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Martínez-Ruiz M, Robeson MS, Piccolo BD. Fueling the fire: colonocyte metabolism and its effect on the colonic epithelia. Crit Rev Food Sci Nutr 2025:1-20. [PMID: 40405692 DOI: 10.1080/10408398.2025.2507701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Colonic permeability is a major consequence of dysbiosis and diseases affecting the colon, further contributing to inflammation and extraintestinal diseases. Recent advances have shed light on the association between colonocyte energy utilization and the mechanisms that support epithelial function and homeostasis. One unifying theme is the induction of colonocyte hypoxia, driven by the aerobic oxidation of microbial-derived butyrate, as a critical factor promoting multiple cellular processes that support intestinal barrier function, mucus secretion, and the maintenance of synergistic luminal microbes. Particular attention will be focused on experimental evidence supporting beta-oxidation via activation of peroxisome proliferators-activated receptor-γ (PPAR) and upregulation and activation of processes that promote barrier function by hypoxia-inducible factor (HIF) signaling. Growing evidence suggests that colonocyte energy utilization is tightly regulated and switches between beta-oxidation of butyrate and anaerobic glycolysis, the latter being associated with several disease states. As most of the primary literature associated with colonocyte energy utilization has focused on adult models, evidence supporting butyrate oxidation in the neonatal gut is lacking. Thus, this review details the current state of knowledge linking colonocyte substrate utilization to mechanisms supporting gut health, but also highlights the counterindications of colonic butyrate availability and utilization in developmental periods.
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Affiliation(s)
- Manuel Martínez-Ruiz
- USDA-ARS Arkansas Children's Nutrition Center, Little Rock, AR, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Michael S Robeson
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Brian D Piccolo
- USDA-ARS Arkansas Children's Nutrition Center, Little Rock, AR, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Xu J, Zhao X, Yang S, Tang M, Zhao R, Hu S. Chlorogenic acid and intestinal health: mechanistic insights and therapeutic applications. Food Funct 2025. [PMID: 40357998 DOI: 10.1039/d5fo00853k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Chlorogenic acid (CGA), a polyphenolic compound found in various plant species, has shown considerable potential in the treatment and management of several diseases due to its potent bioactive properties. Increasing evidence indicates that CGA exerts significant antioxidant, anti-inflammatory, and immunomodulatory effects by modulating key signaling pathways, including MAPK, PTEN/Akt, STAT3, and NF-κB/NLRP3. Furthermore, CGA enhances intestinal barrier function and positively influences the gut microbiota composition, making it a promising natural therapeutic agent for conditions such as inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer. This review provides a comprehensive summary of the most recent research on CGA's role in managing intestinal disorders. It first discusses CGA's chemical structure and pharmacokinetics (including absorption and metabolism), followed by an in-depth analysis of the mechanisms through which CGA mediates its therapeutic effects. These insights aim to advance our understanding of CGA's therapeutic potential in treating intestinal diseases.
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Affiliation(s)
- Jinzhao Xu
- College of Food Science, Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin, 150030, P. R. China.
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, 130018, P. R. China.
| | - Xiao Zhao
- College of Food Science, Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin, 150030, P. R. China.
- College of Equipment Management and Support, Engineering University of PAP, Xi'an, 710086, P. R. China
| | - Shuo Yang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, 130018, P. R. China.
| | - Mengqi Tang
- College of Food Science, Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin, 150030, P. R. China.
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, 130018, P. R. China.
| | - Runan Zhao
- College of Food Science, Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin, 150030, P. R. China.
- College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, Hangzhou 310058, P. R. China
| | - Shumeng Hu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, 130018, P. R. China.
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Ghasemi HA, Azizollahi M, Ajoudani Lahroudi M, Taherpour K, Hajkhodadadi I, Akhavan-Salamat H, Afsar A, Khodaei-Motlagh M, Rahmatnejad E. Guanidinoacetic acid in laying hen diets with varying dietary energy: Productivity, antioxidant status, yolk fatty acid profile, hepatic lipid metabolism, and gut health. Poult Sci 2025; 104:105159. [PMID: 40267570 PMCID: PMC12051624 DOI: 10.1016/j.psj.2025.105159] [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: 01/09/2025] [Revised: 04/11/2025] [Accepted: 04/13/2025] [Indexed: 04/25/2025] Open
Abstract
This study aimed to investigate the effects of GAA supplementation in diets differing in ME levels on productive performance, egg quality, blood parameters, yolk fatty acid profiles, hepatic expression of genes related to lipid metabolism, gut morphology, and nutrient digestibility in laying hens during their post-peak production phase. Over a 12-week period (52-64 weeks of age), 288 laying hens were randomly assigned to 6 treatments. Each treatment consisted of 8 replicates, with 6 hens per replicate. The experimental treatments were assigned in a 2 × 3 factorial arrangement, comprising 2 levels of dietary ME (a recommended level and a low level, the latter characterized by a 100 kcal/kg reduction in ME) and 3 levels of GAA supplementation (0, 0.6, and 1.2 g/kg). The results showed significant interaction effects (P < 0.05) between GAA supplementation and dietary ME levels on laying rate, egg mass, feed conversion ratio, crude protein digestibility, and AMEn. In hens fed the low-ME diet, GAA supplementation, particularly at 1.2 g/kg, significantly improved laying performance. Moreover, at both 0.6 and 1.2 g/kg under low-ME conditions, GAA significantly enhanced crude protein digestibility and AMEn. The low-ME diet was associated with decreased expression of key lipogenic genes, including sterol regulatory element-binding transcription factor 1 (SREBF1), acetyl-coenzyme A carboxylase (ACC), and fatty acid synthase (FAS), alongside increased expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1). Regardless of ME content, GAA supplementation linearly improved eggshell strength, enhanced the polyunsaturated-to-saturated fatty acid ratio in the yolk, elevated serum levels of creatine and total antioxidant capacity, improved intestinal morphology, and increased radical scavenging activity in the yolk (P < 0.05). Furthermore, GAA supplementation linearly increased the relative mRNA expression of several metabolic genes, including SREBF1, ACC, PPARα, and ApoB (P < 0.05). In conclusion, GAA supplementation enhanced productive performance in low-ME diets and exerted positive effects on egg characteristics and lipid metabolism, regardless of dietary ME content.
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Affiliation(s)
- Hossein Ali Ghasemi
- Department of Animal Science, Faculty of Agriculture and Environment, Arak University, 38156-8-8349 Arak, Iran.
| | - Mohammad Azizollahi
- Department of Animal Science, Faculty of Agriculture and Environment, Arak University, 38156-8-8349 Arak, Iran
| | - Mahdi Ajoudani Lahroudi
- Department of Animal Science, Faculty of Agriculture and Environment, Arak University, 38156-8-8349 Arak, Iran
| | - Kamran Taherpour
- Department of Animal Science, Faculty of Agriculture, Ilam University, Ilam, Iran
| | - Iman Hajkhodadadi
- Department of Animal Science, Faculty of Agriculture and Environment, Arak University, 38156-8-8349 Arak, Iran
| | - Hossein Akhavan-Salamat
- Department of Animal Science, Faculty of Agriculture, Khoy Branch, Islamic Azad University, Khoy, Iran
| | - Ali Afsar
- Evonik Iran PJS, 1436935313 Tehran, Iran
| | - Mahdi Khodaei-Motlagh
- Department of Animal Science, Faculty of Agriculture and Environment, Arak University, 38156-8-8349 Arak, Iran
| | - Enayat Rahmatnejad
- Department of Animal Science, Faculty of Agriculture and Natural Resources, Persian Gulf University, Bushehr, 75169, Iran
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Yu H, Nie Y, Zhang B, Xue J, Xue K, Huang X, Zhang X. Creatine supplementation in largemouth bass (Micropterus salmoides) diets: Improving intestinal health and alleviating enteritis. FISH & SHELLFISH IMMUNOLOGY 2025; 159:110164. [PMID: 39894092 DOI: 10.1016/j.fsi.2025.110164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
Creatine plays an important role in regulating intestinal epithelial cell energy metabolism, epithelial integrity, and intestinal barrier function. In this study, three feeds with varying creatine concentrations (0 %, 0.5 %, and 4 %, labeled CR0, CR0.5, and CR4, respectively) were formulated and administered to juvenile largemouth bass (Micropterus salmoides) for 8 weeks. Creatine-containing diets significantly improved growth performance and intestinal villus height. Microbiota analysis revealed that creatine-containing diets changed the beta diversity of gut microbes and increased the relative proportion of Cetobacterium. Enteritis was induced for 7 days using the corresponding feeds containing creatine and 2 % DSS (labeled CR0, DCR0, DCR0.5, and DCR4). Enteritis resulted in an increase in hif1α expression in the DCR0.5 and DCR4 groups and a significant increase expression of creatine transporter SLC6A8. QPCR and Western blotting of intestinal barrier-related genes (e.g., Claudin1, Claudin4, and ZO1), MUC2 immunohistochemistry, and PAS mucus staining were used to show intestinal barrier status, these results suggest that dietary creatine attenuates the extent of intestinal barrier damage. After TUNEL and KI67 immunofluorescence analyses of the intestine and detection of the expression of relevant genes at the protein and transcript levels, the results showed that dietary addition of creatine significantly alleviated intestinal apoptosis and cellular inflammatory responses due to DSS-induced enteritis. These findings indicate long-term dietary supplementation with creatine modulated the microbial composition of the intestinal lumen of juvenile largemouth bass, promoted intestinal health, and improved anti-inflammatory properties following enteritis induction. This study provides a theoretical foundation for largemouth bass feed formulation optimization and fish enteritis control.
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Affiliation(s)
- Haodong Yu
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Yukang Nie
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Boran Zhang
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Jiajie Xue
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Kun Xue
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Xixuan Huang
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Xuezhen Zhang
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China; Research Institute of Huanong-Tianchen, Wuhan, 430070, China.
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Liu P, Liu Q, Tian Y, Cai P, Bai J. Ferroptosis-Related Genes Are Effective Markers for Diagnostic Targets of Crohn's Disease. Immun Inflamm Dis 2025; 13:e70170. [PMID: 40084946 PMCID: PMC11907700 DOI: 10.1002/iid3.70170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 02/06/2025] [Accepted: 02/27/2025] [Indexed: 03/16/2025] Open
Abstract
INTRODUCTION Crohn's disease (CD) is a group of chronic transmural inflammation of gastrointestinal tract, which seriously harms the mental and physical health of adolescents. At present, there are still no specific markers that make the diagnosis of CD extremely difficult and poor prognosis. Iron deficiency is common in CD, yet the role of ferroptosis-related genes in CD has not been elucidated. METHODS The serum iron and ferritin levels were detected in 107 newly diagnosed CD patients and 107 healthy volunteers in our hospital. Bioinformatics analysis was used to analyze the chip sequencing data of CD in GEO database. Immunohistochemical analysis of paired inflammatory and noninflammatory intestinal tissues from CD patients was performed to confirm the differential protein expression pattern of the target genes. RESULTS Patients with CD exhibited significantly reduced serum iron and ferritin levels compared to healthy controls. Transcriptomic analysis identified 40 upregulated and 31 downregulated ferroptosis-associated genes in CD patients versus controls. LASSO regression and SVM-RFE algorithms prioritized 13 hub genes (e.g., CDKN2A, LCN2, STAT3, MT1G), with a ROC curve demonstrating 100% specificity for combined biomarker analysis. Despite robust bioinformatic predictions, serum RNA levels of CDKN2A, LIG3, and MTF1 showed no intergroup differences. Immuno-reactivity score validated protein expression consistency for LCN2, PANX1, LPIN1, PML, STAT3, PARP9, RELA, NEDD4, and MT1G but not PPARD or LCN2. Expression patterns of these genes correlated with M0 macrophage infiltration, resting mast cells, and neutrophil recruitment, suggesting immune-microenvironment interactions in CD progression. CONCLUSION Combined detection of ferroptosis-related genes is of great value in the diagnosis of CD.
