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Chen L, Yin J, Xu K, Cui Y, Zhu S, Li T, Lv T, Song Y, Zhan P. Novel bioengineered drugs with immunotherapies for malignant pleural effusion: Remodulate tumor immune microenvironment and activate immune system. Crit Rev Oncol Hematol 2025; 211:104717. [PMID: 40194717 DOI: 10.1016/j.critrevonc.2025.104717] [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: 02/19/2025] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/09/2025] Open
Abstract
Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.
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Affiliation(s)
- Lu Chen
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jie Yin
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ke Xu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - YuTing Cui
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - SuHua Zhu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin 300100, China.
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Ping Zhan
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Wu S, Gao J, Han Y, Zhang W, Li X, Kong D, Wang H, Zuo L. Balancing act: The dual role of claudin-2 in disease. Ann N Y Acad Sci 2025; 1546:75-89. [PMID: 40101185 DOI: 10.1111/nyas.15311] [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] [Indexed: 03/20/2025]
Abstract
Claudin-2 (CLDN2), a tight junction protein, is predominantly found in leaky epithelial cell layers where it plays a pivotal role in forming paracellular pores necessary for the efficient transport of cations and water. Its abundance is intricately regulated by upstream signals, modulating its synthesis, transport, and localization to adapt to diverse environmental changes. Aberrant expression levels of CLDN2 are observed in numerous pathological conditions including cancer, inflammation, immune disorders, fibrosis, and kidney and biliary stones. Recent advances have uncovered the mechanisms by which the loss or restoration of CLDN2 affects functions such as epithelial barrier, cell proliferation, renewal, migration, invasion, and tissue regeneration. This exerts a dual-directional influence on the pathogenesis, perpetuation, and progression of diseases, indicating the potential to both accelerate and decelerate the course of disease evolution. Here, we discuss these nuanced bidirectional regulatory effects mediated by CLDN2, and how it may contribute to the progression or regression of disease when it becomes unbalanced.
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Affiliation(s)
- Shanshan Wu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Jia Gao
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yiran Han
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Xue Li
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Derun Kong
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hua Wang
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
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3
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Dilmen E, Olde Hanhof CJA, Yousef Yengej FA, Ammerlaan CME, Rookmaaker MB, Orhon I, Jansen J, Verhaar MC, Hoenderop JG. A semi-permeable insert culture model for the distal part of the nephron with human and mouse tubuloid epithelial cells. Exp Cell Res 2025; 444:114342. [PMID: 39566879 DOI: 10.1016/j.yexcr.2024.114342] [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: 08/15/2024] [Revised: 11/14/2024] [Accepted: 11/16/2024] [Indexed: 11/22/2024]
Abstract
Tubuloids are advanced in vitro models obtained from adult human or mouse kidney cells with great potential for modelling kidney function in health and disease. Here, we developed a polarized human and mouse tubuloid epithelium on cell culture inserts, namely Transwell™ filters, as a model of the distal nephron with an accessible apical and basolateral side that allow for characterization of epithelial properties such as leak-tightness and epithelial resistance. Tubuloids formed a leak-tight and confluent epithelium on Transwells™ and the human tubuloids were differentiated towards the distal part of the nephron. Differentiation induced a significant upregulation of mRNA and protein expression of crucial segment transporters/channels NKCC2 (thick ascending limb of the loop of Henle), NCC (distal convoluted tubule), AQP2 (connecting tubule and collecting duct) and Na+/K+-ATPase (all segments) in a polarized fashion. In conclusion, this study illustrates the potential of human and mouse tubuloid epithelium on Transwells™ for studies of tubuloid epithelium formation and tubuloid differentiation towards the distal nephron. This approach holds great promise for assisting future research towards kidney (patho)physiology and transport function.
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Affiliation(s)
- E Dilmen
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - C J A Olde Hanhof
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - F A Yousef Yengej
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
| | - C M E Ammerlaan
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
| | - M B Rookmaaker
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
| | - I Orhon
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - J Jansen
- Department of Internal Medicine, Nephrology, and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands; Department for Renal and Hypertensive Diseases, Rheumatological and Immunological Diseases, Uniklinik RWTH Aachen, Aachen, Germany
| | - M C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
| | - J G Hoenderop
- Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands.
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Er B. Effects of Magnesium Forms on the Magnesium Balance and Jejunal Transporters in Healthy Rats. Prev Nutr Food Sci 2024; 29:405-413. [PMID: 39759820 PMCID: PMC11699571 DOI: 10.3746/pnf.2024.29.4.405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/10/2024] [Accepted: 10/18/2024] [Indexed: 01/07/2025] Open
Abstract
Magnesium (Mg) is a mineral necessary for many biological activities in mammals. Here, we compared the effect of two Mg compounds [Mg picolinate (MgPic) to Mg oxide (MgO)] on Mg bioavailability and intestinal Mg and calcium transporter protein levels. Three groups of 21 male Wistar-Albino rats were randomly allocated and fed a standard diet (control) or a 500 mg/kg Mg-supplemented (MgPic or MgO) diet for 8 weeks. The serum and liver Mg levels, Mg absorptivity, and retentivity were augmented in the MgPic group compared with the MgO group (P<0.05). Only MgPic supplementation elevated the expression of the genes encoding CLDN2, CLDN15, CNNM4, NCX1, PMCA1b, NCX2, and Calbindin-D9k in the jejunum by 1.59, 1.58, 1.70, 1.82, 2.02, 2.03, and 2.31 fold, respectively (P<0.05). Compared to the MgO-fed rats, MgPic rats had higher expression of the genes encoding NCX1, NCX2, PMCA1b, and Calbindin-D9k in the jejunum by 1.43, 1.72, 1.54, and 1.69 fold, respectively (P<0.01). These results suggest that MgPic increases Mg absorptivity and retentivity more than Mg bioavailability. In addition, MgPic can improve the paracellular and transcellular cationic mineral transport process. Thus, Mg deficiency disorders might be alleviated by MgPic more effectively than MgO.
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Affiliation(s)
- Besir Er
- Department of Biology, Faculty of Science, Firat University, Elazig 23100, Türkiye
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5
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Kröse JL, de Baaij JHF. Magnesium biology. Nephrol Dial Transplant 2024; 39:1965-1975. [PMID: 38871680 PMCID: PMC11648962 DOI: 10.1093/ndt/gfae134] [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: 04/03/2024] [Indexed: 06/15/2024] Open
Abstract
Magnesium (Mg2+) is essential for energy metabolism, muscle contraction and neurotransmission. As part of the Mg-ATP complex, it is involved in over 600 enzymatic reactions. Serum Mg2+ levels are tightly regulated between 0.7 and 1.1 mmol/L by interplay of intestinal absorption and renal excretion. In the small intestine, Mg2+ is absorbed paracellularly via claudin-2 and -12. In the colon, transcellular absorption of Mg2+ is facilitated by TRPM6/7 and CNNM4. In the kidney, the proximal tubule reabsorbs only 20% of the filtered Mg2+. The majority of the filtered Mg2+ is reabsorbed in the thick ascending limb, where the lumen-positive transepithelial voltage drives paracellular transport via claudin-16/-19. Fine-tuning of Mg2+ reabsorption is achieved in the distal convoluted tubule (DCT). Here, TRPM6/7 tetramers facilitate apical Mg2+ uptake, which is hormonally regulated by insulin and epidermal growth factor. Basolateral Mg2+ extrusion is Na+ dependent and achieved by CNNM2 and/or SLC41A3. Hypomagnesemia (serum Mg2+ <0.7 mmol/L) develops when intestinal and/or renal Mg2+ (re)absorption is disturbed. Common causes include alcoholism, type 2 diabetes mellitus and the use of pharmacological drugs, such as proton-pump inhibitors, calcineurin inhibitors and thiazide diuretics. Over the last decade, research on rare genetic and acquired Mg2+ disorders have identified Mg2+ channel and transporter activity, DCT length, mitochondrial function and autoimmunity as mechanisms explaining hypomagnesemia. Classically, treatment of hypomagnesemia depended on oral or intravenous Mg2+ supplementation. Recently, prebiotic dietary fibers and sodium-glucose cotransporter 2 inhibitors have been proposed as promising new therapeutic pathways to treat hypomagnesemia.
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Affiliation(s)
- Jana L Kröse
- Department of Medical BioSciences,
Radboudumc, Nijmegen, The
Netherlands
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Mizukami Y, Ito A, Hashimoto S, Ando T, Ishikawa Y, Eguchi H, Yoshino Y, Matsunaga T, Ikari A. Downregulation of chemoresistance by claudin-14 silencing in human colorectal cancer cells. Arch Biochem Biophys 2024; 758:110075. [PMID: 38942107 DOI: 10.1016/j.abb.2024.110075] [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: 04/25/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
An exceptional expression of claudins (CLDNs), tight junction (TJ) proteins, is observed in various solid cancer tissues. However, the pathophysiological roles of CLDNs have not been clarified in detail. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and cultured cancer epithelial cells. We found CLDN14 silencing decreased cell viability without affecting spheroid size in the three-dimensional (3D) spheroid model of DLD-1 cells derived from human CRC. Mitochondria activity and oxidative stress level were reduced by CLDN14 silencing. Furthermore, CLDN14 silencing decreased the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidative genes. CLDN14 was colocalized with ZO-1, a scaffolding protein in the TJ. CLDN14 silencing induced the disruption of TJ barrier such as the reduction of transepithelial electrical resistance and elevation of fluxes of small molecules including glucose in two-dimensional (2D) cultured model,. The depletion of glucose induced the elevation of ROS generation, mitochondria activity, and Nrf2 expression. These results suggest that CLDN14 increases Nrf2 expression in spheroids mediated via the formation of paracellular barrier to glucose. The cytotoxicities of doxorubicin, an anthracycline anticancer drug, and oxaliplatin, a platinum-based agent, were augmented by an Nrf2 activator in 2D cultured cells. The anticancer drug-induced toxicity was enhanced by CLDN14 silencing in 3D spheroids. We suggest that CLDN14 may potentiate chemoresistance mediated by the suppression of paracellular glucose permeability and activation of the Nrf2 signaling pathway in CRC cells.
