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Del Chierico F, Masi L, Petito V, Baldelli V, Puca P, Benvenuto R, Fidaleo M, Palucci I, Lopetuso LR, Caristo ME, Carrozza C, Giustiniani MC, Nakamichi N, Kato Y, Putignani L, Gasbarrini A, Pani G, Scaldaferri F. Solute Transporter OCTN1/Slc22a4 Affects Disease Severity and Response to Infliximab in Experimental Colitis: Role of Gut Microbiota and Immune Modulation. Inflamm Bowel Dis 2024; 30:2259-2270. [PMID: 38944815 PMCID: PMC11630256 DOI: 10.1093/ibd/izae135] [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: 06/08/2023] [Indexed: 07/01/2024]
Abstract
BACKGROUND Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial etiology, still incompletely understood. OCTN1, an organic cation transporter, could have a role in modulating the inflammatory response, and some genetic polymorphisms of this molecule have been associated with increased risk of inflammatory bowel diseases. Until now, limited information exists on its potential in predicting/modulating patient's response to therapies. The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and mucosal immunity in response to infliximab therapy in murine colitis. METHODS A dextran sodium sulphate model of colitis was used to assess the clinical efficacy of infliximab administered intravenously in ocnt1 gene knockout mice and their C57BL/6 controls. Stool, colon, and mesenteric lymph node samples were collected to evaluate differences in gut microbiota composition, histology, and T cell populations, respectively. RESULTS Octn1 -/- influences the microbiota profile and is associated with a worse dysbiosis in mice with colitis. Infliximab treatment attenuates colitis-associated dysbiosis, with an increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1-/- mice have milder disease and a higher baseline percentage of Treg, Tmemory, Th2 and Th17 cells. CONCLUSIONS Our data support the murine model to study OCTN1 genetic contribution to inflammatory bowel diseases. This could be the first step towards the recognition of this membrane transporter as a biomarker in inflammatory conditions and a predictor of response to therapies.
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Affiliation(s)
- Federica Del Chierico
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Letizia Masi
- Department of Medical and Surgical Science, Digestive Disease Center (CeMAD) Translational Research Laboratories, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
| | - Valentina Petito
- Department of Medical and Surgical Science, Digestive Disease Center (CeMAD) Translational Research Laboratories, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
| | - Valerio Baldelli
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Pierluigi Puca
- Department of Medical and Surgical Sciences, UOS Inflammatory Bowel Diseases, Center for Diseases of Digestive System (CeMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
| | - Roberta Benvenuto
- Department of Pathology, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italy
| | - Marco Fidaleo
- Department of Biology and Biotechnologies Charles Darwin, Università La Sapienza, Rome, Italy
| | - Ivana Palucci
- Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italy
- Institute of Microbiology, Catholic University of the Sacred Heart, Rome, Italy
| | - Loris Riccardo Lopetuso
- Department of Medical and Surgical Sciences, UOS Inflammatory Bowel Diseases, Center for Diseases of Digestive System (CeMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Medicine and Ageing Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
| | | | - Cinzia Carrozza
- Department of Clinical Biochemistry, Laboratory and Infectious Science, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italy
| | | | - Noritaka Nakamichi
- Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, 370-0033, Takasaki, Gunma, Japan
| | - Yukio Kato
- Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Lorenza Putignani
- Unit of Microbiology and Diagnostic Immunology, Unit of Microbiomics and Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Science, Digestive Disease Center (CeMAD) Translational Research Laboratories, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
- Department of Medical and Surgical Science, Digestive Disease Center (CeMAD), Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
| | - Giovambattista Pani
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
| | - Franco Scaldaferri
- Department of Medical and Surgical Sciences, UOS Inflammatory Bowel Diseases, Center for Diseases of Digestive System (CeMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
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Mazza T, Scalise M, Console L, Galluccio M, Giangregorio N, Tonazzi A, Pochini L, Indiveri C. Carnitine traffic and human fertility. Biochem Pharmacol 2024; 230:116565. [PMID: 39368751 DOI: 10.1016/j.bcp.2024.116565] [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: 07/31/2024] [Revised: 09/18/2024] [Accepted: 10/01/2024] [Indexed: 10/07/2024]
Abstract
Carnitine is a vital molecule in human metabolism, prominently involved in fatty acid β-oxidation within mitochondria. Predominantly sourced from dietary intake, carnitine also derives from endogenous synthesis. This review delves into the complex network of carnitine transport and distribution, emphasizing its pivotal role in human fertility. Together with its role in fatty acid oxidation, carnitine modulates the acety-CoA/CoA ratio, influencing carbohydrate metabolism, lipid biosynthesis, and gene expression. The intricate regulation of carnitine homeostasis involves a network of membrane transporters, notably OCTN2, which is central in its absorption, reabsorption, and distribution. OCTN2 dysfunction, results in Primary Carnitine Deficiency (PCD), characterized by systemic carnitine depletion and severe clinical manifestations, including fertility issues. In the male reproductive system, carnitine is crucial for sperm maturation and motility. In the female reproductive system, carnitine supports mitochondrial function necessary for oocyte quality, folliculogenesis, and embryonic development. Indeed, deficiencies in carnitine or its transporters have been linked to asthenozoospermia, reduced sperm quality, and suboptimal fertility outcomes in couples. Moreover, the antioxidant properties of carnitine protect spermatozoa from oxidative stress and help in managing conditions like polycystic ovary syndrome (PCOS) and endometriosis, enhancing sperm viability and fertilization potential of oocytes. This review summarizes the key role of membrane transporters in guaranteeing carnitine homeostasis with a special focus on the implications in fertility and possible treatments of infertility and other related disorders.
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Affiliation(s)
- Tiziano Mazza
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Mariafrancesca Scalise
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Lara Console
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Michele Galluccio
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy
| | - Nicola Giangregorio
- CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy
| | - Annamaria Tonazzi
- CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy
| | - Lorena Pochini
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy; CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy.
| | - Cesare Indiveri
- Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via P. Bucci 4C, Arcavacata di Rende 87036, Italy; CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), via Amendola 122/O, Bari 70126, Italy.
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Galluccio M, Tripicchio M, Pochini L. The Human OCTN Sub-Family: Gene and Protein Structure, Expression, and Regulation. Int J Mol Sci 2024; 25:8743. [PMID: 39201429 PMCID: PMC11354717 DOI: 10.3390/ijms25168743] [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: 07/10/2024] [Revised: 08/01/2024] [Accepted: 08/08/2024] [Indexed: 09/02/2024] Open
Abstract
OCTN1 and OCTN2 are membrane transport proteins encoded by the SLC22A4 and SLC22A5 genes, respectively. Even though several transcripts have been predicted by bioinformatics for both genes, only one functional protein isoform has been described for each of them. Both proteins are ubiquitous, and depending on the physiopathological state of the cell, their expression is regulated by well-known transcription factors, although some aspects have been neglected. A plethora of missense variants with uncertain clinical significance are reported both in the dbSNP and the Catalogue of Somatic Mutations in Cancer (COSMIC) databases for both genes. Due to their involvement in human pathologies, such as inflammatory-based diseases (OCTN1/2), systemic primary carnitine deficiency (OCTN2), and drug disposition, it would be interesting to predict the impact of variants on human health from the perspective of precision medicine. Although the lack of a 3D structure for these two transport proteins hampers any speculation on the consequences of the polymorphisms, the already available 3D structures for other members of the SLC22 family may provide powerful tools to perform structure/function studies on WT and mutant proteins.
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Affiliation(s)
- Michele Galluccio
- Laboratory of Biochemistry, Molecular Biotechnology, and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende, Italy;
| | - Martina Tripicchio
- Laboratory of Biochemistry, Molecular Biotechnology, and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende, Italy;
| | - Lorena Pochini
- Laboratory of Biochemistry, Molecular Biotechnology, and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende, Italy;
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), National Research Council (CNR), Via Amendola 122/O, 70126 Bari, Italy
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Pochini L. Involvement of mammalian SoLute Carriers (SLC) in the traffic of polyamines. Front Mol Biosci 2024; 11:1452184. [PMID: 39130372 PMCID: PMC11310933 DOI: 10.3389/fmolb.2024.1452184] [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: 06/20/2024] [Accepted: 07/10/2024] [Indexed: 08/13/2024] Open
Abstract
Polyamines interact with different molecular targets to regulate a vast range of cellular processes. A network of enzymes and transport systems is crucial for the maintenance of polyamine homeostasis. Indeed, polyamines after synthesis must be distributed to the various tissues and some intracellular organelles. Differently from the well characterized enzymes devoted to polyamine synthesis, the transport systems are not unequivocally identified or characterized. Besides some ATPases which have been identified as polyamine transporters, much less is known about solute carriers (SLC) involved in the transport of these compounds. Only two SLCs have been unequivocally identified as polyamine transporters: SLC18B1 (VPAT) and SLC22A4 (OCTN1). Transport studies have been performed with cells transfected with the cDNAs encoding the two and other SLCs or, in the case of OCTN1, also by in vitro assay using proteoliposomes harboring the recombinant human protein. According to the role proposed for OCTN1, polyamines have been associated with prolonged and quality of life. This review provides an update on the most recent findings concerning the polyamine transporters or the prediction of the putative ones.
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Affiliation(s)
- Lorena Pochini
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze Della Terra), University of Calabria, Rende, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), Bari, Italy
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Hou D, Yu T, Lu X, Hong JY, Yang M, Zi Y, Ho TT, Lin H. Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis. Proc Natl Acad Sci U S A 2024; 121:e2319833121. [PMID: 38648480 PMCID: PMC11066986 DOI: 10.1073/pnas.2319833121] [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: 11/29/2023] [Accepted: 03/03/2024] [Indexed: 04/25/2024] Open
Abstract
Sirt2 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylase that can remove both acetyl group and long-chain fatty acyl groups from lysine residues of many proteins. It was reported to affect inflammatory bowel disease (IBD) symptoms in a mouse model. However, conflicting roles were reported, with genetic knockout aggravating while pharmacological inhibition alleviating IBD symptoms. These seemingly conflicting reports cause confusion and deter further efforts in developing Sirt2 inhibitors as a potential treatment strategy for IBD. We investigated these conflicting reports and elucidated the role of Sirt2 in the mouse model of IBD. We essentially replicated these conflicting results and confirmed that Sirt2 inhibitors' protective effect is not through off-targets as two very different Sirt2 inhibitors (TM and AGK2) showed similar protection in the IBD mouse model. We believe that the differential effects of inhibitors and knockout are due to the fact that the Sirt2 inhibitors only inhibit some but not all the activities of Sirt2. This hypothesis is confirmed by the observation that a PROTAC degrader of Sirt2 did not protect mice in the IBD model, similar to Sirt2 knockout. Our study provides an interesting example where genetic knockout and pharmacological inhibition do not align and emphasizes the importance of developing substrate-dependent inhibitors. Importantly, we showed that the effect of Sirt2 inhibition in IBD is through regulating the gut epithelium barrier by inhibiting Arf6-mediated endocytosis of E-cadherin, a protein important for the intestinal epithelial integrity. This mechanistic understanding further supports Sirt2 as a promising therapeutic target for treating IBD.
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Affiliation(s)
- Dan Hou
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
| | - Tao Yu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
- HHMI, Cornell University, Ithaca, NY14853
| | - Xuan Lu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
| | - Jun Young Hong
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
| | - Min Yang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
| | - Yanlin Zi
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
| | - Thanh Tu Ho
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
| | - Hening Lin
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY14853
- HHMI, Cornell University, Ithaca, NY14853
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY14853
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Pochini L, Galluccio M, Console L, Scalise M, Eberini I, Indiveri C. Inflammation and Organic Cation Transporters Novel (OCTNs). Biomolecules 2024; 14:392. [PMID: 38672410 PMCID: PMC11048549 DOI: 10.3390/biom14040392] [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: 02/15/2024] [Revised: 03/20/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Inflammation is a physiological condition characterized by a complex interplay between different cells handled by metabolites and specific inflammatory-related molecules. In some pathological situations, inflammation persists underlying and worsening the pathological state. Over the years, two membrane transporters namely OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been shown to play specific roles in inflammation. These transporters form the OCTN subfamily within the larger SLC22 family. The link between these proteins and inflammation has been proposed based on their link to some chronic inflammatory diseases such as asthma, Crohn's disease (CD), and rheumatoid arthritis (RA). Moreover, the two transporters show the ability to mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation. In the present review, we wish to provide a state of the art on OCTN1 and OCTN2 transport function and regulation in relationships with inflammation and inflammatory diseases focusing on the metabolic signature collected in different body districts and gene polymorphisms related to inflammatory diseases.