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Affiliation(s)
| | - Qing Liu
- The Fourth Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Ye Tian
- The First Affiliated Hospital with Nanjing Medical UniversityNanjingJiangsuChina
| | - Pengpeng Cai
- The Affiliated Sir Run Run Hospital of Nanjing Medical UniversityNanjingJiangsuChina
| | - Jianan Bai
- The First Affiliated Hospital with Nanjing Medical UniversityNanjingJiangsuChina
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Jiang L, Zhang J, Zhu B, Bao X, Tian J, Li Y, Zhang G, Wang L, Zhang W, Tang Y, Lu G, Guo Y, Long F. The aqueous extract of Reynoutria japonica ameliorates damp-heat ulcerative colitis in mice by modulating gut microbiota and metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119042. [PMID: 39515678 DOI: 10.1016/j.jep.2024.119042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Reynoutria japonica has been utilized as a potential treatment for gastrointestinal disorders in Traditional Chinese Medicine (TCM). However, the efficacy and mechanism of its aqueous extracts on damp-heat ulcerative colitis (UC) remains unclear. AIM OF THE STUDY Investigating the modulating effect of aqueous extracts of Reynoutria japonica (AERJ) on gut microbiota and fecal metabolisms in mice with damp-heat UC. METHODS UPLC-Q-TOF-MS was used for the compositional characterization of the AERJ. BALB/c mice were used as a model for establishing damp-heat UC. Hematoxylin-eosin (HE) staining and immunohistochemistry (IHC) method were conducted to observe the pathological changes in the colon. Enzyme-linked immunosorbent assay (ELISA) was used for quantitative analysis of relevant physiological indicators. 16 S rRNA gene sequencing was employed to detect changes in gut microbiota in mice. In addition, metabolomics analysis was performed on mice feces. Finally, the aforementioned indicators underwent correlation analysis. RESULTS Seven components within the AERJ were qualitatively identified by chromatographic analysis. The AERJ alleviated the symptoms in damp-heat UC mice, suppressed the expression of inflammatory factors, attenuated mucosal damage, improved water-fluid metabolism, and regulated the gut microbiota composition. Differential metabolites in feces were mainly enriched in the amino acid metabolic pathway, and AERJ was able to upregulate the expression levels of short chain fatty acids (SCFAs). Meanwhile, the present study found that physiological indicators were significantly correlated with both the gut microbiota and SCFAs. CONCLUSION AERJ showed significant therapeutic effects on damp-heat UC mice, and its mechanism of action may be related to altering the composition of gut microbiota, regulating amino acid metabolism and the content of SCFAs and thus restoring the mucosal integrity and inflammatory response.
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Affiliation(s)
- Liyuan Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Jin Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Baojie Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Xiaoming Bao
- Shimadzu (China) Co., Ltd., Chengdu, 610023, China.
| | - Junzhou Tian
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yangsong Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Guirong Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Ling Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Wenli Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yanan Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Guanghua Lu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yiping Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Fei Long
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Zhu S, He Y, Lei JN, Liu YF, Xu YJ. The chemical and biological characteristics of fatty acid esters of hydroxyl fatty acids. Nutr Rev 2025; 83:e427-e442. [PMID: 38412339 DOI: 10.1093/nutrit/nuae005] [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: 02/29/2024] Open
Abstract
With the continuous advancements in detection methods and the exploration of unknown substances, an increasing number of bioactive compounds are being discovered. Fatty acid esters of hydroxyl fatty acids (FAHFAs), a class of endogenous lipids found in 2014, exhibit various physiological activities, such as improving glucose tolerance and insulin sensitivity, stimulating insulin secretion, and demonstrating broad anti-inflammatory effects. Moreover, some FAHFAs are closely linked to intestinal health and can serve as potential biomarkers for gut health. Various FAHFAs have been observed in food, including palmitic acid esters of hydroxy stearic acids (PAHSA), oleic acid esters of hydroxy stearic acids (OAHSA), linoleic acid esters of hydroxy linoleic acid (LAHLA). As a type of lipid regularly consumed in the daily diet, it is highly important to ascertain the types and quantities of FAHFAs present in the diet. This article, based on existing research, provides a review of the analysis methods for FAHFAs, particularly focusing on the separation of chiral isomers. It also summarizes the sources and contents of dietary FAHFAs, emphasizing their bioavailability and impact on the gut. Understanding the beneficial effects of these lipids in the diet can serve as a valuable reference for the development of specific functional foods.
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Affiliation(s)
- Shuang Zhu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, National Engineering Research Center for Functional Food, National Engineering Laboratory for Cereal Fermentation Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu, People's Republic of China
| | - Yuan He
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, National Engineering Research Center for Functional Food, National Engineering Laboratory for Cereal Fermentation Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu, People's Republic of China
| | - Jing-Nan Lei
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, National Engineering Research Center for Functional Food, National Engineering Laboratory for Cereal Fermentation Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu, People's Republic of China
| | - Yuan-Fa Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, National Engineering Research Center for Functional Food, National Engineering Laboratory for Cereal Fermentation Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu, People's Republic of China
| | - Yong-Jiang Xu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, National Engineering Research Center for Functional Food, National Engineering Laboratory for Cereal Fermentation Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu, People's Republic of China
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Liu Z, Wang M, Hu Y, Li J, Gong W, Guo X, Song S, Zhu B. Ulva lactuca polysaccharides combined with fecal microbiota transplantation ameliorated dextran sodium sulfate-induced colitis in C57BL/6J mice. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025; 105:422-432. [PMID: 39212113 DOI: 10.1002/jsfa.13839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/26/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Fecal microbiota transplantation (FMT) of healthy donors improves ulcerative colitis (UC) patients by restoring the balance of the gut microbiota. However, donors vary in microbial diversity and composition, often resulting in weak or even ineffective FMT. Improving the efficacy of FMT through combination treatment has become a promising strategy. Ulva lactuca polysaccharides (ULP) have been found to benefit host health by regulating gut microbiota. The effect of the combination of ULP and FMT in ameliorating UC has not yet been evaluated. RESULTS The present study found that supplementation with ULP combined with FMT showed better effects in ameliorating UC than supplementation with FMT alone. Results suggested that FMT or ULP combined with FMT alleviated the symptoms of UC in mice, as evidenced by prevention of body weight loss, improvement of disease activity index and protection of the intestinal mucus. Notably, ULP in combination with FMT was more effective than FMT in reducing levels of cytokines and related inflammatory enzymes. In addition, ULP combined with FMT effectively restored the dysbiosis induced by dextran sulfate sodium (DSS) and further enriched probiotics (such as Bifidobacterium). The production of short-chain fatty acids, especially acetic acid, was also significantly enriched by ULP combined with FMT. CONCLUSION Supplementation of ULP combined with FMT could significantly ameliorate DSS-induced colitis in mice by inhibiting inflammation and restoring dysbiosis of gut microbiota. These results suggested that ULP combined with FMT has potential application in ameliorating UC. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Zhengqi Liu
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
- National Engineering Research Center of Seafood, National and Local Joint Engineering Laboratory for Marine Bioactive Polysaccharide Development and Application, School of Food Science and Technology, Dalian Polytechnic University, Dalian, PR China
| | - Menghui Wang
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
| | - Yuanyuan Hu
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
| | - Jinjin Li
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
| | - Wei Gong
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
| | - Xiaoming Guo
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
| | - Shuang Song
- National Engineering Research Center of Seafood, National and Local Joint Engineering Laboratory for Marine Bioactive Polysaccharide Development and Application, School of Food Science and Technology, Dalian Polytechnic University, Dalian, PR China
| | - Beiwei Zhu
- Shenzhen Key Laboratory of Food Nutrition and Health, College of Chemistry and Environmental Engineering, Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, PR China
- National Engineering Research Center of Seafood, National and Local Joint Engineering Laboratory for Marine Bioactive Polysaccharide Development and Application, School of Food Science and Technology, Dalian Polytechnic University, Dalian, PR China
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Xu MR, Lin CH, Wang CH, Wang SY. Investigate the metabolic changes in intestinal diseases by employing a 1H-NMR-based metabolomics approach on Caco-2 cells treated with cedrol. Biofactors 2025; 51:e2132. [PMID: 39415440 DOI: 10.1002/biof.2132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 10/01/2024] [Indexed: 10/18/2024]
Abstract
Mitochondrial dysfunction may precipitate intestinal dysfunction, while inflammatory bowel disease manifests as a chronic inflammatory ailment affecting the gastrointestinal tract. This condition disrupts the barrier function of the intestinal epithelium and alters metabolic products. Increasing mitochondrial adenosine triphosphate (ATP) synthesis in intestinal epithelial cells presents a promising avenue for colitis treatments. Nevertheless, the impact of cedrol on ATP and the intestinal barrier remains unexplored. Hence, this study is dedicated to examining the cedrol's protective effect on an inflammatory cocktail (IC)-induced intestinal epithelial barrier dysfunction in Caco-2 cells. The finding reveals that cedrol enhances ATP content and the transepithelial electrical resistance value in the intestinal epithelial barrier. Moreover, cedrol mitigates the IC-induced decrease in the messenger ribonucleic acid (mRNA) expression of tight junction proteins (ZO-1, Occludin, and Claudin-1), thereby ameliorating intestinal epithelial barrier dysfunction. Furthermore, nuclear magnetic resonance (NMR)-based metabolomic analysis indicated that IC-exposed Caco-2 cells are restored by cedrol treatments. Notably, cedrol elevates metabolites such as amino acids, thereby enhancing the intestinal barrier. In conclusion, cedrol alleviates IC-induced intestinal epithelial barrier dysfunction by promoting ATP-dependent proliferation of Caco-2 cells and bolstering amino acid levels to sustain tight junction messenger ribonucleic acid expression.
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Affiliation(s)
- Mo-Rong Xu
- Doctoral Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taichung, Taiwan
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan
| | - Chia-Hsin Lin
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan
| | - Chung Hsuan Wang
- Special Crop and Metabolome Discipline Cluster, Academy Circle Economy, National Chung Hsing University, Taichung, Taiwan
| | - Sheng-Yang Wang
- Doctoral Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taichung, Taiwan
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan
- Special Crop and Metabolome Discipline Cluster, Academy Circle Economy, National Chung Hsing University, Taichung, Taiwan
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
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10
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Kuribayashi S, Fukuhara S, Kitakaze H, Tsujimura G, Imanaka T, Ueda N, Takezawa K, Ikawa M, Nonomura N. Intratesticular creatine maintains spermatogenesis by defining tight junctions. Sci Rep 2024; 14:30692. [PMID: 39730393 DOI: 10.1038/s41598-024-77986-3] [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: 06/26/2024] [Accepted: 10/28/2024] [Indexed: 12/29/2024] Open
Abstract
One in five couples who wish to conceive is infertile, and half of these couples have male infertility. However, the causes of male infertility are still largely unknown. Creatine is stored in the body as an energy buffer, and the testes are its second-largest reservoir after muscles. Further, even though intratesticular creatine levels have long been known to decrease in male patients with infertility, its role in the testis is unknown. We investigated the intratesticular role of creatine, specifically in the context of the creatine synthesizing enzyme Gamt, and the creatine transporter Slc6a8. The Slc6a8 knockout mice showed no abnormalities in spermatogenesis. While Gamt knockout mice formed spermatozoa, they demonstrated reduced sperm count and decreased sperm motility and fertilization rate. Additionally, intratesticular creatine in Gamt knockout mice was significantly decreased, resulting in the disruption of tight junctions, which could be rectified by creatine supplementation, as was evidenced by the improved sperm count and fertilization rate in these mice. In conclusion, we identified creatine as being required for the maintenance of the tight junction in the testis.
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Affiliation(s)
- Sohei Kuribayashi
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
- Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Shinichiro Fukuhara
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan.
| | - Hiroaki Kitakaze
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
- Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Go Tsujimura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
| | - Takahiro Imanaka
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
| | - Norichika Ueda
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
| | - Kentaro Takezawa
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
| | - Masahito Ikawa
- Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan
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11
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Zhang Z, Fang Y, He Y, Farag MA, Zeng M, Sun Y, Peng S, Jiang S, Zhang X, Chen K, Xu M, Han Z, Zhang J. Bifidobacterium animalis Probio-M8 improves sarcopenia physical performance by mitigating creatine restrictions imposed by microbial metabolites. NPJ Biofilms Microbiomes 2024; 10:144. [PMID: 39632843 PMCID: PMC11618631 DOI: 10.1038/s41522-024-00618-1] [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: 03/31/2024] [Accepted: 11/20/2024] [Indexed: 12/07/2024] Open
Abstract
Sarcopenia is a major health challenge due to an aging population. Probiotics may improve muscle function through gut-muscle axis, but their efficacy and mechanisms in treating sarcopenia remain unclear. This study investigated the impact of Bifidobacterium animalis subsp. lactis Probio-M8 (Probio-M8) on old mice and sarcopenia patients. We analyzed 43 subjects, including gut microbiome, fecal metabolome, and serum metabolome, using a multi-omics approach to assess whether Probio-M8 can improve sarcopenia by modulating gut microbial metabolites. Probio-M8 significantly improved muscle function in aged mice and enhanced physical performance in sarcopenia patients. It reduced pathogenic gut species and increased beneficial metabolites such as indole-3-lactic acid, acetoacetic acid, and creatine. Mediating effect analyses revealed that Probio-M8 effectively reduced n-dodecanoyl-L-homoserine lactone level in gut concurrent with increased creatine circulation, to significantly enhance host physical properties. These findings provide new insights into probiotics as a potential treatment for sarcopenia by modulating gut microbiota metabolism.
