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1.
Molecules ; 27(3)2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1674736

ABSTRACT

Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.


Subject(s)
Butyrates/pharmacology , COVID-19/drug therapy , SARS-CoV-2/metabolism , Antiviral Agents/pharmacology , Butyrates/metabolism , COVID-19/metabolism , Caco-2 Cells , Enterocytes/drug effects , Enterocytes/metabolism , Gene Expression/genetics , Gene Expression Regulation/genetics , Humans , Intestines/drug effects , Intestines/metabolism , Male , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
2.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(2): 159070, 2022 02.
Article in English | MEDLINE | ID: covidwho-1596012

ABSTRACT

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of ß-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed ß-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in ß-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal ß-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1-/- and Bco2-/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.


Subject(s)
Fenretinide/pharmacology , Vitamin A/pharmacology , beta Carotene/metabolism , Animals , Body Weight/drug effects , Dioxygenases/metabolism , Intestinal Absorption/drug effects , Intestines/drug effects , Liver/drug effects , Liver/pathology , Mice, Inbred C57BL , Models, Biological , Retinol-Binding Proteins, Plasma/deficiency , Retinol-Binding Proteins, Plasma/metabolism , Vitamin A/blood , Vitamin A Deficiency/blood , Vitamin A Deficiency/pathology , Vitamin E/blood , Vitamin E/metabolism , beta Carotene/blood
4.
mSphere ; 6(6): e0062321, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1501544

ABSTRACT

Human noroviruses (HuNoVs) are acute viral gastroenteritis pathogens that affect all age groups, yet no approved vaccines and drugs to treat HuNoV infection are available. In this study, we screened an antiviral compound library to identify compound(s) showing anti-HuNoV activity using a human intestinal enteroid (HIE) culture system in which HuNoVs are able to replicate reproducibly. Dasabuvir (DSB), which has been developed as an anti-hepatitis C virus agent, was found to inhibit HuNoV infection in HIEs at micromolar concentrations. Dasabuvir also inhibited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human rotavirus A (RVA) infection in HIEs. To our knowledge, this is the first study to screen an antiviral compound library for HuNoV using HIEs, and we successfully identified dasabuvir as a novel anti-HuNoV inhibitor that warrants further investigation. IMPORTANCE Although there is an urgent need to develop effective antiviral therapy directed against HuNoV infection, compound screening to identify anti-HuNoV drug candidates has not been reported so far. Using a human HIE culture system, our compound screening successfully identified dasabuvir as a novel anti-HuNoV inhibitor. Dasabuvir's inhibitory effect was also demonstrated in the cases of SARS-CoV-2 and RVA infection, highlighting the usefulness of the HIE platform for screening antiviral agents against various viruses that target the intestines.


Subject(s)
2-Naphthylamine/pharmacology , Antiviral Agents/pharmacology , Intestines/virology , Organoids/virology , Small Molecule Libraries/pharmacology , Sulfonamides/pharmacology , Uracil/analogs & derivatives , Biopsy , COVID-19/drug therapy , Caliciviridae Infections/drug therapy , Cell Line , Humans , Intestines/drug effects , Intestines/pathology , Organoids/drug effects , Rotavirus/drug effects , Rotavirus Infections/drug therapy , SARS-CoV-2/drug effects , Uracil/pharmacology
5.
Int Immunol ; 33(12): 787-790, 2021 11 25.
Article in English | MEDLINE | ID: covidwho-1398105

ABSTRACT

Dysbiosis is alterations in the microbial composition compared with a healthy microbiota and often features a reduction in gut microbial diversity and a change in microbial taxa. Dysbiosis, especially in the gut, has also been proposed to play a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. A body of evidence has shown that intestinal polymeric immunoglobulin A (IgA) antibodies are important to regulate the gut microbiota as well as to exclude pathogenic bacteria or viral infection such as influenza and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) at mucosal sites. Since the 1970s, trials for oral administration of therapeutic IgA or IgG have been performed mainly to treat infectious enteritis caused by pathogenic Escherichia coli or Clostridium difficile. However, few of them have been successfully developed for clinical application up to now. In addition to the protective function against intestinal pathogens, IgA is well known to modulate the gut commensal microbiota leading to symbiosis. Nevertheless, the development of therapeutic IgA drugs to treat dysbiosis is not progressing. In this review, the advantages of therapeutic IgA antibodies and the problems for their development will be discussed.


Subject(s)
Bacteria/drug effects , Gastrointestinal Microbiome/drug effects , Immunoglobulin A/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Intestines/drug effects , Animals , Bacteria/immunology , Dysbiosis , Host-Pathogen Interactions , Humans , Immunoglobulin A/adverse effects , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/microbiology , Intestines/immunology , Intestines/microbiology , Species Specificity
6.
Gastroenterology ; 160(3): 809-822.e7, 2021 02.
Article in English | MEDLINE | ID: covidwho-990009

ABSTRACT

BACKGROUND AND AIMS: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls. METHODS: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents/therapeutic use , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Intestines/drug effects , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Anti-Inflammatory Agents/adverse effects , COVID-19/enzymology , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Colitis, Ulcerative/enzymology , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Crohn Disease/enzymology , Crohn Disease/genetics , Crohn Disease/immunology , Databases, Genetic , Female , Gene Expression Regulation, Enzymologic , Host-Pathogen Interactions , Humans , Intestines/enzymology , Intestines/immunology , Male , Middle Aged , North America , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/immunology , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor Inhibitors/adverse effects , Tumor Necrosis Factor-alpha/metabolism , Young Adult
7.
Trop Anim Health Prod ; 52(2): 511-515, 2020 Mar.
Article in English | MEDLINE | ID: covidwho-829118

ABSTRACT

The current experiment was performed to find the potential effect of inorganic and organic forms of zinc (Zn) on growth, intestinal histomorphology, immune response, and paraoxonase (PON1) activity in broiler. In this experiment, a total of 450 broiler chickens were assigned to four experimental and control groups. The birds received organic Zn at the rate of 50 mg/kg (OZ-50) and 60 mg/kg (OZ-60) or inorganic Zn at the rate of 50 mg/kg (IZ-50) and 60 mg/kg (IZ-60) for an experimental period of 30 days. Significantly (P < 0.05) higher feed consumption, body weight, feed conversion ratio, and production efficiency factor (PEF) were recorded in OZ-50. Similarly, antibody titer against infectious bronchitis (IB) and PON1 activity was higher (P < 0.05) in OZ-50 compared with the control group. In addition, significantly (P < 0.05) higher villus dimensions and goblet cell count were recorded for the group OZ-50 compared with other treatments. It was concluded that the organic form of Zn was superior in improving the growth, histological features of intestines, humoral response, and PON1 activity in broiler.


Subject(s)
Chickens/growth & development , Chickens/metabolism , Immunity, Innate/drug effects , Intestines/anatomy & histology , Zinc Compounds/metabolism , Zinc/metabolism , Animal Feed/analysis , Animals , Aryldialkylphosphatase/metabolism , Avian Proteins/metabolism , Diet/veterinary , Dietary Supplements/analysis , Dose-Response Relationship, Drug , Intestines/drug effects , Zinc/administration & dosage , Zinc Compounds/administration & dosage
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