity of both glycoproteins. Thus far, recombinant S-glycoprotein and ACE2 have been produced primarily in mammalian cells, which is an expensive process. Therefore, benefiting from a cheaper cell-based biofactory would be a good value added to the development of cost-effective recombinant vaccines and biopharmaceuticals directed against COVID-19. To this end, efficient protein synthesis machinery and the ability to properly impose post-translational modifications make microalgae an eco-friendly platform for the production of pharmaceutical glycoproteins. Notably, several microalgae (e.g., Chlamydomonas reinhardtii, Dunaliella bardawil, and Chlorella species) are already approved by the U.S. Food and Drug Administration (FDA) as safe human food. Because microalgal cells contain a rigid cell wall that could act as a natural encapsulation to protect the recombinant proteins from the aggressive environment of the stomach, this feature could be used for the rapid production and edible targeted delivery of S-glycoprotein and soluble ACE2 for the treatment/inhibition of SARS-CoV-2. Herein, we have reviewed the pathogenesis mechanism of SARS-CoV-2 and then highlighted the potential of microalgae for the treatment/inhibition of COVID-19 infection.
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Affiliation(s)
- Jaber Dehghani
- Université de Rouen Normandie, Laboratoire GlycoMEV UR 4358, SFR Normandie Végétal FED 4277, Innovation Chimie Carnot, F-76000 Rouen, France
| | - Ali Movafeghi
- Department of Plant, Cell and Molecular Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 5166616471, Iran
| | - Elodie Mathieu-Rivet
- Université de Rouen Normandie, Laboratoire GlycoMEV UR 4358, SFR Normandie Végétal FED 4277, Innovation Chimie Carnot, F-76000 Rouen, France
| | - Narimane Mati-Baouche
- Université de Rouen Normandie, Laboratoire GlycoMEV UR 4358, SFR Normandie Végétal FED 4277, Innovation Chimie Carnot, F-76000 Rouen, France
| | - Sébastien Calbo
- Université de Rouen Normandie, Inserm U1234, F-76000 Rouen, France
| | - Patrice Lerouge
- Université de Rouen Normandie, Laboratoire GlycoMEV UR 4358, SFR Normandie Végétal FED 4277, Innovation Chimie Carnot, F-76000 Rouen, France
| | - Muriel Bardor
- Université de Rouen Normandie, Laboratoire GlycoMEV UR 4358, SFR Normandie Végétal FED 4277, Innovation Chimie Carnot, F-76000 Rouen, France
- Correspondence: ; Tel.: +33-2-35-14-67-51
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29
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Chen L, Sun X, Han D, Zhong J, Zhang H, Zheng L. Visceral adipose tissue and risk of COVID-19 susceptibility, hospitalization, and severity: A Mendelian randomization study. Front Public Health 2022; 10:1023935. [PMID: 36339142 PMCID: PMC9634527 DOI: 10.3389/fpubh.2022.1023935] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/05/2022] [Indexed: 01/28/2023] Open
Abstract
Background Coronavirus Disease 2019 (COVID-19) has rapidly evolved as a global pandemic. Observational studies found that visceral adipose tissue (VAT) increased the likelihood of worse clinical outcomes in COVID-19 patients. Whereas, whether VAT is causally associated with the susceptibility, hospitalization, or severity of COVID-19 remains unconfirmed. We aimed to investigate the causal associations between VAT and susceptibility, hospitalization, and severity of COVID-19. Methods We applied a two-sample Mendelian randomization (MR) study to infer causal associations between VAT and COVID-19 outcomes. Single-nucleotide polymorphisms significantly associated with VAT were derived from a large-scale genome-wide association study. The random-effects inverse-variance weighted method was used as the main MR approach, complemented by three other MR methods. Additional sensitivity analyses were also performed. Results Genetically predicted higher VAT mass was causally associated with higher risks of COVID-19 susceptibility [odds ratios (ORs) = 1.13; 95% confidence interval (CI), 1.09-1.17; P = 4.37 × 10-12], hospitalization (OR = 1.51; 95% CI = 1.38-1.65; P = 4.14 × 10-20), and severity (OR = 1.58; 95% CI = 1.38-1.82; P = 7.34 × 10-11). Conclusion This study provided genetic evidence that higher VAT mass was causally associated with higher risks of susceptibility, hospitalization, and severity of COVID-19. VAT can be a useful tool for risk assessment in the general population and COVID-19 patients, as well as an important prevention target.