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Affiliation(s)
- Zeng Zhang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Yajing Fang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Yangli He
- Department of Health Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Cairo, Egypt
| | - Min Zeng
- Department of Health Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Yukai Sun
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Siqi Peng
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Shuaiming Jiang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Xian Zhang
- Department of Endocrinology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Kaining Chen
- Department of Endocrinology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Meng Xu
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Zhe Han
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China
| | - Jiachao Zhang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou, Hainan, China.
- One Health Institute, Hainan University, Haikou, Hainan, China.
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12
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Huai M, Pei M, Chen J, Duan X, Zhu Y, Yang F, Ge W. Oral creatine-modified selenium-based hyaluronic acid nanogel mediated mitochondrial energy recovery to drive the treatment of inflammatory bowel disease. J Nanobiotechnology 2024; 22:740. [PMID: 39609811 PMCID: PMC11603945 DOI: 10.1186/s12951-024-03007-0] [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: 06/18/2024] [Accepted: 11/11/2024] [Indexed: 11/30/2024] Open
Abstract
The damnification of mitochondrion is often considered to be an important culprit of inflammatory bowel disease (IBD), however, there are fewer reports of mechanisms of mitochondria-mediated IBD treatment. Therefore, we first proposed to reboot mitochondrial energy metabolism to treat IBD by capturing the double-sided factor of ROS and creatine (Cr)-assisted energy adjustment. Herein, an oral Cr-modified selenium-based hyaluronic acid (HA) nanogel (HASe-Cr nanogel) was fabricated for treatment of IBD, through ROS elimination and energy metabolism upgradation. More concretely, due to IBD lesion-specific positive charge and the high expression of CD44, HASe-Cr nanogel exhibited dual targeted inflammatory bio-functions, and ROS-driven degradation properties in high-yield ROS levels in inflammation areas. As expected, multifunctional HASe-Cr nanogel could effectively ameliorate IBD-related symptoms, such as mitochondrial biological function restoration, inhibition of M1-like macrophage polarization, gut mucosal reconstruction, microbial ecological repair, etc., thus excellently treating IBD. Overall, the proposed strategy underlined that the great potentiality of HASe-Cr nanogel by restarting mitochondrial metabolic energy in colitis lesions, providing new a pavement of mitochondrion-mediated colitis treatment in clinical applications.
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Affiliation(s)
- Manxiu Huai
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, P. R. China
| | - Mingliang Pei
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Jie Chen
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No.241 West Huaihai Road, Shanghai, 200030, P. R. China
| | - Xiaoyan Duan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, P. R. China
| | - Yun Zhu
- Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fan Yang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Wensong Ge
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, P. R. China.
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13
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Wang T, Wang RX, Colgan SP. Physiologic hypoxia in the intestinal mucosa: a central role for short-chain fatty acids. Am J Physiol Cell Physiol 2024; 327:C1087-C1093. [PMID: 39159391 PMCID: PMC11482044 DOI: 10.1152/ajpcell.00472.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024]
Abstract
The intestinal mucosa is a dynamic surface that facilitates interactions between the host and an outside world that includes trillions of microbes, collectively termed the microbiota. This fine balance is regulated by an energetically demanding physical and biochemical barrier that is formed by the intestinal epithelial cells. In addition, this homeostasis exists at an interface between the anaerobic colonic lumen and a highly oxygenated, vascularized lamina propria. The resultant oxygen gradient within the intestine establishes "physiologic hypoxia" as a central metabolic feature of the mucosa. Although oxygen is vital for energy production to meet cellular metabolism needs, the availability of oxygen has far-reaching influences beyond just energy provision. Recent studies have shown that the intestinal mucosa has purposefully adapted to use differential oxygen levels largely through the presence of short-chain fatty acids (SCFAs), particularly butyrate (BA). Intestinal epithelial cells use butyrate for a multitude of functions that promote mucosal homeostasis. In this review, we explore how the physiologic hypoxia profile interfaces with SCFAs to benefit host mucosal tissues.
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Affiliation(s)
- Timothy Wang
- Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Healthcare Studies, University of Texas Dallas, Richardson, Texas, United States
| | - Ruth X Wang
- Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Department of Dermatology, University of California San Diego, San Diego, California, United States
| | - Sean P Colgan
- Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, United States
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14
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Kang SJ, Lee JH, Rhee WJ. Engineered plant-derived extracellular vesicles for targeted regulation and treatment of colitis-associated inflammation. Theranostics 2024; 14:5643-5661. [PMID: 39310109 PMCID: PMC11413791 DOI: 10.7150/thno.97139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/31/2024] [Indexed: 09/25/2024] Open
Abstract
Rationale: Inflammatory bowel disease (IBD) is a chronic disorder characterized by persistent inflammation of the gastrointestinal tract. Due to the elusive causes and complex mechanisms of this disorder, the development of highly effective therapeutic drugs is crucial. Extracellular vesicles (EVs) are small membrane-bound structures released by cells into the surrounding environment. Recent research has witnessed a substantial surge in the utilization of plant-derived EVs that offer advantages such as high productivity, low production costs, diverse biological functions, and low cytotoxicity. Herein, Red cabbage-derived EVs (Rabex) were investigated and engineered as potential therapeutic agents for IBD. Methods: Rabex was engineered by surface conjugation with hyaluronic acid (t-Rabex) to simultaneously enhance the targeting of intestinal epithelial and immune cells, thereby improving their therapeutic targeting and efficacy. The properties and therapeutic potential of t-Rabex were assessed through both in vitro studies and in vivo experiments, focusing on their capacity to reach the gastrointestinal tract and exert a therapeutic effect compared to unmodified Rabex. Results: Rabex exhibited dual functions, including the suppression of inflammation in macrophages and promotion of colon epithelial cell regeneration, both of which are critical for effective IBD treatment. In vitro and in vivo studies of t-Rabex have demonstrated its superior targeting efficiency to the gastrointestinal tract and therapeutic efficacy compared to Rabex, making it a promising and more effective IBD treatment. Understanding the mechanism of action of t-Rabex in colonic tissues highlighted its anti-inflammatory, antioxidative, and tight-junction maintenance properties. Conclusions: These findings underscore the potential of t-Rabex as a precise therapeutic agent for IBD and shed light on the diverse applications of plant-derived EVs.
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Affiliation(s)
- Su Jin Kang
- Department of Bioengineering and Nano-Bioengineering, Incheon National University Incheon 22012, Republic of Korea
| | - Jeong Hyun Lee
- Department of Bioengineering and Nano-Bioengineering, Incheon National University Incheon 22012, Republic of Korea
| | - Won Jong Rhee
- Department of Bioengineering and Nano-Bioengineering, Incheon National University Incheon 22012, Republic of Korea
- Division of Bioengineering, Incheon National University Incheon 22012, Republic of Korea
- Research Center for Bio Materials & Process Development, Incheon National University, Incheon 22012, Republic of Korea
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15
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Kumar A, Vaiphei KK, Singh N, Datta Chigurupati SP, Paliwal SR, Paliwal R, Gulbake A. Nanomedicine for colon-targeted drug delivery: strategies focusing on inflammatory bowel disease and colon cancer. Nanomedicine (Lond) 2024; 19:1347-1368. [PMID: 39105753 PMCID: PMC11318742 DOI: 10.1080/17435889.2024.2350356] [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: 01/16/2024] [Accepted: 04/29/2024] [Indexed: 08/07/2024] Open
Abstract
The nanostructured drug-delivery systems for colon-targeted drug delivery are a promising field of research for localized diseases particularly influencing the colonic region, in other words, ulcerative colitis, Crohn's disease, and colorectal cancer. There are various drug-delivery approaches designed for effective colonic disease treatment, including stimulus-based formulations (enzyme-triggered systems, pH-sensitive systems) and magnetically driven drug-delivery systems. In addition, targeted drug delivery by means of overexpressed receptors also offers site specificity and reduces drug resistance. It also covers GI tract-triggered emulsifying systems, nontoxic plant-derived nanoformulations as advanced drug-delivery techniques as well as nanotechnology-based clinical trials toward colonic diseases. This review gives insight into advancements in colon-targeted drug delivery to meet site specificity or targeted drug-delivery requirements.
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Affiliation(s)
- Ankaj Kumar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
| | - Klaudi K Vaiphei
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
| | - Naveen Singh
- Nanomedicine & Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, 484887, India
| | - Sri Pada Datta Chigurupati
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
| | - Shivani Rai Paliwal
- Department of Pharmacy, Guru Ghasidas Vishwavidhyalaya (A Central University), Koni Bilaspur, Chhattisgarh, 495009, India
| | - Rishi Paliwal
- Nanomedicine & Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, 484887, India
| | - Arvind Gulbake
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
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16
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Sawant H, Selvaraj R, Manogaran P, Borthakur A. Intestinal Epithelial Creatine Transporter SLC6A8 Dysregulation in Inflammation and in Response to Adherent Invasive E. coli Infection. Int J Mol Sci 2024; 25:6537. [PMID: 38928243 PMCID: PMC11204174 DOI: 10.3390/ijms25126537] [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: 05/27/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal epithelial cells (IECs). The impact of CrT1 deficiency on the pathogenesis of various psychiatric and neurological disorders has been extensively investigated. However, there are no studies on its regulation in IECs in health and disease. Current studies have determined differential expression of CrT1 along the length of the mammalian intestine and its dysregulation in inflammatory bowel disease (IBD)-associated inflammation and Adherent Invasive E. coli (AIEC) infection. CrT1 mRNA and protein levels in normal intestines and their alterations in inflammation and following AIEC infection were determined in vitro in model IECs (Caco-2/IEC-6) and in vivo in SAMP1/YitFc mice, a model of spontaneous ileitis resembling human IBD. CrT1 is differentially expressed in different regions of mammalian intestines with its highest expression in jejunum. In vitro, CrT1 function (Na+-dependent 14C-Cr uptake), expression and promoter activity significantly decreased following TNFα/IL1β treatments and AIEC infection. SAMP1 mice and ileal organoids generated from SAMP1 mice also showed decreased CrT1 mRNA and protein compared to AKR controls. Our studies suggest that Cr deficiency in IECs secondary to CrT1 dysregulation could be a key factor contributing to IBD pathogenesis.
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Affiliation(s)
| | | | | | - Alip Borthakur
- Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.S.); (R.S.); (P.M.)
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17
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Huang S, Xie X, Xu B, Pan Z, Liang J, Zhang M, Pan S, Wang X, Zhao M, Wang Q, Chen J, Li Y, Zhou L, Luo X. Paeoniflorin ameliorates chronic colitis via the DR3 signaling pathway in group 3 innate lymphoid cells. J Pharm Anal 2024; 14:100940. [PMID: 39027912 PMCID: PMC11255901 DOI: 10.1016/j.jpha.2024.01.008] [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: 08/29/2023] [Revised: 01/22/2024] [Accepted: 01/28/2024] [Indexed: 07/20/2024] Open
Abstract
Inhibiting the death receptor 3 (DR3) signaling pathway in group 3 innate lymphoid cells (ILC3s) presents a promising approach for promoting mucosal repair in individuals with ulcerative colitis (UC). Paeoniflorin, a prominent component of Paeonia lactiflora Pall., has demonstrated the ability to restore barrier function in UC mice, but the precise mechanism remains unclear. In this study, we aimed to delve into whether paeoniflorin may promote intestinal mucosal repair in chronic colitis by inhibiting DR3 signaling in ILC3s. C57BL/6 mice were subjected to random allocation into 7 distinct groups, namely the control group, the 2 % dextran sodium sulfate (DSS) group, the paeoniflorin groups (25, 50, and 100 mg/kg), the anti-tumor necrosis factor-like ligand 1A (anti-TL1A) antibody group, and the IgG group. We detected the expression of DR3 signaling pathway proteins and the proportion of ILC3s in the mouse colon using Western blot and flow cytometry, respectively. Meanwhile, DR3-overexpressing MNK-3 cells and 2 % DSS-induced Rag1-/- mice were used for verification. The results showed that paeoniflorin alleviated DSS-induced chronic colitis and repaired the intestinal mucosal barrier. Simultaneously, paeoniflorin inhibited the DR3 signaling pathway in ILC3s and regulated the content of cytokines (Interleukin-17A, Granulocyte-macrophage colony stimulating factor, and Interleukin-22). Alternatively, paeoniflorin directly inhibited the DR3 signaling pathway in ILC3s to repair mucosal damage independently of the adaptive immune system. We additionally confirmed that paeoniflorin-conditioned medium (CM) restored the expression of tight junctions in Caco-2 cells via coculture. In conclusion, paeoniflorin ameliorates chronic colitis by enhancing the intestinal barrier in an ILC3-dependent manner, and its mechanism is associated with the inhibition of the DR3 signaling pathway.