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Affiliation(s)
- Yuko Mizukami
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Ayaka Ito
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Shotaro Hashimoto
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Tomoka Ando
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Yoshinobu Ishikawa
- Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, 16-10 Kamishinano, Totsuka-ku, Yokohama, 244-0806, Japan
| | - Hiroaki Eguchi
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Yuta Yoshino
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Toshiyuki Matsunaga
- Laboratory of Bioinformatics, Gifu Pharmaceutical University, Gifu, 502-8585, Japan
| | - Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
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Shen X, Mu X. Systematic Insights into the Relationship between the Microbiota-Gut-Brain Axis and Stroke with the Focus on Tryptophan Metabolism. Metabolites 2024; 14:399. [PMID: 39195495 DOI: 10.3390/metabo14080399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 08/29/2024] Open
Abstract
Stroke, as a serious cerebral vascular disease with high incidence and high rates of disability and mortality, has limited therapeutic options due to the narrow time window. Compelling evidence has highlighted the significance of the gut microbiota and gut-brain axis as critical regulatory factors affecting stroke. Along the microbiota-gut-brain axis, tryptophan metabolism further acquires increasing attention for its intimate association with central nervous system diseases. For the purpose of exploring the potential role of tryptophan metabolism in stroke and providing systematic insights into the intricate connection of the microbiota-gut-brain axis with the pathological procedure of stroke, this review first summarized the practical relationship between microbiota and stroke by compiling the latest case-control research. Then, the microbiota-gut-brain axis, as well as its interaction with stroke, were comprehensively elucidated on the basis of the basic anatomical structure and physiological function. Based on the crosstalk of microbiota-gut-brain, we further focused on the tryptophan metabolism from the three major metabolic pathways, namely, the kynurenine pathway, serotonin pathway, and microbial pathway, within the axis. Moreover, the effects of tryptophan metabolism on stroke were appreciated and elaborated here, which is scarcely found in other reviews. Hopefully, the systematic illustration of the mechanisms and pathways along the microbiota-gut-brain axis will inspire more translational research from metabolic perspectives, along with more attention paid to tryptophan metabolism as a promising pharmaceutical target in order to reduce the risk of stroke, mitigate the stroke progression, and ameliorate the stroke prognosis.
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Affiliation(s)
- Xinyu Shen
- Genomics Research Center, Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Xiaoqin Mu
- Genomics Research Center, Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
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Rini DM, Nakamichi Y, Morita T, Inoue H, Mizukami Y, Yamamoto Y, Suzuki T. Xylobiose treatment strengthens intestinal barrier function by regulating claudin 2 and heat shock protein 27 expression in human Caco-2 cells. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:2518-2525. [PMID: 37938188 DOI: 10.1002/jsfa.13111] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Xylobiose, a non-digestible disaccharide, largely contributes to the beneficial physiological effects of xylooligosaccharides. However, there is insufficient evidence to assess the direct effect of xylobiose on intestinal barrier function. Here, we investigated the intestinal barrier function in human intestinal Caco-2 cells treated with xylobiose. RESULTS In total, 283 genes were upregulated and 256 genes were downregulated in xylobiose-treated Caco-2 cells relative to the controls. We focused on genes related to intestinal barrier function, such as tight junction (TJ) and heat shock protein (HSP). Xylobiose decreased the expression of the TJ gene Claudin 2 (CLDN2) and increased the expression of the cytoprotective HSP genes HSPB1 and HSPA1A, which encode HSP27 and HSP70, respectively. Immunoblot analysis confirmed that xylobiose suppressed CLDN2 expression and enhanced HSP27 and HSP70 expression. A quantitative reverse transcription-PCR and promoter assays indicated that xylobiose post-transcriptionally regulated CLDN2 and HSPB1 levels. Additionally, selective inhibition of phosphatidyl-3-inositol kinase (PI3K) inhibited xylobiose-mediated CLDN2 expression, whereas HSP27 expression induced by xylobiose was sensitive to the inhibition of PI3K, mitogen-activated protein kinase kinase and Src. CONCLUSION The results of the present study reveal that xylobiose suppresses CLDN2 and increases HSP27 expression in intestinal Caco-2 cells via post-transcriptional regulation, potentially strengthening intestinal barrier integrity; however, these effects seem to occur via different signaling pathways. Our findings may help to assess the physiological role of xylobiose. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Dina Mustika Rini
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
- Department of Food Technology, Faculty of Engineering, Universitas Pembangunan Nasional "Veteran" Jawa Timur, Surabaya, Indonesia
| | - Yusuke Nakamichi
- Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, Higashi-Hiroshima, Japan
| | - Tomotake Morita
- Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, Higashi-Hiroshima, Japan
| | - Hiroyuki Inoue
- Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, Higashi-Hiroshima, Japan
| | - Yoichi Mizukami
- Institute of Gene Research, Yamaguchi University Science Research Center, Ube, Japan
| | - Yoshinari Yamamoto
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Takuya Suzuki
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
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9
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Salinas M, López-Garrigós M, Flores E, Leiva-Salinas C. Improving diagnosis and treatment of hypomagnesemia. Clin Chem Lab Med 2024; 62:234-248. [PMID: 37503587 DOI: 10.1515/cclm-2023-0537] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/18/2023] [Indexed: 07/29/2023]
Abstract
Magnesium is one of the most abundant cations in the body and acts as a cofactor in more than 600 biochemical reactions. Hypomagnesemia is a highly prevalent condition, especially in subjects with comorbid conditions, but has received less attention than other electrolyte disturbances. This review will discuss magnesium physiology, absorption, storage, distribution across the body, and kidney excretion. After reviewing the regulation of magnesium homeostasis, we will focus on the etiology and clinical presentation of hypomagnesemia. The role of laboratory medicine in hypomagnesemia will be the main purpose of this review, and we will discuss the laboratory tests and different samples and methods for its measurement. Although free magnesium is physiologically active, total serum magnesium is the most commonly used measurement in laboratory medicine and is apt for clinical purposes; however, it is not appropriately used, and many patients with hypomagnesemia remain undiagnosed and not treated. Using information technologies, laboratory medicine can largely improve the diagnosis and treatment of hypomagnesemia through the design and establishment of automatic demand management and result management interventions by acting in the first and last steps of the laboratory cycle, test requests, and actions taken after test results, to unmask patients with hypomagnesemia and improve the number of patients undergoing treatment.
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Affiliation(s)
- Maria Salinas
- Clinical Laboratory, Hospital Universitario de San Juan, San Juan de Alicante, Alicante, Spain
| | - Maite López-Garrigós
- Clinical Laboratory, Hospital Universitario de San Juan, San Juan de Alicante, Alicante, Spain
- Department of Biochemistry and Molecular Biology, Universidad Miguel Hernandez, San Juan de Alicante, Spain
- CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Emilio Flores
- Clinical Laboratory, Hospital Universitario de San Juan, San Juan de Alicante, Alicante, Spain
- Department of Clinic Medicine, Universidad Miguel Hernández, San Juan de Alicante, Spain
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10
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Zhu H, Wang W, Li Y. The interplay between microbiota and brain-gut axis in epilepsy treatment. Front Pharmacol 2024; 15:1276551. [PMID: 38344171 PMCID: PMC10853364 DOI: 10.3389/fphar.2024.1276551] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/12/2024] [Indexed: 08/12/2024] Open
Abstract
The brain-gut axis plays a vital role in connecting the cognitive and emotional centers of the brain with the intricate workings of the intestines. An imbalance in the microbiota-mediated brain-gut axis extends far beyond conditions like Irritable Bowel Syndrome (IBS) and obesity, playing a critical role in the development and progression of various neurological disorders, including epilepsy, depression, Alzheimer's disease (AD), and Parkinson's disease (PD). Epilepsy, a brain disorder characterized by unprovoked seizures, affects approximately 50 million people worldwide. Accumulating evidence suggests that rebuilding the gut microbiota through interventions such as fecal microbiota transplantation, probiotics, and ketogenic diets (KD) can benefit drug-resistant epilepsy. The disturbances in the gut microbiota could contribute to the toxic side effects of antiepileptic drugs and the development of drug resistance in epilepsy patients. These findings imply the potential impact of the gut microbiota on epilepsy and suggest that interventions targeting the microbiota, such as the KD, hold promise for managing and treating epilepsy. However, the full extent of the importance of microbiota in epilepsy treatment is not yet fully understood, and many aspects of this field remain unclear. Therefore, this article aims to provide an overview of the clinical and animal evidence supporting the regulatory role of gut microbiota in epilepsy, and of potential pathways within the brain-gut axis that may be influenced by the gut microbiota in epilepsy. Furthermore, we will discuss the recent advancements in epilepsy treatment, including the KD, fecal microbiota transplantation, and antiseizure drugs, all from the perspective of the gut microbiota.
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Affiliation(s)
- Hanxiao Zhu
- Department of Neurology, The First Affiliated Hospital of Dali University, Dali, China
- Clinical Medical School, Dali University, Dali, China
| | - Wei Wang
- Neurobiology Laboratory, China Agricultural University, Beijing, China
| | - Yun Li
- Department of Neurology, The First Affiliated Hospital of Dali University, Dali, China
- Clinical Medical School, Dali University, Dali, China
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11
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Sun M, Ji W, Ye H, Cai Y, Yun Y, Wei X, Wang C, Mao H. Sodium butyrate administration improves intestinal development of suckling lambs. J Anim Sci 2024; 102:skae028. [PMID: 38285605 PMCID: PMC10889743 DOI: 10.1093/jas/skae028] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/25/2024] [Indexed: 01/31/2024] Open
Abstract
This study was conducted to investigate the effects of sodium butyrate (SB) supplementation on growth performance, intestinal barrier functions, and intestinal bacterial communities in sucking lambs. Forty lambs of 7 d old, with an average body weight (BW) of 4.46 ± 0.45 kg, were allocated into the control (CON) or SB group, with each group having five replicate pens (n = 5). Lambs were orally administered SB at 1.8 mL/kg BW in the SB group or the same volume of saline in the CON group. Treatments were administered from 7 to 35 d of age, when one lamb from each replicate was slaughtered to obtain intestinal tissues and contents. The results showed that supplementation with SB tended to increase the BW (P = 0.079) and the starter intake (P = 0.089) of lambs at 35 d of age. The average daily gain of lambs in the SB group was significantly greater than that in the CON group (P < 0.05). The villus height of jejunum in the SB group was markedly higher (P < 0.05) than that in the CON group. In ileum, lambs in the SB group had lower (P < 0.05) crypt depth and greater (P < 0.05) villus-to-crypt ratio than those in the CON group. Compared with the CON group, the mRNA and protein expressions of Claudin-1 and Occludin were increased (P < 0.05) in the SB group. Supplementation with SB decreased the relative abundances of pathogenic bacteria, including Clostridia_UCG-014 (P = 0.094) and Romboutsia (P < 0.05), which were negatively associated with the intestinal barrier function genes (P < 0.05). The relative abundance of Succiniclasticum (P < 0.05) was higher in the SB group, and it was positively correlated with the ratio of villi height to crypt depth in the jejunum (P < 0.05). Compared with the CON group, the function "Metabolism of Cofactors and Vitamins" was increased in the SB group lambs (P < 0.05). In conclusion, SB orally administration during suckling period could improve the small intestine development and growth performance of lambs by inhibiting the harmful bacteria (Clostridia_UCG-014, Romboutsia) colonization, and enhancing intestinal barrier functions.