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Pisoschi AM, Iordache F, Stanca L, Gajaila I, Ghimpeteanu OM, Geicu OI, Bilteanu L, Serban AI. Antioxidant, Anti-inflammatory, and Immunomodulatory Roles of Nonvitamin Antioxidants in Anti-SARS-CoV-2 Therapy. J Med Chem 2022; 65:12562-12593. [PMID: 36136726 PMCID: PMC9514372 DOI: 10.1021/acs.jmedchem.2c01134] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Indexed: 11/28/2022]
Abstract
Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.
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Affiliation(s)
- Aurelia Magdalena Pisoschi
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
| | - Florin Iordache
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
| | - Loredana Stanca
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
| | - Iuliana Gajaila
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
| | - Oana Margarita Ghimpeteanu
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
| | - Ovidiu Ionut Geicu
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
- Faculty of Biology, Department Biochemistry and
Molecular Biology, University of Bucharest, 91-95 Splaiul
Independentei, 050095Bucharest, Romania
| | - Liviu Bilteanu
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
- Molecular Nanotechnology Laboratory,
National Institute for Research and Development in
Microtechnologies, 126A Erou Iancu Nicolae Street, 077190Bucharest,
Romania
| | - Andreea Iren Serban
- Faculty of Veterinary Medicine, Department Preclinical
Sciences, University of Agronomic Sciences and Veterinary Medicine of
Bucharest, 105 Splaiul Independentei, 050097Bucharest,
Romania
- Faculty of Biology, Department Biochemistry and
Molecular Biology, University of Bucharest, 91-95 Splaiul
Independentei, 050095Bucharest, Romania
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SARS-CoV-2 Variants, Current Vaccines and Therapeutic Implications for COVID-19. Vaccines (Basel) 2022; 10:vaccines10091538. [PMID: 36146616 PMCID: PMC9504858 DOI: 10.3390/vaccines10091538] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
Over the past two years, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of infections, resulting in an unprecedented pandemic of coronavirus disease 2019 (COVID-19). As the virus spreads through the population, ongoing mutations and adaptations are being discovered. There is now substantial clinical evidence that demonstrates the SARS-CoV-2 variants have stronger transmissibility and higher virulence compared to the wild-type strain of SARS-CoV-2. Hence, development of vaccines against SARS-CoV-2 variants to boost individual immunity has become essential. However, current treatment options are limited for COVID-19 caused by the SARS-CoV-2 variants. In this review, we describe current distribution, variation, biology, and clinical features of COVID-19 caused by SARS-CoV-2 variants (including Alpha (B.1.1.7 Lineage) variant, Beta (B.1.351 Lineage) variant, Gamma (P.1 Lineage) variant, Delta (B.1.617.2 Lineage) variant, and Omicron (B.1.1.529 Lineage) variant and others. In addition, we review currently employed vaccines in clinical or preclinical phases as well as potential targeted therapies in an attempt to provide better preventive and treatment strategies for COVID-19 caused by different SARS-CoV-2 variants.
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Zhou L, Chen Z, Jiang R, Hu Y, Zhu B, Yang C, Yang L, Liu C. Coronavirus Disease 2019 and Takotsubo Syndrome. Rev Cardiovasc Med 2022; 23:298. [PMID: 39077710 PMCID: PMC11262341 DOI: 10.31083/j.rcm2309298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/12/2022] [Accepted: 06/21/2022] [Indexed: 07/31/2024] Open
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global public health emergency. As the number of confirmed cases increases, cardiovascular complications, such as myocardial injury and cardiac dysfunction, are evidenced. Takotsubo syndrome (TTS), which is common in the intensive care unit, is diagnosed among COVID-19 patients. There have been 68 more cases reports with over 119 patients since a COVID-19 patient with TTS was first reported on April 14, 2020. Angiotensin-converting enzyme 2 (ACE2), which is widely expressed in the lungs and heart, is the virus receptor. Nevertheless, randomized studies on COVID-19 related TTS are lacking, and the pathogenesis and pathophysiology are still unclear. Therefore, this review provides an overview of the potential pathogenesis, pathophysiology, clinical manifestations, diagnosis, and treatment strategy for TTS in the COVID-19 era based on current practices.
