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1.
IUBMB Life ; 74(1): 62-73, 2022 01.
Article in English | MEDLINE | ID: covidwho-1850068

ABSTRACT

Airborne pollution has become a leading cause of global death in industrialized cities and the exposure to environmental pollutants has been demonstrated to have adverse effects on human health. Among the pollutants, particulate matter (PM) is one of the most toxic and although its exposure has been more commonly correlated with respiratory diseases, gastrointestinal (GI) complications have also been reported as a consequence to PM exposure. Due to its composition, PM is able to exert on intestinal mucosa both direct damaging effects, (by reaching it either via direct ingestion of contaminated food and water or indirect inhalation and consequent macrophagic mucociliary clearance) and indirect ones via generation of systemic inflammation. The relationship between respiratory and GI conditions is well described by the lung-gut axis and more recently, has become even clearer during coronavirus disease 2019 (COVID-19) pandemic, when respiratory symptoms were associated with gastrointestinal conditions. This review aims at pointing out the mechanisms and the models used to evaluate PM induced GI tract damage.


Subject(s)
COVID-19/etiology , Gastrointestinal Tract/injuries , Particulate Matter/toxicity , SARS-CoV-2 , Administration, Inhalation , Administration, Oral , COVID-19/physiopathology , COVID-19/prevention & control , Gastrointestinal Tract/physiopathology , Humans , Intestinal Mucosa/injuries , Intestinal Mucosa/physiopathology , Masks , Microplastics/toxicity , Models, Biological , Mucociliary Clearance/physiology , Nutrition Policy , Pandemics/prevention & control , Particulate Matter/administration & dosage , Respiratory System/injuries , Respiratory System/physiopathology
2.
Clin Gastroenterol Hepatol ; 20(6): 1197-1200, 2022 06.
Article in English | MEDLINE | ID: covidwho-1850806
3.
Viruses ; 14(4)2022 03 29.
Article in English | MEDLINE | ID: covidwho-1820405

ABSTRACT

Coronavirus disease 19 (COVID-19) clinical manifestations include the involvement of the gastrointestinal tract, affecting around 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children. In the present work, the consequence of a short time of viral absorption (5, 15, 30 and 60 min) was tested on the Caco-2 intestinal epithelial cell line. Our findings show that Caco-2 cells are highly permissive to SARS-CoV-2 infection, even after 5 min of viral inoculation at a multiplicity of infection of 0.1. No cytopathic effect was evident during the subsequent 7 days of monitoring; nevertheless, the immunofluorescence staining for the viral nucleocapsid confirmed the presence of intracellular SARS-CoV-2. Our findings highlight the very short time during which SARS-CoV-2 is able to infect these cells in vitro.


Subject(s)
COVID-19 , Caco-2 Cells , Child , Cytopathogenic Effect, Viral , Gastrointestinal Tract , Humans , SARS-CoV-2
4.
PLoS One ; 17(4): e0267112, 2022.
Article in English | MEDLINE | ID: covidwho-1817491

ABSTRACT

BACKGROUND: During the coronavirus-19 disease (COVID-19) pandemic, gastroenterology guidelines recommended the suspension or reduction of non-urgent endoscopy. We aimed to assess the appropriateness and safety of endoscopic activity during the pandemic first wave lockdown using European Society of Gastrointestinal Endoscopy (ESGE) recommendations. METHODS: We identified scheduled patients from the onset of the lockdown in Spain since March 16, 2020) to April 14, 2020. Daily hospital COVID-19-related burden was also registered. A similar cohort from a period immediately before the lockdown was studied (pre-lockdown cohort) to compare appropriateness. RESULTS: 454 endoscopy procedures were performed during the studied period, comprising a 49.7% reduction compared to the pre-lockdown cohort (n = 913). There was a significant increase in ESGE high-priority indications (62.1% vs. 45.6%, p<0.001) associated with an increase in relevant endoscopic findings (p = 0.006), advanced neoplasia/cancer (p = 0.004) and cancer detection rate (p = 0.010). There were no differences in the rate of admissions or infection among scheduled patients in the lockdown cohort. None of the staff members tested positive for COVID-19 in the 7 days after the adoption of protective measures. CONCLUSION: A prioritized endoscopic activity is not associated with higher contagion after adopting protective measures. In addition, a triage of procedures that follow the ESGE criteria increases the rate of relevant endoscopic findings. These considerations may reduce the impact of the delays of diagnosis after the pandemic.