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Affiliation(s)
- Mengzhen Sun
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
| | - Wenwen Ji
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
| | - Hongwei Ye
- Hangzhou Lin ‘an District Agroforestry Technology Extension Center, Lin’an 311300, China
| | - Yitao Cai
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
| | - Yan Yun
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
| | - Xiaoshi Wei
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
| | - Chong Wang
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
| | - Huiling Mao
- College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang A & F University; Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Lin’an 311300, China
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12
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Markov AG, Livanova AA, Fedorova AA, Kravtsova VV, Krivoi II. Chronic Ouabain Targets Pore-Forming Claudin-2 and Ameliorates Radiation-Induced Damage to the Rat Intestinal Tissue Barrier. Int J Mol Sci 2023; 25:278. [PMID: 38203449 PMCID: PMC10778734 DOI: 10.3390/ijms25010278] [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: 11/04/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Ionizing radiation (IR) causes disturbances in the functions of the gastrointestinal tract. Given the therapeutic potential of ouabain, a specific ligand of the Na,K-ATPase, we tested its ability to protect against IR-induced disturbances in the barrier and transport properties of the jejunum and colon of rats. Male Wistar rats were subjected to 6-day intraperitoneal injections of vehicle or ouabain (1 µg/kg/day). On the fourth day of injections, rats were exposed to total-body X-ray irradiation (10 Gy) or a sham irradiation. Isolated tissues were examined 72 h post-irradiation. Electrophysiological characteristics and paracellular permeability for sodium fluorescein were measured in an Ussing chamber. Histological analysis and Western blotting were also performed. In the jejunum tissue, ouabain exposure did not prevent disturbances in transepithelial resistance, paracellular permeability, histological characteristics, as well as changes in the expression of claudin-1, -3, -4, tricellulin, and caspase-3 induced by IR. However, ouabain prevented overexpression of occludin and the pore-forming claudin-2. In the colon tissue, ouabain prevented electrophysiological disturbances and claudin-2 overexpression. These observations may reveal a mechanism by which circulating ouabain maintains tight junction integrity under IR-induced intestinal dysfunction.
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Affiliation(s)
- Alexander G. Markov
- Department of General Physiology, St. Petersburg State University, 199034 St. Petersburg, Russia; (A.A.L.); (A.A.F.); (V.V.K.); (I.I.K.)
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13
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Molotla-Torres DE, Guzmán-Mejía F, Godínez-Victoria M, Drago-Serrano ME. Role of Stress on Driving the Intestinal Paracellular Permeability. Curr Issues Mol Biol 2023; 45:9284-9305. [PMID: 37998758 PMCID: PMC10670774 DOI: 10.3390/cimb45110581] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/05/2023] [Accepted: 11/13/2023] [Indexed: 11/25/2023] Open
Abstract
The gut epithelium is a polarized monolayer that exhibits apical and basolateral membrane surfaces. Monolayer cell components are joined side by side via protein complexes known as tight junction proteins (TJPs), expressed at the most apical extreme of the basolateral membrane. The gut epithelium is a physical barrier that determinates intestinal permeability, referred to as the measurement of the transit of molecules from the intestinal lumen to the bloodstream or, conversely, from the blood to the gut lumen. TJPs play a role in the control of intestinal permeability that can be disrupted by stress through signal pathways triggered by the ligation of receptors with stress hormones like glucocorticoids. Preclinical studies conducted under in vitro and/or in vivo conditions have addressed underlying mechanisms that account for the impact of stress on gut permeability. These mechanisms may provide insights for novel therapeutic interventions in diseases in which stress is a risk factor, like irritable bowel syndrome. The focus of this study was to review, in an integrative context, the neuroendocrine effects of stress, with special emphasis on TJPs along with intestinal permeability.
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Affiliation(s)
- Daniel Efrain Molotla-Torres
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Calzada del Hueso No. 1100, Ciudad de México CP 04960, Mexico;
| | - Fabiola Guzmán-Mejía
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso No. 1100, Ciudad de México CP 04960, Mexico
| | - Marycarmen Godínez-Victoria
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Ciudad de México CP 11340, Mexico;
| | - Maria Elisa Drago-Serrano
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, Calzada del Hueso No. 1100, Ciudad de México CP 04960, Mexico
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14
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Kundu S, Nayak S, Rakshit D, Singh T, Shukla R, Khatri DK, Mishra A. The microbiome-gut-brain axis in epilepsy: pharmacotherapeutic target from bench evidence for potential bedside applications. Eur J Neurol 2023; 30:3557-3567. [PMID: 36880679 DOI: 10.1111/ene.15767] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
The gut-brain axis augments the bidirectional communication between the gut and brain and modulates gut homeostasis and the central nervous system through the hypothalamic-pituitary-adrenal axis, enteroendocrine system, neuroendocrine system, inflammatory and immune pathways. Preclinical and clinical reports showed that gut dysbiosis might play a major regulatory role in neurological diseases such as epilepsy, Parkinson's, multiple sclerosis, and Alzheimer's disease. Epilepsy is a chronic neurological disease that causes recurrent and unprovoked seizures, and numerous risk factors are implicated in developing epilepsy. Advanced consideration of the gut-microbiota-brain axis can reduce ambiguity about epilepsy pathology, antiepileptic drugs, and effective therapeutic targets. Gut microbiota sequencing analysis reported that the level of Proteobacteria, Verrucomicrobia, Fusobacteria, and Firmicutes was increased and the level of Actinobacteria and Bacteroidetes was decreased in epilepsy patients. Clinical and preclinical studies also indicated that probiotics, ketogenic diet, faecal microbiota transplantation, and antibiotics can improve gut dysbiosis and alleviate seizure by enhancing the abundance of healthy biota. This study aims to give an overview of the connection between gut microbiota, and epilepsy, how gut microbiome changes may cause epilepsy, and whether gut microbiome restoration could be used as a treatment for epilepsy.
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Affiliation(s)
- Snehashis Kundu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Sudipta Nayak
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Debarati Rakshit
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas, USA
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Raebareli, Lucknow, India
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
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15
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Mengoli M, Conti G, Fabbrini M, Candela M, Brigidi P, Turroni S, Barone M. Microbiota-gut-brain axis and ketogenic diet: how close are we to tackling epilepsy? MICROBIOME RESEARCH REPORTS 2023; 2:32. [PMID: 38045924 PMCID: PMC10688818 DOI: 10.20517/mrr.2023.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 08/01/2023] [Accepted: 08/21/2023] [Indexed: 12/05/2023]
Abstract
The microbiota-gut-brain axis refers to the intricate bidirectional communication between commensal microorganisms residing in the digestive tract and the central nervous system, along neuroendocrine, metabolic, immune, and inflammatory pathways. This axis has been suggested to play a role in several neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and epilepsy, paving the way for microbiome-based intervention strategies for the mitigation and treatment of symptoms. Epilepsy is a multifaceted neurological condition affecting more than 50 million individuals worldwide, 30% of whom do not respond to conventional pharmacological therapies. Among the first-hand microbiota modulation strategies, nutritional interventions represent an easily applicable option in both clinical and home settings. In this narrative review, we summarize the mechanisms underlying the microbiota-gut-brain axis involvement in epilepsy, discuss the impact of antiepileptic drugs on the gut microbiome, and then the impact of a particular dietary pattern, the ketogenic diet, on the microbiota-gut-brain axis in epileptic patients. The investigation of the microbiota response to non-pharmacological therapies is an ever-expanding field with the potential to allow the design of increasingly accessible and successful intervention strategies.
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Affiliation(s)
- Mariachiara Mengoli
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Gabriele Conti
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Fabbrini
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Candela
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Patrizia Brigidi
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Monica Barone
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
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16
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Huang J, Fan Y, Lei Z, Yu Z, Ni D, Chen Y. The inhibitory effect and mechanism of theaflavins on fluoride transport and uptake in HIEC-6 cell model. Food Chem Toxicol 2023:113939. [PMID: 37433353 DOI: 10.1016/j.fct.2023.113939] [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: 03/30/2023] [Revised: 07/05/2023] [Accepted: 07/07/2023] [Indexed: 07/13/2023]
Abstract
Fluoride (F-) is widely present in nature, while long-term excessive F- intake can lead to fluorosis. Theaflavins are an important bioactive ingredient of black and dark tea, and black and dark tea water extracts showed a significantly lower F- bioavailability than NaF solutions in previous studies. In this study, the effect and mechanism of four theaflavins (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, theaflavin-3,3'-digallate) on F- bioavailability were investigated using normal human small intestinal epithelial cells (HIEC-6) as a model. The results showed that theaflavins could inhibit the absorptive (apical - basolateral) transport of F- while promote its secretory (basolateral - apical) transport in HIEC-6 cell monolayers in a time- and concentration-dependent (5-100 μg/mL) manner, and significantly reduce the cellular F- uptake. Moreover, the HIEC-6 cells treated with theaflavins showed a reduction in cell membrane fluidity and cell surface microvilli. Transcriptome, qRT-PCR and Western blot analysis revealed that theaflavin-3-gallate (TF3G) addition could significantly enhance the mRNA and protein expression levels of tight junction-related genes in HIEC-6 cells, such as claudin-1, occludin and zonula occludens-1 (ZO-1). Overall, theaflavins may reduce F- absorptive transport by regulating tight junction-related proteins, and decreasing intracellular F- accumulation by affecting the cell membrane structure and properties in HIEC-6 cells.
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Affiliation(s)
- Jiasheng Huang
- National Key Laboratory for Germplasm Innovation & Utilization of Horticultural Crops, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China; College of Horticulture & Forestry Sciences, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China
| | - Yueqin Fan
- National Key Laboratory for Germplasm Innovation & Utilization of Horticultural Crops, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China; College of Horticulture & Forestry Sciences, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China
| | - Zhendong Lei
- National Key Laboratory for Germplasm Innovation & Utilization of Horticultural Crops, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China; College of Horticulture & Forestry Sciences, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China
| | - Zhi Yu
- National Key Laboratory for Germplasm Innovation & Utilization of Horticultural Crops, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China; College of Horticulture & Forestry Sciences, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China
| | - Dejiang Ni
- National Key Laboratory for Germplasm Innovation & Utilization of Horticultural Crops, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China; College of Horticulture & Forestry Sciences, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China
| | - Yuqiong Chen
- National Key Laboratory for Germplasm Innovation & Utilization of Horticultural Crops, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China; College of Horticulture & Forestry Sciences, Huazhong Agricultural University, Wuhan, Hubei, 430070, PR China.
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17
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Houillier P, Lievre L, Hureaux M, Prot-Bertoye C. Mechanisms of paracellular transport of magnesium in intestinal and renal epithelia. Ann N Y Acad Sci 2023; 1521:14-31. [PMID: 36622354 DOI: 10.1111/nyas.14953] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.
