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      Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19

      review-article
      a , b , * , c , d , a , e , f , g , h , i , j , i , k , b , d , l , m , n , o , p , q , r , s , t , u , v , w , x , y , z , A , B , C , D , E , F , G , H , I , J , k , K , L , M , N , u , O , P , Q , i , j , R , S
      International Archives of Allergy and Immunology
      S. Karger AG
      COVID-19, Nrf2, TRAP-1, Broccoli, Pungent foods, Cough challenge

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          Abstract

          In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.

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          Most cited references194

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          Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis

          Summary Background The prevalence and prognosis of digestive system involvement, including gastrointestinal symptoms and liver injury, in patients with COVID-19 remains largely unknown. We aimed to quantify the effects of COVID-19 on the digestive system. Methods In this systematic review and meta-analysis, we systematically searched PubMed, Embase, and Web of Science for studies published between Jan 1, 2020, and April 4, 2020. The websites of WHO, CDC, and major journals were also searched. We included studies that reported the epidemiological and clinical features of COVID-19 and the prevalence of gastrointestinal findings in infected patients, and excluded preprints, duplicate publications, reviews, editorials, single case reports, studies pertaining to other coronavirus-related illnesses, and small case series (<10 cases). Extracted data included author; date; study design; country; patient demographics; number of participants in severe and non-severe disease groups; prevalence of clinical gastrointestinal symptoms such as vomiting, nausea, diarrhoea, loss of appetite, abdominal pain, and belching; and digestive system comorbidities including liver disease and gastrointestinal diseases. Raw data from studies were pooled to determine effect estimates. Findings We analysed findings from 35 studies, including 6686 patients with COVID-19, that met inclusion criteria. 29 studies (n=6064) reported gastrointestinal symptoms in patients with COVID-19 at diagnosis, and the pooled prevalence of digestive system comorbidities was 4% (95% CI 2–5; range 0–15; I 2=74%). The pooled prevalence of digestive symptoms was 15% (10–21; range: 2–57; I 2=96%) with nausea or vomiting, diarrhoea, and loss of appetite being the three most common symptoms. The pooled prevalence of abnormal liver functions (12 studies, n=1267) was 19% (9–32; range 1–53; I 2=96%). Subgroup analysis showed patients with severe COVID-19 had higher rates of gastrointestinal symptoms (odds ratio [OR] 1·60 [95% CI 1·09–2·36]; p=0·0020; I 2=44%) and liver injury (2·20 [1·60–3·02]; p<0·00001; I 2=36%) compared with those with non-severe disease. Patients in Hubei province, where the initial COVID-19 outbreak occurred, were more likely to present with abnormal liver functions (p<0·0001) compared with those outside of Hubei. Paediatric patients with COVID-19 had a similar prevalence of gastrointestinal symptoms to those of adult patients. 10% (95% CI 4–19; range 3–23; I 2=97%) of patients presented with gastrointestinal symptoms alone without respiratory features. Patients who presented with gastrointestinal system involvement had delayed diagnosis (standardised mean difference 2·85 [95% CI 0·22–5·48]; p=0·030; I 2=73%). Patients with gastrointestinal involvement had a higher prevalence of complication (OR 2·51 [95% CI 1·62–3·89]; p<0·0001; I 2=0%). Interpretation Our study showed that digestive symptoms and liver injury are not uncommon in patients with COVID-19. Increased attention should be paid to the care of this unique group of patients. Funding None.
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            Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

            Abstract: Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) – the causal agent in COVID-19 – affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.
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              Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis

              Highlights • Fever and cough are the most common symptoms in patients with COVID-19. • The most prevalent comorbidities are hypertension and diabetes which are associated with the severity of COVID-19. • ARDS and ACI may be the main obstacles to treatment recovery for patients. • The case severe rate and mortality is lower than that of SARS and MERS.
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                Author and article information