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Affiliation(s)
- Ling Zhou
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China
| | - Zijun Chen
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China
| | - Riyue Jiang
- Department of Ultrasound Imaging, Renmin Hospital, Wuhan University, 430060 Wuhan, Hubei, China
| | - Yimin Hu
- Department of Anesthesiology, The Second Affiliated Changzhou People's Hospital of Nanjing Medical University, 213000 Changzhou, Jiangsu, China
| | - Bin Zhu
- Department of Critical Care Medicine, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China
| | - Chun Yang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China
| | - Ling Yang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China
| | - Cunming Liu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China
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Khaledi M, Sameni F, Yahyazade S, Radandish M, Owlia P, Bagheri N, Afkhami H, Mahjoor M, Esmaelpour Z, Kohansal M, Aghaei F. COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy. Front Med (Lausanne) 2022; 9:961027. [PMID: 36111104 PMCID: PMC9469902 DOI: 10.3389/fmed.2022.961027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Recent evidence proposed that the severity of the coronavirus disease 2019 (COVID-19) in patients is a consequence of cytokine storm, characterized by increased IL-1β, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing the cytokine storm by drugs has been suggested for the treatment of patients with severe COVID-19. Several of the proinflammatory cytokines involved in the pathogenesis of COVID-19 infection recruit a distinct intracellular signaling pathway mediated by JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, and tofacitinib, may represent an effective therapeutic strategy for controlling the JAK to treat COVID-19. This study indicates the mechanism of cytokine storm and JAK/STAT pathway in COVID-19 as well as the medications used for JAK/STAT inhibitors.
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Affiliation(s)
- Mansoor Khaledi
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Fatemeh Sameni
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Sheida Yahyazade
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maedeh Radandish
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parviz Owlia
- Molecular Microbiology Research Center, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Parviz Owlia ;
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Nader Bagheri
| | | | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Esmaelpour
- Reference Laboratory for Bovine Tuberculosis, Razi Vaccine and Serum Research Institute, Karaj, Iran
| | - Maryam Kohansal
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzad Aghaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Ning L, Liu M, Gou Y, Yang Y, He B, Huang J. Development and application of ribonucleic acid therapy strategies against COVID-19. Int J Biol Sci 2022; 18:5070-5085. [PMID: 35982905 PMCID: PMC9379410 DOI: 10.7150/ijbs.72706] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/16/2022] [Indexed: 11/17/2022] Open
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), remaining a global health crisis since its outbreak until now. Advanced biotechnology and research findings have revealed many suitable viral and host targets for a wide range of therapeutic strategies. The emerging ribonucleic acid therapy can modulate gene expression by post-transcriptional gene silencing (PTGS) based on Watson-Crick base pairing. RNA therapies, including antisense oligonucleotides (ASO), ribozymes, RNA interference (RNAi), aptamers, etc., were used to treat SARS-CoV whose genome is similar to SARV-CoV-2, and the past experience also applies for the treatment of COVID-19. Several studies against SARS-CoV-2 based on RNA therapeutic strategy have been reported, and a dozen of relevant preclinical or clinical trials are in process globally. RNA therapy has been a very active and important part of COVID-19 treatment. In this review, we focus on the progress of ribonucleic acid therapeutic strategies development and application, discuss corresponding problems and challenges, and suggest new strategies and solutions.
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Affiliation(s)
- Lin Ning
- School of Healthcare Technology, Chengdu Neusoft University, Sichuan, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
| | - Mujiexin Liu
- Ineye Hospital of Chengdu University of TCM, Sichuan, China
| | - Yushu Gou
- School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
| | - Yue Yang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
| | - Bifang He
- Medical College, Guizhou University, Guizhou, China
| | - Jian Huang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
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Kjertakov M. Commentary: Moderate exercise may prevent the development of severe forms of COVID-19, whereas high-intensity exercise may result in the opposite. Front Physiol 2022; 13:902739. [PMID: 36072850 PMCID: PMC9441653 DOI: 10.3389/fphys.2022.902739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022] Open
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Computational Analysis of Short Linear Motifs in the Spike Protein of SARS-CoV-2 Variants Provides Possible Clues into the Immune Hijack and Evasion Mechanisms of Omicron Variant. Int J Mol Sci 2022; 23:ijms23158822. [PMID: 35955954 PMCID: PMC9368778 DOI: 10.3390/ijms23158822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/29/2022] [Accepted: 08/05/2022] [Indexed: 11/22/2022] Open
Abstract
Short linear motifs (SLiMs) are short linear sequences that can mediate protein–protein interaction. Mimicking eukaryotic SLiMs to compete with extra- or intracellular binding partners, or to sequester host proteins is the crucial strategy of viruses to pervert the host system. Evolved proteins in viruses facilitate minimal protein–protein interactions that significantly affect intracellular signaling networks. Unfortunately, very little information about SARS-CoV-2 SLiMs is known, especially across SARS-CoV-2 variants. Through the ELM database-based sequence analysis of spike proteins from all the major SARS-CoV-2 variants, we identified four overriding SLiMs in the SARS-CoV-2 Omicron variant, namely, LIG_TRFH_1, LIG_REV1ctd_RIR_1, LIG_CaM_NSCaTE_8, and MOD_LATS_1. These SLiMs are highly likely to interfere with various immune functions, interact with host intracellular proteins, regulate cellular pathways, and lubricate viral infection and transmission. These cellular interactions possibly serve as potential therapeutic targets for these variants, and this approach can be further exploited to combat emerging SARS-CoV-2 variants.
