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1.
Int J Mol Sci ; 23(6)2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1742487

ABSTRACT

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care-but also medical prophylactic and therapeutic care in general-to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.


Subject(s)
Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/metabolism , Micronutrients/metabolism , Vitamin A/metabolism , Vitamin D/metabolism , Zinc/metabolism , Animals , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Humans , Micronutrients/pharmacology , Pandemics/prevention & control , SARS-CoV-2/physiology , Tight Junctions/drug effects , Tight Junctions/metabolism , Vitamin A/pharmacology , Vitamin D/pharmacology , Vitamins/metabolism , Vitamins/pharmacology , Zinc/pharmacology
2.
Int J Mol Sci ; 21(11)2020 May 29.
Article in English | MEDLINE | ID: covidwho-1456326

ABSTRACT

In the development of inflammatory bowel disease (IBD), the gut microbiota has been established as a key factor. Recently, metabolomics has become important for understanding the functional relevance of gut microbial changes in disease. Animal models for IBD enable the study of factors involved in disease development. However, results from animal studies may not represent the human situation. The aim of this study was to investigate whether results from metabolomics studies on animal models for IBD were similar to those from studies on IBD patients. Medline and Embase were searched for relevant studies up to May 2017. The Covidence systematic review software was used for study screening, and quality assessment was conducted for all included studies. Data showed a convergence of ~17% for metabolites differentiated between IBD and controls in human and animal studies with amino acids being the most differentiated metabolite subclass. The acute dextran sodium sulfate model appeared as a good model for analysis of systemic metabolites in IBD, but analytical platform, age, and biological sample type did not show clear correlations with any significant metabolites. In conclusion, this systematic review highlights the variation in metabolomics results, and emphasizes the importance of expanding the applied detection methods to ensure greater coverage and convergence between the various different patient phenotypes and animal models of inflammatory bowel disease.


Subject(s)
Inflammatory Bowel Diseases/metabolism , Metabolome , Metabolomics/methods , /methods , Animals , Disease Models, Animal , Humans , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/pathology , Mice , Sodium Dodecyl Sulfate/toxicity
3.
Sci Rep ; 11(1): 13533, 2021 06 29.
Article in English | MEDLINE | ID: covidwho-1387483

ABSTRACT

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10-4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Crohn Disease/pathology , Adolescent , Adult , Angiotensin-Converting Enzyme 2/genetics , Crohn Disease/metabolism , Crohn Disease/surgery , Female , Humans , Ileum/metabolism , Ileum/pathology , Immunohistochemistry , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Male , Prognosis , Proportional Hazards Models , RNA, Messenger/chemistry , RNA, Messenger/metabolism , Risk Factors , Sequence Analysis, RNA , Young Adult
5.
United European Gastroenterol J ; 9(7): 750-765, 2021 09.
Article in English | MEDLINE | ID: covidwho-1287407

ABSTRACT

BACKGROUND: The COVID-19 pandemic has created unprecedented challenges in all fields of society with social, economic, and health-related consequences worldwide. In this context, gastroenterology patients and healthcare systems and professionals have seen their routines changed and were forced to adapt, adopting measures to minimize the risk of infection while guaranteeing continuous medical care to chronic patients. OBJECTIVE: At this point, it is important to evaluate the impact of the pandemic on this field to further improve the quality of the services provided in this context. METHODS/RESULTS/CONCLUSION: We performed a literature review that summarizes the main aspects to consider in gastroenterology, during the pandemic crisis, and includes a deep discussion on the main changes affecting gastroenterology patients and healthcare systems, anticipating the pandemic recovery scenario with future practices and policies.


Subject(s)
COVID-19/physiopathology , Delivery of Health Care , Gastroenterology , Immunosuppressive Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Liver Diseases/physiopathology , Biomarkers , COVID-19/complications , COVID-19/immunology , Disease Management , Endoscopy, Digestive System , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/physiopathology , Humans , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/metabolism , Liver Diseases/complications , Liver Diseases/surgery , Liver Transplantation , Pancreas/metabolism , Pancreas/physiopathology , Risk Factors , SARS-CoV-2 , Telemedicine
7.
Int J Mol Sci ; 22(2)2021 Jan 14.
Article in English | MEDLINE | ID: covidwho-1030147

ABSTRACT

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.


Subject(s)
Cannabinoids/pharmacology , Cannabis/chemistry , Drug Discovery , Phytochemicals/pharmacology , Terpenes/pharmacology , Animals , COVID-19/drug therapy , Cannabinoids/chemistry , Cannabinoids/therapeutic use , Drug Synergism , Endocannabinoids/metabolism , Epilepsy/drug therapy , Epilepsy/metabolism , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Phytochemicals/chemistry , Phytochemicals/therapeutic use , Receptors, Cannabinoid/metabolism , Schizophrenia/drug therapy , Schizophrenia/metabolism , Terpenes/chemistry , Terpenes/therapeutic use , Tourette Syndrome/drug therapy , Tourette Syndrome/metabolism
8.
Clin Sci (Lond) ; 134(21): 2823-2833, 2020 11 13.
Article in English | MEDLINE | ID: covidwho-899996

ABSTRACT

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.


Subject(s)
Amino Acid Transport Systems, Neutral/metabolism , Betacoronavirus/pathogenicity , Coronavirus Infections/enzymology , Intestinal Absorption , Intestinal Mucosa/enzymology , Membrane Transport Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/virology , Protein Multimerization , SARS-CoV-2
10.
Inflamm Bowel Dis ; 26(12): 1787-1795, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-872998

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) has been highlighted for its role as a receptor for SARS-CoV-2, responsible for the current COVID-19 pandemic. This review summarizes current knowledge about ACE2 as a multifunctional protein, focusing on its relevance in inflammatory bowel disease (IBD). As an enzyme, ACE2 may be protective in IBD because it favors the counter-regulatory arm of the renin-angiotensin system or deleterious because it metabolizes other anti-inflammatory/repairing elements. Meanwhile, as a receptor for SARS-CoV-2, the impact of ACE2 expression/activity on infection is still under debate because no direct evidence has been reported and, again, both protective and deleterious pathways are possible. Research has shown that ACE2 regulates the expression of the neutral amino acid transporter B0AT1, controlling tryptophan-associated intestinal inflammation and nutritional status. Finally, intact membrane-bound or shed soluble ACE2 can also trigger integrin signaling, modulating the response to anti-integrin biologic drugs used to treat IBD (such as vedolizumab) and fibrosis, a long-term complication of IBD. As such, future studies on ACE2 expression/activity in IBD can improve monitoring of the disease and explore an alternative pharmacological target.


Subject(s)
Angiotensin-Converting Enzyme 2/physiology , Inflammatory Bowel Diseases/metabolism , SARS-CoV-2/physiology , Amino Acid Transport Systems, Neutral/physiology , COVID-19/virology , Humans , Inflammatory Bowel Diseases/physiopathology , Renin-Angiotensin System/physiology
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