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Affiliation(s)
- Lorena Pochini
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via Bucci 4C, 6C, 87036 Arcavacata di Rende, Italy; (M.G.); (L.C.); (M.S.)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), Via Amendola 122/O, 70126 Bari, Italy
| | - Michele Galluccio
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via Bucci 4C, 6C, 87036 Arcavacata di Rende, Italy; (M.G.); (L.C.); (M.S.)
| | - Lara Console
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via Bucci 4C, 6C, 87036 Arcavacata di Rende, Italy; (M.G.); (L.C.); (M.S.)
| | - Mariafrancesca Scalise
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via Bucci 4C, 6C, 87036 Arcavacata di Rende, Italy; (M.G.); (L.C.); (M.S.)
| | - Ivano Eberini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Cesare Indiveri
- Laboratory of Biochemistry, Molecular Biotechnology and Molecular Biology, Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via Bucci 4C, 6C, 87036 Arcavacata di Rende, Italy; (M.G.); (L.C.); (M.S.)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), Via Amendola 122/O, 70126 Bari, Italy
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Kapur N, Alam MA, Hassan SA, Patel PH, Wempe LA, Bhogoju S, Goretsky T, Kim JH, Herzog J, Ge Y, Awuah SG, Byndloss M, Baumler AJ, Zadeh MM, Sartor RB, Barrett T. Enhanced mucosal mitochondrial function corrects dysbiosis and OXPHOS metabolism in IBD. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.14.584471. [PMID: 38559035 PMCID: PMC10979996 DOI: 10.1101/2024.03.14.584471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Background Mitochondrial (Mito) dysfunction in IBD reduces mucosal O2 consumption and increases O2 delivery to the microbiome. Increased enteric O2 promotes blooms of facultative anaerobes (eg. Proteobacteria ) and restricts obligate anaerobes (eg. Firmicutes ). Dysbiotic metabolites negatively affect host metabolism and immunity. Our novel compound (AuPhos) upregulates intestinal epithelial cell (IEC) mito function, attenuates colitis and corrects dysbiosis in humanized Il10-/- mice. We posit that AuPhos corrects IBD-associated dysbiotic metabolism. Methods Primary effect of AuPhos on mucosal Mito respiration and healing process was studied in ex vivo treated human colonic biopsies and piroxicam-accelerated (Px) Il10-/- mice. Secondary effect on microbiome was tested in DSS-colitis WT B6 and germ-free 129.SvEv WT or Il10-/- mice reconstituted with human IBD stool (Hu- Il10-/- ). Mice were treated orally with AuPhos (10- or 25- mg/kg; q3d) or vehicle, stool samples collected for fecal lipocalin-2 (f-LCN2) assay and microbiome analyses using 16S rRNA sequencing. AuPhos effect on microbial metabolites was determined using untargeted global metabolomics. AuPhos-induced hypoxia in IECs was assessed by Hypoxyprobe-1 staining in sections from pimonidazole HCl-infused DSS-mice. Effect of AuPhos on enteric oxygenation was assessed by E. coli Nissle 1917 WT (aerobic respiration-proficient) and cytochrome oxidase (cydA) mutant (aerobic respiration-deficient). Results Metagenomic (16S) analysis revealed AuPhos reduced relative abundances of Proteobacteria and increased blooms of Firmicutes in uninflamed B6 WT, DSS-colitis, Hu-WT and Hu- Il10-/- mice. AuPhos also increased hypoxyprobe-1 staining in surface IECs suggesting enhanced O2 utilization. AuPhos-induced anaerobiosis was confirmed by a significant increase in cydA mutant compared to WT (O2-utlizing) E.coli . Ex vivo treatment of human biopsies with AuPhos showed significant increase in Mito mass, and complexes I and IV. Further, gene expression analysis of AuPhos-treated biopsies showed increase in stem cell markers (Lgr4, Lgr5, Lrig1), with concomitant decreases in pro-inflammatory markers (IL1β,MCP1, RankL). Histological investigation of AuPhos-fed Px- Il10-/- mice showed significantly decreased colitis score in AuPhos-treated Px- Il10-/- mice, with decrease in mRNA of pro-inflammatory cytokines and increase in Mito complexes ( ND5 , ATP6 ). AuPhos significantly altered microbial metabolites associated with SCFA synthesis, FAO, TCA cycle, tryptophan and polyamine biosynthesis pathways. AuPhos increased pyruvate, 4-hydroxybutyrate, 2-hydroxyglutarate and succinate, suggesting an upregulation of pyruvate and glutarate pathways of butyrate production. AuPhos reduced IBD-associated primary bile acids (BA) with concomitant increase in secondary BA (SBA). AuPhos treatment significantly decreased acylcarnitines and increased L-carnitine reflective of enhanced FAO. AuPhos increases TCA cycle intermediates and creatine, energy reservoir substrates indicating enhanced OxPHOS. Besides, AuPhos also upregulates tryptophan metabolism, decreases Kynurenine and its derivatives, and increases polyamine biosynthesis pathway (Putresceine and Spermine). Conclusion These findings indicate that AuPhos-enhanced IEC mitochondrial function reduces enteric O2 delivery, which corrects disease-associated metabolomics by restoring short-chain fatty acids, SBA, AA and IEC energy metabolism. Graphical abstract
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Hui R, Scheib CL, D’Atanasio E, Inskip SA, Cessford C, Biagini SA, Wohns AW, Ali MQ, Griffith SJ, Solnik A, Niinemäe H, Ge XJ, Rose AK, Beneker O, O’Connell TC, Robb JE, Kivisild T. Genetic history of Cambridgeshire before and after the Black Death. SCIENCE ADVANCES 2024; 10:eadi5903. [PMID: 38232165 PMCID: PMC10793959 DOI: 10.1126/sciadv.adi5903] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 12/14/2023] [Indexed: 01/19/2024]
Abstract
The extent of the devastation of the Black Death pandemic (1346-1353) on European populations is known from documentary sources and its bacterial source illuminated by studies of ancient pathogen DNA. What has remained less understood is the effect of the pandemic on human mobility and genetic diversity at the local scale. Here, we report 275 ancient genomes, including 109 with coverage >0.1×, from later medieval and postmedieval Cambridgeshire of individuals buried before and after the Black Death. Consistent with the function of the institutions, we found a lack of close relatives among the friars and the inmates of the hospital in contrast to their abundance in general urban and rural parish communities. While we detect long-term shifts in local genetic ancestry in Cambridgeshire, we find no evidence of major changes in genetic ancestry nor higher differentiation of immune loci between cohorts living before and after the Black Death.
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Affiliation(s)
- Ruoyun Hui
- Alan Turing Institute, London, UK
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
| | - Christiana L. Scheib
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
- Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia
- St John’s College, University of Cambridge, Cambridge, UK
| | | | - Sarah A. Inskip
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
- School of Archaeology and Ancient History, University of Leicester, Leicester, UK
| | - Craig Cessford
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
- Cambridge Archaeological Unit, Department of Archaeology, University of Cambridge, Cambridge, UK
| | | | - Anthony W. Wohns
- School of Medicine, Stanford University, Stanford, CA, USA
- Department of Genetics and Biology, Stanford University, Stanford, CA, USA
| | | | - Samuel J. Griffith
- Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Anu Solnik
- Core Facility, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Helja Niinemäe
- Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Xiangyu Jack Ge
- Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK
| | - Alice K. Rose
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
- Department of Archaeology, University of Durham, Durham, UK
| | - Owyn Beneker
- Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Tamsin C. O’Connell
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
| | - John E. Robb
- Department of Archaeology, University of Cambridge, Cambridge, UK
| | - Toomas Kivisild
- McDonald Institute for Archaeological Research, University of Cambridge, Cambridge, UK
- Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia
- Department of Human Genetics, KU Leuven, Leuven, Belgium
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Lu D, Cai H, Li Y, Chang W, Liu X, Dai Q, Yu W, Chen W, Qiao G, Xie H, Xiao X, Li Z. Investigating the ID3/SLC22A4 as immune-related signatures in ischemic stroke. Aging (Albany NY) 2023; 15:14803-14829. [PMID: 38112574 PMCID: PMC10781493 DOI: 10.18632/aging.205308] [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: 08/03/2023] [Accepted: 11/03/2023] [Indexed: 12/21/2023]
Abstract
BACKGROUND Ischemic stroke (IS) is a fearful disease that can cause a variety of immune events. Nevertheless, precise immune-related mechanisms have yet to be systematically elucidated. This study aimed to identify immune-related signatures using machine learning and to validate them with animal experiments and single cell analysis. METHODS In this study, we screened 24 differentially expressed genes (DEGs) while identifying immune-related signatures that may play a key role in IS development through a comprehensive strategy between least absolute shrinkage and selection operation (LASSO) regression, support vector machine (SVM) and immune-related genes. In addition, we explored immune infiltration using the CIBERSORT algorithm. Finally, we performed validation in mouse brain tissue and single cell analysis. RESULTS We identified 24 DEGs for follow-up analysis. ID3 and SLC22A4 were finally identified as the better immune-related signatures through a comprehensive strategy among DEGs, LASSO, SVM and immune-related genes. RT-qPCR, western blot, and immunofluorescence revealed a significant decrease in ID3 and a significant increase in SLC22A4 in the middle cerebral artery occlusion group. Single cell analysis revealed that ID3 was mainly concentrated in endothelial_2 cells and SLC22A4 in astrocytes in the MCAO group. A CIBERSORT finds significantly altered levels of immune infiltration in IS patients. CONCLUSIONS This study focused on immune-related signatures after stroke and ID3 and SLC22A4 may be new therapeutic targets to promote functional recovery after stroke. Furthermore, the association of ID3 and SLC22A4 with immune cells may be a new direction for post-stroke immunotherapy.
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Affiliation(s)
- Dading Lu
- Department of Stroke Center, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
- Department of Neurology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
- Department of Neurosurgery, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
| | - Heng Cai
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Yugang Li
- Department of Stroke Center, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
| | - Wenyuan Chang
- Department of Neurology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
| | - Xiu Liu
- The First Clinical College, China Medical University, Shenbei, Shenyang, China
| | - Qiwei Dai
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Wanning Yu
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Wangli Chen
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Guomin Qiao
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Haojie Xie
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Xiong Xiao
- Department of Neurosurgery, Shengjing Hospital, Shenyang, China medical University, Heping, Shenyang, China
| | - Zhiqing Li
- Department of Stroke Center, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
- Department of Neurology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
- Department of Neurosurgery, The First Hospital of China Medical University, Heping, Shenyang, Liaoning, China
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10
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Wang X, Hu S, Wang J, Zhang T, Ye K, Wen A, Zhu G, Vegas A, Zhang L, Yan W, Liu X, Liu P. Biochemical and Structural Characterization of OvoA Th2: A Mononuclear Nonheme Iron Enzyme from Hydrogenimonas thermophila for Ovothiol Biosynthesis. ACS Catal 2023; 13:15417-15426. [PMID: 38058600 PMCID: PMC10696552 DOI: 10.1021/acscatal.3c04026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/27/2023] [Accepted: 10/30/2023] [Indexed: 12/08/2023]
Abstract
Ovothiol A and ergothioneine are thiol-histidine derivatives with sulfur substitutions at the δ-carbon or ε-carbon of the l-histidine imidazole ring, respectively. Both ovothiol A and ergothioneine have protective effects on many aging-related diseases, and the sulfur substitution plays a key role in determining their chemical and biological properties, while factors governing sulfur incorporation regioselectivities in ovothiol and ergothioneine biosynthesis in the corresponding enzymes (OvoA, Egt1, or EgtB) are not yet known. In this study, we have successfully obtained the first OvoA crystal structure, which provides critical information to explain their C-S bond formation regioselectivity. Furthermore, OvoATh2 exhibits several additional activities: (1) ergothioneine sulfoxide synthase activity akin to Egt1 in ergothioneine biosynthesis; (2) cysteine dioxygenase activity using l-cysteine and l-histidine analogues as substrates; (3) cysteine dioxygenase activity upon mutation of an active site tyrosine residue (Y406). The structural insights and diverse chemistries demonstrated by OvoATh2 pave the way for future comprehensive structure-function correlation studies.