Subject(s)
COVID-19 , COVID-19/epidemiology , COVID-19/prevention & control , Communicable Disease Control , Endoscopy, Gastrointestinal/adverse effects , Endoscopy, Gastrointestinal/methods , Gastrointestinal Tract , Humans , Spain/epidemiology
7.
Nat Rev Gastroenterol Hepatol ; 19(6): 345-346, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1778603
8.
Eur J Med Chem ; 228: 114030, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1768048

ABSTRACT

The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CLpro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CLpro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CLpro inhibition activity, with IC50 values of 1.55 ± 0.21 µM and 1.81 ± 0.17 µM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CLprovia a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CLpro inhibitor.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery/methods , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gastrointestinal Tract/metabolism , Humans , Kinetics , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , Structure-Activity Relationship , Viral Nonstructural Proteins/antagonists & inhibitors
10.
Commun Biol ; 5(1): 225, 2022 03 10.
Article in English | MEDLINE | ID: covidwho-1740485

ABSTRACT

Late 2020, SARS-CoV-2 Alpha variant emerged in United Kingdom and gradually replaced G614 strains initially involved in the global spread of the pandemic. In this study, we use a Syrian hamster model to compare a clinical strain of Alpha variant with an ancestral G614 strain. The Alpha variant succeed to infect animals and to induce a pathology that mimics COVID-19. However, both strains replicate to almost the same level and induced a comparable disease and immune response. A slight fitness advantage is noted for the G614 strain during competition and transmission experiments. These data do not corroborate the epidemiological situation observed during the first half of 2021 in humans nor reports that showed a more rapid replication of Alpha variant in human reconstituted bronchial epithelium. This study highlights the need to combine data from different laboratories using various animal models to decipher the biological properties of newly emerging SARS-CoV-2 variants.


Subject(s)
COVID-19 , Disease Models, Animal , Mesocricetus , SARS-CoV-2/physiology , Animals , Antibodies, Neutralizing/blood , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Female , Gastrointestinal Tract/virology , Genome, Viral , Lung/virology , Nasal Lavage Fluid/virology , SARS-CoV-2/genetics , Virus Replication
11.
Gut ; 69(6): 997-1001, 2020 06.
Article in English | MEDLINE | ID: covidwho-1723830

ABSTRACT

OBJECTIVE: To study the GI symptoms in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. DESIGN: We analysed epidemiological, demographic, clinical and laboratory data of 95 cases with SARS-CoV-2 caused coronavirus disease 2019. Real-time reverse transcriptase PCR was used to detect the presence of SARS-CoV-2 in faeces and GI tissues. RESULTS: Among the 95 patients, 58 cases exhibited GI symptoms of which 11 (11.6%) occurred on admission and 47 (49.5%) developed during hospitalisation. Diarrhoea (24.2%), anorexia (17.9%) and nausea (17.9%) were the main symptoms with five (5.3%), five (5.3%) and three (3.2%) cases occurred on the illness onset, respectively. A substantial proportion of patients developed diarrhoea during hospitalisation, potentially aggravated by various drugs including antibiotics. Faecal samples of 65 hospitalised patients were tested for the presence of SARS-CoV-2, including 42 with and 23 without GI symptoms, of which 22 (52.4%) and 9 (39.1%) were positive, respectively. Six patients with GI symptoms were subjected to endoscopy, revealing oesophageal bleeding with erosions and ulcers in one severe patient. SARS-CoV-2 RNA was detected in oesophagus, stomach, duodenum and rectum specimens for both two severe patients. In contrast, only duodenum was positive in one of the four non-severe patients. CONCLUSIONS: GI tract may be a potential transmission route and target organ of SARS-CoV-2.


