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Hsueh W, Wu Y, Weng M, Liu S, Santavanond JP, Liu Y, Lin C, Lai C, Lu Y, Hsu JY, Gao H, Lee J, Wei S, Lyu P, Poon IKH, Hsieh H, Chiu Y. Novel Naphthyridones Targeting Pannexin 1 for Colitis Management. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2411538. [PMID: 39739600 PMCID: PMC11831487 DOI: 10.1002/advs.202411538] [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: 09/19/2024] [Revised: 10/29/2024] [Indexed: 01/02/2025]
Abstract
Pannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. While inhibiting dysregulated PANX1 has been proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy, or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, hit-to-lead optimization is performed and a naphthyridone, compound 12, is identified as a new PANX1 inhibitor with an IC50 of 0.73 µm that does not affect pannexin-homologous LRRC8/SWELL1 channels. Using structure-activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, it is revealed that compound 12 directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, it is found that compound 12 markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof-of-concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, uncover the binding site for future drug design, and present a targeted strategy for treating IBD.
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Affiliation(s)
- Wen‐Yun Hsueh
- Department of ChemistryNational Tsing Hua UniversityHsinchu300044Taiwan
- Institute of Biotechnology and Pharmaceutical ResearchNational Health Research InstitutesMiaoli County350401Taiwan
| | - Yi‐Ling Wu
- Institute of BiotechnologyNational Tsing Hua UniversityHsinchu300044Taiwan
| | - Meng‐Tzu Weng
- Department of Internal MedicineNational Taiwan University HospitalTaipei City100229Taiwan
- Department of Medical ResearchNational Taiwan University HospitalHsin‐Chu BranchHsinchu302058Taiwan
| | - Shin‐Yun Liu
- Department of Internal MedicineNational Taiwan University HospitalTaipei City100229Taiwan
| | - Jascinta P Santavanond
- Department of Biochemistry and ChemistryLa Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVIC3086Australia
- Research Centre for Extracellular VesiclesLa Trobe UniversityVIC3086Australia
| | - Yi‐Chung Liu
- Institute of Population Health SciencesNational Health Research InstitutesMiaoli County350401Taiwan
| | - Ching‐I Lin
- Department of Internal MedicineNational Taiwan University HospitalTaipei City100229Taiwan
| | - Cheng‐Nong Lai
- Institute of BiotechnologyNational Tsing Hua UniversityHsinchu300044Taiwan
| | - Yi‐Ru Lu
- Institute of BiotechnologyNational Tsing Hua UniversityHsinchu300044Taiwan
| | - Jing Yin Hsu
- Institute of BiotechnologyNational Tsing Hua UniversityHsinchu300044Taiwan
| | - Hong‐Yu Gao
- Institute of BiotechnologyNational Tsing Hua UniversityHsinchu300044Taiwan
| | - Jinq‐Chyi Lee
- Institute of Biotechnology and Pharmaceutical ResearchNational Health Research InstitutesMiaoli County350401Taiwan
| | - Shu‐Chen Wei
- Department of Internal MedicineNational Taiwan University HospitalTaipei City100229Taiwan
| | - Ping‐Chiang Lyu
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchu300044Taiwan
| | - Ivan K H Poon
- Department of Biochemistry and ChemistryLa Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVIC3086Australia
- Research Centre for Extracellular VesiclesLa Trobe UniversityVIC3086Australia
| | - Hsing‐Pang Hsieh
- Department of ChemistryNational Tsing Hua UniversityHsinchu300044Taiwan
- Institute of Biotechnology and Pharmaceutical ResearchNational Health Research InstitutesMiaoli County350401Taiwan
| | - Yu‐Hsin Chiu
- Institute of BiotechnologyNational Tsing Hua UniversityHsinchu300044Taiwan
- Departments of Medical Science, Life Science, and MedicineNational Tsing Hua UniversityHsinchu300044Taiwan
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Li Y, Xu Y, Hu X, Li C, Wei L, Wang X, Jin Y, Hu Z. Water-Soluble Se-Containing Proteins from Chicken Alleviate DSS-Induced Ulcerative Colitis in Mice via Inhibiting TLR4/MyD88 Pathway and Protecting the Goblet Cell Pathway. Biol Trace Elem Res 2024; 202:3767-3780. [PMID: 37950138 DOI: 10.1007/s12011-023-03952-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023]
Abstract
The influence of water-soluble selenium-containing proteins (WSSeP) in chicken on ulcerative colitis (UC) is not known. This work aims to investigate the effect of two WSSeP including h-Se with 1.78 μg Se/g and l-Se with 1.04 μg Se/g on mice UC induced by dextran sodium sulfate (DSS) versus 5-aminosalicylic acid (5-ASA). Seventy C57BL/6 mice were randomly divided into seven groups: groups 1 and 7 were given normal saline. Group 2 to group 4 were administrated orally 500, 1500, and 3000 mg/kg/day h-Se, respectively. Group 5 was given 1500 mg/kg/day l-Se as the control of group 3. From day 14 to day 21, groups 2 to 7 were fed with 3% DSS. Synchronously, group 6 was fed with 150 mg/kg/day 5-ASA. On day 21, the disease activity index, colon length, the histopathological changes, the expressions of claudin-1, occludin, ZO-1, TLR4, and MyD88 in colons, the levels of inflammatory cytokines (IFN-γ, IL-1β, IL-6, TNF-α), and antioxidant markers (LPS, GSH-Px, SOD, MDA) in serum were determined. WSSeP can effectively improve the damages of DSS to the colon, thymus, and spleen, which present protein and Se dose-dependent. 1.50 g h-Se dose can significantly promote the expression levels of claudin-1, occludin, and ZO-1, to surround crypt gland and goblet and epithelial cells and inhibit the attack of DSS, suppress TLR4/MyD88 pathway, decrease the levels of IL-1β, IL-6, TNF-α, IFN-γ, LPS, and MDA, and increase the activities of GSH-Px and SOD, which are better than those of 5-ASA. Therefore, WSSeP would be a natural and potential anti-inflammatory agent for UC.