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Affiliation(s)
- Shaowei Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Xueqian Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Bo Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Zengfeng Pan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Junjie Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Meiling Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Simin Pan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, 510000, China
| | - Xiaojing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Meng Zhao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Jinyan Chen
- School of Basic Medicine, Guangzhou University of Chinese Medicine, 510006, China
| | - Yanyang Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, China
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18
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Yin N, Xu B, Huang Z, Fu Y, Huang H, Fan J, Huang C, Mei Q, Zeng Y. Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis. FASEB J 2024; 38:e23618. [PMID: 38651689 DOI: 10.1096/fj.202400039r] [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: 01/06/2024] [Revised: 03/22/2024] [Accepted: 04/04/2024] [Indexed: 04/25/2024]
Abstract
Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.
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Affiliation(s)
- Nuoming Yin
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Binqiang Xu
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Zehua Huang
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yang Fu
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Huizheng Huang
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - Junjie Fan
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Chunlan Huang
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Qixiang Mei
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yue Zeng
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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19
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Luo J, Luo M, Kaminga AC, Wei J, Dai W, Peng Y, Zhao K, Duan Y, Xiao X, Ouyang S, Yao Z, Liu Y, Pan X. Integrative metabolomics highlights gut microbiota metabolites as novel NAFLD-related candidate biomarkers in children. Microbiol Spectr 2024; 12:e0523022. [PMID: 38445874 PMCID: PMC10986516 DOI: 10.1128/spectrum.05230-22] [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: 12/21/2022] [Accepted: 12/29/2023] [Indexed: 03/07/2024] Open
Abstract
Altered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota (Butyricicoccus and Alistipes), increased inflammation (IL-1β), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function. IMPORTANCE Altered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota (Butyricicoccus and Alistipes) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.
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Affiliation(s)
- Jiayou Luo
- Pediatrics Research Institute of Hunan Province, Hunan Children’s Hospital, Changsha, China
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Miyang Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | | | - Jia Wei
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Wen Dai
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yunlong Peng
- Department of Epidemiology and Health Statistics, Medical College of Soochow University, Suzhou, China
| | - Kunyan Zhao
- School of Public Health, University of South China, Hengyang, China
| | - Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - SiSi Ouyang
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Zhenzhen Yao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yixu Liu
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiongfeng Pan
- Pediatrics Research Institute of Hunan Province, Hunan Children’s Hospital, Changsha, China
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
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20
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Callahan RC, Bhagavatula G, Curry J, Staley AW, Schaefer REM, Minhajuddin F, Zhou L, Neuhart R, Atif SM, Orlicky DJ, Cartwright IM, Gerich M, Theiss AL, Hall CHT, Colgan SP, Onyiah JC. Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.06.583112. [PMID: 38496569 PMCID: PMC10942430 DOI: 10.1101/2024.03.06.583112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Colorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 ( Hmox1 ) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis. Ferroptosis culminates in excessive lipid peroxidation that is constrained by the antioxidative glutathione pathway. We observed increased mucosal markers of ferroptosis and glutathione metabolism in the setting of murine and human colitis, as well as murine colonic neoplasia. We obtained similar results in murine and human colonic epithelial organoids exposed to heme and the ferroptosis activator erastin, especially induction of Hmox1 . RNA sequencing of colonic organoids from mice with deletion of intestinal epithelial Hmox1 (Hmox1 ΔIEC ) revealed increased ferroptosis and activated glutathione metabolism after heme exposure. In a colitis-associated cancer model we observed significantly fewer and smaller tumors in Hmox1 ΔIEC mice compared to littermate controls. Transcriptional profiling of Hmox1 ΔIEC tumors and tumor organoids revealed increased ferroptosis and oxidative stress markers in tumor epithelial cells. In total, our findings reveal ferroptosis as an important colitis-associated cancer signature pathway, and Hmox1 as a key regulator in the tumor microenvironment.
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Jin Y, Wu J, Huang K, Liang Z. Heat-Killed Saccharomyces boulardii Alleviates Dextran Sulfate Sodium-Induced Ulcerative Colitis by Restoring the Intestinal Barrier, Reducing Inflammation, and Modulating the Gut Microbiota. Nutrients 2024; 16:702. [PMID: 38474831 DOI: 10.3390/nu16050702] [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: 02/06/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Ulcerative colitis (UC) is a global intestinal disease, and conventional therapeutic drugs often fail to meet the needs of patients. There is an urgent need to find efficient and affordable novel biological therapies. Saccharomyces boulardii has been widely used in food and pharmaceutical research due to its anti-inflammatory properties and gut health benefits. However, there is still a relatively limited comparison and evaluation of different forms of S. boulardii treatment for UC. This study aimed to compare the therapeutic effects of S. boulardii, heat-killed S. boulardii, and S. boulardii β-glucan on UC, to explore the potential of heat-killed S. boulardii as a new biological therapy. The results demonstrate that all three treatments were able to restore body weight, reduce the disease activity index (DAI), inhibit splenomegaly, shorten colon length, and alleviate histopathological damage to colonic epithelial tissues in DSS-induced colitis mice. The oral administration of S. boulardii, heat-killed S. boulardii, and S. boulardii β-glucan also increased the levels of tight junction proteins (Occludin and ZO-1), decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the serum, and suppressed the expressions of TNF-α, IL-1β, and IL-6 mRNA in the colon. In particular, in terms of gut microbiota, S. boulardii, heat-killed S. boulardii, and S. boulardii β-glucan exhibited varying degrees of modulation on DSS-induced dysbiosis. Among them, heat-killed S. boulardii maximally restored the composition, structure, and functionality of the intestinal microbiota to normal levels. In conclusion, heat-killed S. boulardii showed greater advantages over S. boulardii and S. boulardii β-glucan in the treatment of intestinal diseases, and it holds promise as an effective novel biological therapy for UC. This study is of great importance in improving the quality of life for UC patients and reducing the burden of the disease.
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Affiliation(s)
- Yuxin Jin
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Jingwei Wu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Kunlun Huang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Zhihong Liang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
- Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
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22
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Ding P, Du Y, Jiang X, Chen H, Huang L. Establishment and analysis of a novel diagnostic model for systemic juvenile idiopathic arthritis based on machine learning. Pediatr Rheumatol Online J 2024; 22:18. [PMID: 38243323 PMCID: PMC10797915 DOI: 10.1186/s12969-023-00949-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 12/21/2023] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND Systemic juvenile idiopathic arthritis (SJIA) is a form of childhood arthritis with clinical features such as fever, lymphadenopathy, arthritis, rash, and serositis. It seriously affects the growth and development of children and has a high rate of disability and mortality. SJIA may result from genetic, infectious, or autoimmune factors since the precise source of the disease is unknown. Our study aims to develop a genetic-based diagnostic model to explore the identification of SJIA at the genetic level. METHODS The gene expression dataset of peripheral blood mononuclear cell (PBMC) samples from SJIA was collected from the Gene Expression Omnibus (GEO) database. Then, three GEO datasets (GSE11907-GPL96, GSE8650-GPL96 and GSE13501) were merged and used as a training dataset, which included 125 SJIA samples and 92 health samples. GSE7753 was used as a validation dataset. The limma method was used to screen differentially expressed genes (DEGs). Feature selection was performed using Lasso, random forest (RF)-recursive feature elimination (RFE) and RF classifier. RESULTS We finally identified 4 key genes (ALDH1A1, CEACAM1, YBX3 and SLC6A8) that were essential to distinguish SJIA from healthy samples. And we combined the 4 key genes and performed a grid search as well as 10-fold cross-validation with 5 repetitions to finally identify the RF model with optimal mtry. The mean area under the curve (AUC) value for 5-fold cross-validation was greater than 0.95. The model's performance was then assessed once more using the validation dataset, and an AUC value of 0.990 was obtained. All of the above AUC values demonstrated the strong robustness of the SJIA diagnostic model. CONCLUSIONS We successfully developed a new SJIA diagnostic model that can be used for a novel aid in the identification of SJIA. In addition, the identification of 4 key genes that may serve as potential biomarkers for SJIA provides new insights to further understand the mechanisms of SJIA.
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Affiliation(s)
- Pan Ding
- Department of Medical Record Statistics, Wenzhou People's Hospital, Wenzhou, China
| | - Yi Du
- Lianyungang Maternal and Child Health Hospital, Lianyungang, China
| | - Xinyue Jiang
- Zhoushan Center for Disease Control and Prevention, Zhoushan, China
| | - Huajian Chen
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
| | - Li Huang
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
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23
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Qi Y, Wang X, Zhang Y, Leng Y, Liu X, Wang X, Wu D, Wang J, Min W. Walnut-Derived Peptide Improves Cognitive Impairment in Colitis Mice Induced by Dextran Sodium Sulfate via the Microbiota-Gut-Brain Axis (MGBA). JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:19501-19515. [PMID: 38039336 DOI: 10.1021/acs.jafc.3c04807] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2023]
Abstract
In this study, we investigated the protective mechanism of walnut-derived peptide LPLLR (LP-5) against cognitive impairment induced in a dextran sodium sulfate (DSS)-induced colitis mouse model, with emphasis on the microbiota-gut-brain axis (MGBA). The results revealed that LP-5 could improve the learning ability and memory of mice with cognitive impairment and mitigate colitis symptoms, including weight loss, bloody stools, colon shortening, and histopathological changes. Additionally, LP-5 protected the integrity of the intestinal barrier by promoting the expression of tight junction proteins (TJs) while attenuating colonic inflammation by suppressing proinflammatory cytokine and epithelial cell apoptosis. Western blotting indicated that LP-5 treatment suppressed the inflammatory NF-κB/MLCK/MLC signaling pathway activity. Furthermore, LP-5 ameliorated hippocampal neuron damage and protected blood-brain barrier (BBB) integrity by downregulating microglia marker protein Iba-1, increasing TJ protein expression, and restoring the deterioration of synaptic proteins. Importantly, 16S rRNA sequencing results indicated that LP-5 reshaped the abundance of a wide range of gut microbiota at the phylum and genus levels, with increased Prevotella and Akkermansia associated with tryptophan (TRP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). These findings suggest that LP-5 could maintain intestinal barrier and BBB integrity, reverse gut dysbiosis, and improve learning and memory ability in colitis mice, providing novel insights into alterations of gut microbes in colitis and a potential new mechanism by which it causes cognitive impairment.
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Affiliation(s)
- Yuan Qi
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Xuehang Wang
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
- College of Food and Health, Zhejiang A&F University, No. 666 Wusu Street, Hangzhou 311300, P. R. China
| | - Yaoxin Zhang
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Yue Leng
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Xiaoting Liu
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Xiyan Wang
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Dan Wu
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Ji Wang
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
| | - Weihong Min
- College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun 130118, Jilin, P. R. China
- College of Food and Health, Zhejiang A&F University, No. 666 Wusu Street, Hangzhou 311300, P. R. China
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Sánchez-Quintero MJ, Rodríguez-Díaz C, Rodríguez-González FJ, Fernández-Castañer A, García-Fuentes E, López-Gómez C. Role of Mitochondria in Inflammatory Bowel Diseases: A Systematic Review. Int J Mol Sci 2023; 24:17124. [PMID: 38069446 PMCID: PMC10707203 DOI: 10.3390/ijms242317124] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 12/18/2023] Open
Abstract
Mitochondria are key cellular organelles whose main function is maintaining cell bioenergetics by producing ATP through oxidative phosphorylation. However, mitochondria are involved in a much higher number of cellular processes. Mitochondria are the home of key metabolic pathways like the tricarboxylic acid cycle and β-oxidation of fatty acids, as well as biosynthetic pathways of key products like nucleotides and amino acids, the control of the redox balance of the cell and detoxifying the cell from H2S and NH3. This plethora of critical functions within the cell is the reason mitochondrial function is involved in several complex disorders (apart from pure mitochondrial disorders), among them inflammatory bowel diseases (IBD). IBD are a group of chronic, inflammatory disorders of the gut, mainly composed of ulcerative colitis and Crohn's disease. In this review, we present the current knowledge regarding the impact of mitochondrial dysfunction in the context of IBD. The role of mitochondria in both intestinal mucosa and immune cell populations are discussed, as well as the role of mitochondrial function in mechanisms like mucosal repair, the microbiota- and brain-gut axes and the development of colitis-associated colorectal cancer.