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Govender N, Khaliq O, Moodley J, Naicker T. Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension: A Risk Factor for COVID-19. Curr Hypertens Rev 2022; 18:130-137. [PMID: 36508271 DOI: 10.2174/1573402118666220816090809] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19. METHODS AND RESULTS Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa. CONCLUSION Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.
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Affiliation(s)
- Nalini Govender
- Department of Basic Medical Sciences, Faculty of Health Sciences, Durban University of Technology, Durban 4001, South Africa
| | - Olive Khaliq
- The Department of Paediatrics and Child Health, Faculty of Health Sciences, The University of the Free State, Bloemfontein 9300, South Africa
| | - Jagidesa Moodley
- Women's Health and HIV Research Group, Department of Obstetrics and Gynaecology, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
| | - Thajasvarie Naicker
- Optics & Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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Li Y, Xiao P, Liu N, Zhang Z. Efficacy and Safety of Chinese Medicine Lianhua Qingwen for Treating COVID-19: An Updated meta-Analysis. Front Pharmacol 2022; 13:888820. [PMID: 35721166 PMCID: PMC9204491 DOI: 10.3389/fphar.2022.888820] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/19/2022] [Indexed: 12/14/2022] Open
Abstract
The traditional Chinese medicine formula Lianhua Qingwen (LQ) combined with western medicine therapy is beneficial to coronavirus disease-19 (COVID-19), but there is still a lack of strong evidence-based. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LQ combined with western medicine for patients with COVID-19. Seven databases (Chinese and English) were searched by two independent reviewers. Search for relevant keywords such as “Chinese medicine,” “Chinese herbal medicine,” and “Lianhua Qingwen” in the titles and abstracts of articles retrieved in the databases. Randomized controlled trials or case-control studies that reported sufficient data of participants before and after the intervention were included. Two researchers independently reviewed the studies and extracted the data. Fixed-or random-effect model was used to calculate the overall pooled risk estimates. Forest plots were generated to show pooled results. Seven studies involving 916 participants were included in the meta-analysis. Overall, compared with the control group, the total efficacy (OR = 2.23, 95% CI 1.56, 3.18), adverse events (OR = 0.42, 95% CI 0.18, 0.97), chest computed tomography manifestations (OR = 1.74, 95% CI 1.12, 2.72), and aggravation rate of conversion to severe cases (OR = 0.47, 95% CI 0.30, 0.75) of the intervention group were better. Moreover, the intervention group has an advantage over the control group in improving clinical symptoms (fever, cough, fatigue, chest tightness, shortness of breath, and expectoration) and shortening the fever duration (p < 0.05). Our findings indicate that LQ combined with western medicine may be more effective in treating COVID-19. However, due to the urgency of SARS-CoV-2 outbreaks leading to low methodological quality and not rigorous designs. This meta-analysis cannot draw clear conclusions. PROSPERO registration number: CRD42020190757
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Affiliation(s)
- Yapeng Li
- Rehabilitation Therapy Center, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, China
| | - Peng Xiao
- Medical Experimental Research Center, Orthopedic Institute of Henan Province, Luoyang, China
| | - Nanyang Liu
- Department of Geratology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhijie Zhang
- Rehabilitation Therapy Center, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, China
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Pouremamali A, Babaei A, Malekshahi SS, Abbasi A, Rafiee N. Understanding the pivotal roles of ACE2 in SARS-CoV-2 infection: from structure/function to therapeutic implication. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022; 23:103. [PMID: 37521846 PMCID: PMC9206724 DOI: 10.1186/s43042-022-00314-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/12/2022] [Indexed: 01/08/2023] Open
Abstract
In December 2019, a novel respiratory tract infection, from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in China that rapidly spread around the world. This virus possesses spike (S) glycoproteins on the surface of mature virions, like other members of coronaviridae. The S glycoprotein is a crucial viral protein for binding, fusion, and entry into the target cells. Binding the receptor-binding domain (RBD) of S protein to angiotensin-converting enzyme 2 (ACE 2), a cell-surface receptor, mediates virus entry into cells; thus, understanding the basics of ACE2 and S protein, their interactions, and ACE2 targeting could be a potent priority for inhibition of virus infection. This review presents current knowledge of the SARS-CoV-2 basics and entry mechanism, structure and organ distribution of ACE2, and also its function in SARS-CoV-2 entry and pathogenesis. Furthermore, it highlights ACE2 targeting by recombinant ACE2 (rACE2), ACE2 activators, ACE inhibitor, and angiotensin II (Ang II) receptor blocker to control the SARS-CoV-2 infection.