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Affiliation(s)
- Yuancheng Li
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Yanlong Xu
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Xin Hu
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Chenxi Li
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Lulu Wei
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Xinlei Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Yi Jin
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China
| | - Zhongqiu Hu
- College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China.
- Laboratory of Quality & Safety Risk Assessment for Agro-Products (Yangling), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Yangling, 712100, Shaanxi, China.
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Xu J, Xu H, Guo X, Zhao H, Wang J, Li J, He J, Huang H, Huang C, Zhao C, Li Y, Zhou Y, Peng Y, Nie Y. Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses. BMC Microbiol 2024; 24:91. [PMID: 38500062 PMCID: PMC10946100 DOI: 10.1186/s12866-024-03251-2] [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: 10/24/2023] [Accepted: 03/07/2024] [Indexed: 03/20/2024] Open
Abstract
BACKGROUND Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.
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Affiliation(s)
- Jing Xu
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Haoming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Xue Guo
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Hailan Zhao
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Jiaqi Wang
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Jianhong Li
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Jie He
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Hongli Huang
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Chen Huang
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Chong Zhao
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Yingfei Li
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China
| | - Youlian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China.
| | - Yao Peng
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China.
| | - Yuqiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China.
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Bass K, Sivaprakasam S, Dharmalingam-Nandagopal G, Thangaraju M, Ganapathy V. Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice. Biochem J 2024; 481:295-312. [PMID: 38372391 PMCID: PMC10903465 DOI: 10.1042/bcj20230403] [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: 09/25/2023] [Revised: 02/01/2024] [Accepted: 02/04/2024] [Indexed: 02/20/2024]
Abstract
Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.
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Affiliation(s)
- Kevin Bass
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
| | - Sathish Sivaprakasam
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
| | | | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, U.S.A
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
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Li YQ, Yan XY, Xiao XJ, Ma PT, Wang SQ, Liu HL, Zhang W, Chen M, Yao JP, Li Y. The gut microbiome and metabolites are altered and interrelated in patients with functional constipation. Front Microbiol 2023; 14:1320567. [PMID: 38125567 PMCID: PMC10731029 DOI: 10.3389/fmicb.2023.1320567] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/06/2023] [Indexed: 12/23/2023] Open
Abstract
Introduction Gut microbiota and metabolites have been identified to contribute to the pathogenesis of functional constipation (FC); however, the underlying mechanism(s) have not been elucidated, and the relationship between the gut microbiota and metabolites in FC has received limited attention in the literature. Methods 16S rDNA sequencing and non-targeted metabolomic detection based on liquid chromatography-mass spectrometry (LC-MS/MS) technologies were combined to analyze the altered gut microbiome and metabolic profile of fecal samples from FC patients and healthy individuals (healthy control; HC). Results The richness and diversity of gut microbiota significantly (p < 0.01) increased in FC patients. Compared to the HC group, 18 genera, including Intestinibacter, Klebsiella, and Akkermansia, exhibited statistically significant changes (p < 0.05). Metabolic analysis showed that metabolic profiles were also markedly altered with 79 metabolites, such as (-)-caryophyllene oxide, chenodeoxycholic acid, and biliverdin, indicating significant inter-group differences (p < 0.05). Besides, the primary bile acid biosynthesis, as well as the metabolic profile of porphyrin and chlorophyll, were the most dominant enriched pathways (FDR < 0.01), in which chenodeoxycholic acid and biliverdin were significantly enriched, respectively. Correlation analysis demonstrated a strong relationship between 10 genera and 19 metabolites (r > 0.6, FDR < 0.05), and notably, Intestinibacter showed a negative correlation with biliverdin (FDR < 0.001), which highlighted the interplay of the gut microbiota and metabolites in the pathogenesis of FC. Conclusion Our research describes the characteristics of the gut microbiota and metabolic profiles and the correlation between the gut microbiota and metabolites in FC patients. This may contribute to the understanding of the underlying mechanisms involved in FC pathogenesis and may provide novel insights into therapeutic interventions.