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Affiliation(s)
- Xinye Wang
- State
Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Sha Hu
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Jun Wang
- School
of Life Sciences and Biotechnology, Shanghai
Jiao Tong University, Shanghai 200240, China
| | - Tao Zhang
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Ke Ye
- State
Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Aiwen Wen
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Guoliang Zhu
- State
Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Arturo Vegas
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Lixin Zhang
- State
Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Wupeng Yan
- School
of Life Sciences and Biotechnology, Shanghai
Jiao Tong University, Shanghai 200240, China
| | - Xueting Liu
- State
Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Pinghua Liu
- Department
of Chemistry, Boston University, Boston, Massachusetts 02215, United States
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11
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Lemons JMS, Conrad M, Tanes C, Chen J, Friedman ES, Roggiani M, Curry D, Chau L, Hecht AL, Harling L, Vales J, Kachelries KE, Baldassano RN, Goulian M, Bittinger K, Master SR, Liu L, Wu GD. Enterobacteriaceae Growth Promotion by Intestinal Acylcarnitines, a Biomarker of Dysbiosis in Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2023; 17:131-148. [PMID: 37739064 PMCID: PMC10694575 DOI: 10.1016/j.jcmgh.2023.09.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 09/12/2023] [Accepted: 09/12/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND & AIMS Altered plasma acylcarnitine levels are well-known biomarkers for a variety of mitochondrial fatty acid oxidation disorders and can be used as an alternative energy source for the intestinal epithelium when short-chain fatty acids are low. These membrane-permeable fatty acid intermediates are excreted into the gut lumen via bile and are increased in the feces of patients with inflammatory bowel disease (IBD). METHODS Herein, based on studies in human subjects, animal models, and bacterial cultures, we show a strong positive correlation between fecal carnitine and acylcarnitines and the abundance of Enterobacteriaceae in IBD where they can be consumed by bacteria both in vitro and in vivo. RESULTS Carnitine metabolism promotes the growth of Escherichia coli via anaerobic respiration dependent on the cai operon, and acetylcarnitine dietary supplementation increases fecal carnitine levels with enhanced intestinal colonization of the enteric pathogen Citrobacter rodentium. CONCLUSIONS In total, these results indicate that the increased luminal concentrations of carnitine and acylcarnitines in patients with IBD may promote the expansion of pathobionts belonging to the Enterobacteriaceae family, thereby contributing to disease pathogenesis.
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Affiliation(s)
- Johanna M S Lemons
- Dairy and Functional Foods Research Unit, Eastern Regional Research Center, Agricultural Research Service, US Department of Agriculture, Wyndmoor, Pennsylvania
| | - Maire Conrad
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Ceylan Tanes
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jie Chen
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Elliot S Friedman
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Manuela Roggiani
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Dylan Curry
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lillian Chau
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Aaron L Hecht
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lisa Harling
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jennifer Vales
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kelly E Kachelries
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Robert N Baldassano
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Mark Goulian
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kyle Bittinger
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Stephen R Master
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - LinShu Liu
- Dairy and Functional Foods Research Unit, Eastern Regional Research Center, Agricultural Research Service, US Department of Agriculture, Wyndmoor, Pennsylvania.
| | - Gary D Wu
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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12
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Caliendo G, D'Elia G, Makker J, Passariello L, Albanese L, Molinari AM, Vietri MT. Biological, genetic and epigenetic markers in ulcerative colitis. Adv Med Sci 2023; 68:386-395. [PMID: 37813048 DOI: 10.1016/j.advms.2023.09.010] [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: 11/17/2022] [Revised: 04/15/2023] [Accepted: 09/18/2023] [Indexed: 10/11/2023]
Abstract
In this review, we have summarized the existing knowledge of ulcerative colitis (UC) markers based on current literature, specifically, the roles of potential new biomarkers, such as circulating, fecal, genetic, and epigenetic alterations, in UC onset, disease activity, and in therapy response. UC is a complex multifactorial inflammatory disease. There are many invasive and non-invasive diagnostic methods in UC, including several laboratory markers which are employed in diagnosis and disease assessment; however, colonoscopy remains the most widely used method. Common laboratory abnormalities currently used in the clinical practice include inflammation-induced alterations, serum autoantibodies, and antibodies against bacterial antigens. Other new serum and fecal biomarkers are supportive in diagnosis and monitoring disease activity and therapy response; and potential salivary markers are currently being evaluated as well. Several UC-related genetic and epigenetic alterations are implied in its pathogenesis and therapeutic response. Moreover, the use of artificial intelligence in the integration of laboratory biomarkers and big data could potentially be useful in clinical translation and precision medicine in UC management.
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Affiliation(s)
- Gemma Caliendo
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanna D'Elia
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Jasmine Makker
- Department of GKT School of Medical Education, King's College London, London, UK
| | - Luana Passariello
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luisa Albanese
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Maria Molinari
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Teresa Vietri
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
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13
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Shmuel-Galia L, Humphries F, Vierbuchen T, Jiang Z, Santos N, Johnson J, Shklyar B, Joannas L, Mustone N, Sherman S, Ward D, Houghton J, Baer CE, O'Hara A, Henao-Mejia J, Hoebe K, Fitzgerald KA. The lncRNA HOXA11os regulates mitochondrial function in myeloid cells to maintain intestinal homeostasis. Cell Metab 2023; 35:1441-1456.e9. [PMID: 37494932 DOI: 10.1016/j.cmet.2023.06.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/25/2023] [Accepted: 06/29/2023] [Indexed: 07/28/2023]
Abstract
This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS). As a result, HOXA11os-deficient mice develop spontaneous intestinal inflammation and are hypersusceptible to colitis. Collectively, these studies identify a new regulatory axis whereby a lncRNA maintains intestinal homeostasis and restricts inflammation in the colon through the regulation of complex I activity.
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Affiliation(s)
- Liraz Shmuel-Galia
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
| | - Fiachra Humphries
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Tim Vierbuchen
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Zhaozhao Jiang
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Nolan Santos
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - John Johnson
- Immunology Discovery, Janssen Research and Development LLC, Spring House, PA 19477, USA
| | - Boris Shklyar
- Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
| | - Leonel Joannas
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas Mustone
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Shany Sherman
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Doyle Ward
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Center for Microbiome Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - JeanMarie Houghton
- Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Christina E Baer
- Sanderson Center for Optical Imaging and Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Aisling O'Hara
- Immunology Discovery, Janssen Research and Development LLC, Spring House, PA 19477, USA
| | - Jorge Henao-Mejia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kasper Hoebe
- Immunology Discovery, Janssen Research and Development LLC, Spring House, PA 19477, USA
| | - Katherine A Fitzgerald
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
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14
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Uwada J, Nakazawa H, Muramatsu I, Masuoka T, Yazawa T. Role of Muscarinic Acetylcholine Receptors in Intestinal Epithelial Homeostasis: Insights for the Treatment of Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:ijms24076508. [PMID: 37047478 PMCID: PMC10095461 DOI: 10.3390/ijms24076508] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is an intestinal disorder that causes prolonged inflammation of the gastrointestinal tract. Currently, the etiology of IBD is not fully understood and treatments are insufficient to completely cure the disease. In addition to absorbing essential nutrients, intestinal epithelial cells prevent the entry of foreign antigens (micro-organisms and undigested food) through mucus secretion and epithelial barrier formation. Disruption of the intestinal epithelial homeostasis exacerbates inflammation. Thus, the maintenance and reinforcement of epithelial function may have therapeutic benefits in the treatment of IBD. Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors for acetylcholine that are expressed in intestinal epithelial cells. Recent studies have revealed the role of mAChRs in the maintenance of intestinal epithelial homeostasis. The importance of non-neuronal acetylcholine in mAChR activation in epithelial cells has also been recognized. This review aimed to summarize recent advances in research on mAChRs for intestinal epithelial homeostasis and the involvement of non-neuronal acetylcholine systems, and highlight their potential as targets for IBD therapy.
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15
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Hirasawa T, Shimoyamada Y, Tachikawa Y, Satoh Y, Kawano Y, Dairi T, Ohtsu I. Ergothioneine production by Corynebacterium glutamicum harboring heterologous biosynthesis pathways. J Biosci Bioeng 2023; 135:25-33. [PMID: 36334975 DOI: 10.1016/j.jbiosc.2022.10.002] [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: 07/06/2022] [Revised: 09/21/2022] [Accepted: 10/03/2022] [Indexed: 11/06/2022]
Abstract
In this study, Corynebacterium glutamicum was engineered to produce ergothioneine, an amino acid derivative with high antioxidant activity. The ergothioneine biosynthesis genes, egtABCDE, from Mycolicibacterium smegmatis were introduced into wild-type and l-cysteine-producing strains of C. glutamicum to evaluate their ergothioneine production. In the l-cysteine-producing strain, ergothioneine production reached approximately 40 mg L-1 after 2 weeks, and the amount was higher than that in the wild-type strain. As C. glutamicum possesses an ortholog of M. smegmatis egtA, which encodes an enzyme responsible for γ-glutamyl-l-cysteine synthesis, the effect of introducing egtBCDE genes on ergothioneine production in the l-cysteine-producing strain was evaluated, revealing that a further increase to more than 70 mg L-1 was achieved. As EgtBs from Methylobacterium bacteria are reported to use l-cysteine as a sulfur donor in ergothioneine biosynthesis, egtB from Methylobacterium was expressed with M. smegmatis egtDE in the l-cysteine-producing strain. As a result, ergothioneine production was further improved to approximately 100 mg L-1. These results indicate that utilization of the l-cysteine-producing strain and introduction of heterologous biosynthesis pathways from M. smegmatis and Methylobacterium bacteria are effective for improved ergothioneine production by C. glutamicum.
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Affiliation(s)
- Takashi Hirasawa
- School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.
| | - Yuki Shimoyamada
- School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
| | - Yukio Tachikawa
- School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
| | - Yasuharu Satoh
- Graduate School of Engineering, Hokkaido University, N13 & W8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
| | - Yusuke Kawano
- Gradutate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Tohru Dairi
- Graduate School of Engineering, Hokkaido University, N13 & W8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
| | - Iwao Ohtsu
- Gradutate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
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16
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Dumitrescu DG, Gordon EM, Kovalyova Y, Seminara AB, Duncan-Lowey B, Forster ER, Zhou W, Booth CJ, Shen A, Kranzusch PJ, Hatzios SK. A microbial transporter of the dietary antioxidant ergothioneine. Cell 2022; 185:4526-4540.e18. [PMID: 36347253 PMCID: PMC9691600 DOI: 10.1016/j.cell.2022.10.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/16/2022] [Accepted: 10/07/2022] [Indexed: 11/09/2022]
Abstract
Low-molecular-weight (LMW) thiols are small-molecule antioxidants required for the maintenance of intracellular redox homeostasis. However, many host-associated microbes, including the gastric pathogen Helicobacter pylori, unexpectedly lack LMW-thiol biosynthetic pathways. Using reactivity-guided metabolomics, we identified the unusual LMW thiol ergothioneine (EGT) in H. pylori. Dietary EGT accumulates to millimolar levels in human tissues and has been broadly implicated in mitigating disease risk. Although certain microorganisms synthesize EGT, we discovered that H. pylori acquires this LMW thiol from the host environment using a highly selective ATP-binding cassette transporter-EgtUV. EgtUV confers a competitive colonization advantage in vivo and is widely conserved in gastrointestinal microbes. Furthermore, we found that human fecal bacteria metabolize EGT, which may contribute to production of the disease-associated metabolite trimethylamine N-oxide. Collectively, our findings illustrate a previously unappreciated mechanism of microbial redox regulation in the gut and suggest that inter-kingdom competition for dietary EGT may broadly impact human health.
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Affiliation(s)
- Daniel G Dumitrescu
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
| | - Elizabeth M Gordon
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
| | - Yekaterina Kovalyova
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
| | - Anna B Seminara
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Brianna Duncan-Lowey
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Emily R Forster
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA; Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Wen Zhou
- Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Carmen J Booth
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Aimee Shen
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Philip J Kranzusch
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Stavroula K Hatzios
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA.