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Affiliation(s)
- María José Sánchez-Quintero
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (M.J.S.-Q.); (C.R.-D.); (A.F.-C.)
- Unidad de Gestión Clínica Cardiología y Cirugía Cardiovascular, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Cristina Rodríguez-Díaz
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (M.J.S.-Q.); (C.R.-D.); (A.F.-C.)
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
| | - Francisco J. Rodríguez-González
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (M.J.S.-Q.); (C.R.-D.); (A.F.-C.)
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
| | - Alejandra Fernández-Castañer
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (M.J.S.-Q.); (C.R.-D.); (A.F.-C.)
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
| | - Eduardo García-Fuentes
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (M.J.S.-Q.); (C.R.-D.); (A.F.-C.)
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carlos López-Gómez
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain; (M.J.S.-Q.); (C.R.-D.); (A.F.-C.)
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
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25
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Wang Y, Lai H, Zhang T, Wu J, Tang H, Liang X, Ren D, Huang J, Li W. Mitochondria of intestinal epithelial cells in depression: Are they at a crossroads of gut-brain communication? Neurosci Biobehav Rev 2023; 153:105403. [PMID: 37742989 DOI: 10.1016/j.neubiorev.2023.105403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/11/2023] [Accepted: 09/20/2023] [Indexed: 09/26/2023]
Abstract
The role of gut dysbiosis in depression is well established. However, recent studies have shown that gut microbiota is regulated by intestinal epithelial cell (IEC) mitochondria, which has yet to receive much attention. This review summarizes the recent developments about the critical role of IEC mitochondria in actively maintaining gut microbiota, intestinal metabolism, and immune homeostasis. We propose that IEC mitochondrial dysfunction alters gut microbiota composition, participates in cell fate, mediates oxidative stress, activates the peripheral immune system, causes peripheral inflammation, and transmits peripheral signals through the vagus and enteric nervous systems. These pathological alterations lead to brain inflammation, disruption of the blood-brain barrier, activation of the hypothalamic-pituitary-adrenal axis, activation of microglia and astrocytes, induction of neuronal loss, and ultimately depression. Furthermore, we highlight the prospect of treating depression through the mitochondria of IECs. These new findings suggest that the mitochondria of IECs may be a newly found important factor in the pathogenesis of depression and represent a potential new strategy for treating depression.
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Affiliation(s)
- Yi Wang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Han Lai
- School of Foreign Languages, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Tian Zhang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Jing Wu
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Huiling Tang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Xuanwei Liang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Dandan Ren
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China
| | - Jinzhu Huang
- School of Nursing, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China.
| | - Weihong Li
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610000, PR China.
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26
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Lee SA, McMahon GM. A spurious elevation of serum creatinine level in a patient with Crohn's disease without histologic kidney damage: a case report and review of the literature. J Bras Nefrol 2023; 45:497-501. [PMID: 37930142 PMCID: PMC10726663 DOI: 10.1590/2175-8239-jbn-2023-0071en] [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: 05/24/2023] [Accepted: 08/22/2023] [Indexed: 11/07/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are prone to develop kidney injury. Renal involvement in IBD patients is usually diagnosed by the measurement of serum creatinine and the estimation of the glomerular filtration rate. We describe a patient with IBD who presented with large fluctuations in his serum creatinine level (~3.0-fold) without significant histologic abnormalities and with a normal cystatin C level. This appears to be related to a high-protein diet and intermittent fasting. Even though the impact of a high-protein diet on mild elevations of the serum creatinine level has been described, large fluctuations in serum creatinine from diet alone, as seen in this case, have never been reported, raising the question about the potential contribution of inflamed bowel on gut absorption or metabolism of creatinine. This case highlights the importance of a detailed history, including the dietary habits, when encountering a patient with increased serum creatinine level, and careful interpretation of serum creatinine in a patient with a creatinine high-protein diet or underlying IBD.
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Affiliation(s)
- Sul A Lee
- Brigham and Women’s Hospital, Division of Nephrology, Boston, MA, USA
| | - Gearoid Michael McMahon
- Brigham and Women’s Hospital, Division of Nephrology, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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27
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Xu X, Ocansey DKW, Pei B, Zhang Y, Wang N, Wang Z, Mao F. Resveratrol alleviates DSS-induced IBD in mice by regulating the intestinal microbiota-macrophage-arginine metabolism axis. Eur J Med Res 2023; 28:319. [PMID: 37660064 PMCID: PMC10474707 DOI: 10.1186/s40001-023-01257-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/31/2023] [Indexed: 09/04/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a global disease with a growing public health concern and is associated with a complex interplay of factors, including the microbiota and immune system. Resveratrol, a natural anti-inflammatory and antioxidant agent, is known to relieve IBD but the mechanism involved is largely unexplored. METHODS This study examines the modulatory effect of resveratrol on intestinal immunity, microbiota, metabolites, and related functions and pathways in the BALB/c mice model of IBD. Mouse RAW264.7 macrophage cell line was used to further explore the involvement of the macrophage-arginine metabolism axis. The treatment outcome was assessed through qRT-PCR, western blot, immunofluorescence, immunohistochemistry, and fecal 16S rDNA sequencing and UHPLC/Q-TOF-MS. RESULTS Results showed that resveratrol treatment significantly reduced disease activity index (DAI), retained mice weight, repaired colon and spleen tissues, upregulated IL-10 and the tight junction proteins Occludin and Claudin 1, and decreased pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Resveratrol reduced the number of dysregulated metabolites and improved the gut microbial community structure and diversity, including reversing changes in the phyla Bacteroidetes, Proteobacteria, and Firmicutes, increasing 'beneficial' genera, and decreasing potential pathogens such as Lachnoclostridium, Acinobacter, and Serratia. Arginine-proline metabolism was significantly different between the colitis-treated and untreated groups. In the colon mucosa and RAW264.7 macrophage, resveratrol regulated arginine metabolism towards colon protection by increasing Arg1 and Slc6a8 and decreasing iNOS. CONCLUSION This uncovers a previously unknown mechanism of resveratrol treatment in IBD and provides the microbiota-macrophage-arginine metabolism axis as a potential therapeutic target for intestinal inflammation.
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Affiliation(s)
- Xinwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
- School of Materials Science and Engineering, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Bing Pei
- The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, 223800, Jiangsu, People's Republic of China
| | - Yaqin Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Naijian Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China
| | - Zengxu Wang
- Zhenjiang Hospital of Chinese Traditional And Western Medicine, 18 Tuanshan Road, Runzhou District, Zhenjiang, 212000, Jiangsu, People's Republic of China.
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People's Republic of China.
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28
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Hall CH, Lanis JM, Dowdell AS, Murphy EM, Colgan SP. Fundamental role for the creatine kinase pathway in protection from murine colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.07.544110. [PMID: 37333192 PMCID: PMC10274769 DOI: 10.1101/2023.06.07.544110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Inflammatory diseases of the digestive tract, including inflammatory bowel disease (IBD), cause metabolic stress within mucosal tissue. Creatine is a key energetic regulator. We previously reported a loss of creatine kinases (CKs) and the creatine transporter expression in IBD patient intestinal biopsy samples and that creatine supplementation was protective in a dextran sulfate sodium (DSS) colitis mouse model. In the present studies, we evaluated the role of CK loss in active inflammation using the DSS colitis model. Mice lacking expression of CKB/CKMit (CKdKO) showed increased susceptibility to DSS colitis (weight loss, disease activity, permeability, colon length and histology). In a broad cytokine profiling, CKdKO mice expressed near absent IFN-γ levels. We identified losses in IFN-γ production from CD4 + and CD8 + T cells isolated from CKdKO mice. Addback of IFN-γ during DSS treatment resulted in partial protection for CKdKO mice. We identified basal stabilization of the transcription factor hypoxia-inducible factor (HIF) in CKdKO splenocytes and pharmacological stabilization of HIF resulted in reduced IFN-γ production by control splenocytes. Thus, the loss of IFN-γ production by CD4 + and CD8 + T cells in CKdKO mice resulted in increased colitis susceptibility and indicates that CK is protective in active mucosal inflammation.
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Cao Y, Teng Y, Liu H, Li J, Zhu B, Xia X. Rhopilema esculentum polysaccharides enhance epithelial cell barrier in vitro and alleviate chronic colitis in mice. Int J Biol Macromol 2023; 241:124560. [PMID: 37088192 DOI: 10.1016/j.ijbiomac.2023.124560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 04/10/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
The purposes of this study were to characterize polysaccharides from Rhopilema esculentum and to explore their impacts on gut barrier function and inflammation in vitro and in mice with chronic colitis triggered by long-term administration of dextran sulfate sodium (DSS). Two polysaccharides were isolated and purified from Rhopilema esculentum, named REP-1 and REP-2. REP-1 with a molecular weight of 8.21 kDa was composed of mannose, glucosamine, galactosamine, glucose, galactose, and arabinose with a molar ratio of 0.04:0.03:0.38:1:1.36:0.06, and REP-2 with a molecular weight of 10.11 kDa mainly consisted of mannose, glucuronic acid, galactosamine, glucose, galactose, and arabinose with a molar ratio of 0.04:0.12:0.41:1:1.2:0.06. Compared to REP-1, REP-2 displayed better ability to up-regulate the expression of genes related to tight junctions and mucus in LPS-stimulated Caco-2 cells and better immunomodulatory activities in RAW264.7 macrophages. Then mice experiments showed that REP-2 efficiently attenuated the symptoms of colitis, decreased the secretion of pro-inflammatory cytokines, and restored intestinal barrier function in mice with chronic colitis. These results demonstrate that REP-2 might be a promising agent for protecting intestinal and mucus barrier and mitigating inflammation-associated intestinal diseases such as ulcerative colitis.
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Affiliation(s)
- Yu Cao
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yue Teng
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Huanhuan Liu
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Jiahui Li
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Beiwei Zhu
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
| | - Xiaodong Xia
- State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
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Stary D, Bajda M. Taurine and Creatine Transporters as Potential Drug Targets in Cancer Therapy. Int J Mol Sci 2023; 24:ijms24043788. [PMID: 36835201 PMCID: PMC9964810 DOI: 10.3390/ijms24043788] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Cancer cells are characterized by uncontrolled growth, proliferation, and impaired apoptosis. Tumour progression could be related to poor prognosis and due to this fact, researchers have been working on novel therapeutic strategies and antineoplastic agents. It is known that altered expression and function of solute carrier proteins from the SLC6 family could be associated with severe diseases, including cancers. These proteins were noticed to play important physiological roles through transferring nutrient amino acids, osmolytes, neurotransmitters, and ions, and many of them are necessary for survival of the cells. Herein, we present the potential role of taurine (SLC6A6) and creatine (SLC6A8) transporters in cancer development as well as therapeutic potential of their inhibitors. Experimental data indicate that overexpression of analyzed proteins could be connected with colon or breast cancers, which are the most common types of cancers. The pool of known inhibitors of these transporters is limited; however, one ligand of SLC6A8 protein is currently tested in the first phase of clinical trials. Therefore, we also highlight structural aspects useful for ligand development. In this review, we discuss SLC6A6 and SLC6A8 transporters as potential biological targets for anticancer agents.