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Affiliation(s)
- Yan-qiu Li
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiang-yun Yan
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xian-jun Xiao
- School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Pei-tao Ma
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Si-qi Wang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Hui-lin Liu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Wei Zhang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Min Chen
- Anorectal Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jun-peng Yao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Ying Li
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Liao TS, Chen CY, Lin CS, Chang CWT, Takemoto JY, Lin YY. Mesobiliverdin IXα-enriched microalgae feed additive eliminates reliance on antibiotic tylosin to promote intestinal health of weaning piglets. J Anim Physiol Anim Nutr (Berl) 2023; 107:1368-1375. [PMID: 37539819 DOI: 10.1111/jpn.13867] [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: 06/03/2022] [Revised: 06/23/2023] [Accepted: 07/24/2023] [Indexed: 08/05/2023]
Abstract
Weaning is a critical period in raising pigs. Novel animal feed additives that promote gut health and regulate immune function of piglets without antibiotics are needed. In this study, we aimed to test the ability of mesobiliverdin IXα-enriched microalgae (MBV IXα-enriched microalgae) to eliminate reliance on antibiotics to promote intestinal health in piglets. Eighty 28-day-old weaned piglets were randomly allocated to four groups each with four replicate pens and five piglets per pen. The dietary treatments were a basal diet as control (NC), basal diet plus 0.05% tylosin (PC), basal diet plus 0.1% or 0.5% MBV IXα-enriched microalgae as low (MBV-SP1) or high (MBV-SP2) dose respectively. All treated animals showed no significant differences in live weight, average daily gain and feed efficiency compared to control animals. Histological examination showed that MBV-SP1 and particularly MBV-SP2 increased the ratio of villus height to crypt depth in the jejunum and ileum compared to NC (p < 0.05). Similarly, tylosin treatment also increased villi lengths and the ratio of villus height to crypt depth in the jejunum and ileum compared to the NC (p < 0.05). MBV-SP1 and particularly MBV-SP2 reduced the levels of inflammatory cytokines interleukin-6 and tumour necrosis factor-alpha in the small intestine. MBV-SP2 and tylosin similarly reduced the lipid peroxidation marker (TBARS value) in the duodenum and ileum. In conclusion, feed supplementation with MBV IXα-enriched microalgae improved gut health by villus height and production of immunomodulators that correlated with down-regulated secretion of inflammatory cytokines.