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Affiliation(s)
- Pascal Houillier
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France
- Centre de Référence des Maladies Rares du Calcium et du Phosphate, Paris, France
| | - Loïc Lievre
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Marguerite Hureaux
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
- Paris Centre de Recherche Cardio-vasculaire, INSERM, Université Paris Cité, Paris, France
| | - Caroline Prot-Bertoye
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France
- Centre de Référence des Maladies Rares du Calcium et du Phosphate, Paris, France
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18
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Hudock KM, Collins MS, Imbrogno MA, Kramer EL, Brewington JJ, Ziady A, Zhang N, Snowball J, Xu Y, Carey BC, Horio Y, O’Grady SM, Kopras EJ, Meeker J, Morgan H, Ostmann AJ, Skala E, Siefert ME, Na CL, Davidson CR, Gollomp K, Mangalmurti N, Trapnell BC, Clancy JP. Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function. Front Immunol 2023; 13:1023553. [PMID: 36703990 PMCID: PMC9872031 DOI: 10.3389/fimmu.2022.1023553] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/30/2022] [Indexed: 01/12/2023] Open
Abstract
Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT.
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Affiliation(s)
- K. M. Hudock
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,*Correspondence: K. M. Hudock,
| | - M. S. Collins
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - M. A. Imbrogno
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - E. L. Kramer
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - J. J. Brewington
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - A. Ziady
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - N. Zhang
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - J. Snowball
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Y. Xu
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Divisions of Biomedical Informatics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - B. C. Carey
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Translational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Y. Horio
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States,Department of Respiratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto-shi, Kumamoto, Japan
| | - S. M. O’Grady
- Departments of Animal Science, University of Minnesota, St. Paul, MN, United States,Department of Integrative Biology and Physiology, University of Minnesota, St. Paul, MN, United States
| | - E. J. Kopras
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - J. Meeker
- Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - H. Morgan
- Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - A. J. Ostmann
- Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - E. Skala
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - M. E. Siefert
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - C. L. Na
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - C. R. Davidson
- Division of Pediatric Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - K. Gollomp
- Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - N. Mangalmurti
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States,Pennsylvania Lung Biology Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - B. C. Trapnell
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States,Translational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - J. P. Clancy
- Cystic Fibrosis Foundation, Bethesda, MD, United States
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19
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The Chinese Herbal Formula Huoxiang Zhengqi Dropping Pills Prevents Acute Intestinal Injury Induced by Heatstroke by Increasing the Expression of Claudin-3 in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9230341. [PMID: 35958934 PMCID: PMC9357687 DOI: 10.1155/2022/9230341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/01/2022] [Indexed: 11/17/2022]
Abstract
Intestinal injury has been regarded as an important causative factor for systemic inflammation during heatstroke, and maintaining intestinal integrity has been a potential target for the prevention of HS. Huoxiang Zhengqi Dropping Pills (HZPD) is a modern preparation of Huoxiang Zhengqi and widely used to prevent HS. The present study aims to explore the protective effect of HZDP on intestinal injury during heatstroke and analyze its potential pharmacodynamic basis. Male rats in the control and HS groups were given normal saline, and those in the HZDP groups were given HZDP (0.23, 0.46, and 0.92 g/kg) before induction of HS. Serum contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), intestinal fatty acid-binding protein (iFABP), and diamine oxidase (DAO) were determined using ELISA. Histopathology of intestinal injury was observed following H&E staining. The expression of claudin-3 was determined using western blot, immunohistochemistry, and immunofluorescence techniques. Moreover, network pharmacological tools were used to analyze the potential pharmacodynamic basis and the mechanism of HZDP. Treatment with HZDP significantly prolonged the time to reach Tc. Compared with the control group, the contents of TNF-α, IL-6, iFABP, and DAO in HS rats increased markedly. HZDP treatments reduced these levels significantly, and the effects in the middle dose group (0.46 g/kg) were most obvious. HZDP also attenuated intestinal injury and significantly reversed the decrease in claudin-3 expression. Bioinformatics analysis suggested that 35 active ingredients and 128 target genes of HZDP were screened from TCMSP and 93 target genes intersected with heatstroke target genes, which were considered potential therapeutic targets. TNF-α and IL-6 were the main inflammatory target genes of HZDP correlated with HS. These results indicated that HZDP effectively protected intestinal barrier function and prevented acute intestinal injury by increasing the expression of claudin-3 in rats, eventually improving heat resistance.
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Abstract
Phosphate homeostasis is dependent on the interaction and coordination of four main organ systems: thyroid/parathyroids, gastrointestinal tract, bone and kidneys, and three key hormonal regulators, 1,25-hydroxyvitamin D3, parathyroid hormone and FGF23 with its co- factor klotho. Phosphorus is a critical nutritional element for normal cellular function, but in excess can be toxic to tissues, particularly the vasculature. As phosphate, it also has an important interaction and inter-dependence with calcium and calcium homeostasis sharing some of the same controlling hormones, although this is not covered in our article. We have chosen to provide a current overview of phosphate homeostasis only, focusing on the role of two major organ systems, the gastrointestinal tract and kidneys, and their contribution to the control of phosphate balance. We describe in some detail the mechanisms of intestinal and renal phosphate transport, and compare and contrast their regulation. We also consider a significant example of phosphate imbalance, with phosphate retention, which is chronic kidney disease; why consequent hyperphosphatemia is important, and some of the newer means of managing it.
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Affiliation(s)
- Joanne Marks
- Department of Neuroscience, Physiology & Pharmacology, University College London, London, United Kingdom
| | - Robert J Unwin
- Department of Neuroscience, Physiology & Pharmacology, University College London, London, United Kingdom; Department of Renal Medicine, University College London, London, United Kingdom.
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21
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Wu D, Fan Z, Li J, Zhang Y, Xu Q, Wang L, Wang L. Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio). Front Immunol 2022; 13:915657. [PMID: 35720284 PMCID: PMC9200961 DOI: 10.3389/fimmu.2022.915657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
To investigate the effects of alpha-ketoglutarate (AKG) supplementation in a low protein (LP) diet on the growth performance, immune response, and intestinal health of common carp (Cyprinus carpio), 600 carp were randomly divided into five dietary groups: a normal protein (NP) diet containing 32% crude protein, an LP diet formulated with 28% crude protein, and LP with AKG at 0.4%, 0.8%, and 1.2% (dry matter). After an 8-week trial period, the results demonstrated that an LP diet led to a decrease in performance, immune response, and intestinal barrier function. Compared with the LP group, the final body weight and weight gain rate in the LP+0.4% AKG group were significantly higher, the feed conversion ratio was significantly decreased with the addition of 0.4% and 0.8% AKG. The supplementation with 0.4% and 0.8% AKG markedly increased the activities of T-SOD and GSH-Px, as well as the expression levels of GPX1a and GPX1b relative to the LP group, whereas the MDA content was significantly decreased in the LP+0.4% AKG group. In addition, the expression levels of tight junctions including claudin-3, claudin-7, ZO-1, and MLCK were significantly up-regulated in the LP+0.4% AKG group, and the relative expression levels of the pro-inflammatory factors IL-1β and IL-6α were significantly lower with the addition of 0.4%, 0.8%, and 1.2% AKG. Moreover, the abundance of Proteobacteria in the LP+0.4% AKG group was lower than that in the LP group, and the abundance of Firmicutes and Fusobacteria was higher at the phylum level. The abundance of Citrobacter in the LP+0.4% AKG group was decreased compared to the LP group, while the abundance of Aeromonas was increased at the genus level. In short, the effects of AKG on the intestinal health of the common carp were systematically and comprehensively evaluated from the perspectives of intestinal physical barrier, chemical barrier, biological barrier, and immune barrier. We found that an LP diet supplemented with 0.4% AKG was beneficial to the growth performance and intestinal health of common carp.
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Affiliation(s)
- Di Wu
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Ze Fan
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Jinnan Li
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Yuanyuan Zhang
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Qiyou Xu
- School of Life Science, Huzhou University, Huzhou, China
| | - Liang Wang
- AHP Application Research Institute, Weifang Addeasy Bio-Technology Co., Ltd, Weifang, China
| | - Liansheng Wang
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
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22
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Gommers LMM, Hoenderop JGJ, de Baaij JHF. Mechanisms of proton pump inhibitor-induced hypomagnesemia. Acta Physiol (Oxf) 2022; 235:e13846. [PMID: 35652564 PMCID: PMC9539870 DOI: 10.1111/apha.13846] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022]
Abstract
Proton pump inhibitors (PPIs) reliably suppress gastric acid secretion and are therefore the first-line treatment for gastric acid-related disorders. Hypomagnesemia (serum magnesium [Mg2+ ] <0.7 mmol/L) is a commonly reported side effect of PPIs. Clinical reports demonstrate that urinary Mg2+ excretion is low in PPI users with hypomagnesemia, suggesting a compensatory mechanism by the kidney for malabsorption of Mg2+ in the intestines. However, the exact mechanism by which PPIs cause impaired Mg2+ absorption is still unknown. In this review, we show that current experimental evidence points toward reduced Mg2+ solubility in the intestinal lumen. Moreover, the absorption pathways in both the small intestine and the colon may be reduced by changes in the expression and activity of key transporter proteins. Additionally, the gut microbiome may contribute to the development of PPI-induced hypomagnesemia, as PPI use affects the composition of the gut microbiome. In this review, we argue that the increase of the luminal pH during PPI treatment may contribute to several of these mechanisms. Considering the fact that bacterial fermentation of dietary fibers results in luminal acidification, we propose that targeting the gut microbiome using dietary intervention might be a promising treatment strategy to restore hypomagnesemia in PPI users.
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Affiliation(s)
- Lisanne M. M. Gommers
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
| | - Joost G. J. Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
| | - Jeroen H. F. de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
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Droessler L, Cornelius V, Boehm E, Stein L, Brunner N, Amasheh S. Barrier Perturbation in Porcine Peyer’s Patches by Tumor Necrosis Factor is Associated With a Dysregulation of Claudins. Front Physiol 2022; 13:889552. [PMID: 35707009 PMCID: PMC9189282 DOI: 10.3389/fphys.2022.889552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/26/2022] [Indexed: 12/22/2022] Open
Abstract
The proinflammatory cytokine tumor necrosis factor (TNF) has been described as one of the main mediators of intestinal inflammatory diseases, affecting the composition of tight junction (TJ) proteins and leading to a disruption of the epithelial barrier. An intact intestinal barrier is mandatory, because the follicle-associated epithelium of Peyer’s patches represents the first defense line of the intestinal immune system and ensures a controlled uptake of antigens from the gut lumen. In the current study, we have analyzed the detailed effects of TNF on the follicle-associated epithelium of porcine Peyer’s patches by applying the Ussing chamber technique. Epithelial tissue specimens of Peyer’s patches and the surrounding villus epithelium were mounted into conventional Ussing chambers and incubated with TNF for 10 h. The transepithelial resistance, representing epithelial barrier function of the tissue, was recorded. A reduction of transepithelial resistance was detected after 8 h in Peyer’s patch tissue specimens, whereas the villus epithelium was not significantly affected by TNF. Subsequent molecular analysis of TJ protein expression revealed a marked decrease of claudin-1 and -4, and an increase of claudin-2. In neighboring villus epithelium, no significant changes in the expression of TJ proteins could be shown. A strong increase of TNF receptor-2 (TNFR-2) could also be detected in Peyer’s patches, in agreement with the major role of this receptor in Peyer’s patches. Our findings were in accordance with changes detected by confocal laser scanning immunofluorescence microscopy. The regulation of TNF effects via myosin light chain kinase (MLCK) was analyzed in blocking experiments. Our detailed analysis is the first to show that TNF affects the barrier function of the follicle-associated epithelium of porcine Peyer’s patches but has no effects on the villus epithelium. These findings reveal not only the basic differences of epithelial barrier function between the two structures, but also the significance of Peyer’s patches as a primary mucosal immune defense.