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Affiliation(s)
- Amir Pouremamali
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abouzar Babaei
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nastaran Rafiee
- Department of Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Gastrointestinal Involvement in SARS-CoV-2 Infection. Viruses 2022; 14:v14061188. [PMID: 35746659 PMCID: PMC9228950 DOI: 10.3390/v14061188] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
SARS-CoV-2 has evolved into a virus that primarily results in mild or asymptomatic disease, making its transmission more challenging to control. In addition to the respiratory tract, SARS-CoV-2 also infects the digestive tract. Some gastrointestinal symptoms occur with or before respiratory symptoms in patients with COVID-19. Respiratory infections are known to cause intestinal immune impairment and gastrointestinal symptoms. When the intestine is inflamed, cytokines affect the lung immune response and inflammation through blood circulation. The gastrointestinal microbiome may be a modifiable factor in determining the risk of SARS-CoV-2 infection and disease severity. The development of oral SARS-CoV-2 vaccine candidates and the maintenance of gut microbiota profiles may contribute to the early control of COVID-19 outbreaks. To this end, this review summarizes information on the gastrointestinal complications caused by SARS-CoV-2, SARS-CoV-2 infection, the gastrointestinal–lung axis immune response, potential control strategies for oral vaccine candidates and maintaining intestinal microbiota homeostasis.
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Demyashkin G, Gorokhov K, Zorin I, Shchekin V, Shegay P, Kaprin A. Angiotensin-Converting Enzyme 2 and Furin Expression in the Appendix of Children with COVID-19. Surg Infect (Larchmt) 2022; 23:470-474. [PMID: 35612424 DOI: 10.1089/sur.2021.311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: The sudden outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in more than 261 million infections and an estimated 5.1 million deaths. Some vital organs such as the kidneys, heart, intestines, and lungs could be damaged by SARS-CoV-2. Questions remain regarding the effect of SARS-CoV-2 on the mucous membrane of the appendix in children. The aim of this study was to evaluate the knowledge of cytologic processes in appendix tissue in children with coronavirus disease 2019 (COVID-19). Patients and Methods: Fragments of the appendices of children with confirmed COVID-19 (n = 42) were studied by real-time polymerase chain reaction (PCR) to determine the expression of SARS-CoV-2 RNA and genes encoding protein complexes: ACE-2 and Furin. Results: We found traces of coronavirus genetic material in the appendices of children with COVID-19. We also found increased expression of ACE-2 and Furin in the tissue, which indicates favorable conditions for coronavirus infection. Conclusions: Viral load in the appendices of children can be reported based on the results of real-time PCR for SARS-CoV-2 and the expression of ACE-2 and Furin.
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Affiliation(s)
- Grigory Demyashkin
- Department of Pathomorphology, National Medical Research Center of 8Radiology, Obninsk, Russia
- Institute of Translational Medicine, Sechenov University, Moscow, Russia
| | - Konstantin Gorokhov
- Department of Pathomorphology, National Medical Research Center of 8Radiology, Obninsk, Russia
| | - Ilya Zorin
- Institute of Clinical Medicine named after N.V. Sklifosovsky, Sechenov University, Moscow, Russia
| | - Vladimir Shchekin
- Institute of Clinical Medicine named after N.V. Sklifosovsky, Sechenov University, Moscow, Russia
| | - Petr Shegay
- Centre of Innovational Radiological and Regenerative Technologies, National Medical Research Center of Radiology, Obninsk, Russia
| | - Andrei Kaprin
- Department of Oncology, Academician of the Russian Academy of Sciences, Moscow, Russia
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Yang S, Tong Y, Chen L, Yu W. Human Identical Sequences, hyaluronan, and hymecromone ─ the new mechanism and management of COVID-19. MOLECULAR BIOMEDICINE 2022; 3:15. [PMID: 35593963 PMCID: PMC9120813 DOI: 10.1186/s43556-022-00077-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/04/2022] [Indexed: 02/08/2023] Open
Abstract
COVID-19 caused by SARS-CoV-2 has created formidable damage to public health and market economy. Currently, SARS-CoV-2 variants has exacerbated the transmission from person-to-person. Even after a great deal of investigation on COVID-19, SARS-CoV-2 is still rampaging globally, emphasizing the urgent need to reformulate effective prevention and treatment strategies. Here, we review the latest research progress of COVID-19 and provide distinct perspectives on the mechanism and management of COVID-19. Specially, we highlight the significance of Human Identical Sequences (HIS), hyaluronan, and hymecromone ("Three-H") for the understanding and intervention of COVID-19. Firstly, HIS activate inflammation-related genes to influence COVID-19 progress through NamiRNA-Enhancer network. Accumulation of hyaluronan induced by HIS-mediated HAS2 upregulation is a substantial basis for clinical manifestations of COVID-19, especially in lymphocytopenia and pulmonary ground-glass opacity. Secondly, detection of plasma hyaluronan can be effective for evaluating the progression and severity of COVID-19. Thirdly, spike glycoprotein of SARS-CoV-2 may bind to hyaluronan and further serve as an allergen to stimulate allergic reaction, causing sudden adverse effects after vaccination or the aggravation of COVID-19. Finally, antisense oligonucleotides of HIS or inhibitors of hyaluronan synthesis (hymecromone) or antiallergic agents could be promising therapeutic agents for COVID-19. Collectively, Three-H could hold the key to understand the pathogenic mechanism and create effective therapeutic strategies for COVID-19.