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Affiliation(s)
- Tz-Shian Liao
- Department of Animal Science and Technology, National Taiwan University, Taipei City, Taiwan
| | - Ching-Yi Chen
- Department of Animal Science and Technology, National Taiwan University, Taipei City, Taiwan
| | - Chuan-Shun Lin
- Animal Technology Research Center, Agricultural Technology Research Institute, Miaoli County, Taiwan
| | - Cheng-Wei T Chang
- Department of Chemistry and Biochemistry, Utah State University, Logan, Utah, USA
| | - Jon Y Takemoto
- Department of Biology, Utah State University, Logan, Utah, USA
| | - Yuan-Yu Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei City, Taiwan
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Tavares EDA, Guerra GCB, da Costa Melo NM, Dantas-Medeiros R, da Silva ECS, Andrade AWL, de Souza Araújo DF, da Silva VC, Zanatta AC, de Carvalho TG, de Araújo AA, de Araújo-Júnior RF, Zucolotto SM. Toxicity and Anti-Inflammatory Activity of Phenolic-Rich Extract from Nopalea cochenillifera (Cactaceae): A Preclinical Study on the Prevention of Inflammatory Bowel Diseases. PLANTS (BASEL, SWITZERLAND) 2023; 12:594. [PMID: 36771677 PMCID: PMC9921826 DOI: 10.3390/plants12030594] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 01/11/2023] [Indexed: 06/18/2023]
Abstract
Phenolic compounds have been scientifically recognized as beneficial to intestinal health. The cactus Nopalea cochenillifera, used as anti-inflammatory in traditional medicine, is a rich source of these bioactive compounds. The present study aimed to investigate the phytochemical profile of N. cochenillifera extract and evaluate its acute toxicity and anti-inflammatory effect on 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis in rats. The total phenolic content per gram of dry extract was 67.85 mg. Through HPLC-IES-MSn, a total of 25 compounds such as saccharides, organic acids, phenolic acids and flavonoids were characterized. The dose of 2000 mg/kg of extract by an oral route showed no signs of toxicity, mortality or significant changes in biochemical and hematological parameters. Regarding intestinal anti-inflammatory effects, animals were treated with three different doses of extract or sulfasalazine. Macroscopic analysis of the colon indicated that the extract decreased the disease activity index. Levels of IL-1β and TNF-α decreased, IL-10 increased and MDA and MPO enzyme levels decreased when compared with the control group. In addition, a down-regulation of MAPK1/ERK2 and NF-κB p65 pathway markers in colon tissue was observed. The epithelial integrity was improved according to histopathological and immunohistological analysis. Thus, the extract provided strong preclinical evidence of being effective in maintaining the remission of colitis.
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Affiliation(s)
- Emanuella de Aragão Tavares
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Gerlane Coelho Bernardo Guerra
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Graduate Program in Pharmaceutical Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
| | - Nadja Maria da Costa Melo
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Renato Dantas-Medeiros
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | - Anderson Wilbur Lopes Andrade
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | | | - Valéria Costa da Silva
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Ana Caroline Zanatta
- Department of Biomolecular Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, São Paulo University, São Paulo, Ribeirão Preto 14040-903, Brazil
| | - Thaís Gomes de Carvalho
- Program Degree in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
| | - Aurigena Antunes de Araújo
- Department of Biophysics and Pharmacology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Graduate Program in Pharmaceutical Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
- Program Degree in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
| | - Raimundo Fernandes de Araújo-Júnior
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Program Degree in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
- Cancer and Inflammation Research Laboratory, Morphology Department, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Silvana Maria Zucolotto
- Graduate Program in Drug Development and Technological Innovation, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
- Graduate Program in Pharmaceutical Science, Federal University of Rio Grande do Norte (UFRN), Natal 59078-970, Brazil
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8
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Reiländer S, Schmehl W, Popp K, Nuss K, Kronen P, Verdino D, Wiezorek C, Gutmann M, Hahn L, Däubler C, Meining A, Raschig M, Kaiser F, von Rechenberg B, Scherf-Clavel O, Meinel L. Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime. ACS Biomater Sci Eng 2022. [DOI: 10.1021/acsbiomaterials.2c00464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Simon Reiländer
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Wolfgang Schmehl
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Kevin Popp
- German Plastics Center (SKZ), Friedrich-Bergius-Ring 22, Wuerzburg97076, Germany
| | - Katja Nuss
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Peter Kronen
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Dagmar Verdino
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Christina Wiezorek
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Marcus Gutmann
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Lukas Hahn
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Christof Däubler
- Department of Internal Medicine II, Gastroenterology, University Hospital Wuerzburg, Oberdürrbacherstr. 6, Wuerzburg97080, Germany
| | - Alexander Meining
- Department of Internal Medicine II, Gastroenterology, University Hospital Wuerzburg, Oberdürrbacherstr. 6, Wuerzburg97080, Germany
| | - Martina Raschig