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Livzan MA, Bicbavova GR, Romanyuk AE. Ulcerative colitis: focus on colonic mucosal resistance. BULLETIN OF SIBERIAN MEDICINE 2022; 21:121-132. [DOI: 10.20538/1682-0363-2022-1-121-132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
In recent decades, following cooperation between scientists in various specialties, new unique data on the pathogenesis of ulcerative colitis have been obtained. The role of an impaired immune response to antigens of gut microbiota in genetically predisposed individuals under the effect of certain environmental factors was proven. Assessing the interaction between the colonic mucosa and gut microbiota will help to understand the mechanisms of ulcerative colitis and develop new treatment strategies for the disease.This review presents modern views on the pathogenesis of ulcerative colitis with a focus on the imbalance between local protective and aggressive factors of the gastric and intestinal mucosa. The structure and role of the epithelial barrier both under normal conditions and in ulcerative colitis are considered in detail.The aim of this review was to summarize the data on resistance of the colonic mucosa and its damage in ulcerative colitis.
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25
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Wan Y, Yang L, Jiang S, Qian D, Duan J. Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis. Inflamm Bowel Dis 2022; 28:639-648. [PMID: 34871402 DOI: 10.1093/ibd/izab277] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.
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Affiliation(s)
- Yue Wan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Lei Yang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Shu Jiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
| | - Dawei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, PR China
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Wu D, Meng Q, Wang Y, Wang M, Xu E, Xiao L, Xu M. Dietary supplementation of free or two fat-coated sodium butyrate with varying release times on gastrointestinal development and tight junctions in preweaning Holstein calves. Anim Feed Sci Technol 2022. [DOI: 10.1016/j.anifeedsci.2022.115224] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Kaminsky LW, Al-Sadi R, Ma TY. IL-1β and the Intestinal Epithelial Tight Junction Barrier. Front Immunol 2021; 12:767456. [PMID: 34759934 PMCID: PMC8574155 DOI: 10.3389/fimmu.2021.767456] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn's disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1β (IL-1β), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1β-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1β-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1β on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1β modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.
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Affiliation(s)
- Lauren W Kaminsky
- Section of Allergy, Asthma, and Immunology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Rana Al-Sadi
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Thomas Y Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
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Ding M, Lang Y, Shu H, Shao J, Cui L. Microbiota-Gut-Brain Axis and Epilepsy: A Review on Mechanisms and Potential Therapeutics. Front Immunol 2021; 12:742449. [PMID: 34707612 PMCID: PMC8542678 DOI: 10.3389/fimmu.2021.742449] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/17/2021] [Indexed: 12/16/2022] Open
Abstract
The gut-brain axis refers to the bidirectional communication between the gut and brain, and regulates intestinal homeostasis and the central nervous system via neural networks and neuroendocrine, immune, and inflammatory pathways. The development of sequencing technology has evidenced the key regulatory role of the gut microbiota in several neurological disorders, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Epilepsy is a complex disease with multiple risk factors that affect more than 50 million people worldwide; nearly 30% of patients with epilepsy cannot be controlled with drugs. Interestingly, patients with inflammatory bowel disease are more susceptible to epilepsy, and a ketogenic diet is an effective treatment for patients with intractable epilepsy. Based on these clinical facts, the role of the microbiome and the gut-brain axis in epilepsy cannot be ignored. In this review, we discuss the relationship between the gut microbiota and epilepsy, summarize the possible pathogenic mechanisms of epilepsy from the perspective of the microbiota gut-brain axis, and discuss novel therapies targeting the gut microbiota. A better understanding of the role of the microbiota in the gut-brain axis, especially the intestinal one, would help investigate the mechanism, diagnosis, prognosis evaluation, and treatment of intractable epilepsy.
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Affiliation(s)
| | | | | | | | - Li Cui
- Department of Neurology, First Hospital of Jilin University, Changchun, China
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Bao J, Zhang Y, Zhang L, Gong X, Shi W, Liu L, Wang X. Therapeutic effect of Schisandrin A on avian colibacillosis through gut-liver axis. Poult Sci 2021; 100:101371. [PMID: 34481217 PMCID: PMC8417393 DOI: 10.1016/j.psj.2021.101371] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/25/2021] [Accepted: 06/25/2021] [Indexed: 11/12/2022] Open
Abstract
This study evaluated the therapeutic efficacy of Schisandrin A on systemic colibacillosis of chickens. One hundred and eighty, 1-day-old Hailan Brown chickens were divided into 6 groups of 30 chickens each and assigned to the following treatments: 1) uninfected/untreated control; 2) infected Escherichia coli; 3) infected-plus low dose of Schisandrin A therapy (50 mg/kg); 4) infected-plus medium dose of Schisandrin A therapy (100 mg/kg); 5) infected-plus high dose of Schisandrin A therapy (200 mg/kg) and 6) infected-plus antimicrobial therapy (florfenicol). Each group of chickens was placed in cages with a photoperiod of 12 h of light and 12 h of dark. Feed and water for all groups were provided ad libitum for the duration of the study. On d 14, all the chickens except the uninfected control group were intraperitoneally inoculated with a fresh culture of E. coli containing 1 × 108 CFU/mL. The parameters measured included: average daily weight gain (ADG), percent survivability, liver index, serum activity of enzymes (ALT and AST), hepatic and intestinal concentrations of TNF-α, IL-1β, IL-6, IL-8, and LPS, expression of tight junction proteins (occludin, ZO-1, and claudin-1), relative abundance of bacterial species and histopathological changes in hepatic and intestinal tissue. The results showed that the medium and high doses of Schisandrin A ameliorated the detrimental effects of colibacillosis on weight gain. Regarding organ indexes, E. coli infection induced a significant increase in liver index, all the doses of Schisandrin A produced a significant reduction of liver index in comparison to the E. coli infected control. Serum activity of ALT and AST enzymes significantly increased due to E. coli infection, with the exception of the low dose of Schisandrin A for AST enzyme activity, all the Schisandrin A treatments significantly lowered enzyme activity in comparison to the E. coli infected control. Regarding concentrations of inflammatory markers in hepatic and intestinal, E. coli infection caused a significant increase in TNF-α, IL-1β, IL-6, and IL-8, except the lowest dose of Schisandrin A for IL-1β, the rest of the doses tested were able to significantly reduced the concentrations of inflammatory markers. Concentrations of LPS in hepatic and intestinal tissues were significantly increased by E. coli infection, all doses of Schisandrin A significantly reduced the concentration of LPS in hepatic and intestinal tissue. E. coli infection significantly reduced the expression of 2 tight junction proteins (ZO-1 and Claudin-1), the higher doses of Schisandrin A were effective in significantly increasing the expression of these tight junction proteins when compared with the E. coli infected control. Taken together, these results show that Schisandrin A has potential as an alternative therapy for the treatment of colibacillosis in chickens.
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Affiliation(s)
- Jialu Bao
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding 071001, China
| | - Yan Zhang
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding 071001, China
| | - Linchao Zhang
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding 071001, China
| | - Xincheng Gong
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding 071001, China; Hebei Provincial Engineering Center for Chinese Veterinary Herbal Medicine, Baoding 071001, China
| | - Wanyu Shi
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding 071001, China; Hebei Provincial Engineering Center for Chinese Veterinary Herbal Medicine, Baoding 071001, China
| | - Liantao Liu
- College of Agronomy, Hebei Agricultural University, Baoding, 071001, China
| | - Xiaodan Wang
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding 071001, China; Hebei Provincial Engineering Center for Chinese Veterinary Herbal Medicine, Baoding 071001, China.
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Asowata EO, Olusanya O, Abaakil K, Chichger H, Srai SKS, Unwin RJ, Marks J. Diet-induced iron deficiency in rats impacts small intestinal calcium and phosphate absorption. Acta Physiol (Oxf) 2021; 232:e13650. [PMID: 33749990 DOI: 10.1111/apha.13650] [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: 07/10/2020] [Revised: 02/26/2021] [Accepted: 03/17/2021] [Indexed: 12/31/2022]
Abstract
AIMS Recent reports suggest that iron deficiency impacts both intestinal calcium and phosphate absorption, although the exact transport pathways and intestinal segment responsible have not been determined. Therefore, we aimed to systematically investigate the impact of iron deficiency on the cellular mechanisms of transcellular and paracellular calcium and phosphate transport in different regions of the rat small intestine. METHODS Adult, male Sprague-Dawley rats were maintained on a control or iron-deficient diet for 2 weeks and changes in intestinal calcium and phosphate uptake were determined using the in situ intestinal loop technique. The circulating levels of the hormonal regulators of calcium and phosphate were determined by ELISA, while the expression of transcellular calcium and phosphate transporters, and intestinal claudins were determined using qPCR and western blotting. RESULTS Diet-induced iron deficiency significantly increased calcium absorption in the duodenum but had no impact in the jejunum and ileum. In contrast, phosphate absorption was significantly inhibited in the duodenum and to a lesser extent the jejunum, but remained unchanged in the ileum. The changes in duodenal calcium and phosphate absorption in the iron-deficient animals were associated with increased claudin 2 and 3 mRNA and protein levels, while levels of parathyroid hormone, fibroblast growth factor-23 and 1,25-dihydroxy vitamin D3 were unchanged. CONCLUSION We propose that iron deficiency alters calcium and phosphate transport in the duodenum. This occurs via changes to the paracellular pathway, whereby upregulation of claudin 2 increases calcium absorption and upregulation of claudin 3 inhibits phosphate absorption.