Subject(s)
Betacoronavirus , Coronavirus Infections , Gastrointestinal Tract , Pandemics , Pneumonia, Viral , Adult , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Female , Gastrointestinal Tract/physiopathology , Gastrointestinal Tract/virology , Humans , Male , Middle Aged , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , SARS-CoV-2
12.
J Med Virol ; 94(4): 1315-1329, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1718396

ABSTRACT

In December 2019, novel severe acute respiratory syndrome coronavirus 2 (nSARS-CoV-2) virus outbreaks emerged from Wuhan, China, and spread all over the world, including India. Molecular diagnosis of Coronavirus Disease 2019 (COVID) 19 for densely and highly populated countries like India is time-consuming. A few reports have described the successful diagnosis of nSARS-CoV-2 virus from sewage and wastewater samples contaminated with fecal matter, suggesting the diagnosis of COVID 19 from the same to raise an alarm about the community transmission of virus for implementation of evacuation and lockdown strategies. So far, the association between the detection of virus and its concentration in stool samples with severity of the disease and the presence or absence of gastrointestinal symptoms have been rarely reported. We led the search utilizing multiple databases, specifically PubMed (Medline), EMBASE, and Google Scholar. We conducted a literature survey on gastrointestinal infection and the spread of this virus through fecal-oral transmission. Reports suggested that the existence and persistence of nSARS-CoV-2 in anal/rectal swabs and stool specimens for a longer period of time than in nasopharyngeal swabs provides a strong tenable outcome of gastrointestinal contamination and dissemination of this infection via potential fecal-oral transmission. This review may be helpful to conduct further studies to address the enteric involvement and excretion of nSARS-CoV-2 RNA in feces and control the community spread in both COVID-19 patients ahead of the onset of symptoms and in asymptomatic individuals through wastewater and sewage surveillance as an early indication of infection. The existence of the viral genome and active viral particle actively participate in genomic variations. Hence, we comprehended the enteric spread of different viruses amongst communities with special reference to nSARS-CoV-2.


Subject(s)
COVID-19/virology , Disease Transmission, Infectious , Gastrointestinal Diseases/virology , SARS-CoV-2/isolation & purification , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/transmission , Disease Transmission, Infectious/prevention & control , Feces/virology , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/prevention & control , Gastrointestinal Tract/virology , Humans , India/epidemiology , SARS-CoV-2/genetics , Sewage/virology , Water Purification
13.
Mol Med Rep ; 25(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1715860

ABSTRACT

In addition to the angiotensin­converting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with non­small cell lung cancer with concurrent coronavirus disease 2019 (COVID­19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID­19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extra­pulmonary) COVID­19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.


Subject(s)
COVID-19/pathology , Gastrointestinal Tract/pathology , Lung Neoplasms/pathology , Lung/pathology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/virology , Gastrointestinal Tract/virology , Humans , Immunohistochemistry , Lung/virology , Lung Neoplasms/complications , Male , Membrane Proteins/analysis , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/analysis , Virus Internalization
14.
Clin Infect Dis ; 74(6): 1081-1084, 2022 03 23.
Article in English | MEDLINE | ID: covidwho-1707490

ABSTRACT

The clinical significance of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) RNA in stool remains uncertain. We found that extrapulmonary dissemination of infection to the gastrointestinal tract, assessed by the presence of SARS-CoV-2 RNA in stool, is associated with decreased coronavirus disease 2019 (COVID-19) survival. Measurement of SARS-CoV-2 RNA in stool may have utility for clinical risk assessment.