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Affiliation(s)
- Shuai Yang
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China
| | - Ying Tong
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China
| | - Lu Chen
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China
| | - Wenqiang Yu
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China.
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Immunosuppressant Therapies in COVID-19: Is the TNF Axis an Alternative? Pharmaceuticals (Basel) 2022; 15:ph15050616. [PMID: 35631442 PMCID: PMC9147078 DOI: 10.3390/ph15050616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 02/05/2023] Open
Abstract
The study of cytokine storm in COVID-19 has been having different edges in accordance with the knowledge of the disease. Various cytokines have been the focus, especially to define specific treatments; however, there are no conclusive results that fully support any of the options proposed for emergency treatment. One of the cytokines that requires a more exhaustive review is the tumor necrosis factor (TNF) and its receptors (TNFRs) as increased values of soluble formats for both TNFR1 and TNFR2 have been identified. TNF is a versatile cytokine with different impacts at the cellular level depending on the action form (transmembrane or soluble) and the receptor to which it is associated. In that sense, the triggered mechanisms can be diversified. Furthermore, there is the possibility of the joint action provided by synergism between one or more cytokines with TNF, where the detonation of combined cellular processes has been suggested. This review aims to discuss some roles of TNF and its receptors in the pro-inflammatory stage of COVID-19, understand its ways of action, and let to reposition this cytokine or some of its receptors as therapeutic targets.
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Hochuli JE, Jain S, Melo-filho C, Sessions ZL, Bobrowski T, Choe J, Zheng J, Eastman R, Talley DC, Rai G, Simeonov A, Tropsha A, Muratov EN, Baljinnyam B, Zakharov AV. Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents.. [PMID: 35313579 PMCID: PMC8936107 DOI: 10.1101/2022.03.15.484484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
AbstractThe COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2’s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection.Abstract FigureTOC Graphic: Overall study design.
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Zhao S, Feng P, Meng W, Jin W, Li X, Li X. Modulated Gut Microbiota for Potential COVID-19 Prevention and Treatment. Front Med (Lausanne) 2022; 9:811176. [PMID: 35308540 PMCID: PMC8927624 DOI: 10.3389/fmed.2022.811176] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained global attention. SARS-CoV-2 identifies and invades human cells via angiotensin-converting enzyme 2 receptors, which is highly expressed both in lung tissues and intestinal epithelial cells. The existence of the gut-lung axis in disease could be profoundly important for both disease etiology and treatment. Furthermore, several studies reported that infected patients suffer from gastrointestinal symptoms. The gut microbiota has a noteworthy effect on the intestinal barrier and affects many aspects of human health, including immunity, metabolism, and the prevention of several diseases. This review highlights the function of the gut microbiota in the host's immune response, providing a novel potential strategy through the use of probiotics, gut microbiota metabolites, and dietary products to enhance the gut microbiota as a target for COVID-19 prevention and treatment.
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Affiliation(s)
- Shuai Zhao
- Intersection Laboratory of Life Medicine, School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Pengya Feng
- Intersection Laboratory of Life Medicine, School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Wenbo Meng
- Medical Frontier Innovation Research Center, Institute of Cancer Neuroscience, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Weilin Jin
- Medical Frontier Innovation Research Center, Institute of Cancer Neuroscience, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xun Li
- Medical Frontier Innovation Research Center, Institute of Cancer Neuroscience, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xiangkai Li
- Intersection Laboratory of Life Medicine, School of Life Sciences, Lanzhou University, Lanzhou, China
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Jain M, Vadboncoeur J, Garg SJ, Biswas J. Bacille Calmette-Guérin: An ophthalmic perspective. Surv Ophthalmol 2022; 67:307-320. [PMID: 34343536 PMCID: PMC8325561 DOI: 10.1016/j.survophthal.2021.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 01/20/2023]
Abstract
Vaccines such as bacille Calmette-Guérin (BCG) are known for their heterologous effects mediated through a number of mechanisms, including trained immunity constituted by monocyte-macrophage based innate immunity. Other events such as direct hematogenous spread and induction of autoimmunity are also described. There has been a resurgent interest in harnessing some of the benefits of trained immunity in the management of COVID-19, even as several specific vaccines have been approved. We summarize the current knowledge of ocular effects of BCG. Potential effect of granulomatous inflammation on angiotensin converting enzyme activity and accentuation of cytokine storm that may result in undesirable ocular and systemic effects are also discussed.