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Affiliation(s)
- Evans O. Asowata
- Department of Neuroscience, Physiology & Pharmacology University College London London UK
| | - Oluwatobi Olusanya
- Department of Neuroscience, Physiology & Pharmacology University College London London UK
| | - Kaoutar Abaakil
- Department of Neuroscience, Physiology & Pharmacology University College London London UK
| | - Havovi Chichger
- Biomedical Research Group School of Life Sciences Anglia Ruskin University Cambridge UK
| | - Surjit K. S. Srai
- Institute of Structural and Molecular Biology University College London London UK
| | - Robert J. Unwin
- Department of Renal Medicine University College London London UK
| | - Joanne Marks
- Department of Neuroscience, Physiology & Pharmacology University College London London UK
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Wang K, Ding Y, Xu C, Hao M, Li H, Ding L. Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial integrity. Oncoimmunology 2021; 10:1923910. [PMID: 34026335 PMCID: PMC8118418 DOI: 10.1080/2162402x.2021.1923910] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 02/08/2023] Open
Abstract
Intestinal epithelial barrier protects intestine from infection and injury, while chronic inflammation is a trigger for tumorigenesis. As a member of tight junctions (TJs) family, Claudin-7 (Cldn-7) is dedicated to maintaining cell polarity and TJs barrier integrity, and closely related to the development of inflammation and tumors. However, potential roles of Cldn-7 in intestinal inflammation and colitis-associated colorectal cancer (CAC) have not been well characterized in vivo. Here, we analyzed the expression profile of Cldn-7 in inflammatory bowel disease (IBD) and CAC. Colitis and colitis-cancer transformation models were established based on inducible intestinal conditional Cldn-7 gene knockout mice (Cldn7fl/fl;villin-CreERT2), by intraperitoneal injection of azomethane (AOM) and dextran sodium sulfate (DSS) feeding. Cldn-7 knockout promoted susceptibility to colitis and CAC, aggravated clinical symptoms, severely damaged intestinal epithelium, increased mucosal inflammation accompanied dysregulated cell proliferation-apoptosis. Epithelial barrier integrity was destroyed, and intercellular permeability was increased. After AOM/DSS induction, tumor burden and volume were increased, characterized by enhanced proliferation and activation of Wnt/β-catenin signaling pathway. Mechanistically, Cldn-7 deficiency promoted colitis and subsequently malignant transformation by destroying TJs integrity and increasing inflammatory cascade. Overall, based on Cldn-7 knockout mouse model, we have first demonstrated the key roles of Cldn-7 in maintaining intestinal homeostasis and preventing IBD and consequent CAC. Abbreviations: AJs: adherens junctions; AOM: azomethane; Cldn-7: Claudin-7; CRC: colorectal cancer; CAC: colitis-associated colorectal cancer; CD: Crohn's disease; DSS: dextran sodium sulfate; DAI: disease activity index; EMT: epithelial-mesenchymal transition; FITC: fluorescence isothiocyanate; HB: hemoglobin; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; ISCs: intestinal stem cells; PLT: platelet; RBC: red blood cell; ROS: reactive oxygen species; TAM: tamoxifen; TJs: tight junctions; TCF/LEF: T-cell factor/lymphoid enhancer factor; UC: ulcerative colitis; WBC: white blood cell.
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Affiliation(s)
- Kun Wang
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Yuhan Ding
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Chang Xu
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Hepato-Pancreato-Biliary Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Mengdi Hao
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Huimin Li
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
| | - Lei Ding
- Department of Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Oncology Surgery, Ninth School of Clinical Medicine, Peking University, Beijing, China
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Iwaya M, Hayashi H, Nakajima T, Matsuda K, Kinugawa Y, Tobe Y, Tateishi Y, Iwaya Y, Uehara T, Ota H. Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. Histopathology 2021; 79:227-237. [PMID: 33590909 DOI: 10.1111/his.14358] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/02/2021] [Accepted: 02/15/2021] [Indexed: 01/09/2023]
Abstract
AIMS Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs. METHODS AND RESULTS We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs. CONCLUSIONS These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.
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Affiliation(s)
- Mai Iwaya
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Hiroyuki Hayashi
- Department of Pathology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Tomoyuki Nakajima
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Kazuyuki Matsuda
- Department of Clinical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto, Japan
| | - Yasuhiro Kinugawa
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Yosuke Tobe
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Yoko Tateishi
- Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yugo Iwaya
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyoshi Ota
- Department of Clinical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto, Japan
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Mg 2+ Transporters in Digestive Cancers. Nutrients 2021; 13:nu13010210. [PMID: 33450887 PMCID: PMC7828344 DOI: 10.3390/nu13010210] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 02/08/2023] Open
Abstract
Despite magnesium (Mg2+) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg2+ homeostasis is regulated by Mg2+ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg2+ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg2+ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg2+ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg2+ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.
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Kahya U, Köseer AS, Dubrovska A. Amino Acid Transporters on the Guard of Cell Genome and Epigenome. Cancers (Basel) 2021; 13:E125. [PMID: 33401748 PMCID: PMC7796306 DOI: 10.3390/cancers13010125] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.
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Affiliation(s)
- Uğur Kahya
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
| | - Ayşe Sedef Köseer
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Anna Dubrovska
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Al Alawi AM, Al Badi A, Al Huraizi A, Falhammar H. Magnesium: The recent research and developments. ADVANCES IN FOOD AND NUTRITION RESEARCH 2021; 96:193-218. [PMID: 34112353 DOI: 10.1016/bs.afnr.2021.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Magnesium is the fourth most abundant mineral in the human body, which facilitates more than 300 enzymatic reactions. Magnesium is essential for nucleic material and protein synthesis, neuromuscular conduction, cardiac contractility, energy metabolism, and immune system function. Gastrointestinal system and kidneys closely regulate magnesium absorption and elimination to maintain adequate storage of magnesium. Magnesium deficiency has been linked to many diseases and poor health outcomes. Magnesium has also been proven to be an effective therapeutic agent in many diseases, such as bronchial asthma, cardiac arrhythmia, and pre-eclampsia.
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Affiliation(s)
- Abdullah M Al Alawi
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman; Oman Medical Specialty Board, Muscat, Oman.
| | | | - Aisha Al Huraizi
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
| | - Henrik Falhammar
- Department of Endocrinology, Metabolism, and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
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Abstract
Phosphorus plays a vital role in diverse biological processes including intracellular signaling, membrane integrity, and skeletal biomineralization; therefore, the regulation of phosphorus homeostasis is essential to the well-being of the organism. Cells and whole organisms respond to changes in inorganic phosphorus (Pi) concentrations in their environment by adjusting Pi uptake and altering biochemical processes in cells (local effects) and distant organs (endocrine effects). Unicellular organisms, such as bacteria and yeast, express specific Pi-binding proteins on the plasma membrane that respond to changes in ambient Pi availability and transduce intracellular signals that regulate the expression of genes involved in cellular Pi uptake. Multicellular organisms, including humans, respond at a cellular level to adapt to changes in extracellular Pi concentrations and also have endocrine pathways which integrate signals from various organs (e.g., intestine, kidneys, parathyroid glands, bone) to regulate serum Pi concentrations and whole-body phosphorus balance. In mammals, alterations in the concentrations of extracellular Pi modulate type III sodium-phosphate cotransporter activity on the plasma membrane, and trigger changes in cellular function. In addition, elevated extracellular Pi induces activation of fibroblast growth factor receptor, Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) and Akt pathways, which modulate gene expression in various mammalian cell types. Excessive Pi exposure, especially in patients with chronic kidney disease, leads to endothelial dysfunction, accelerated vascular calcification, and impaired insulin secretion.
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Affiliation(s)
- Kittrawee Kritmetapak
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
- Division of Nephrology and Hypertension, Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, 55902, USA
| | - Rajiv Kumar
- Division of Nephrology and Hypertension, Departments of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, 55902, USA.
- Nephrology Research, Medical Sciences 1-120, 200 First Street Southwest, Rochester, MN, 55902, USA.
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Wang Y, Zhao H, Nie X, Guo M, Jiang G, Xing M. Zinc application alleviates the adverse renal effects of arsenic stress in a protein quality control way in common carp. ENVIRONMENTAL RESEARCH 2020; 191:110063. [PMID: 32818499 DOI: 10.1016/j.envres.2020.110063] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 06/11/2023]
Abstract
The potential antagonistic mechanism between zinc (Zn) and arsenic (As) on renal toxicity was investigated in common carp. The results showed that by increased Zn efflux and retention (as reflected by zinc transporter 1 (ZnT-1), Zrt- and Irt- 1ike protein (ZIP) and metallothionein (MT) expression), Zn co-administration significantly recovered the antioxidant function (catalase, CAT) and the level of renal barrier function (Occludin, Claudins and Zonula Occludens) in comparison to As treatment. Interestingly, Zn co-administration with As resulted in carps undergoing reduction of heat shock response (HSPs), a low induction of autophagy flux (Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (P62)) and decreased endoplasmic reticulum (ER) stress (activating transcription factor 6 (ATF-6), inositol requiring-1α (IRE1) and PKR-like ER kinase (PERK)) in the aspect of mRNA or protein levels. All these alleviated protein quality control processes induced by Zn under As stress was correlated with the no longer loosen tight connection, less swollen endoplasmic reticulum as well as reduced formation of autophagosomes and autophagic vesicles. Mechanically, post-transcriptional regulated protein quantities compromising phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway was demonstrated true causative forces inside the cell for Zn against As poisoning. In conclusion, we suggested the potential renal protective effect of Zn supplementation against As exposure by the modulation of protein quality control processes.
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Affiliation(s)
- Yu Wang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Hongjing Zhao
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Xiaopan Nie
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Menghao Guo
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China
| | - Guangshun Jiang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Mingwei Xing
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
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Holmes M, Flaminio Z, Vardhan M, Xu F, Li X, Devinsky O, Saxena D. Cross talk between drug-resistant epilepsy and the gut microbiome. Epilepsia 2020; 61:2619-2628. [PMID: 33140419 DOI: 10.1111/epi.16744] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/16/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
One-third of epilepsy patients have drug-resistant epilepsy (DRE), which is often complicated by polydrug toxicity and psychiatric and cognitive comorbidities. Advances in understanding the microbiome and gut-brain-axis are likely to shed light on epilepsy pathogenesis, anti-seizure medication (ASM) resistance, and potential therapeutic targets. Gut dysbiosis is associated with inflammation, blood-brain barrier disruption, and altered neuromodulators. High-throughput and metagenomic sequencing has advanced the characterization of microbial species and functional pathways. DRE patients show altered gut microbiome composition compared to drug-sensitive patients and healthy controls. The ketogenic and modified Atkins diets can reduce seizures in some patients with DRE. These low-carbohydrate dietary therapies alter the taxonomic and functional composition of the gut microbiome, and composition varies between diet responders and nonresponders. Murine models suggest that specific phyla are necessary to confer efficacy from the diet, and antibiotic treatment may eliminate efficacy. The impact of diet might involve alterations in microbiota, promotion of select microbial interactions, and variance in brain neurotransmitter levels that then influence seizures. Understanding the mechanics of how diet manipulates seizures may suggest novel therapies. Most ASMs act on neuronal transmission via effects on ion channels and neurotransmitters. However, ASMs may also assert their effects via the gut microbiota. In animal models, the microbiota composition (eg, abundance of certain phyla) can vary with ASM active drug metabolites. Given the developing understanding of the gut microbiome in DRE, probiotics are another potential therapy. Probiotics alter the microbiota composition, and small studies suggest that these supplements can reduce seizures in some patients. DRE has enormous consequences to patients and society, and the gut microbiome holds promise as a potential therapeutic target. However, the exact mechanism and recognition of which patients are likely to be responders remain elusive. Further studies are warranted.