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Affiliation(s)
- Dorota Stary
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Cracow, Poland
- Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 16 St., 31-530 Cracow, Poland
| | - Marek Bajda
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Cracow, Poland
- Correspondence:
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Kuribayashi S, Fukuhara S, Tsujimura G, Imanaka T, Okada K, Ueda N, Takezawa K, Kiuchi H, Saito S, Takahashi Y, Kioka H, Oura S, Shimada K, Ikawa M, Nonomura N. Evaluation of the efficacy of creatine chemical exchange saturation transfer imaging in assessing testicular maturity. Reprod Med Biol 2023; 22:e12507. [PMID: 36845001 PMCID: PMC9949363 DOI: 10.1002/rmb2.12507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/25/2023] Open
Abstract
Purpose Microscopic testicular sperm extraction is the most effective treatment for NOA, but the sperm retrieval rate is low and depends on testicular maturity. However, there are limited useful tests to assess testicular maturity. Chemical exchange saturation transfer (CEST) imaging is a new magnetic resonance imaging (MRI) technique that can image the distribution of trace substances in vivo. We focused on the potential role of creatine (Cr) in testes and hypothesized that Cr-CEST could indicate intratesticular spermatogenesis. Methods We performed Cr-CEST by using 7T MRI on wild-type C57B6/J mice and several types of male infertility models such as Sertoli-cell only (SCO) (Kitw/Kitwv), maturation arrest (MA) (Zfp541 knockout mouse and Kctd19 knockout mouse), and teratozoospermia (Tbc1d21 knockout mouse). After performing Cr-CEST, histological analysis was performed. Results The SCO and MA models showed decreased CEST signal intensity (p < 0.05), while no reduction was observed in the teratozoospermia model (p = 1.0). CEST signal intensity increased as the spermatogenesis stage progressed from the SCO model to the MA and teratozoospermia models. Furthermore, CEST signal intensity was reduced in 4-week-old wild-type mice with immature testes (p < 0.05). Conclusions This study suggests that Cr-CEST evaluates intratesticular spermatogenesis noninvasively and provides a new therapeutic strategy for treating male infertility.
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Affiliation(s)
- Sohei Kuribayashi
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | | | - Go Tsujimura
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | - Takahiro Imanaka
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | - Koichi Okada
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | - Norichika Ueda
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | - Kentaro Takezawa
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | - Hiroshi Kiuchi
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
| | - Shigeyoshi Saito
- Department of Medical Physics and Engineering, Division of Health SciencesOsaka University Graduate School of MedicineSuitaJapan
- Department of Advanced Medical TechnologiesNational Cerebral and Cardiovascular Research CenterSuitaJapan
| | - Yusuke Takahashi
- Department of Cardiovascular MedicineOsaka University Graduate School of MedicineSuitaJapan
- Department of Molecular PharmacologyNational Cerebral and Cardiovascular Center Research InstituteSuitaJapan
| | - Hidetaka Kioka
- Department of Cardiovascular MedicineOsaka University Graduate School of MedicineSuitaJapan
| | - Seiya Oura
- Research Institute for Microbial DiseasesOsaka UniversitySuitaJapan
| | - Keisuke Shimada
- Research Institute for Microbial DiseasesOsaka UniversitySuitaJapan
| | - Masahito Ikawa
- Research Institute for Microbial DiseasesOsaka UniversitySuitaJapan
- Graduate School of Pharmaceutical SciencesOsaka UniversitySuitaJapan
| | - Norio Nonomura
- Department of UrologyOsaka University Graduate School of MedicineSuitaJapan
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Establishment of Epithelial Inflammatory Injury Model Using Intestinal Organoid Cultures. Stem Cells Int 2023; 2023:3328655. [PMID: 36926182 PMCID: PMC10014157 DOI: 10.1155/2023/3328655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/05/2023] [Accepted: 02/10/2023] [Indexed: 03/09/2023] Open
Abstract
Intestinal epithelial dysfunction is critical in the development of inflammatory bowel disease (IBD). However, most cellular experiments related to epithelial barrier studies in IBD have been based on tumor cell line that lack a variety of intestinal epithelial cell types. Thus, intestinal organoids can present the three-dimensional structure and better simulate the physiological structure and function of the intestinal epithelium in vitro. Here, the crypts were isolated from the small intestine of mice; with the participation of major cytokines (EGF, Noggin, and R-Spondin 1 included), the intestinal organoids were established at a density of 100 crypts per well, containing intestinal stem cells (ISC), Paneth cells, goblet cells, and intestinal endocrine cells. We found that tumor necrosis factor-alpha (TNF-α) could induce the inflammatory response of intestinal organoids, and a dose of 10 ng/mL could maintain stable passaging of organoids for dynamic observation. After stimulation with TNF-α, the intestinal organoid cultures showed lower expression of the cell proliferation-related protein identified by monoclonal antibody Ki 67 (Ki67), the ISC marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), and the intestinal tight junction proteins occludin (Ocln) and claudin-1 (Cldn1) while higher expression of the inflammatory cytokine interleukin- (IL-) 15 and the chemokines C-X-C motif ligand 2 (Cxcl2) and Cxcl10 significantly. In this study, we successfully established an epithelial inflammatory injury model of intestinal organoids, which provides an effective in vitro model for studying the pathogenesis and treatment of IBD.
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Colgan SP, Wang RX, Hall CH, Bhagavatula G, Lee JS. Revisiting the "starved gut" hypothesis in inflammatory bowel disease. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e0016. [PMID: 36644501 PMCID: PMC9831042 DOI: 10.1097/in9.0000000000000016] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/22/2022] [Indexed: 01/17/2023]
Abstract
Active episodes of inflammatory bowel disease (IBD), which include ulcerative colitis and Crohn's disease, coincide with profound shifts in the composition of the microbiota and host metabolic energy demand. Intestinal epithelial cells (IEC) that line the small intestine and colon serve as an initial point for contact for the microbiota and play a central role in innate immunity. In the 1980s, Roediger et al proposed the hypothesis that IBD represented a disease of diminished mucosal nutrition and energy deficiency ("starved gut") that strongly coincided with the degree of inflammation. These studies informed the scientific community about the important contribution of microbial-derived metabolites, particularly short-chain fatty acids (SCFA) such as butyrate, to overall energy homeostasis. Decades later, it is appreciated that disease-associated shifts in the microbiota, termed dysbiosis, places inordinate demands on energy acquisition within the mucosa, particularly during active inflammation. Here, we review the topic of tissue energetics in mucosal health and disease from the original perspective of that proposed by the starved gut hypothesis.
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Affiliation(s)
- Sean P. Colgan
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
- Rocky Mountain Veterans Hospital, Aurora, CO, USA
| | - Ruth X. Wang
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
| | - Caroline H.T. Hall
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado, Aurora, CO, USA
| | - Geetha Bhagavatula
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado, Aurora, CO, USA
| | - J. Scott Lee
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
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Walaas GA, Gopalakrishnan S, Bakke I, Skovdahl HK, Flatberg A, Østvik AE, Sandvik AK, Bruland T. Physiological hypoxia improves growth and functional differentiation of human intestinal epithelial organoids. Front Immunol 2023; 14:1095812. [PMID: 36793710 PMCID: PMC9922616 DOI: 10.3389/fimmu.2023.1095812] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/09/2023] [Indexed: 01/31/2023] Open
Abstract
Background The epithelium in the colonic mucosa is implicated in the pathophysiology of various diseases, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial organoids from the colon (colonoids) can be used for disease modeling and personalized drug screening. Colonoids are usually cultured at 18-21% oxygen without accounting for the physiological hypoxia in the colonic epithelium (3% to <1% oxygen). We hypothesize that recapitulating the in vivo physiological oxygen environment (i.e., physioxia) will enhance the translational value of colonoids as pre-clinical models. Here we evaluate whether human colonoids can be established and cultured in physioxia and compare growth, differentiation, and immunological responses at 2% and 20% oxygen. Methods Growth from single cells to differentiated colonoids was monitored by brightfield images and evaluated with a linear mixed model. Cell composition was identified by immunofluorescence staining of cell markers and single-cell RNA-sequencing (scRNA-seq). Enrichment analysis was used to identify transcriptomic differences within cell populations. Pro-inflammatory stimuli induced chemokines and Neutrophil gelatinase-associated lipocalin (NGAL) release were analyzed by Multiplex profiling and ELISA. Direct response to a lower oxygen level was analyzed by enrichment analysis of bulk RNA sequencing data. Results Colonoids established in a 2% oxygen environment acquired a significantly larger cell mass compared to a 20% oxygen environment. No differences in expression of cell markers for cells with proliferation potential (KI67 positive), goblet cells (MUC2 positive), absorptive cells (MUC2 negative, CK20 positive) and enteroendocrine cells (CGA positive) were found between colonoids cultured in 2% and 20% oxygen. However, the scRNA-seq analysis identified differences in the transcriptome within stem-, progenitor- and differentiated cell clusters. Both colonoids grown at 2% and 20% oxygen secreted CXCL2, CXCL5, CXCL10, CXCL12, CX3CL1 and CCL25, and NGAL upon TNF + poly(I:C) treatment, but there appeared to be a tendency towards lower pro-inflammatory response in 2% oxygen. Reducing the oxygen environment from 20% to 2% in differentiated colonoids altered the expression of genes related to differentiation, metabolism, mucus lining, and immune networks. Conclusions Our results suggest that colonoids studies can and should be performed in physioxia when the resemblance to in vivo conditions is important.
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Affiliation(s)
- Gunnar Andreas Walaas
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway
| | - Shreya Gopalakrishnan
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway
| | - Ingunn Bakke
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Helene Kolstad Skovdahl
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Centre of Molecular Inflammation Research (CEMIR), NTNU - Norwegian University of Science and Technology, Trondheim, Norway
| | - Arnar Flatberg
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Central Administration, St. Olav's University Hospital, Trondheim, Norway
| | - Ann Elisabet Østvik
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Arne Kristian Sandvik
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Centre of Molecular Inflammation Research (CEMIR), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Torunn Bruland
- Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
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Li W, Zhou Y, Pang N, Hu Q, Li Q, Sun Y, Ding Y, Gu Y, Xiao Y, Gao M, Ma S, Pan J, Fang EF, Zhang Z, Yang L. NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function. Nutrients 2022; 15:nu15010174. [PMID: 36615829 PMCID: PMC9823589 DOI: 10.3390/nu15010174] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The epithelial tight junction is an important intestinal barrier whose disruption can lead to the release of harmful intestinal substances into the circulation and cause damage to systemic injury. The maintenance of intestinal epithelial tight junctions is closely related to energy homeostasis and mitochondrial function. Nicotinamide riboside (NR) is a NAD booster that can enhance mitochondrial biogenesis in liver. However, whether NR can prevent ethanol-induced intestinal barrier dysfunction and the underlying mechanisms remain unclear. METHODS We applied the mouse NIAAA model (chronic plus binge ethanol feeding) and Caco-2 cells to explore the effects of NR on ethanol-induced intestinal barrier dysfunction and the underlying mechanisms. NAD homeostasis and mitochondrial function were measured. In addition, knockdown of SirT1 in Caco-2 cells was further applied to explore the role of SirT1 in the protection of NR. RESULTS We found that ethanol increased intestinal permeability, increased the release of LPS into the circulation and destroyed the intestinal epithelial barrier structure in mice. NR supplementation attenuated intestinal barrier injury. Both in vivo and in vitro experiments showed that NR attenuated ethanol-induced decreased intestinal tight junction protein expressions and maintained NAD homeostasis. In addition, NR supplementation activated SirT1 activity and increased deacetylation of PGC-1α, and reversed ethanol-induced mitochondrial dysfunction and mitochondrial biogenesis. These effects were diminished with the knockdown of SirT1 in Caco-2 cells. CONCLUSION Boosting NAD by NR alleviates ethanol-induced intestinal epithelial barrier damage via protecting mitochondrial function in a SirT1-dependent manner.
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Affiliation(s)
- Wenli Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
- Department of Immunization Programmes, Guangzhou Huadu District Center for Disease Control and Prevention, Guangzhou 510080, China
| | - Yujia Zhou
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Nengzhi Pang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Qianrong Hu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Qiuyan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Yan Sun
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Yijie Ding
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Yingying Gu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Ying Xiao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Mengqi Gao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Sixi Ma
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Jie Pan
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
| | - Evandro Fei Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
| | - Zhenfeng Zhang
- Radiology Center, Translational Medicine Center, Guangzhou Key Laboratory for Research and Development of Nano-Biomedical Technology for Diagnosis and Therapy, Guangdong Provincial Education Department, Key Laboratory of Nano-Immunoregulation Tumour Microenvironment, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
- Correspondence: (Z.Z.); (L.Y.)
| | - Lili Yang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74 Zhongshan Road 2, Yuexiu District, Guangzhou 510080, China
- Correspondence: (Z.Z.); (L.Y.)