                Journal
                Int Arch Allergy Immunol
                Int Arch Allergy Immunol
                IAA
                International Archives of Allergy and Immunology
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1018-2438
                1423-0097
                10 February 2021
                : 182
                : 4
                : 324-338
                Affiliations
                [1] aDepartment of Dermatology and Allergy, Comprehensive Allergy Center, Charité, and Berlin Institute of Health, Comprehensive Allergy Center, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
                [01] ADivision of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland
                [2] bUniversity Hospital and MACVIA France, Montpellier, France
                [02] BCenter of Excellence in Asthma and Allergy, Médica Sur Clinical Foundation and Hospital, Mexico City, Mexico
                [3] cMedical Consulting Czarlewski, Levallois, France
                [03] CInstitute for Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
                [4] dMASK-air, Montpellier, France
                [04] DInstitute of Environmental Medicine, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden
                [5] eRhinology Unit & Smell Clinic, ENT Department, Hospital Clinic - Clinical & Experimental Respiratory Immunoallergy, IDIBAPS, CIBERES, Universitat de Barcelona, Barcelona, Spain
                [05] EDepartment of Otorhinolaryngology, Chiba University Hospital, Chiba, Japan
                [6] fDepartment of Geriatrics, Montpellier University Hospital, Montpellier, France
                [06] FDivision of Infection, Immunity & Respiratory Medicine, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom
                [7] gLaboratoire de Biochimie et Hormonologie, PhyMedExp, Université de Montpellier, INSERM, CNRS, CHU de, Montpellier, France
                [07] GAllergy Department, 2nd Pediatric Clinic, Athens General Children's Hospital “P&A Kyriakou,” University of Athens, Athens, Greece
                [8] hCIBER Fisiopatologia de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
                [08] HSection of Rhinology and Allergy, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
                [9] iIMIM (Hospital del Mar Research Institute), Barcelona, Spain
                [09] IAllergy and Clinical Immunology Unit, Centro Hospitalar e Universitário de Coimbra, Faculty of Medicine, Institute of Immunology, University of Coimbra, Coimbra, Portugal
                [10] jDepartament de Ciències Experimentals i de la Salut Toxicologia, Universitat Pompeu Fabra (UPF), Barcelona, Spain
                [010] JFaculty of Medicine, ICBR - Institute for Clinical and Biomedical Research, CIBB, University of Coimbra, Coimbra, Portugal
                [11] kMaladies Infectieuses et Tropicales, CHU, Montpellier, France
                [011] KCHU Toulouse, Toulouse, France
                [12] lFaculty of Medicine, Transylvania University, Brasov, Romania
                [012] LDepartment of Otolaryngology-Head and Neck Surgery, Eye and Ear University Hospital, Beirut, Lebanon
                [13] mChristine Kühne - Center for Allergy Research and Education (CK-CARE), Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Zurich, Switzerland
                [013] MDepartment of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland
                [14] nPersonalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS and Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
                [014] NUsher Institute, The University of Edinburgh, Edinburgh, United Kingdom
                [15] oFundação ProAR, Federal University of Bahia and GARD/WHO Planning Group, Salvador, Brazil
                [015] OVilnius University Faculty of Medicine, Institute of Clinical Medicine & Institute of Health Sciences, Vilnius, Lithuania
                [16] pDivision of Allergy, The Bambino Gesù Children's Research Hospital IRCCS, Rome, Italy
                [016] PResearch and Development Division, Microbiology and Functionality Research Group, World Institute of Kimchi, Gwangju, Republic of Korea
                [17] qCINTESIS, Center for Research in Health Technologies and Information Systems, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
                [017] QStrategy and Planning Division, SME Service Department, World Institute of Kimchi, Gwangju, Republic of Korea
                [18] rMEDIDA, Lda, Porto, Portugal
                [018] RCIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
                [19] sGreenUPorto - Sustainable Agrifood Production Research Centre, DGAOT, Faculty of Sciences, University of Porto, Vila do Conde, Portugal
                [019] SISGlobAL, Barcelona, Centre for Research in Environmental Epidemiology, Barcelona, Spain
                [20] tDepartment of Pulmonary Diseases, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Turkey
                [21] uSkin and Allergy Hospital, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland
                [22] vInterdepartmental Center of Research on Hypertension and Related Conditions CIRIAPA, Federico II University, Napoli, Italy
                [23] wServicio de Alergia e Immunologia, Clinica Santa Isabel, Buenos Aires, Argentina
                [24] xDepartment of Clinical Immunology, Wrocław Medical University and ALL-MED Medical Research Institute, Wrocław, Poland
                [25] yCenter for Rhinology and Allergology, Wiesbaden, Germany
                [26] zDepartment of Otorhinolaryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary
                Author notes
                *Jean Bousquet, Department of Allergology, Macvia France, 273 Avenue d'Occitanie, FR–34090 Montpellier (France), jean.bousquet@ 123456orange.fr

                Edited by: H.-U. Simon, Bern.

                Article
                iaa-0182-0324
                10.1159/000514204
                8018185
                33567446
                78cc3e9c-c4aa-47b3-a985-b38b66a7617b
                Copyright © 2021 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 3 December 2020
                : 15 December 2020
                : 2021
                Page count
                Figures: 2, Tables: 1, References: 196, Pages: 15
                Categories
                Clinical Immunology − Review Article

                Immunology
                covid-19,nrf2,trap-1,broccoli,pungent foods,cough challenge
                Immunology
                covid-19, nrf2, trap-1, broccoli, pungent foods, cough challenge

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