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Affiliation(s)
- Manisha Holmes
- NYU Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Health, New York, NY, USA
| | - Zia Flaminio
- Department of Molecular Pathobiology, New York University College of Dentistry and Department of Surgery, New York University School of Medicine, New York, NY, USA
| | - Mridula Vardhan
- Department of Molecular Pathobiology, New York University College of Dentistry and Department of Surgery, New York University School of Medicine, New York, NY, USA
| | - Fangxi Xu
- Department of Molecular Pathobiology, New York University College of Dentistry and Department of Surgery, New York University School of Medicine, New York, NY, USA
| | - Xin Li
- Department of Molecular Pathobiology, New York University College of Dentistry and Department of Surgery, New York University School of Medicine, New York, NY, USA
| | - Orrin Devinsky
- NYU Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Health, New York, NY, USA
| | - Deepak Saxena
- Department of Molecular Pathobiology, New York University College of Dentistry and Department of Surgery, New York University School of Medicine, New York, NY, USA
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Circulating Ouabain Modulates Expression of Claudins in Rat Intestine and Cerebral Blood Vessels. Int J Mol Sci 2020; 21:ijms21145067. [PMID: 32709081 PMCID: PMC7404321 DOI: 10.3390/ijms21145067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/20/2022] Open
Abstract
The ability of exogenous low ouabain concentrations to affect claudin expression and therefore epithelial barrier properties was demonstrated previously in cultured cell studies. We hypothesized that chronic elevation of circulating ouabain in vivo can affect the expression of claudins and tight junction permeability in different tissues. We tested this hypothesis in rats intraperitoneally injected with ouabain (1 μg/kg) for 4 days. Rat jejunum, colon and brain frontal lobes, which are variable in the expressed claudins and tight junction permeability, were examined. Moreover, the porcine jejunum cell line IPEC-J2 was studied. In IPEC-J2-cells, ouabain (10 nM, 19 days of incubation) stimulated epithelial barrier formation, increased transepithelial resistance and the level of cSrc-kinase activation by phosphorylation, accompanied with an increased expression of claudin-1, -5 and down-regulation of claudin-12; the expression of claudin-3, -4, -8 and tricellulin was not changed. In the jejunum, chronic ouabain increased the expression of claudin-1, -3 and -5 without an effect on claudin-2 and -4 expression. In the colon, only down-regulation of claudin-3 was observed. Chronic ouabain protected the intestine transepithelial resistance against functional injury induced by lipopolysaccharide treatment or by modeled acute microgravity; this regulation was most pronounced in the jejunum. Claudin-1 was also up-regulated in cerebral blood vessels. This was associated with reduction of claudin-3 expression while the expression of claudin-5 and occludin was not affected. Altogether, our results confirm that circulating ouabain can functionally and tissue-specifically affect barrier properties of epithelial and endothelial tissues via Na,K-ATPase-mediated modulation of claudins expression.
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Tang X, Liu C, Li T, Lin C, Hao Z, Zhang H, Zhao G, Chen Y, Guo A, Hu C. Gambogic acid alleviates inflammation and apoptosis and protects the blood-milk barrier in mastitis induced by LPS. Int Immunopharmacol 2020; 86:106697. [PMID: 32585608 DOI: 10.1016/j.intimp.2020.106697] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 11/28/2022]
Abstract
Mastitis is one of the most common diseases among dairy cows. There is still much debate worldwide as to whether antibiotic therapy should be given to dairy cows, or if natural products should be taken as a substitute for antibacterial therapy. As the antibiotic treatment leads to the bacterial resistance and drug residue in milk, introducing natural products for mastitis is becoming a trend. This study investigates the mechanisms of the protective effects of the natural product gambogic acid (GA) in lipopolysaccharide (LPS)-induced mastitis. For in vitro treatments, it was found that GA reduced IL-6, TNF-α, and IL-1β levels by inhibiting the phosphorylation of proteins in the nuclear factor κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathway. GA also maintained a stable membrane mitochondrial potential and inhibited the overproduction of reactive oxygen species, which protected the cells from apoptosis. On the other hand, in vivo treatments with GA were found to reduce pathological symptoms markedly, and protected the blood-milk barrier from damage induced by LPS. The results demonstrate that GA plays a vital role in suppressing inflammation, alleviating the apoptosis effect, and protecting the blood-milk barrier in mastitis induced by LPS. Thus, these results suggest that the natural product GA plays a potential role in mastitis treatment.
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Affiliation(s)
- Xin Tang
- Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Chang Liu
- Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Ting Li
- Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Changjie Lin
- Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Zhiyu Hao
- Department of Preventive Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Hui Zhang
- Department of Preventive Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Gang Zhao
- Department of Preventive Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Yingyu Chen
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Aizhen Guo
- Department of Preventive Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Changmin Hu
- Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China.
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Nakato R, Wada Y, Nakaki R, Nagae G, Katou Y, Tsutsumi S, Nakajima N, Fukuhara H, Iguchi A, Kohro T, Kanki Y, Saito Y, Kobayashi M, Izumi-Taguchi A, Osato N, Tatsuno K, Kamio A, Hayashi-Takanaka Y, Wada H, Ohta S, Aikawa M, Nakajima H, Nakamura M, McGee RC, Heppner KW, Kawakatsu T, Genno M, Yanase H, Kume H, Senbonmatsu T, Homma Y, Nishimura S, Mitsuyama T, Aburatani H, Kimura H, Shirahige K. Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells. Epigenetics Chromatin 2019; 12:77. [PMID: 31856914 PMCID: PMC6921469 DOI: 10.1186/s13072-019-0319-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 12/03/2019] [Indexed: 01/19/2023] Open
Abstract
Background Endothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Their phenotypes and physiological functions are initially regulated by developmental signals and extracellular stimuli. The underlying molecular mechanisms responsible for the diverse phenotypes of ECs from different organs are not well understood. Results To characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histone marks in nine types of human ECs (generating 148 genome-wide datasets) and carried out a comprehensive analysis with chromatin interaction data. We developed a robust procedure for comparative epigenome analysis that circumvents variations at the level of the individual and technical noise derived from sample preparation under various conditions. Through this approach, we identified 3765 EC-specific enhancers, some of which were associated with disease-associated genetic variations. We also identified various candidate marker genes for each EC type. We found that the nine EC types can be divided into two subgroups, corresponding to those with upper-body origins and lower-body origins, based on their epigenomic landscape. Epigenomic variations were highly correlated with gene expression patterns, but also provided unique information. Most of the deferentially expressed genes and enhancers were cooperatively enriched in more than one EC type, suggesting that the distinct combinations of multiple genes play key roles in the diverse phenotypes across EC types. Notably, many homeobox genes were differentially expressed across EC types, and their expression was correlated with the relative position of each organ in the body. This reflects the developmental origins of ECs and their roles in angiogenesis, vasculogenesis and wound healing. Conclusions This comprehensive analysis of epigenome characterization of EC types reveals diverse transcriptional regulation across human vascular systems. These datasets provide a valuable resource for understanding the vascular system and associated diseases.
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Affiliation(s)
- Ryuichiro Nakato
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.,Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan
| | - Youichiro Wada
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan. .,Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan.
| | - Ryo Nakaki
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Genta Nagae
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Yuki Katou
- Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan
| | - Shuichi Tsutsumi
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Natsu Nakajima
- Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan
| | - Hiroshi Fukuhara
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Atsushi Iguchi
- Department of Cardiovascular Surgery, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan
| | - Takahide Kohro
- Department of Clinical Informatics, Jichi Medical University School of Medicine, Shimotsuke, 329-0498, Japan
| | - Yasuharu Kanki
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan
| | - Yutaka Saito
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.,Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), 3-4-1 Okubo, Shinjuku-ku, Tokyo, 169-8555, Japan
| | - Mika Kobayashi
- Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan
| | | | - Naoki Osato
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Kenji Tatsuno
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Asuka Kamio
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Yoko Hayashi-Takanaka
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, 226-8503, Japan
| | - Hiromi Wada
- Isotope Science Center, The University of Tokyo, Tokyo, 113-0032, Japan.,Brain Attack Center, Ohta Memorial Hospital, Fukuyama, 720-0825, Japan
| | - Shinzo Ohta
- Brain Attack Center, Ohta Memorial Hospital, Fukuyama, 720-0825, Japan
| | - Masanori Aikawa
- The Center for Excellence in Vascular Biology and the Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Hiroyuki Nakajima
- Department of Cardiovascular Surgery, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan
| | - Masaki Nakamura
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | | | | | - Tatsuo Kawakatsu
- Bio-Medical Department, Kurabo Industries Ltd., Neyagawa, Osaka, 572-0823, Japan
| | - Michiru Genno
- Bio-Medical Department, Kurabo Industries Ltd., Neyagawa, Osaka, 572-0823, Japan
| | - Hiroshi Yanase
- Bio-Medical Department, Kurabo Industries Ltd., Neyagawa, Osaka, 572-0823, Japan
| | - Haruki Kume
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Takaaki Senbonmatsu
- Department of Cardiology, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan
| | - Yukio Homma
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Shigeyuki Nishimura
- Department of Cardiology, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan
| | - Toutai Mitsuyama
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Hiroyuki Aburatani
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.,Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Hiroshi Kimura
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan. .,Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, 226-8503, Japan. .,Laboratory of Functional Nuclear Imaging, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.
| | - Katsuhiko Shirahige
- Japan Agency for Medical Research and Development (AMED-CREST), AMED, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan. .,Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.