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Liang B, Wu C, Wang C, Sun W, Chen W, Hu X, Liu N, Xing D. New insights into bacterial mechanisms and potential intestinal epithelial cell therapeutic targets of inflammatory bowel disease. Front Microbiol 2022; 13:1065608. [PMID: 36590401 PMCID: PMC9802581 DOI: 10.3389/fmicb.2022.1065608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
The global incidence of inflammatory bowel disease (IBD) has increased rapidly in recent years, but its exact etiology remains unclear. In the past decade, IBD has been reported to be associated with dysbiosis of gut microbiota. Although not yet proven to be a cause or consequence of IBD, the common hypothesis is that at least some alterations in the microbiome are protective or pathogenic. Furthermore, intestinal epithelial cells (IECs) serve as a protective physical barrier for gut microbiota, essential for maintaining intestinal homeostasis and actively contributes to the mucosal immune system. Thus, dysregulation within the intestinal epithelium increases intestinal permeability, promotes the entry of bacteria, toxins, and macromolecules, and disrupts intestinal immune homeostasis, all of which are associated with the clinical course of IBD. This article presents a selective overview of recent studies on bacterial mechanisms that may be protective or promotive of IBD in biological models. Moreover, we summarize and discuss the recent discovery of key modulators and signaling pathways in the IECs that could serve as potential IBD therapeutic targets. Understanding the role of the IECs in the pathogenesis of IBD may help improve the understanding of the inflammatory process and the identification of potential therapeutic targets to help ameliorate this increasingly common disease.
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Affiliation(s)
- Bing Liang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Changhao Wu
- Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Chao Wang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenshe Sun
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wujun Chen
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaokun Hu
- Intervention Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ning Liu
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China,*Correspondence: Ning Liu, ; Dongming Xing,
| | - Dongming Xing
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China,School of Life Sciences, Tsinghua University, Beijing, China,*Correspondence: Ning Liu, ; Dongming Xing,
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37
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Adolph TE, Meyer M, Schwärzler J, Mayr L, Grabherr F, Tilg H. The metabolic nature of inflammatory bowel diseases. Nat Rev Gastroenterol Hepatol 2022; 19:753-767. [PMID: 35906289 DOI: 10.1038/s41575-022-00658-y] [Citation(s) in RCA: 144] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/23/2022] [Indexed: 02/06/2023]
Abstract
Crohn's disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism. Genetic IBD risk partly affects metabolism and stress signalling of innate immunity, and immunometabolism controls susceptibility to gut inflammation. Epidemiological and clinical studies indicate that specific nutrients in the Western diet pose a risk for the development of IBD and a poor disease course. Translational studies in IBD indicate perturbation of energy metabolism in immune cells and perturbation of gut microbial metabolism, which can be shaped by diet. In turn, dietary restriction by exclusive enteral nutrition induces remission in patients with IBD. Collectively, these studies support a metabolic underpinning of gut inflammation in IBD as described for metabolic inflammation in obesity and related disorders.
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Affiliation(s)
- Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
| | - Moritz Meyer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria.
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38
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Steiner CA, Cartwright IM, Taylor CT, Colgan SP. Hypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis. Am J Physiol Cell Physiol 2022; 323:C866-C878. [PMID: 35912990 PMCID: PMC9467472 DOI: 10.1152/ajpcell.00227.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/07/2022] [Accepted: 07/23/2022] [Indexed: 11/22/2022]
Abstract
The healthy mammalian intestine is lined by a single layer of epithelial cells. These cells provide a selectively permeable barrier to luminal contents and normally do so in an efficient and effective manner. Barrier function in the healthy mucosa is provided via several mechanisms including epithelial junctional complexes, mucus production, as well as mucosal-derived antimicrobial proteins. As tissue metabolism is central to the maintenance of homeostasis in the mucosa, intestinal [Formula: see text] levels are uniquely low due to counter-current blood flow and the presence of the microbiota, resulting in the stabilization of the transcription factor hypoxia-inducible factor (HIF). Ongoing studies have revealed that HIF molds normal intestinal metabolism and is central to the coordination of barrier regulation during both homeostasis and active disease. During acute inflammation, HIF is central to controlling the rapid restitution of the epithelium consistent with normal wound healing responses. In contrast, HIF may also contribute to the fibrostenotic response associated with chronic, nonresolving inflammation. As such, HIF may function as a double-edged sword in the overall course of the inflammatory response. Here, we review recent literature on the contribution of HIF to mucosal barrier function, wound healing, and fibrosis.
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Affiliation(s)
- Calen A Steiner
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
| | - Ian M Cartwright
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Cormac T Taylor
- School of Medicine, Conway Institute and Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Sean P Colgan
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
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39
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Li JY, Guo YC, Zhou HF, Yue TT, Wang FX, Sun F, Wang WZ. Arginine metabolism regulates the pathogenesis of inflammatory bowel disease. Nutr Rev 2022; 81:578-586. [PMID: 36040377 PMCID: PMC10086623 DOI: 10.1093/nutrit/nuac070] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg–nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg–urea (catalyzed by arginases) pathways in IBD are debatable; the Arg–polyamine and Arg–creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration.
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Affiliation(s)
- Jun-Yi Li
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital , Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan-Chao Guo
- Huazhong University of Science and Technology Department of Clinical Nutrition, Tongji Medical College, , Wuhan, China
| | - Hai-Feng Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital , Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tian-Tian Yue
- Huazhong University of Science and Technology Department of Clinical Nutrition, Tongji Medical College, , Wuhan, China
| | - Fa-Xi Wang
- Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, China
| | - Fei Sun
- Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, China
| | - Wen-Zhu Wang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital , Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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40
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Du C, Zhao Y, Wang K, Nan X, Chen R, Xiong B. Effects of Milk-Derived Extracellular Vesicles on the Colonic Transcriptome and Proteome in Murine Model. Nutrients 2022; 14:nu14153057. [PMID: 35893911 PMCID: PMC9332160 DOI: 10.3390/nu14153057] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/20/2022] [Accepted: 07/20/2022] [Indexed: 12/29/2022] Open
Abstract
Evidence shows that effective nutritional intervention can prevent or mitigate the risk and morbidity of inflammatory bowel disease (IBD). Bovine milk extracellular vesicles (mEVs), a major bioactive constituent of milk, play an important role in maintaining intestinal health. The aims of this study were to assess the effects of mEV pre-supplementation on the colonic transcriptome and proteome in dextran sulphate sodium (DSS)-induced acute colitis, in order to understand the underlying molecular mechanisms of mEV protection against acute colitis. Our results revealed that dietary mEV supplementation alleviated the severity of acute colitis, as evidenced by the reduced disease activity index scores, histological damage, and infiltration of inflammatory cells. In addition, transcriptome profiling analysis found that oral mEVs significantly reduced the expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17A and IL-33), chemokine ligands (CXCL1, CXCL2, CXCL3, CXCL5, CCL3 and CCL11) and chemokine receptors (CXCR2 and CCR3). Moreover, oral mEVs up-regulated 109 proteins and down-regulated 150 proteins in the DSS-induced murine model, which were involved in modulating amino acid metabolism and lipid metabolism. Collectively, this study might provide new insights for identifying potential targets for the therapeutic effects of mEVs on colitis.
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41
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Lucafò M, Muzzo A, Marcuzzi M, Giorio L, Decorti G, Stocco G. Patient-derived organoids for therapy personalization in inflammatory bowel diseases. World J Gastroenterol 2022; 28:2636-2653. [PMID: 35979165 PMCID: PMC9260862 DOI: 10.3748/wjg.v28.i24.2636] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/21/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries. Knowledge of IBD pathogenesis is still incomplete, and the most widely-accepted interpretation considers genetic factors, environmental stimuli, uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD, leading to dysfunction of the intestinal epithelial functions. In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture. An important innovation is represented by organoids, 3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures. Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile. These models are powerful pharmacological tools to better understand IBD pathogenesis, to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD, and to evaluate novel target-directed molecules which could improve therapeutic strategies. The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.
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Affiliation(s)
- Marianna Lucafò
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
| | - Antonella Muzzo
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Martina Marcuzzi
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Lorenzo Giorio
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Giuliana Decorti
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Gabriele Stocco
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
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Tao Y, Qiao S, Lv C, Yun X, Yue M, Fang Y, Wei Z, Dai Y, Xia Y. Phytoestrogen arctigenin preserves the mucus barrier in inflammatory bowel diseases by inhibiting goblet cell apoptosis via the
ERβ
/
TRIM21
/
PHB1
pathway. Phytother Res 2022; 36:3248-3264. [DOI: 10.1002/ptr.7495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/26/2022] [Accepted: 04/30/2022] [Indexed: 01/17/2023]
Affiliation(s)
- Yu Tao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
- Jiangsu Province Hospital of Chinese Medicine The Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing China
| | - Si‐miao Qiao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Chang‐jun Lv
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Xin‐ming Yun
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Meng‐fan Yue
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Yu‐lai Fang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Zhi‐feng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
| | - Yu‐feng Xia
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University Nanjing China
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Joshi A, Soni A, Acharya S. In vitro models and ex vivo systems used in inflammatory bowel disease. IN VITRO MODELS 2022; 1:213-227. [PMID: 37519330 PMCID: PMC9036838 DOI: 10.1007/s44164-022-00017-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal condition. Ulcerative colitis and Crohn's disease are types of inflammatory bowel disease. Over many decades, the disease has been a topic of study, with experts still trying to figure out its cause and pathology. Researchers have established many in vivo animal models, in vitro cell lines, and ex vivo systems to understand its cause ultimately and adequately identify a therapy. However, in vivo animal models cannot be regarded as good models for studying IBD since they cannot completely simulate the disease. Furthermore, because species differences are a crucial subject of concern, in vitro cell lines and ex vivo systems can be employed to recreate the condition properly. In vitro models serve as the starting point for biological and medical research. Ex vivo and in vitro models for replicating gut physiology have been developed. This review aims to present a clear understanding of several in vitro and ex vivo models of IBD and provide insights into their benefits and limits and their value in understanding intestinal physiology.
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Affiliation(s)
- Abhishek Joshi
- Department of Pharmacology, SSR College of Pharmacy, Union Territory of Dadra 396230 Sayli, Silvassa, India
| | - Arun Soni
- Department of Pharmacology, SSR College of Pharmacy, Union Territory of Dadra 396230 Sayli, Silvassa, India
| | - Sanjeev Acharya
- Department of Pharmacognosy, SSR College of Pharmacy, Union Territory of Dadra 396230 Sayli, Silvassa, India
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Ornelas A, Dowdell AS, Lee JS, Colgan SP. Microbial Metabolite Regulation of Epithelial Cell-Cell Interactions and Barrier Function. Cells 2022; 11:cells11060944. [PMID: 35326394 PMCID: PMC8946845 DOI: 10.3390/cells11060944] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/04/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
Epithelial cells that line tissues such as the intestine serve as the primary barrier to the outside world. Epithelia provide selective permeability in the presence of a large constellation of microbes, termed the microbiota. Recent studies have revealed that the symbiotic relationship between the healthy host and the microbiota includes the regulation of cell–cell interactions at the level of epithelial tight junctions. The most recent findings have identified multiple microbial-derived metabolites that influence intracellular signaling pathways which elicit activities at the epithelial apical junction complex. Here, we review recent findings that place microbiota-derived metabolites as primary regulators of epithelial cell–cell interactions and ultimately mucosal permeability in health and disease.
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Affiliation(s)
- Alfredo Ornelas
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - Alexander S. Dowdell
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - J. Scott Lee
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
| | - Sean P. Colgan
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Mailstop B146, Aurora, CO 80045, USA; (A.O.); (A.S.D.); (J.S.L.)
- Rocky Mountain Regional Veterans Affairs Medical Center, 1700 N. Wheeling St., Aurora, CO 80045, USA
- Correspondence:
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45
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Fernandes-Pires G, Braissant O. Current and potential new treatment strategies for creatine deficiency syndromes. Mol Genet Metab 2022; 135:15-26. [PMID: 34972654 DOI: 10.1016/j.ymgme.2021.12.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 12/16/2022]
Abstract
Creatine deficiency syndromes (CDS) are inherited metabolic disorders caused by mutations in GATM, GAMT and SLC6A8 and mainly affect central nervous system (CNS). AGAT- and GAMT-deficient patients lack the functional brain endogenous creatine (Cr) synthesis pathway but express the Cr transporter SLC6A8 at blood-brain barrier (BBB), and can thus be treated by oral supplementation of high doses of Cr. For Cr transporter deficiency (SLC6A8 deficiency or CTD), current treatment strategies benefit one-third of patients. However, as their phenotype is not completely reversed, and for the other two-thirds of CTD patients, the development of novel more effective therapies is needed. This article aims to review the current knowledge on Cr metabolism and CDS clinical aspects, highlighting their current treatment possibilities and the most recent research perspectives on CDS potential therapeutics designed, in particular, to bring new options for the treatment of CTD.