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17
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Pharmacogenetic Variation and Its Clinical Relevance in a Latin American Rural Population. Int J Mol Sci 2022; 23:ijms231911758. [PMID: 36233078 PMCID: PMC9570141 DOI: 10.3390/ijms231911758] [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: 08/29/2022] [Revised: 09/21/2022] [Accepted: 09/27/2022] [Indexed: 11/17/2022] Open
Abstract
Latin-American populations have been largely underrepresented in genomic studies of drug response and disease susceptibility. In this paper, we present a genome-wide Chilean dataset from Talca based on the Illumina Global Screening Array. This let us to compare the frequency of gene variants involved in response to drugs among our population and others, taking data from the 1000 Genomes Project. We found four single-nucleotide polymorphisms with low prevalence in Chileans when compared with African, Amerindian, East and South Asian, and European populations: rs2819742 (RYR2), rs2631367 (SLC22A5), rs1063320 (HLA-G), and rs1042522 (TP53). Moreover, two markers showed significant differences between lower and higher proportion of Mapuche ancestry groups: rs1719247 (located in an intergenic region in chromosome 15; p-value = 6.17 × 10−5, Bonferroni corrected p-value = 0.02) and rs738409 (A nonsynonymous gene variant in the PNPLA3 gene; p-value = 9.02 × 10−5, Bonferroni corrected p-value = 0.04). All of these polymorphisms have been shown to be associated with diverse pathologies, such as asthma, cancer, or chronic hepatitis B, or to be involved in a different response to drugs, such as metformin, HMG-CoA reductase inhibitors, or simvastatin. The present work provides a pharmacogenetic landscape of an understudied Latin American rural population and supports the notion that pharmacogenetic studies in admixed populations should consider ancestry for a higher accuracy of the results. Our study stresses the relevance of the pharmacogenomic research to provide guidance for a better choice of the best treatment for each individual in a population with admixed ancestry.
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18
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Zheng PF, Chen LZ, Liu P, Pan HW, Fan WJ, Liu ZY. Identification of immune-related key genes in the peripheral blood of ischaemic stroke patients using a weighted gene coexpression network analysis and machine learning. J Transl Med 2022; 20:361. [PMID: 35962388 PMCID: PMC9373395 DOI: 10.1186/s12967-022-03562-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/30/2022] [Indexed: 11/28/2022] Open
Abstract
Background The immune system plays a vital role in the pathological process of ischaemic stroke. However, the exact immune-related mechanism remains unclear. The current research aimed to identify immune-related key genes associated with ischaemic stroke. Methods CIBERSORT was utilized to reveal the immune cell infiltration pattern in ischaemic stroke patients. Meanwhile, a weighted gene coexpression network analysis (WGCNA) was utilized to identify meaningful modules significantly correlated with ischaemic stroke. The characteristic genes correlated with ischaemic stroke were identified by the following two machine learning methods: the support vector machine-recursive feature elimination (SVM-RFE) algorithm and least absolute shrinkage and selection operator (LASSO) logistic regression. Results The CIBERSORT results suggested that there was a decreased infiltration of naive CD4 T cells, CD8 T cells, resting mast cells and eosinophils and an increased infiltration of neutrophils, M0 macrophages and activated memory CD4 T cells in ischaemic stroke patients. Then, three significant modules (pink, brown and cyan) were identified to be significantly associated with ischaemic stroke. The gene enrichment analysis indicated that 519 genes in the above three modules were mainly involved in several inflammatory or immune-related signalling pathways and biological processes. Eight hub genes (ADM, ANXA3, CARD6, CPQ, SLC22A4, UBE2S, VIM and ZFP36) were revealed to be significantly correlated with ischaemic stroke by the LASSO logistic regression and SVM-RFE algorithm. The external validation combined with a RT‒qPCR analysis revealed that the expression levels of ADM, ANXA3, SLC22A4 and VIM were significantly increased in ischaemic stroke patients and that these key genes were positively associated with neutrophils and M0 macrophages and negatively correlated with CD8 T cells. The mean AUC value of ADM, ANXA3, SLC22A4 and VIM was 0.80, 0.87, 0.91 and 0.88 in the training set, 0.85, 0.77, 0.86 and 0.72 in the testing set and 0.87, 0.83, 0.88 and 0.91 in the validation samples, respectively. Conclusions These results suggest that the ADM, ANXA3, SLC22A4 and VIM genes are reliable serum markers for the diagnosis of ischaemic stroke and that immune cell infiltration plays a crucial role in the occurrence and development of ischaemic stroke. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03562-w.
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Affiliation(s)
- Peng-Fei Zheng
- Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.,Clinical Research Center for Heart Failure in Hunan Province, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.,Institute of Cardiovascular Epidemiology, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China
| | - Lu-Zhu Chen
- Department of Cardiology, The Central Hospital of ShaoYang, No.36 QianYuan Lane, Daxiang District, Shaoyang, 422000, Hunan, China
| | - Peng Liu
- Department of Cardiology, The Central Hospital of ShaoYang, No.36 QianYuan Lane, Daxiang District, Shaoyang, 422000, Hunan, China
| | - Hong Wei Pan
- Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.,Clinical Research Center for Heart Failure in Hunan Province, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.,Institute of Cardiovascular Epidemiology, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China
| | - Wen-Juan Fan
- Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China. .,Clinical Research Center for Heart Failure in Hunan Province, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China. .,Institute of Cardiovascular Epidemiology, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.
| | - Zheng-Yu Liu
- Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China. .,Clinical Research Center for Heart Failure in Hunan Province, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China. .,Institute of Cardiovascular Epidemiology, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.
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19
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Alrubia S, Al-Majdoub ZM, Achour B, Rostami-Hodjegan A, Barber J. Quantitative Assessment of the Impact of Crohn's Disease on Protein Abundance of Human Intestinal Drug-Metabolising Enzymes and Transporters. J Pharm Sci 2022; 111:2917-2929. [PMID: 35872023 DOI: 10.1016/j.xphs.2022.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/17/2022] [Accepted: 07/17/2022] [Indexed: 10/17/2022]
Abstract
Crohn's disease affects the mucosal layer of the intestine, predominantly ileum and colon segments, with the potential to affect the expression of intestinal enzymes and transporters, and consequently, oral drug bioavailability. We carried out a quantitative proteomic analysis of inflamed and non-inflamed ileum and colon tissues from Crohn's disease patients and healthy donors. Homogenates from samples in each group were pooled and protein abundance determined by liquid chromatography-mass spectrometry (LC-MS). In inflamed Crohn's ileum, CYP3A4, CYP20A1, CYP51A1, ADH1B, ALPI, FOM1, SULT1A2, SULT1B1 and ABCB7 showed ≥10-fold reduction in abundance compared with healthy baseline. By contrast, only MGST1 showed ≥10 fold reduction in inflamed colon. Ileal UGT1A1, MGST1, MGST2, and MAOA levels increased by ≥2 fold in Crohn's patients, while only ALPI showed ≥2 fold increase in the colon. Counter-intuitively, non-inflamed ileum had a higher magnitude of fold change than inflamed tissue when compared with healthy tissue. Marked but non-uniform alterations were observed in the expression of various enzymes and transporters in ileum and colon compared with healthy samples. Modelling will allow improved understanding of the variable effects of Crohn's disease on bioavailability of orally administered drugs.
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Affiliation(s)
- Sarah Alrubia
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK; Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
| | - Brahim Achour
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, the University of Rhode Island, Kingston, Rhode Island, USA
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK; Certara UK Ltd, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, UK
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
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20
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Abstract
Significance: Ergothioneine (ET) is an unusual sulfur-containing amino acid derived from histidine, acquired predominantly from food. Its depletion is associated with deleterious consequences in response to stress stimuli in cell culture models, prompting us to classify it as a vitamin in 2010, which was later supported by in vivo studies. ET is obtained from a variety of foods and is taken up by a selective transporter. ET possesses antioxidant and anti-inflammatory properties that confer cytoprotection. ET crosses the blood-brain barrier and has been reported to have beneficial effects in the brain. In this study, we discuss the cytoprotective and neuroprotective properties of ET, which may be harnessed for combating neurodegeneration and decline during aging. Recent Advances: The designation of ET as a stress vitamin is gaining momentum, opening a new field of investigation involving small molecules that are essential for optimal physiological functioning and maintenance of health span. Critical Issues: Although ET was discovered more than a century ago, its physiological functions are still being elucidated, especially in the brain. As ET is present in most foods, toxicity associated with its deprivation has been difficult to assess. Future Directions: Using genetically engineered cells and mice, it may now be possible to elucidate roles of ET. This coupled with advances in genomics and metabolomics may lead to identification of ET function. As ET is a stable antioxidant with anti-inflammatory properties, whose levels decline during aging, supplementing ET in the diet or consuming an ET-rich diet may prove beneficial. Antioxid. Redox Signal. 36, 1306-1317.
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Affiliation(s)
- Bindu D Paul
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of The Solomon H. Snyder Department of Neuroscience, and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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21
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Shaheen A, Alam SM, Azam F, Saleem SA, Khan M, Hasan SS, Liaquat A. Lack of impact of OCTN1 gene polymorphisms on clinical outcomes of gabapentinoids in Pakistani patients with neuropathic pain. PLoS One 2022; 17:e0266559. [PMID: 35559956 PMCID: PMC9106170 DOI: 10.1371/journal.pone.0266559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 03/22/2022] [Indexed: 11/29/2022] Open
Abstract
Background and objective Gabapentinoids are the first-line drugs for neuropathic pain. These drugs are the substrate of organic cation transporter (OCTN1) for renal excretion and absorption across the intestinal epithelium. Gabapentinoids exhibit wide interindividual variability in daily dosage and therapeutic efficacy which makes titration regimens prolonged for optimal efficacy. The present study aimed to investigate the possible influence of the single nucleotide polymorphism (SNP) of OCTN1 on therapeutic efficacy and safety of gabapentinoids in neuropathic pain patients of the Pakistani population. Methods Four hundred and twenty-six patients were enrolled in the study. All participants were genotyped for OCTN1 rs1050152 and rs3792876 by PCR-RFLP method and followed up for eight weeks. The therapeutic outcomes of gabapentinoids, reduction in pain score, inadequate or complete lack of response, adverse events (AEs) in responders and discontinuation of treatment on account of AEs were recorded for all patients. Results There was no significant association of genotypes and alleles of both SNPs on the clinical response of gabapentinoids (P ˃ 0.05). Similarly, significant differences were not found in the reduction of pain scores and AEs among different genotypes in the responders. The present study has reported the association of OCTN1 rs1050152 and rs3792876 polymorphisms with clinical outcomes of gabapentinoids for the first time in the real-world clinical setting. Conclusion Our results suggest a lack of influence of OCTN1 genetic variants in the determination of clinical response to gabapentinoids in patients with neuropathic pain in the Pakistani population. These findings signify the role of renal functions in predicting the interindividual variability to therapeutic responsiveness of gabapentinoids.
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Affiliation(s)
- Abida Shaheen
- Department of Pharmacology & Therapeutics, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
- * E-mail:
| | - Syed Mahboob Alam
- Department of Pharmacology & Therapeutics, Basic Medical Sciences Institute, JPMC, Karachi, Pakistan
| | - Fahad Azam
- Department of Pharmacology & Therapeutics, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Salman Ahmad Saleem
- Department of Pain Clinic, Shifa International Hospital, Islamabad, Pakistan
| | - Moosa Khan
- Department of Pharmacology & Therapeutics, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Syed Saud Hasan
- Department of Pharmacology & Therapeutics, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Afrose Liaquat
- Department of Biochemistry, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
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22
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Cordell GA, Lamahewage SNS. Ergothioneine, Ovothiol A, and Selenoneine-Histidine-Derived, Biologically Significant, Trace Global Alkaloids. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27092673. [PMID: 35566030 PMCID: PMC9103826 DOI: 10.3390/molecules27092673] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/15/2022] [Accepted: 04/16/2022] [Indexed: 11/16/2022]
Abstract
The history, chemistry, biology, and biosynthesis of the globally occurring histidine-derived alkaloids ergothioneine (10), ovothiol A (11), and selenoneine (12) are reviewed comparatively and their significance to human well-being is discussed.