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42
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The behavioural and pathophysiological effects of the ketogenic diet on mild traumatic brain injury in adolescent rats. Behav Brain Res 2019; 376:112225. [DOI: 10.1016/j.bbr.2019.112225] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/16/2019] [Accepted: 09/09/2019] [Indexed: 02/07/2023]
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43
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Sundell K, Wrange AL, Jonsson PR, Blomberg A. Osmoregulation in Barnacles: An Evolutionary Perspective of Potential Mechanisms and Future Research Directions. Front Physiol 2019; 10:877. [PMID: 31496949 PMCID: PMC6712927 DOI: 10.3389/fphys.2019.00877] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/24/2019] [Indexed: 11/13/2022] Open
Abstract
Barnacles form a globally ubiquitous group of sessile crustaceans that are particularly common in the coastal intertidal. Several barnacle species are described as highly euryhaline and a few species even have the ability to colonize estuarine and brackish habitats below 5 PSU. However, the physiological and/or morphological adaptations that allow barnacles to live at low salinities are poorly understood and current knowledge is largely based on classical eco-physiological studies offering limited insight into the molecular mechanisms. This review provides an overview of available knowledge of salinity tolerance in barnacles and what is currently known about their osmoregulatory strategies. To stimulate future studies on barnacle euryhalinity, we briefly review and compare barnacles to other marine invertebrates with known mechanisms of osmoregulation with focus on crustaceans. Different mechanisms are described based on the current understanding of molecular biology and integrative physiology of osmoregulation. We focus on ion and water transport across epithelial cell layers, including transport mechanisms across cell membranes and paracellular transfer across tight junctions as well as on the use of intra- and extracellular osmolytes. Based on this current knowledge, we discuss the osmoregulatory mechanisms possibly present in barnacles. We further discuss evolutionary consequences of barnacle osmoregulation including invasion-success in new habitats and life-history evolution. Tolerance to low salinities may play a crucial role in determining future distributions of barnacles since forthcoming climate-change scenarios predict decreased salinity in shallow coastal areas. Finally, we outline future research directions to identify osmoregulatory tissues, characterize physiological and molecular mechanisms, and explore ecological and evolutionary implications of osmoregulation in barnacles.
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Affiliation(s)
- Kristina Sundell
- Department of Biological and Environmental Sciences and Swedish Mariculture Research Center (SWEMARC), University of Gothenburg, Gothenburg, Sweden
| | - Anna-Lisa Wrange
- IVL Swedish Environmental Research Institute, Fiskebäckskil, Sweden
| | - Per R Jonsson
- Department of Marine Sciences, Tjärnö Marine Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Anders Blomberg
- Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
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44
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Zhu L, Han J, Li L, Wang Y, Li Y, Zhang S. Claudin Family Participates in the Pathogenesis of Inflammatory Bowel Diseases and Colitis-Associated Colorectal Cancer. Front Immunol 2019; 10:1441. [PMID: 31316506 PMCID: PMC6610251 DOI: 10.3389/fimmu.2019.01441] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 06/07/2019] [Indexed: 12/17/2022] Open
Abstract
Claudins are a multigene transmembrane protein family comprising at least 27 members. In gastrointestinal tract, claudins are mainly located in the intestinal epithelia; many types of claudins form a network of strands in tight junction plaques within the intercellular space of neighboring epithelial cells and build paracellular selective channels, while others act as signaling proteins and mediates cell behaviors. Claudin dysfunction may contribute to epithelial permeation disorder and multiple intestinal diseases. Over recent years, the importance of claudins in the pathogenesis of inflammatory bowel diseases (IBD) has gained focus and is being investigated. This review analyzes the expression pattern and regulatory mechanism of claudins based on existing evidence and elucidates the fact that claudin dysregulation correlates with increased intestinal permeability, sustained activation of inflammation, epithelial-to-mesenchymal transition (EMT), and tumor progression in IBD as well as consequent colitis-associated colorectal cancer (CAC), possibly shedding new light on further etiologic research and clinical treatments.
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Affiliation(s)
| | | | | | | | | | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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45
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Gut Microbiota Disorder, Gut Epithelial and Blood-Brain Barrier Dysfunctions in Etiopathogenesis of Dementia: Molecular Mechanisms and Signaling Pathways. Neuromolecular Med 2019; 21:205-226. [PMID: 31115795 DOI: 10.1007/s12017-019-08547-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 05/17/2019] [Indexed: 12/12/2022]
Abstract
Emerging evidences indicate a critical role of the gut microbiota in etiopathogenesis of dementia, a debilitating multifactorial disorder characterized by progressive deterioration of cognition and behavior that interferes with the social and professional functions of the sufferer. Available data suggest that gut microbiota disorder that triggers development of dementia is characterized by substantial reduction in specific species belonging to the Firmicutes and Bacteroidetes phyla and presence of pathogenic species, predominantly, pro-inflammatory bacteria of the Proteobacteria phylum. These changes in gut microbiota microecology promote the production of toxic metabolites and pro-inflammatory cytokines, and reduction in beneficial substances such as short chain fatty acids and other anti-inflammatory factors, thereby, enhancing destruction of the gut epithelial barrier with concomitant activation of local and distant immune cells as well as dysregulation of enteric neurons and glia. This subsequently leads to blood-brain barrier dysfunctions that trigger neuroinflammatory reactions and predisposes to apoptotic neuronal and glial cell death, particularly in the hippocampus and cerebral cortex, which underlie the development of dementia. However, the molecular switches that control these processes in the histo-hematic barriers of the gut and brain are not exactly known. This review integrates very recent data on the molecular mechanisms that link gut microbiota disorder to gut epithelial and blood-brain barrier dysfunctions, underlying the development of dementia. The signaling pathways that link gut microbiota disorder with impairment in cognition and behavior are also discussed. The review also highlights potential therapeutic options for dementia.
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46
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Zeisel MB, Dhawan P, Baumert TF. Tight junction proteins in gastrointestinal and liver disease. Gut 2019; 68:547-561. [PMID: 30297438 PMCID: PMC6453741 DOI: 10.1136/gutjnl-2018-316906] [Citation(s) in RCA: 212] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/16/2018] [Accepted: 08/19/2018] [Indexed: 12/11/2022]
Abstract
Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of GI and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signalling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterised roles of TJ proteins in liver disease biology is their function as cell entry receptors for HCV-one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.
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Affiliation(s)
- Mirjam B. Zeisel
- Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Thomas F. Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
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47
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Oliveira R, Canuto L, Collares-Buzato C. Intestinal luminal content from high-fat-fed prediabetic mice changes epithelial barrier function in vitro. Life Sci 2019; 216:10-21. [DOI: 10.1016/j.lfs.2018.11.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 10/29/2018] [Accepted: 11/05/2018] [Indexed: 12/19/2022]
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48
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Marks J. The role of SLC34A2 in intestinal phosphate absorption and phosphate homeostasis. Pflugers Arch 2018; 471:165-173. [PMID: 30343332 PMCID: PMC6325986 DOI: 10.1007/s00424-018-2221-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 12/13/2022]
Abstract
There has recently been significant interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in patients with chronic kidney disease. However, we do not have a complete understanding of the cellular mechanisms that govern dietary phosphate absorption. Studies in the 1970s documented both active and passive pathways for intestinal phosphate absorption. However, following the cloning of the intestinal SLC34 cotransporter, NaPi-IIb, much of the research focused on the role of this protein in active transcellular phosphate absorption and the factors involved in its regulation. Generation of a conditional NaPi-IIb knockout mouse has demonstrated that this protein is critical for the maintenance of skeletal integrity during periods of phosphate restriction and that under normal physiological conditions, the passive sodium-independent pathway is likely be the more dominant pathway for intestinal phosphate absorption. The review aims to summarise the most recent developments in our understanding of the role of the intestine in phosphate homeostasis, including the acute and chronic renal adaptations that occur in response to dietary phosphate intake. Evidence regarding the overall contribution of the transcellular and paracellular pathways for phosphate absorption will be discussed, together with the clinical benefit of inhibiting these pathways for the treatment of hyperphosphatemia in chronic kidney disease.
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Affiliation(s)
- Joanne Marks
- Department of Neuroscience, Physiology and Pharmacology, Royal Free Campus, University College London, Rowland Hill Street, London, NW3 2PF, UK.
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49
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Maares M, Keil C, Thomsen S, Günzel D, Wiesner B, Haase H. Characterization of Caco-2 cells stably expressing the protein-based zinc probe eCalwy-5 as a model system for investigating intestinal zinc transport. J Trace Elem Med Biol 2018; 49:296-304. [PMID: 29395783 DOI: 10.1016/j.jtemb.2018.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/22/2017] [Accepted: 01/17/2018] [Indexed: 12/30/2022]
Abstract
Intestinal zinc resorption, in particular its regulation and mechanisms, are not yet fully understood. Suitable intestinal cell models are needed to investigate zinc uptake kinetics and the role of labile zinc in enterocytes in vitro. Therefore, a Caco-2 cell clone was produced, stably expressing the genetically encoded zinc biosensor eCalwy-5. The aim of the present study was to reassure the presence of characteristic enterocyte-specific properties in the Caco-2-eCalwy clone. Comparison of Caco-2-WT and Caco-2-eCalwy cells revealed only slight differences regarding subcellular localization of the tight junction protein occludin and alkaline phosphatase activity, which did not affect basic integrity of the intestinal barrier or the characteristic brush border membrane morphology. Furthermore, introduction of the additional zinc-binding protein in Caco-2 cells did not alter mRNA expression of the major intestinal zinc transporters (zip4, zip5, znt-1 and znt-5), but increased metallothionein 1a-expression and cellular resistance to higher zinc concentrations. Moreover, this study examines the effect of sensor expression level on its saturation with zinc. Fluorescence cell imaging indicated considerable intercellular heterogeneity in biosensor-expression. However, FRET-measurements confirmed that these differences in expression levels have no effect on fractional zinc-saturation of the probe.
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Affiliation(s)
- Maria Maares
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany
| | - Claudia Keil
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany
| | - Susanne Thomsen
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany
| | - Dorothee Günzel
- Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | | | - Hajo Haase
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Berlin, Germany; TraceAge-DFG Research Unit on Interactions of essential trace elements in healthy and diseased elderly, Potsdam-Berlin-Jena, Germany.
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50
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Welcome MO. Current Perspectives and Mechanisms of Relationship between Intestinal Microbiota Dysfunction and Dementia: A Review. Dement Geriatr Cogn Dis Extra 2018; 8:360-381. [PMID: 30483303 PMCID: PMC6244112 DOI: 10.1159/000492491] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/26/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Accumulating data suggest a crucial role of the intestinal microbiota in the development and progression of neurodegenerative diseases. More recently, emerging reports have revealed an association between intestinal microbiota dysfunctions and dementia, a debilitating multifactorial disorder, characterized by progressive deterioration of cognition and behavior that interferes with the social and professional life of the sufferer. However, the mechanisms of this association are not fully understood. SUMMARY In this review, I discuss recent data that suggest mechanisms of cross-talk between intestinal microbiota dysfunction and the brain that underlie the development of dementia. Potential therapeutic options for dementia are also discussed. The pleiotropic signaling of the metabolic products of the intestinal microbiota together with their specific roles in the maintenance of both the intestinal and blood-brain barriers as well as regulation of local, distant, and circulating immunocytes, and enteric, visceral, and central neural functions are integral to a healthy gut and brain. KEY MESSAGES Research investigating the effect of intestinal microbiota dysfunctions on brain health should focus on multiple interrelated systems involving local and central neuroendocrine, immunocyte, and neural signaling of microbial products and transmitters and neurohumoral cells that not only maintain intestinal, but also blood brain-barrier integrity. The change in intestinal microbiome/dysbiome repertoire is crucial to the development of dementia.
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Affiliation(s)
- Menizibeya O. Welcome
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Nile University of Nigeria, Abuja, Nigeria
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