Subject(s)
COVID-19 , SARS-CoV-2 , Feces , Gastrointestinal Tract , Humans , RNA, Viral , SARS-CoV-2/genetics
15.
Clin Med (Lond) ; 22(2): 181-183, 2022 03.
Article in English | MEDLINE | ID: covidwho-1675217

ABSTRACT

Although COVID-19 was first recognised as an acute respiratory illness, extra-pulmonary manifestations are increasingly being recognised. Acute gastrointestinal side effects have been well reported with COVID-19 infection and are estimated to affect around 17% of patients. With COVID-19 still being a relatively new illness, the chronic gastrointestinal symptoms are less well characterised. Post-infectious irritable bowel syndrome (IBS) can occur following bacterial and viral infections, and with ACE-2 receptors being shown to be present in the gastrointestinal tract and SARS-Cov-2 RNA being present in stool, SARS-CoV-2 is now appreciated as an enteric pathogen. In our study, we survey acute and chronic gastrointestinal symptoms after COVID-19 infection. We have conducted one of the few UK studies on gastrointestinal symptoms, with the longest follow-up duration of 6 months. We have found that gastrointestinal symptoms are common at 6 months, affecting 43.8% of our patients. Further research is needed to explore whether this represents a new post-COVID-19 IBS, which has not previous been described in the literature, including its clinical course and response to any potential medical therapies.


Subject(s)
COVID-19 , COVID-19/complications , Gastrointestinal Tract , Humans , RNA, Viral , SARS-CoV-2 , United Kingdom/epidemiology
16.
Indian J Gastroenterol ; 40(5): 449-452, 2021 10.
Article in English | MEDLINE | ID: covidwho-1661746
17.
Eur J Med Chem ; 228: 114030, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1654355

ABSTRACT

The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CLpro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CLpro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CLpro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CLpro inhibition activity, with IC50 values of 1.55 ± 0.21 µM and 1.81 ± 0.17 µM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CLprovia a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CLpro inhibitor.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery/methods , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gastrointestinal Tract/metabolism , Humans , Kinetics , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , Structure-Activity Relationship , Viral Nonstructural Proteins/antagonists & inhibitors
18.
Eur J Gastroenterol Hepatol ; 33(1S Suppl 1): e59-e65, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1642429

ABSTRACT

Since December 2019, the severe acute respiratory syndrome coronavirus 2 has constituted a serious threat to global health. So far, there is little published evidence on the laboratory features of coronavirus disease 2019 (COVID-19). We have reviewed laboratory findings from multiple studies, mostly relating to the digestive system, since the virus outbreak. Laboratory data from older coronaviruses endemics, as well as other RNA viruses, were also reported. Although the main route of transmission is considered to be respiratory droplets, the distribution of ACE2 receptors in the gastrointestinal tract in combination with the detection of the virus in feces may imply a potential fecal-oral transmission route, and thus, emphasis should be given to patients with gastrointestinal symptoms. Interestingly, there is evidence that severe acute respiratory syndrome coronavirus 2 displays similar laboratory and clinical findings with older members of the coronavirus family, and so, comparable diagnostic and therapeutic approaches may be used. Regarding laboratory abnormalities, lymphopenia appears to be the most common finding, together with coagulation disorders and inflammatory markers elevation, reflecting a sustained systemic response. Abnormal liver and, occasionally, pancreatic tests are also common and even more severe in patients with gastrointestinal symptoms or diseases. Thus, the aim of this study is to focus on the laboratory and pathophysiologic side of this novel disease in order to strengthen current knowledge and urge further research. Detailed investigation of numerous studies may suggest a common laboratory pattern between COVID-19 patients. It is important for clinicians not to underestimate patients with gastrointestinal comorbidities, as they have been associated with severe COVID-19 disease.


Subject(s)
COVID-19 , Pandemics , Gastrointestinal Tract , Humans , Laboratories , SARS-CoV-2
20.
N Engl J Med ; 386(3): 220-229, 2022 01 20.
Article in English | MEDLINE | ID: covidwho-1632249

ABSTRACT

BACKGROUND: Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed. RESULTS: Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination. CONCLUSIONS: In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).


Subject(s)
Clostridioides difficile , Clostridium Infections/therapy , Firmicutes , Aged , Anti-Bacterial Agents/adverse effects , Double-Blind Method , Feces/microbiology , Female , Gastrointestinal Tract/microbiology , Humans , Intention to Treat Analysis , Male , Microbiota/drug effects , Middle Aged , Recurrence , Secondary Prevention , Spores, Bacterial
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