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Affiliation(s)
- Gabriella Fernandes-Pires
- Service of Clinical Chemistry, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland
| | - Olivier Braissant
- Service of Clinical Chemistry, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.
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46
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Chen M, He QD, Guo JJ, Wu QB, Zhang Q, Yau YM, Xie YF, Guo ZY, Tong ZY, Yang ZB, Xiao L. Electro-Acupuncture Regulates Metabolic Disorders of the Liver and Kidney in Premature Ovarian Failure Mice. Front Endocrinol (Lausanne) 2022; 13:882214. [PMID: 35957829 PMCID: PMC9359440 DOI: 10.3389/fendo.2022.882214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/31/2022] [Indexed: 11/26/2022] Open
Abstract
As per the theory of traditional Chinese medicine (TCM), the liver and kidney dysfunction are important pathogenies for premature ovarian failure (POF). POF is a common gynecological disease that reduced the pregnancy rate. Electro-acupuncture (EA) is a useful non-pharmaceutical therapy that supposedly regulates the function of the liver and kidney in the treatment of POF with TCM. However, the underlying mechanism of EA in the treatment of POF has not been adequately studied through metabonomics with reference to the theory of TCM. Accordingly, we investigated the effect of EA on the liver and kidney metabolites in POF mice through metabolomics. POF mice were established via intraperitoneal injection of cisplatin. Both Sanyinjiao (SP6) and Guanyuan (CV4) were stimulated by EA for 3 weeks. The biological samples (including the serum and the ovary, liver, and kidney tissues) were evaluated by histopathology, molecular biology, and hydrogen-1 nuclear magnetic resonance (1HNMR)-based metabolomics to assess the efficacy of EA. 1HNMR data were analyzed by the orthogonal partial least squares discriminant analysis (OPLS-DA). The results revealed that EA was beneficial to ovarian function and the menstrual cycle of POF. Both the energy metabolism and neurotransmitter metabolism in the liver and kidney were regulated by EA. Notably, EA played an important role in regulating energy-related metabolism in the kidney, and the better effect of neurotransmitter-related metabolism in the liver was regulated by EA. These findings indicated that the ovarian functions could be improved and the metabolic disorder of the liver and kidney caused by POF could be regulated by EA. Our study results thus suggested that the EA therapy, based on the results for the liver and kidney, were related to POF in TCM, as preliminarily confirmed through metabolomics.
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Affiliation(s)
- Min Chen
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
- Department of Chinese Medicine, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China
- *Correspondence: Min Chen, ; Zong-bao Yang, ; Lu Xiao,
| | - Qi-da He
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Jing-jing Guo
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Qi-biao Wu
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
- Zhuhai MUST Science and Technology Research Institute, Zhuhai, China
| | - Qi Zhang
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Yuen-ming Yau
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Yu-feng Xie
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Zi-yi Guo
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Zi-yan Tong
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Zong-bao Yang
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, China
- *Correspondence: Min Chen, ; Zong-bao Yang, ; Lu Xiao,
| | - Lu Xiao
- Department of Basic Medicine, Zunyi Medical University, Zhuhai, China
- *Correspondence: Min Chen, ; Zong-bao Yang, ; Lu Xiao,
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Wang S, Huang J, Liu F, Tan KS, Deng L, Lin Y, Tan W. Isosteviol Sodium Exerts Anti-Colitic Effects on BALB/c Mice with Dextran Sodium Sulfate-Induced Colitis Through Metabolic Reprogramming and Immune Response Modulation. J Inflamm Res 2021; 14:7107-7130. [PMID: 34992409 PMCID: PMC8709797 DOI: 10.2147/jir.s344990] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/08/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Inflammatory bowel diseases (IBDs) are global health problems that are associated with immune regulation, but clinical IBDs treatment is currently inadequate. Effective preventive or therapeutic methods for immune disorders rely on controlling the function of immune cells. Isosteviol sodium (STV-Na) has antioxidant activity, but the therapeutic effect of STV-Na against IBD remain undocumented. Herein, we investigated the therapeutic effect of STV-Na in mice models with IBDs. METHODS Mice received 3.5% DSS for 7 days to establish IBD models. Intraperitoneal STV-Na was given 2 days before DSS and lasted for 9 days. Commercially available drugs used in treating IBDs (5-aminosalicylic acid, dexamethasone, and infliximab) were used as positive controls. Samples were collected 7 days after colitis induction. Histopathological score, biochemical parameters, molecular biology methods, and metabolomics were used for evaluating the therapeutic effect of STV-Na. RESULTS Our data revealed that STV-Na could significantly alleviate colon inflammation in mice with colitis. Specifically, STV-Na treatment improved body weight loss, increased colon length, decreased histology scores, and restored the hematological parameters of mice with colitis. The untargeted metabolomics analysis revealed that metabolic profiles were restored by STV-Na treatment. Furthermore, STV-Na therapy suppressed the number of CD68 macrophages and F4/80 cell infiltration. And STV-Na suppressed M1 and M2 macrophage numbers along with the mRNA expressions of proinflammatory cytokines. Moreover, STV-Na administration increased the number of regulatory T (Treg) cells while decreasing Th1/Th2/Th17 cell counts in the spleen. Additionally, STV-Na treatment restored intestinal barrier disruption in DSS-triggered colitis tissues by ameliorating the TJ proteins, increasing goblet cell proportions, and mucin protein production, and decreasing the permeability to FITC-dextran, which was accompanied by decreased plasma LPS and DAO contents. CONCLUSION These results indicate that STV-Na can ameliorate colitis by modulating immune responses along with metabolic reprogramming, and could therefore be a promising therapeutic strategy for IBDs.
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Affiliation(s)
- Shanping Wang
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People’s Republic of China
| | - Jiandong Huang
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People’s Republic of China
| | - Fei Liu
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People’s Republic of China
| | - Keai Sinn Tan
- College of Pharmacy, Jinan University, Guangzhou, People’s Republic of China
- Post-Doctoral Innovation Site, Jinan University, Yuanzhi Health Technology Co, Ltd, Zhuhai, People’s Republic of China
| | - Liangjun Deng
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People’s Republic of China
| | - Yue Lin
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People’s Republic of China
| | - Wen Tan
- Post-Doctoral Innovation Site, Jinan University, Yuanzhi Health Technology Co, Ltd, Zhuhai, People’s Republic of China
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
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Exosomes as a New Delivery Vehicle in Inflammatory Bowel Disease. Pharmaceutics 2021; 13:pharmaceutics13101644. [PMID: 34683937 PMCID: PMC8539337 DOI: 10.3390/pharmaceutics13101644] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a type of chronic relapsing inflammatory disease. The pathogenesis of IBD is still unclear, which may involve environmental factors, genetic factors, intestinal microbiota disorder, and abnormal immune responses. Exosomes (30–150 nm) are found in various body fluids, including blood, saliva, urine, and cerebrospinal fluid. Exosomes mediate intercellular communication and regulate cell biological activity by carrying non-coding RNAs, proteins, and lipids. There is evidence that exosomes are involved in the pathogenesis of IBD. In view of the important roles of exosomes in the pathogenesis of IBD, this work systematically reviews the latest research progress of exosomes in IBD, especially the roles of exosomes as non-coding RNA delivery systems in the pathogenesis of IBD, including a disordered immune response, barrier function, and intestinal microbiota. The review will help to clarify the pathogenesis of IBD and explore new diagnostic markers and therapeutic targets for patients with IBD.
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Wu J, Niu J, Li M, Miao Y. Keratin 1 maintains the intestinal barrier in ulcerative colitis. Genes Genomics 2021; 43:1389-1402. [PMID: 34562265 DOI: 10.1007/s13258-021-01166-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 09/14/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND The intestinal mechanical barrier plays a key role in the pathogenesis of ulcerative colitis (UC). Our previous study showed keratin 1 (KRT1) was downregulated in UC, but the mechanism by which KRT1 affects the intestinal barrier remains unknown. OBJECTIVES To explore the mechanism of KRT1 in the intestinal barrier in UC. METHODS Colonic tissues were collected from 20 UC patients before and after mucosal healing (MH) and 15 healthy controls. The expression of KRT1 was measured by PCR, western blotting and immunohistochemistry (IHC). A dextran sulfate sodium (DSS)-induced colitis model was established in krt1 transgenic (TG) mice, and the mice were treated with methylprednisolone (MP) to explore the role of KRT1 in the intestinal barrier. Inflammation was evaluated through the DAI score, colon, spleen and H&E. The expression of KRT1 and tight junction (TJ) proteins in mouse was analysed by the same methods. RESULTS The transcription and expression of KRT1 in UC was decreased and recovered after MH but did not reach the level of the healthy controls. Similar to the clinical results, the expression of krt1 was decreased in DSS-induced colitis and upregulated after MP. Moreover, the krt1 TG group exhibited less inflammation than wild-type (WT) group. The expression of Occludin and ZO-1 decreased after DSS induction, the decreases in Occludin and ZO-1 in the krt1 TG group were lower than WT group, which was significantly increased after MP, while the expression of Claudin-2 exhibited the opposite effect. CONCLUSIONS Keratin 1 maintains the intestinal barrier by upregulating TJ proteins in UC.
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Affiliation(s)
- Jing Wu
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming, 650032, Yunnan, China
| | - Junkun Niu
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming, 650032, Yunnan, China
| | - Maojuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming, 650032, Yunnan, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Kunming, 650032, Yunnan, China.
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, Yunnan, China.
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Jomura R, Tanno Y, Akanuma SI, Kubo Y, Tachikawa M, Hosoya KI. Contribution of monocarboxylate transporter 12 to blood supply of creatine on the sinusoidal membrane of the hepatocytes. Am J Physiol Gastrointest Liver Physiol 2021; 321:G113-G122. [PMID: 34075817 DOI: 10.1152/ajpgi.00143.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Creatine (Cr)/phosphocreatine has the ability to buffer the high-energy phosphate, thereby contributing to intracellular energy homeostasis. As Cr biosynthetic enzyme deficiency is reported to increase susceptibility to colitis under conditions of inflammatory stress, Cr is critical for maintaining intestinal homeostasis under inflammatory stress. Cr is mainly produced in the hepatocytes and then distributed to other organs of the body by the circulatory system. Since monocarboxylate transporter 9 (MCT9) and monocarboxylate transporter 12 (MCT12) have been reported to accept Cr as a substrate, these transporters are proposed as candidates for Cr efflux transporter in the liver. The aim of this study was to elucidate the transport mechanism on Cr supply from the hepatocytes. Immunohistochemical staining of the rat liver sections revealed that both MCT9 and MCT12 were localized on the sinusoidal membrane of the hepatocytes. In the transport studies using Xenopus laevis oocyte expression system, [14C]Cr efflux from MCT9- or MCT12-expressing oocytes was significantly greater than that from water-injected oocytes. [14C]Cr efflux from primary cultured hepatocytes was significantly decreased following MCT12 mRNA knockdown, whereas this efflux was not decreased after mRNA knockdown of MCT9. Based on the extent of MCT12 protein downregulation and Cr efflux after knockdown of MCT12 in primary cultured rat hepatocytes, the contribution ratio of MCT12 in Cr efflux was calculated as 76.4%. Our study suggests that MCT12 substantially contributes to the efflux of Cr at the sinusoidal membrane of the hepatocytes.NEW & NOTEWORTHY Our study is the first to identify the role of monocarboxylate transporter 12 (MCT12) as a transporter of creatine (Cr) in the liver. MCT12 was found to significantly contribute to the efflux of Cr on the sinusoidal membrane of the hepatocytes. Since hepatocytes are known to be involved in creatine biosynthesis, the present findings can be beneficial for the regulation of Cr biosynthesis and supply.
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Affiliation(s)
- Ryuta Jomura
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Yu Tanno
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Shin-Ichi Akanuma
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Yoshiyuki Kubo
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Masanori Tachikawa
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Ken-Ichi Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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