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Affiliation(s)
- Manish Jain
- Himalayan Institute of Medical Sciences, Jolly Grant, Dehradun, UK, India
| | - Julie Vadboncoeur
- Department of Ophthalmology, Université de Montréal, Montréal, Uveitis Service, University Ophthalmology Center, Maisonneuve-Rosemont Hospital, Montréal, Canada
| | - Sunir J Garg
- Thomas Jefferson University, Philadelphia, PA USA
| | - Jyotirmay Biswas
- Director of Uveitis & Ocular Pathology Department, Sankara Nethralaya, Chennai, TN, India
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Forero‐Peña DA, Hernandez MM, Mozo Herrera IP, Collado Espinal IB, Páez Paz J, Ferro C, Flora‐Noda DM, Maricuto AL, Velásquez VL, Camejo‐Avila NA, Sordillo EM, Delgado‐Noguera LA, Perez‐Garcia LA, Morantes Rodríguez CG, Landaeta ME, Paniz‐Mondolfi AE. Remitting neuropsychiatric symptoms in COVID-19 patients: Viral cause or drug effect? J Med Virol 2022; 94:1154-1161. [PMID: 34755347 PMCID: PMC8661670 DOI: 10.1002/jmv.27443] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 01/05/2023]
Abstract
Numerous reports of neuropsychiatric symptoms highlighted the pathologic potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relationship the onset and/or exacerbation of mental disease. However, coronavirus disease 2019 (COVID-19) treatments, themselves, must be considered as potential catalysts for new-onset neuropsychiatric symptoms in COVID-19 patients. To date, immediate and long-term neuropsychiatric complications following SARS-CoV-2 infection are currently unknown. Here we report on five patients with SARS-CoV-2 infection with possible associated neuropsychiatric involvement, following them clinically until resolution of their symptoms. We will also discuss the contributory roles of chloroquine and dexamethasone in these neuropsychiatric presentations.
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Affiliation(s)
- David A. Forero‐Peña
- Department of Infectious DiseasesUniversity Hospital of CaracasCaracasVenezuela
- Department of Infectious DiseasesBiomedical Research and Therapeutic Vaccines InstituteCiudadBolivarVenezuela
| | - Matthew M. Hernandez
- Department of Pathology, Molecular and Cell‐based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | | | | | - Joselyn Páez Paz
- Psychiatry DepartmentUniversity Military Hospital ″Dr. Carlos Arvelo ″CaracasVenezuela
| | - Carlos Ferro
- Psychiatry DepartmentUniversity Hospital of CaracasCaracasVenezuela
| | - David M. Flora‐Noda
- Department of Infectious DiseasesUniversity Hospital of CaracasCaracasVenezuela
| | - Andrea L. Maricuto
- Department of Infectious DiseasesUniversity Hospital of CaracasCaracasVenezuela
| | - Viledy L. Velásquez
- Department of Infectious DiseasesUniversity Hospital of CaracasCaracasVenezuela
| | - Natasha A. Camejo‐Avila
- Department of Infectious DiseasesBiomedical Research and Therapeutic Vaccines InstituteCiudadBolivarVenezuela
| | - Emilia M. Sordillo
- Department of Pathology, Molecular and Cell‐based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Lourdes A. Delgado‐Noguera
- Instituto de Investigaciones Biomédicas IDB/Emerging Pathogens Network‐Incubadora Venezolana de la CienciaCabudareVenezuela
| | - Luis A. Perez‐Garcia
- Instituto de Investigaciones Biomédicas IDB/Emerging Pathogens Network‐Incubadora Venezolana de la CienciaCabudareVenezuela
| | | | | | - Alberto E. Paniz‐Mondolfi
- Department of Pathology, Molecular and Cell‐based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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Rezabakhsh A, Sadat‐Ebrahimi S, Ala A, Nabavi SM, Banach M, Ghaffari S. A close-up view of dynamic biomarkers in the setting of COVID-19: Striking focus on cardiovascular system. J Cell Mol Med 2022; 26:274-286. [PMID: 34894069 PMCID: PMC8743667 DOI: 10.1111/jcmm.17122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 10/15/2021] [Accepted: 12/01/2021] [Indexed: 01/08/2023] Open
Abstract
Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.