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Affiliation(s)
- Geoffrey A. Cordell
- Natural Products Inc., Evanston, IL 60202, USA
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
- Correspondence:
| | - Sujeewa N. S. Lamahewage
- Department of Chemistry, Iowa State University, Ames, IA 50011, USA;
- Department of Chemistry, University of Ruhuna, Matara 81000, Sri Lanka
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23
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Qian F, Jiang X, Chai R, Liu D. The Roles of Solute Carriers in Auditory Function. Front Genet 2022; 13:823049. [PMID: 35154281 PMCID: PMC8827148 DOI: 10.3389/fgene.2022.823049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/03/2022] [Indexed: 11/13/2022] Open
Abstract
Solute carriers (SLCs) are important transmembrane transporters with members organized into 65 families. They play crucial roles in transporting many important molecules, such as ions and some metabolites, across the membrane, maintaining cellular homeostasis. SLCs also play important roles in hearing. It has been found that mutations in some SLC members are associated with hearing loss. In this review, we summarize SLC family genes related with hearing dysfunction to reveal the vital roles of these transporters in auditory function. This summary could help us understand the auditory physiology and the mechanisms of hearing loss and further guide future studies of deafness gene identification.
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Affiliation(s)
- Fuping Qian
- School of Life Sciences, Nantong University, Nantong, China
| | - Xiaoge Jiang
- Department of Rehabilitation Medicine, The Second People's Hospital of Nantong, Affiliated Rehabilitation Hospital of Nantong University, Nantong, China
| | - Renjie Chai
- State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.,Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.,Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Dong Liu
- School of Life Sciences, Nantong University, Nantong, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
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24
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Pochini L, Galluccio M, Scalise M, Console L, Pappacoda G, Indiveri C. OCTN1: A Widely Studied but Still Enigmatic Organic Cation Transporter Linked to Human Pathology and Drug Interactions. Int J Mol Sci 2022; 23:ijms23020914. [PMID: 35055100 PMCID: PMC8776198 DOI: 10.3390/ijms23020914] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
The Novel Organic Cation Transporter, OCTN1, is the first member of the OCTN subfamily; it belongs to the wider Solute Carrier family SLC22, which counts many members including cation and anion organic transporters. The tertiary structure has not been resolved for any cation organic transporter. The functional role of OCNT1 is still not well assessed despite the many functional studies so far conducted. The lack of a definitive identification of OCTN1 function can be attributed to the different experimental systems and methodologies adopted for studying each of the proposed ligands. Apart from the contradictory data, the international scientific community agrees on a role of OCTN1 in protecting cells and tissues from oxidative and/or inflammatory damage. Moreover, the involvement of this transporter in drug interactions and delivery has been well clarified, even though the exact profile of the transported/interacting molecules is still somehow confusing. Therefore, OCTN1 continues to be a hot topic in terms of its functional role and structure. This review focuses on the most recent advances on OCTN1 in terms of functional aspects, physiological roles, substrate specificity, drug interactions, tissue expression, and relationships with pathology.
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Affiliation(s)
- Lorena Pochini
- Unit of Biochemistry, Molecular Biotechnology and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, Arcavacata di Rende, 87036 Cosenza, Italy; (L.P.); (M.G.); (M.S.); (L.C.); (G.P.)
| | - Michele Galluccio
- Unit of Biochemistry, Molecular Biotechnology and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, Arcavacata di Rende, 87036 Cosenza, Italy; (L.P.); (M.G.); (M.S.); (L.C.); (G.P.)
| | - Mariafrancesca Scalise
- Unit of Biochemistry, Molecular Biotechnology and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, Arcavacata di Rende, 87036 Cosenza, Italy; (L.P.); (M.G.); (M.S.); (L.C.); (G.P.)
| | - Lara Console
- Unit of Biochemistry, Molecular Biotechnology and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, Arcavacata di Rende, 87036 Cosenza, Italy; (L.P.); (M.G.); (M.S.); (L.C.); (G.P.)
| | - Gilda Pappacoda
- Unit of Biochemistry, Molecular Biotechnology and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, Arcavacata di Rende, 87036 Cosenza, Italy; (L.P.); (M.G.); (M.S.); (L.C.); (G.P.)
| | - Cesare Indiveri
- Unit of Biochemistry, Molecular Biotechnology and Molecular Biology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Via P. Bucci 4c, Arcavacata di Rende, 87036 Cosenza, Italy; (L.P.); (M.G.); (M.S.); (L.C.); (G.P.)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnology (IBIOM), National Research Council—CNR, Via Amendola 122/O, 70126 Bari, Italy
- Correspondence:
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25
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Gründemann D, Hartmann L, Flögel S. The Ergothioneine Transporter (ETT): Substrates and Locations, an Inventory. FEBS Lett 2021; 596:1252-1269. [PMID: 34958679 DOI: 10.1002/1873-3468.14269] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 11/07/2022]
Abstract
In all vertebrates including mammals, the ergothioneine transporter ETT (obsolete name OCTN1; human gene symbol SLC22A4) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). ETT is not expressed ubiquitously and only cells with high ETT cell-surface levels can accumulate ET to high concentration. Without ETT, there is no uptake because the plasma membrane is essentially impermeable to this hydrophilic zwitterion. Here, we review the substrate specificity and localization of ETT, which is prominently expressed in neutrophils, monocytes/macrophages, and developing erythrocytes. Most sites of strong expression are conserved across species, but there are also major differences. In particular, we critically analyze the evidence for the expression of ETT in the brain as well as recent data suggesting that the transporter SLC22A15 may transport also ET. We conclude that, to date, ETT remains the only well-defined biomarker for intracellular ET activity. In humans, the ability to take up, distribute, and retain ET depends principally on this transporter.
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Affiliation(s)
- Dirk Gründemann
- Department of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Lea Hartmann
- Department of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Straße 24, 50931, Cologne, Germany
| | - Svenja Flögel
- Department of Pharmacology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Gleueler Straße 24, 50931, Cologne, Germany
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26
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Ho GT, Theiss AL. Mitochondria and Inflammatory Bowel Diseases: Toward a Stratified Therapeutic Intervention. Annu Rev Physiol 2021; 84:435-459. [PMID: 34614372 DOI: 10.1146/annurev-physiol-060821-083306] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mitochondria serve numerous critical cellular functions, rapidly responding to extracellular stimuli and cellular demands while dynamically communicating with other organelles. Mitochondrial function in the gastrointestinal epithelium plays a critical role in maintaining intestinal health. Emerging studies implicate the involvement of mitochondrial dysfunction in inflammatory bowel disease (IBD). This review presents mitochondrial metabolism, function, and quality control that converge in intestinal epithelial stemness, differentiation programs, barrier integrity, and innate immunity to influence intestinal inflammation. Intestinal and disease characteristics that set the stage for mitochondrial dysfunction being a key factor in IBD, and in turn, pathogenic mitochondrial mechanisms influencing and potentiating the development of IBD, are discussed. These findings establish the basis for potential mitochondrial-targeted interventions for IBD therapy. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Gwo-Tzer Ho
- Edinburgh IBD Science Unit, Centre for Inflammation Research, Queens Medical Research Unit, University of Edinburgh, Edinburgh, United Kingdom
| | - Arianne L Theiss
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA;
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27
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Smith SA, Ogawa SA, Chau L, Whelan KA, Hamilton KE, Chen J, Tan L, Chen EZ, Keilbaugh S, Fogt F, Bewtra M, Braun J, Xavier RJ, Clish CB, Slaff B, Weljie AM, Bushman FD, Lewis JD, Li H, Master SR, Bennett MJ, Nakagawa H, Wu GD. Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines. J Clin Invest 2021; 131:133371. [PMID: 33141762 DOI: 10.1172/jci133371] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 10/09/2020] [Indexed: 12/26/2022] Open
Abstract
As the interface between the gut microbiota and the mucosal immune system, there has been great interest in the maintenance of colonic epithelial integrity through mitochondrial oxidation of butyrate, a short-chain fatty acid produced by the gut microbiota. Herein, we showed that the intestinal epithelium could also oxidize long-chain fatty acids, and that luminally delivered acylcarnitines in bile could be consumed via apical absorption by the intestinal epithelium, resulting in mitochondrial oxidation. Finally, intestinal inflammation led to mitochondrial dysfunction in the apical domain of the surface epithelium that may reduce the consumption of fatty acids, contributing to higher concentrations of fecal acylcarnitines in murine Citrobacter rodentium-induced colitis and human inflammatory bowel disease. These results emphasized the importance of both the gut microbiota and the liver in the delivery of energy substrates for mitochondrial metabolism by the intestinal epithelium.
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Affiliation(s)
- Sarah A Smith
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sayaka A Ogawa
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lillian Chau
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kelly A Whelan
- Fels Institute for Cancer Research and Molecular Biology, Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Kathryn E Hamilton
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Jie Chen
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Lu Tan
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Eric Z Chen
- Department of Informatics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sue Keilbaugh
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Franz Fogt
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Meenakshi Bewtra
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jonathan Braun
- Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ramnik J Xavier
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.,Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Clary B Clish
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA
| | - Barry Slaff
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Aalim M Weljie
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Frederic D Bushman
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James D Lewis
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hongzhe Li
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Stephen R Master
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Michael J Bennett
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hiroshi Nakagawa
- Division of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Research Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Gary D Wu
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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28
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Ma R, Cai TT, Li H. Global and Simultaneous Hypothesis Testing for High-Dimensional Logistic Regression Models. J Am Stat Assoc 2021; 116:984-998. [PMID: 34421157 DOI: 10.1080/01621459.2019.1699421] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
High-dimensional logistic regression is widely used in analyzing data with binary outcomes. In this paper, global testing and large-scale multiple testing for the regression coefficients are considered in both single- and two-regression settings. A test statistic for testing the global null hypothesis is constructed using a generalized low-dimensional projection for bias correction and its asymptotic null distribution is derived. A lower bound for the global testing is established, which shows that the proposed test is asymptotically minimax optimal over some sparsity range. For testing the individual coefficients simultaneously, multiple testing procedures are proposed and shown to control the false discovery rate (FDR) and falsely discovered variables (FDV) asymptotically. Simulation studies are carried out to examine the numerical performance of the proposed tests and their superiority over existing methods. The testing procedures are also illustrated by analyzing a data set of a metabolomics study that investigates the association between fecal metabolites and pediatric Crohn's disease and the effects of treatment on such associations.
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Affiliation(s)
- Rong Ma
- University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104 United States.,The Wharton School - Univ of Pennsylvania, Philadelphia, 19104 United States.,University of Pennsylvania School of Medicine, 215 Blockley Hall, Philadelphia, 19104 United States
| | - T Tony Cai
- University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104 United States.,The Wharton School - Univ of Pennsylvania, Philadelphia, 19104 United States.,University of Pennsylvania School of Medicine, 215 Blockley Hall, Philadelphia, 19104 United States
| | - Hongzhe Li
- University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104 United States.,The Wharton School - Univ of Pennsylvania, Philadelphia, 19104 United States.,University of Pennsylvania School of Medicine, 215 Blockley Hall, Philadelphia, 19104 United States
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29
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Banerjee S, Simonetti FL, Detrois KE, Kaphle A, Mitra R, Nagial R, Söding J. Tejaas: reverse regression increases power for detecting trans-eQTLs. Genome Biol 2021; 22:142. [PMID: 33957961 PMCID: PMC8101255 DOI: 10.1186/s13059-021-02361-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 04/22/2021] [Indexed: 12/18/2022] Open
Abstract
Trans-acting expression quantitative trait loci (trans-eQTLs) account for ≥70% expression heritability and could therefore facilitate uncovering mechanisms underlying the origination of complex diseases. Identifying trans-eQTLs is challenging because of small effect sizes, tissue specificity, and a severe multiple-testing burden. Tejaas predicts trans-eQTLs by performing L2-regularized “reverse” multiple regression of each SNP on all genes, aggregating evidence from many small trans-effects while being unaffected by the strong expression correlations. Combined with a novel unsupervised k-nearest neighbor method to remove confounders, Tejaas predicts 18851 unique trans-eQTLs across 49 tissues from GTEx. They are enriched in open chromatin, enhancers, and other regulatory regions. Many overlap with disease-associated SNPs, pointing to tissue-specific transcriptional regulation mechanisms.