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Affiliation(s)
- Aysa Rezabakhsh
- Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Alireza Ala
- Emergency Medicine Research TeamTabriz University of Medical SciencesTabrizIran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research CenterBaqiyatallah University of Medical SciencesTehranIran
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and HypertensionMedical University of LodzLodzPoland
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI)LodzPoland
| | - Samad Ghaffari
- Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
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49
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Wong CKH, Lui DTW, Lui AYC, Low MCH, Kwok ACY, Lau KTK, Au ICH, Xiong X, Chung MSH, Lau EHY, Cowling BJ. Metformin Use in Relation to Clinical Outcomes and Hyperinflammatory Syndrome Among COVID-19 Patients With Type 2 Diabetes: A Propensity Score Analysis of a Territory-Wide Cohort. Front Endocrinol (Lausanne) 2022; 13:810914. [PMID: 35321338 PMCID: PMC8935075 DOI: 10.3389/fendo.2022.810914] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/25/2022] [Indexed: 01/08/2023] Open
Abstract
AIM This study was conducted in order to evaluate the association between metformin use and clinical outcomes in type 2 diabetes mellitus (T2DM) patients hospitalized with coronavirus disease 2019 (COVID-19). METHODS Patients with T2DM with confirmed diagnosis of COVID-19 and admitted between January 21, 2020, and January 31, 2021 in Hong Kong were identified in our cohort. Exposure was defined as metformin use within 90 days prior to admission until hospital discharge for COVID-19. Primary outcome was defined as clinical improvement of ≥1 point on the WHO Clinical Progression Scale (CPS). Other outcomes were hospital discharge, recovery, in-hospital death, acidosis, hyperinflammatory syndrome, length of hospitalization, and changes in WHO CPS score. RESULTS Metformin use was associated with greater odds of clinical improvement (OR = 2.74, p = 0.009), hospital discharge (OR = 2.26, p = 0.009), and recovery (OR = 2.54, p = 0.005), in addition to lower odds of hyperinflammatory syndrome (OR = 0.71, p = 0.021) and death (OR = 0.41, p = 0.010) than control. Patients on metformin treatment had a shorter hospital stay (-2.76 days, p = 0.017) than their control counterparts. The average WHO CPS scores were significantly lower in metformin users than non-users since day 15 (p < 0.001). However, metformin use was associated with higher odds of acidosis. CONCLUSIONS Metformin use was associated with lower mortality and lower odds for hyperinflammatory syndrome. This provides additional insights into the potential mechanisms of the benefits of metformin use in T2DM patients with COVID-19.
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Affiliation(s)
- Carlos K. H. Wong
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Family Medicine and Primary Care, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health Limited, Hong Kong SAR, China
- *Correspondence: Carlos K. H. Wong,
| | - David T. W. Lui
- Division of Endocrinology and Metabolism, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Angel Y. C. Lui
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Marshall C. H. Low
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ashley C. Y. Kwok
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kristy T. K. Lau
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ivan C. H. Au
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xi Xiong
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Matthew S. H. Chung
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Eric H. Y. Lau
- Laboratory of Data Discovery for Health Limited, Hong Kong SAR, China
- World Health Organization (WHO) Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Benjamin J. Cowling
- Laboratory of Data Discovery for Health Limited, Hong Kong SAR, China
- World Health Organization (WHO) Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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50
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Implications of testicular ACE2 and the renin-angiotensin system for SARS-CoV-2 on testis function. Nat Rev Urol 2022; 19:116-127. [PMID: 34837081 PMCID: PMC8622117 DOI: 10.1038/s41585-021-00542-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2021] [Indexed: 12/16/2022]
Abstract
Although many studies have focused on SARS-CoV-2 infection in the lungs, comparatively little is known about the potential effects of the virus on male fertility. SARS-CoV-2 infection of target cells requires the presence of furin, angiotensin-converting enzyme 2 (ACE2) receptors, and transmembrane protease serine 2 (TMPRSS2). Thus, cells in the body that express these proteins might be highly susceptible to viral entry and downstream effects. Currently, reports regarding the expression of the viral entry proteins in the testes are conflicting; however, other members of the SARS-CoV family of viruses - such as SARS-CoV - have been suspected to cause testicular dysfunction and/or orchitis. SARS-CoV-2, which displays many similarities to SARS-CoV, could potentially cause similar adverse effects. Commonalities between SARS family members, taken in combination with sparse reports of testicular discomfort and altered hormone levels in patients with SARS-CoV-2, might indicate possible testicular dysfunction. Thus, SARS-CoV-2 infection has the potential for effects on testis somatic and germline cells and experimental approaches might be required to help identify potential short-term and long-term effects of SARS-CoV-2 on male fertility.
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