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Affiliation(s)
- Saikat Banerjee
- Quantitative and Computational Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.
| | - Franco L Simonetti
- Quantitative and Computational Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany
| | - Kira E Detrois
- Quantitative and Computational Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.,Georg-August University, Göttingen, 37075, Germany
| | - Anubhav Kaphle
- Quantitative and Computational Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.,Georg-August University, Göttingen, 37075, Germany
| | | | | | - Johannes Söding
- Quantitative and Computational Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany. .,Campus-Institut Data Science (CIDAS), University of Göttingen, Göttingen, 37073, Germany. .,Cluster of Excellence "Multiscale Bioimaging" (MBExC), University of Göttingen, Göttingen, 37075, Germany.
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30
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Gyawali A, Hyeon SJ, Ryu H, Kang YS. The Alteration of L-Carnitine Transport and Pretreatment Effect under Glutamate Cytotoxicity on Motor Neuron-Like NSC-34 Lines. Pharmaceutics 2021; 13:pharmaceutics13040551. [PMID: 33919926 PMCID: PMC8070968 DOI: 10.3390/pharmaceutics13040551] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 12/04/2022] Open
Abstract
L-Carnitine (LC) is essential for transporting fatty acids to the mitochondria for β-oxidation. This study was performed to examine the alteration of the LC transport system in wild type (WT, NSC-34/hSOD1WT) and mutant type (MT, NSC-34/hSOD1G93A) amyotrophic lateral sclerosis (ALS) models. The uptake of [3H]L-carnitine was dependent on time, temperature, concentration, sodium, pH, and energy in both cell lines. The Michaelis–Menten constant (Km) value as well as maximum transport velocity (Vmax) indicated that the MT cell lines showed the higher affinity and lower capacity transport system, compared to that of the WT cell lines. Additionally, LC uptake was inhibited by organic cationic compounds but unaffected by organic anions. OCTN1/slc22a4 and OCTN2/slc22a5 siRNA transfection study revealed both transporters are involved in LC transport in NSC-34 cell lines. Additionally, slc22a4 and slc22a5 was significantly decreased in mouse MT models compared with that in ALS WT littermate models in the immune-reactivity study. [3H]L-Carnitine uptake and mRNA expression pattern showed the pretreatment of LC and acetyl L-carnitine (ALC) attenuated glutamate induced neurotoxicity in NSC-34 cell lines. These findings indicate that LC and ALC supplementation can prevent the neurotoxicity and neuro-inflammation induced by glutamate in motor neurons.
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Affiliation(s)
- Asmita Gyawali
- College of Pharmacy and Drug Information Research Institute, Sookmyung Women’s University, Seoul 04310, Korea;
| | - Seung Jae Hyeon
- Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.J.H.); (H.R.)
| | - Hoon Ryu
- Laboratory for Brain Gene Regulation and Epigenetics, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.J.H.); (H.R.)
| | - Young-Sook Kang
- College of Pharmacy and Drug Information Research Institute, Sookmyung Women’s University, Seoul 04310, Korea;
- Correspondence: ; Tel.: +82-2-710-9562; Fax: +82-2-710-9871
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31
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Kitagaki H. Medical Application of Substances Derived from Non-Pathogenic Fungi Aspergillus oryzae and A. luchuensis-Containing Koji. J Fungi (Basel) 2021; 7:243. [PMID: 33804991 PMCID: PMC8063943 DOI: 10.3390/jof7040243] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023] Open
Abstract
Although most fungi cause pathogenicity toward human beings, dynasties of the East Asian region have domesticated and utilized specific fungi for medical applications. The Japanese dynasty and nation have domesticated and utilized koji fermented with non-pathogenic fungus Aspergillus oryzae for more than 1300 years. Recent research has elucidated that koji contains medicinal substances such as Taka-diastase, acid protease, koji glycosylceramide, kojic acid, oligosaccharides, ethyl-α-d-glucoside, ferulic acid, ergothioneine, pyroglutamyl leucine, pyranonigrin A, resistant proteins, deferriferrichrysin, polyamines, Bifidobacterium-stimulating peptides, angiotensin I-converting enzyme inhibitor peptides, 14-dehydroergosterol, beta-glucan, biotin, and citric acid. This review introduces potential medical applications of such medicinal substances to hyperlipidemia, diabetes, hypertension, cardiovascular and cognitive diseases, chronic inflammation, epidermal permeability barrier disruption, coronavirus disease 2019 (COVID-19), and anti-cancer therapy.
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Affiliation(s)
- Hiroshi Kitagaki
- Graduate School of Advanced Health Sciences, Saga University, Saga 840-8502, Japan
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32
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Cheng R, Lai R, Peng C, Lopez J, Li Z, Naowarojna N, Li K, Wong C, Lee N, Whelan SA, Qiao L, Grinstaff MW, Wang J, Cui Q, Liu P. Implications for an imidazol-2-yl carbene intermediate in the rhodanase-catalyzed C-S bond formation reaction of anaerobic ergothioneine biosynthesis. ACS Catal 2021; 11:3319-3334. [PMID: 34745712 DOI: 10.1021/acscatal.0c04886] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In the anaerobic ergothioneine biosynthetic pathway, a rhodanese domain containing enzyme (EanB) activates tne hercynine's sp2 ε-C-H Dona ana replaces it with a C-S bond to produce ergothioneine. The key intermediate for this trans-sulfuration reaction is the Cys412 persulfide. Substitution of the EanB-Cys412 persulfide with a Cys412 perselenide does not yield the selenium analog of ergothioneine, selenoneine. However, in deuterated buffer, the perselenide-modified EanB catalyzes the deuterium exchange between hercynine's sp2 ε-C-H bond and D2O. Results from QM/MM calculations suggest that the reaction involves a carbene intermediate and that Tyr353 plays a key role. We hypothesize that modulating the pKa of Tyr353 will affect the deuterium-exchange rate. Indeed, the 3,5-difluoro tyrosine containing EanB catalyzes the deuterium exchange reaction with k ex of ~10-fold greater than the wild-type EanB (EanBWT). With regards to potential mechanisms, these results support the involvement of a carbene intermediate in EanB-catalysis, rendering EanB as one of the few carbene-intermediate involving enzymatic systems.
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Affiliation(s)
- Ronghai Cheng
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Rui Lai
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Chao Peng
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China
| | - Juan Lopez
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Zhihong Li
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China
| | - Nathchar Naowarojna
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Kelin Li
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Christina Wong
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Norman Lee
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Stephen A. Whelan
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Lu Qiao
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Mark W. Grinstaff
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA
| | - Jiangyun Wang
- Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China
| | - Qiang Cui
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
| | - Pinghua Liu
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA
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Gasaly N, Hermoso MA, Gotteland M. Butyrate and the Fine-Tuning of Colonic Homeostasis: Implication for Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms22063061. [PMID: 33802759 PMCID: PMC8002420 DOI: 10.3390/ijms22063061] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 02/06/2023] Open
Abstract
This review describes current evidence supporting butyrate impact in the homeostatic regulation of the digestive ecosystem in health and inflammatory bowel diseases (IBDs). Butyrate is mainly produced by bacteria from the Firmicutes phylum. It stimulates mature colonocytes and inhibits undifferentiated malignant and stem cells. Butyrate oxidation in mature colonocytes (1) produces 70–80% of their energetic requirements, (2) prevents stem cell inhibition by limiting butyrate access to crypts, and (3) consumes oxygen, generating hypoxia and maintaining luminal anaerobiosis favorable to the microbiota. Butyrate stimulates the aryl hydrocarbon receptor (AhR), the GPR41 and GPR109A receptors, and inhibits HDAC in different cell types, thus stabilizing the gut barrier function and decreasing inflammatory processes. However, some studies indicate contrary effects according to butyrate concentrations. IBD patients exhibit a lower abundance of butyrate-producing bacteria and butyrate content. Additionally, colonocyte butyrate oxidation is depressed in these subjects, lowering luminal anaerobiosis and facilitating the expansion of Enterobacteriaceae that contribute to inflammation. Accordingly, gut dysbiosis and decreased barrier function in IBD seems to be secondary to the impaired mitochondrial disturbance in colonic epithelial cells.
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Affiliation(s)
- Naschla Gasaly
- Department of Nutrition, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Marcela A. Hermoso
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Martín Gotteland
- Department of Nutrition, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
- Department of Human Nutrition, Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago 7830490, Chile
- Millennium Nucleus in the Biology of Intestinal Microbiota, Santiago 8380453, Chile
- Correspondence: ; Tel.: +56-989-059-222
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Transporter tandems: precise tools for normalizing active transporter in the plasma membrane. Biochem J 2021; 477:4191-4206. [PMID: 33073844 DOI: 10.1042/bcj20200666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/12/2020] [Accepted: 10/19/2020] [Indexed: 12/12/2022]
Abstract
The transport efficiency (TE) describes the performance of a transport protein for a specific substrate. To compare the TE of different transporters, the number of active transporters in the plasma membrane must be monitored, as it may vary for each transporter and experiment. Available methods, like LC-MS quantification of tryptic peptides, fail to discriminate inactive intracellular transporters or, like cell-surface biotinylation followed by affinity chromatography and Western blotting, are imprecise and very laborious. We wanted to normalize active transporters by the activity of a second transporter. A transporter tandem, generated by joining two transporter cDNAs into a single open reading frame, should guarantee a 1 : 1 stoichiometry. Here we created a series of tandems with different linkers between the human ergothioneine (ET) transporter ETT (gene symbol SLC22A4) and organic cation transporter OCT2 (SLC22A2). The linker sequence strongly affected the expression strength. The stoichiometry was validated by absolute peptide quantification and untargeted peptide analysis. Compared with wild-type ETT, the normalized ET clearance of the natural variant L503F was higher (f = 1.34); G462E was completely inactive. The general usefulness of the tandem strategy was demonstrated by linking several transporters with ETT; every construct was active in both parts. Transporter tandems can be used - without membrane isolation or protein quantification - as precise tools for transporter number normalization, to identify, for example, relevant transporters for a drug. It is necessary, however, to find suitable linkers, to check the order of transporters, and to verify the absence of functional interference by saturation kinetics.
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Wei G, Gu Z, Gu J, Yu J, Huang X, Qin F, Li L, Ding R, Huo J. Platinum accumulation in oxaliplatin-induced peripheral neuropathy. J Peripher Nerv Syst 2021; 26:35-42. [PMID: 33462873 PMCID: PMC7986112 DOI: 10.1111/jns.12432] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022]
Abstract
Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high-affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.
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Affiliation(s)
- Guoli Wei
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Zhancheng Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Yu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Xiaofei Huang
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Fengxia Qin
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Lingchang Li
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Rong Ding
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
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Chiereghin C, Robusto M, Mauri L, Primignani P, Castorina P, Ambrosetti U, Duga S, Asselta R, Soldà G. SLC22A4 Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa. Front Genet 2021; 12:606630. [PMID: 33643381 PMCID: PMC7902881 DOI: 10.3389/fgene.2021.606630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/11/2021] [Indexed: 12/17/2022] Open
Abstract
Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling. A large consanguineous family of Moroccan origin affected by autosomal recessive sensorineural hearing loss (ARSNHL) was subjected to genome-wide linkage analysis and exome sequencing. Exome-wide variant analysis and prioritization identified the SLC22A4 p.C113Y missense variant (rs768484124) as the most likely cause of ARSNHL in the family, falling within the unique significant (LOD score>3) linkage region on chromosome 5. Indeed, the same variant was previously reported in two Tunisian ARSNHL pedigrees. The variant is present in the homozygous state in all six affected individuals, but also in one normal-hearing sibling, suggesting incomplete penetrance. The mutation is absent in about 1,000 individuals from the Greater Middle East Variome study cohort, including individuals from the North African population, as well as in an additional seven deaf patients from the same geographical area, recruited and screened for mutations in the SLC22A4 gene. This study represents the first independent replication of the involvement of SLC22A4 in ARSNHL, highlighting the importance of the gene, and of the p.C113Y mutation, at least in the Northwest African population.
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Affiliation(s)
| | - Michela Robusto
- Experimental Therapeutics Program, IFOM-FIRC Institute of Molecular Oncology Foundation, Milan, Italy
| | - Lucia Mauri
- S. S. Genetica Medica, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Paola Primignani
- S. S. Genetica Medica, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Pierangela Castorina
- Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano and Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy
| | - Umberto Ambrosetti
- Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano and Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy
| | - Stefano Duga
- Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Rosanna Asselta
- Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Giulia Soldà
- Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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Cheah IK, Halliwell B. Ergothioneine, recent developments. Redox Biol 2021; 42:101868. [PMID: 33558182 PMCID: PMC8113028 DOI: 10.1016/j.redox.2021.101868] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
There has been a recent surge of interest in the unique low molecular weight dietary thiol/thione, ergothioneine. This compound can accumulate at high levels in the body from diet and may play important physiological roles in human health and development, and possibly in prevention and treatment of disease. Blood levels of ergothioneine decline with age and onset of various diseases. Here we highlight recent advances in our knowledge of ergothioneine.
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Affiliation(s)
- Irwin K Cheah
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore; Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, 117456, Singapore
| | - Barry Halliwell
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore; Life Science Institute, Neurobiology Programme, Centre for Life Sciences, National University of Singapore, 117456, Singapore.
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38
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Betterton RD, Davis TP, Ronaldson PT. Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery. Handb Exp Pharmacol 2021; 266:301-328. [PMID: 33674914 PMCID: PMC8603467 DOI: 10.1007/164_2021_448] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
Therapeutic delivery to the central nervous system (CNS) continues to be a considerable challenge in the pharmacological treatment and management of neurological disorders. This is primarily due to the physiological and biochemical characteristics of brain barrier sites (i.e., blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB)). Drug uptake into brain tissue is highly restricted by expression of tight junction protein complexes and adherens junctions between brain microvascular endothelial cells and choroid plexus epithelial cells. Additionally, efflux transport proteins expressed at the plasma membrane of these same endothelial and epithelial cells act to limit CNS concentrations of centrally acting drugs. In contrast, facilitated diffusion via transporter proteins allows for substrate-specific flux of molecules across the plasma membrane, directing drug uptake into the CNS. Organic Cation Transporters (OCTs) and Novel Organic Cation Transporters (OCTNs) are two subfamilies of the solute carrier 22 (SLC22) family of proteins that have significant potential to mediate delivery of positively charged, zwitterionic, and uncharged therapeutics. While expression of these transporters has been well characterized in peripheral tissues, the functional expression of OCT and OCTN transporters at CNS barrier sites and their role in delivery of therapeutic drugs to molecular targets in the brain require more detailed analysis. In this chapter, we will review current knowledge on localization, function, and regulation of OCT and OCTN isoforms at the BBB and BCSFB with a particular emphasis on how these transporters can be utilized for CNS delivery of therapeutic agents.
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Affiliation(s)
- Robert D Betterton
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Thomas P Davis
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Patrick T Ronaldson
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
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39
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Borodina I, Kenny LC, McCarthy CM, Paramasivan K, Pretorius E, Roberts TJ, van der Hoek SA, Kell DB. The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev 2020; 33:190-217. [PMID: 32051057 PMCID: PMC7653990 DOI: 10.1017/s0954422419000301] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/20/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023]
Abstract
Ergothioneine (ERG) is an unusual thio-histidine betaine amino acid that has potent antioxidant activities. It is synthesised by a variety of microbes, especially fungi (including in mushroom fruiting bodies) and actinobacteria, but is not synthesised by plants and animals who acquire it via the soil and their diet, respectively. Animals have evolved a highly selective transporter for it, known as solute carrier family 22, member 4 (SLC22A4) in humans, signifying its importance, and ERG may even have the status of a vitamin. ERG accumulates differentially in various tissues, according to their expression of SLC22A4, favouring those such as erythrocytes that may be subject to oxidative stress. Mushroom or ERG consumption seems to provide significant prevention against oxidative stress in a large variety of systems. ERG seems to have strong cytoprotective status, and its concentration is lowered in a number of chronic inflammatory diseases. It has been passed as safe by regulatory agencies, and may have value as a nutraceutical and antioxidant more generally.
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Affiliation(s)
- Irina Borodina
- The Novo Nordisk Foundation Center for Biosustainability, Building 220, Chemitorvet 200, Technical University of Denmark, 2800Kongens Lyngby, Denmark
| | - Louise C. Kenny
- Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Crown Street, LiverpoolL8 7SS, UK
| | - Cathal M. McCarthy
- Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork University Maternity Hospital, Cork, Republic of Ireland
- Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Republic of Ireland
| | - Kalaivani Paramasivan
- The Novo Nordisk Foundation Center for Biosustainability, Building 220, Chemitorvet 200, Technical University of Denmark, 2800Kongens Lyngby, Denmark
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
| | - Timothy J. Roberts
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
- Department of Biochemistry, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown Street, LiverpoolL69 7ZB, UK
| | - Steven A. van der Hoek
- The Novo Nordisk Foundation Center for Biosustainability, Building 220, Chemitorvet 200, Technical University of Denmark, 2800Kongens Lyngby, Denmark
| | - Douglas B. Kell
- The Novo Nordisk Foundation Center for Biosustainability, Building 220, Chemitorvet 200, Technical University of Denmark, 2800Kongens Lyngby, Denmark
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, 7602, South Africa
- Department of Biochemistry, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Crown Street, LiverpoolL69 7ZB, UK
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Organic Cation Transporters in the Lung-Current and Emerging (Patho)Physiological and Pharmacological Concepts. Int J Mol Sci 2020; 21:ijms21239168. [PMID: 33271927 PMCID: PMC7730617 DOI: 10.3390/ijms21239168] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Organic cation transporters (OCT) 1, 2 and 3 and novel organic cation transporters (OCTN) 1 and 2 of the solute carrier 22 (SLC22) family are involved in the cellular transport of endogenous compounds such as neurotransmitters, l-carnitine and ergothioneine. OCT/Ns have also been implicated in the transport of xenobiotics across various biological barriers, for example biguanides and histamine receptor antagonists. In addition, several drugs used in the treatment of respiratory disorders are cations at physiological pH and potential substrates of OCT/Ns. OCT/Ns may also be associated with the development of chronic lung diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD) and, thus, are possible new drug targets. As part of the Special Issue "Physiology, Biochemistry and Pharmacology of Transporters for Organic Cations", this review provides an overview of recent findings on the (patho)physiological and pharmacological functions of organic cation transporters in the lung.
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Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology. Int J Mol Sci 2020; 21:ijms21217890. [PMID: 33114309 PMCID: PMC7660683 DOI: 10.3390/ijms21217890] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022] Open
Abstract
Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1–3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed.
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Meisel P, Pagels S, Grube M, Jedlitschky G, Völzke H, Kocher T. Tooth loss and adiposity: possible role of carnitine transporter (OCTN1/2) polymorphisms in women but not in men. Clin Oral Investig 2020; 25:701-709. [PMID: 32964310 PMCID: PMC8208909 DOI: 10.1007/s00784-020-03594-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 09/15/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE SLC22A4/5 single nucleotide polymorphisms (SNPs) have been reported to affect inflammatory diseases. We report the relationship of these polymorphisms with adiposity and tooth loss as elucidated in a 10-year follow-up study. METHODS Participants of the Study of Health in Pomerania (SHIP, N = 4105) were genotyped for the polymorphisms c.1507C > T in SLC22A4 (rs1050152) and -207C > G in SLC22A5 (rs2631367) using allele-specific real-time PCR assays. A total of 1817 subjects, 934 female and 883 male aged 30-80 years, underwent follow-up 10 years later (SHIP-2) and were assessed for adiposity and tooth loss. RESULTS The frequencies of the rarer SLC22A4 TT and SLC22A5 CC alleles were 16.7% and 20.3%, respectively. In women, tooth loss was associated with genotype TT vs. CC with incidence rate ratio IRR = 0.74 (95%C.I. 0.60-0.92) and CC vs. GG IRR = 0.79 (0.65-0.96) for SLC22A4 and SLC22A5 SNPs, respectively. In men, no such associations were observed. In the follow-up examination, the relationship between tooth loss and these SNPs was in parallel with measures of body shape such as BMI, body weight, waist circumference, or body fat accumulation. The association between muscle strength and body fat mass was modified by the genotypes studied. CONCLUSIONS SLC22A4 c.150C > T and SLC22A5 -207C > G polymorphisms are associated with tooth loss and markers of body shape in women but not in men. CLINICAL RELEVANCE Tooth loss may be related to obesity beyond inflammatory mechanisms, conceivably with a genetic background.
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Affiliation(s)
- Peter Meisel
- Department of Periodontology, Dental Clinics, Dental School, University Medicine Greifswald, Fleischmannstrasse 42, 17475, Greifswald, Germany.
| | - Stefanie Pagels
- Department of Periodontology, Dental Clinics, Dental School, University Medicine Greifswald, Fleischmannstrasse 42, 17475, Greifswald, Germany
- Department of Pharmacology of the Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Markus Grube
- Department of Pharmacology of the Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Gabriele Jedlitschky
- Department of Pharmacology of the Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Thomas Kocher
- Department of Periodontology, Dental Clinics, Dental School, University Medicine Greifswald, Fleischmannstrasse 42, 17475, Greifswald, Germany
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Nishiyama M, Nakamichi N, Yoshimura T, Masuo Y, Komori T, Ishimoto T, Matsuo JI, Kato Y. Homostachydrine is a Xenobiotic Substrate of OCTN1/SLC22A4 and Potentially Sensitizes Pentylenetetrazole-Induced Seizures in Mice. Neurochem Res 2020; 45:2664-2678. [PMID: 32844295 DOI: 10.1007/s11064-020-03118-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/10/2020] [Accepted: 08/15/2020] [Indexed: 12/23/2022]
Abstract
Understanding of the underlying mechanism of epilepsy is desired since some patients fail to control their seizures. The carnitine/organic cation transporter OCTN1/SLC22A4 is expressed in brain neurons and transports food-derived antioxidant ergothioneine (ERGO), L-carnitine, and spermine, all of which may be associated with epilepsy. This study aimed to clarify the possible association of this transporter with epileptic seizures. In both pentylenetetrazole (PTZ)-induced acute seizure and kindling models, ocnt1 gene knockout mice (octn1-/-) showed lower seizure scores compared with wild-type mice. Up-regulation of the epilepsy-related genes, c-fos and Arc, and the neurotrophic factor BDNF following PTZ administration was observed in the hippocampus of wild-type, but not octn1-/- mice. To find the OCTN1 substrate associated with the seizure, untargeted metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry was conducted on extracts from the hippocampus, frontal cortex, and plasma of both strains, leading to the identification of a plant alkaloid homostachydrine as a compound present in a lower concentration in octn1-/- mice. OCTN1-mediated uptake of deuterium-labeled homostachydrine was confirmed in OCTN1-transfected HEK293 cells, suggesting that this compound is a substrate of OCTN1. Homostachydrine administration increased PTZ-induced acute seizure scores and the expression of Arc in the hippocampus and that of Arc, Egr1, and BDNF in the frontal cortex. Conversely, administration of the OCTN1 substrate/inhibitor ERGO inhibited PTZ-induced kindling and reduced the plasma homostachydrine concentration. Thus, these results suggest that OCTN1 is at least partially associated with PTZ-induced seizures, which is potentially deteriorated by treatment with homostachydrine, a newly identified food-derived OCTN1 substrate.
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Affiliation(s)
- Misa Nishiyama
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Noritaka Nakamichi
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan. .,Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma, 370-0033, Japan.
| | - Tomoyuki Yoshimura
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Yusuke Masuo
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Tomoe Komori
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Takahiro Ishimoto
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Jun-Ichi Matsuo
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Yukio Kato
- Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
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Lopetuso LR, Ianiro G, Allegretti JR, Bibbò S, Gasbarrini A, Scaldaferri F, Cammarota G. Fecal transplantation for ulcerative colitis: current evidence and future applications. Expert Opin Biol Ther 2020; 20:343-351. [PMID: 32083498 DOI: 10.1080/14712598.2020.1733964] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Established evidence suggests that gut microbiota plays a role in ulcerative colitis (UC). Fecal microbiota transplantation (FMT) is clearly recognized as a highly effective treatment for patients with recurrent Clostridium difficile infection and has been investigated also in patients with UC, with promising results.Areas covered: Literature review was performed to select publications concerning current evidence on the role of gut microbiota in the pathogenesis of UC, and on the effectiveness of FMT in this disorder.Expert opinion: The randomized controlled trials published investigating the use of FMT suggested a potential role for FMT in the treatment of mild to moderate UC. However, given several unanswered questions regarding donor selection, dose, route of administration and duration of therapy, this is not yet recommended as a viable therapy option. FMT has allowed for more in depth investigation with regards to the role the gut microbiota may be playing in UC. This knowledge is critical to identifying where FMT may appropriately fit in the UC treatment paradigm. As our understanding of the role the microbiome plays in this chronic disease, FMT, and then eventually defined microbes, will hopefully serve in a complementary role to conventional IBD therapies.
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Affiliation(s)
- Loris R Lopetuso
- UOC MEDICINA INTERNA E GASTROENTEROLOGIA, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Gianluca Ianiro
- UOC MEDICINA INTERNA E GASTROENTEROLOGIA, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Jessica R Allegretti
- Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Stefano Bibbò
- UOC MEDICINA INTERNA E GASTROENTEROLOGIA, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Antonio Gasbarrini
- UOC MEDICINA INTERNA E GASTROENTEROLOGIA, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Franco Scaldaferri
- UOC MEDICINA INTERNA E GASTROENTEROLOGIA, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Giovanni Cammarota
- UOC MEDICINA INTERNA E GASTROENTEROLOGIA, Area Medicina Interna, Gastroenterologia ed Oncologia Medica, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.,Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, Roma, Italia
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Pochini L, Pappacoda G, Galluccio M, Pastore F, Scalise M, Indiveri C. Effect of Cholesterol on the Organic Cation Transporter OCTN1 (SLC22A4). Int J Mol Sci 2020; 21:ijms21031091. [PMID: 32041338 PMCID: PMC7037232 DOI: 10.3390/ijms21031091] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/02/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023] Open
Abstract
The effect of cholesterol was investigated on the OCTN1 transport activity measured as [14C]-tetraethylamonium or [3H]-acetylcholine uptake in proteoliposomes reconstituted with native transporter extracted from HeLa cells or the human recombinant OCTN1 over-expressed in E. coli. Removal of cholesterol from the native transporter by MβCD before reconstitution led to impairment of transport activity. A similar activity impairment was observed after treatment of proteoliposomes harboring the recombinant (cholesterol-free) protein by MβCD, suggesting that the lipid mixture used for reconstitution contained some cholesterol. An enzymatic assay revealed the presence of 10 µg cholesterol/mg total lipids corresponding to 1% cholesterol in the phospholipid mixture used for the proteoliposome preparation. On the other way around, the activity of the recombinant OCTN1 was stimulated by adding the cholesterol analogue, CHS to the proteoliposome preparation. Optimal transport activity was detected in the presence of 83 µg CHS/ mg total lipids for both [14C]-tetraethylamonium or [3H]-acetylcholine uptake. Kinetic analysis of transport demonstrated that the stimulation of transport activity by CHS consisted in an increase of the Vmax of transport with no changes of the Km. Altogether, the data suggests a direct interaction of cholesterol with the protein. A further support to this interpretation was given by a docking analysis indicating the interaction of cholesterol with some protein sites corresponding to CARC-CRAC motifs. The observed direct interaction of cholesterol with OCTN1 points to a possible direct influence of cholesterol on tumor cells or on acetylcholine transport in neuronal and non-neuronal cells via OCTN1.
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Bene J, Szabo A, Komlósi K, Melegh B. Mass Spectrometric Analysis of L-carnitine and its Esters: Potential Biomarkers of Disturbances in Carnitine Homeostasis. Curr Mol Med 2020; 20:336-354. [PMID: 31729298 PMCID: PMC7231908 DOI: 10.2174/1566524019666191113120828] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/31/2019] [Accepted: 11/01/2019] [Indexed: 12/31/2022]
Abstract
PURPOSE After a golden age of classic carnitine research three decades ago, the spread of mass spectrometry opened new perspectives and a much better understanding of the carnitine system is available nowadays. In the classic period, several human and animal studies were focused on various distinct physiological functions of this molecule and these revealed different aspects of carnitine homeostasis in normal and pathological conditions. Initially, the laboratory analyses were based on the classic or radioenzymatic assays, enabling only the determination of free and total carnitine levels and calculation of total carnitine esters' amount without any information on the composition of the acyl groups. The introduction of mass spectrometry allowed the measurement of free carnitine along with the specific and sensitive determination of different carnitine esters. Beyond basic research, mass spectrometry study of carnitine esters was introduced into the newborn screening program because of being capable to detect more than 30 metabolic disorders simultaneously. Furthermore, mass spectrometry measurements were performed to investigate different disease states affecting carnitine homeostasis, such as diabetes, chronic renal failure, celiac disease, cardiovascular diseases, autism spectrum disorder or inflammatory bowel diseases. RESULTS This article will review the recent advances in the field of carnitine research with respect to mass spectrometric analyses of acyl-carnitines in normal and various pathological states. CONCLUSION The growing number of publications using mass spectrometry as a tool to investigate normal physiological conditions or reveal potential biomarkers of primary and secondary carnitine deficiencies shows that this tool brought a new perspective to carnitine research.
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Affiliation(s)
- Judit Bene
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Andras Szabo
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Katalin Komlósi
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, Pécs, Hungary
| | - Bela Melegh
- Department of Medical Genetics, Clinical Center, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Solute carrier transporters: the metabolic gatekeepers of immune cells. Acta Pharm Sin B 2020; 10:61-78. [PMID: 31993307 PMCID: PMC6977534 DOI: 10.1016/j.apsb.2019.12.006] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/29/2019] [Accepted: 10/31/2019] [Indexed: 02/06/2023] Open
Abstract
Solute carrier (SLC) transporters meditate many essential physiological functions, including nutrient uptake, ion influx/efflux, and waste disposal. In its protective role against tumors and infections, the mammalian immune system coordinates complex signals to support the proliferation, differentiation, and effector function of individual cell subsets. Recent research in this area has yielded surprising findings on the roles of solute carrier transporters, which were discovered to regulate lymphocyte signaling and control their differentiation, function, and fate by modulating diverse metabolic pathways and balanced levels of different metabolites. In this review, we present current information mainly on glucose transporters, amino-acid transporters, and metal ion transporters, which are critically important for mediating immune cell homeostasis in many different pathological conditions.
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Key Words
- 3-PG, 3-phosphoglyceric acid
- ABC, ATP-binding cassette
- AIF, apoptosis-inducing factor
- AP-1, activator protein 1
- ASCT2, alanine serine and cysteine transporter system 2
- ATP, adenosine triphosphate
- BCR, B cell receptor
- BMDMs, bone marrow-derived macrophages
- CD45R, a receptor-type protein tyrosine phosphatase
- CTL, cytotoxic T lymphocytes
- DC, dendritic cells
- EAATs, excitatory amino acid transporters
- ER, endoplasmic reticulum
- ERRα, estrogen related receptor alpha
- FFA, free fatty acids
- G-6-P, glucose 6-phosphate
- GLUT, glucose transporters
- GSH, glutathione
- Glucose
- Glutamine
- HIF-1α, hypoxia-inducible factor 1-alpha
- HIV-1, human immunodeficiency virus type 1
- Hk1, hexokinase-1
- IFNβ, interferon beta
- IFNγ, interferon gamma
- IKK, IκB kinase
- IKKβ, IκB kinase beta subunit
- IL, interleukin
- LDHA, lactate dehydrogenase A
- LPS, lipopolysaccharide
- Lymphocytes
- Lyn, tyrosine-protein kinase
- MAPK, mitogen-activated protein kinase
- MCT, monocarboxylate transporters
- MS, multiple sclerosis
- Metal ion
- NADPH, nicotinamide adenine dinucleotide phosphate
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NO, nitric oxide
- NOD2, nucleotide-binding oligomerization domain containing 2
- PEG2, prostaglandin E2
- PI-3K/AKT, phosphatidylinositol-3-OH kinase/serine–threonine kinase
- PPP, pentose phosphate pathway
- Pfk, phosphofructokinase
- RA, rheumatoid arthritis
- RLR, RIG-I-like receptor
- ROS, reactive oxygen species
- SLC, solute carrier
- SLE, systemic lupus erythematosus
- SNAT, sodium-coupled neutral amino acid transporters
- STAT, signal transducers and activators of transcription
- Solute carrier
- TAMs, tumor-associated macrophages
- TCA, tricarboxylic acid
- TCR, T cell receptor
- TLR, toll-like receptor
- TNF, tumor necrosis factor
- TRPM7, transient receptor potential cation channel subfamily M member 7
- Teffs, effector T cells
- Th1/2/17, type 1/2/17 helper T cells
- Tregs, regulatory T cells
- VEGF, vascular endothelial growth factor
- ZIP, zrt/irt-like proteins
- iNOS, inducible nitric oxide synthase
- iTregs, induced regulatory T cells
- mTORC1, mammalian target of rapamycin complex 1
- α-KG, α-ketoglutaric acid
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Abstract
The organic cation transporters (OCTs) OCT1, OCT2, OCT3, novel OCT (OCTN)1, OCTN2, multidrug and toxin exclusion (MATE)1, and MATE kidney-specific 2 are polyspecific transporters exhibiting broadly overlapping substrate selectivities. They transport organic cations, zwitterions, and some uncharged compounds and operate as facilitated diffusion systems and/or antiporters. OCTs are critically involved in intestinal absorption, hepatic uptake, and renal excretion of hydrophilic drugs. They modulate the distribution of endogenous compounds such as thiamine, L-carnitine, and neurotransmitters. Sites of expression and functions of OCTs have important impact on energy metabolism, pharmacokinetics, and toxicity of drugs, and on drug-drug interactions. In this work, an overview about the human OCTs is presented. Functional properties of human OCTs, including identified substrates and inhibitors of the individual transporters, are described. Sites of expression are compiled, and data on regulation of OCTs are presented. In addition, genetic variations of OCTs are listed, and data on their impact on transport, drug treatment, and diseases are reported. Moreover, recent data are summarized that indicate complex drug-drug interaction at OCTs, such as allosteric high-affinity inhibition of transport and substrate dependence of inhibitor efficacies. A hypothesis about the molecular mechanism of polyspecific substrate recognition by OCTs is presented that is based on functional studies and mutagenesis experiments in OCT1 and OCT2. This hypothesis provides a framework to imagine how observed complex drug-drug interactions at OCTs arise. Finally, preclinical in vitro tests that are performed by pharmaceutical companies to identify interaction of novel drugs with OCTs are discussed. Optimized experimental procedures are proposed that allow a gapless detection of inhibitory and transported drugs.
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Affiliation(s)
- Hermann Koepsell
- Institute of Anatomy and Cell Biology and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Germany
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Abstract
The transport of materials across membranes is a vital process for all aspects of cellular function, including growth, metabolism, and communication. Protein transporters are the molecular gates that control this movement and serve as key points of regulation for these processes, thus representing an attractive class of therapeutic targets. With more than 400 members, the solute carrier (SLC) membrane transport proteins are the largest family of transporters, yet, they are pharmacologically underexploited relative to other protein families and many of the available chemical tools possess suboptimal selectivity and efficacy. Fortuitously, there is increased interest in elucidating the physiological roles of SLCs as well as growing recognition of their therapeutic potential. This Perspective provides an overview of the SLC superfamily, including their biochemical and functional features, as well as their roles in various human diseases. In particular, we explore efforts and associated challenges toward drugging SLCs, as well as highlight opportunities for future drug discovery.
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Affiliation(s)
- Wesley Wei Wang
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Leandro Gallo
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Appaso Jadhav
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Richard Hawkins
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States
| | - Christopher G Parker
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States.,Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
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Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer. Sci Rep 2019; 9:18897. [PMID: 31827213 PMCID: PMC6906452 DOI: 10.1038/s41598-019-55378-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/23/2019] [Indexed: 12/24/2022] Open
Abstract
The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1-/- mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1−/− mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1−/− colons at this early stage, and is composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells and other granulocytes, as well as CD4+ lymphoid cells. Differential susceptibility to CA-CRC of Irf1−/− vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1−/− mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.
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