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Friederike Kaiser
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg, Pleicherwall 2, Würzburg97070, Germany
| | - Brigitte von Rechenberg
- Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
- Competence Center for Applied Biotechnology and Molecular Medicine (CABMM), Vetsuisse Faculty ZH, University of Zuerich, Winterthurerstrasse 260, Zuerich8057, Switzerland
| | - Oliver Scherf-Clavel
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
| | - Lorenz Meinel
- Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074Wuerzburg, Germany
- Helmholtz Institute for RNA-based Infection Biology (HIRI), Würzburg97070, Germany
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9
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Biliverdin modulates the long non-coding RNA H19/microRNA-181b-5p/endothelial cell specific molecule 1 axis to alleviate cerebral ischemia reperfusion injury. Biomed Pharmacother 2022; 153:113455. [PMID: 36076490 DOI: 10.1016/j.biopha.2022.113455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 07/11/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
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10
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Zhao Y, Chen H, Li W, He Q, Liang J, Yan X, Yuan Y, Yue T. Selenium-containing tea polysaccharides ameliorate DSS-induced ulcerative colitis via enhancing the intestinal barrier and regulating the gut microbiota. Int J Biol Macromol 2022; 209:356-366. [PMID: 35405152 DOI: 10.1016/j.ijbiomac.2022.04.028] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/27/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023]
Abstract
Both tea polysaccharides and selenium have certain remission potential for ulcerative colitis (UC), but few reports focused on natural selenium-containing tea polysaccharides. The purpose of this study was to isolate a selenium-containing tea polysaccharide (ASeTP) and determine its structure and effects on UC. Results showed that ASeTP was primarily composed of three purified, β-pyranoside-linked, protein-binding polysaccharides (SeTP-1, SeTP-2, and SeTP-3) with SeOC, OSeO, and SeO linkages. Specifically, SeTP-1 was a neutral heteropolysaccharide principally composed of mannose, glucose, galactose, xylose, and arabinose, while SeTP-2 and SeTP-3 were acidic heteropolysaccharides due to the existence of glucuronic acid. ASeTP effectively alleviated the symptoms of weight loss, colon shortens, and disease activity index scores increase in dextran sodium sulfate (DSS)-induced colitis mice. ASeTP attenuated the histological damage and maintained the colonic mucosal barrier via up-regulating the expression of occludin, claudin-1, and zona occludens-1 (ZO-1). ASeTP suppressed the levels of pro-inflammatory cytokines and enhanced the antioxidant capacity of colon tissue. Besides, ASeTP beneficially increased the selenium content of the colon. Furthermore, ASeTP remodeled the gut microbiota by accelerating the proliferation of beneficial bacteria and inhibiting pathogenic microorganisms. Thus, ASeTP has the potential to be a functional food against colitis.
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Affiliation(s)
- Yuning Zhao
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China
| | - Hong Chen
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China
| | - Wenting Li
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China
| | - Qian He
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China
| | - Jingyimei Liang
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China
| | - Xiaohai Yan
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China
| | - Yahong Yuan
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China.
| | - Tianli Yue
- College of Food Science and Engineering, Northwest A&F University, YangLing, Shaanxi, 712100, China; Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China; College of Food Science and Technology, Northwest University, Xi'an, 710069, China.
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11
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A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene? Antioxidants (Basel) 2022; 11:antiox11020276. [PMID: 35204159 PMCID: PMC8868141 DOI: 10.3390/antiox11020276] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 01/27/2023] Open
Abstract
Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe2+), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.
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12
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Castro-Martinez F, Candelario-Martinez A, Encarnacion-Garcia MR, Piedra-Quintero Z, Bonilla-Moreno R, Betanzos A, Perez-Orozco R, Hernandez-Cueto MA, Muñoz-Medina JE, Patiño-Lopez G, Schnoor M, Villegas-Sepulveda N, Nava P. Rictor/Mammalian Target of Rapamycin Complex 2 Signaling Protects Colonocytes from Apoptosis and Prevents Epithelial Barrier Breakdown. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1537-1549. [PMID: 34139193 DOI: 10.1016/j.ajpath.2021.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/18/2021] [Accepted: 06/07/2021] [Indexed: 11/29/2022]
Abstract
Epithelial barrier impairment is a hallmark of several pathologic processes in the gut, including inflammatory bowel diseases. Several intracellular signals prevent apoptosis in intestinal epithelial cells. Herein, we show that in colonocytes, rictor/mammalian target of rapamycin complex 2 (mTORC2) signaling is a prosurvival stimulus. Mechanistically, mTORC2 activates Akt, which, in turn, inhibits apoptosis by phosphorylating B-cell lymphoma 2 (BCL2) associated agonist of cell death (Bad) and preventing caspase-3 activation. Nevertheless, during inflammation, rictor/mTORC2 signaling declines and Akt activity is reduced. Consequently, active caspase-3 increases in surface colonocytes undergoing apoptosis/anoikis and causes epithelial barrier breakdown. Likewise, Rictor ablation in intestinal epithelial cells interrupts mTORC2/Akt signaling and increases apoptosis/anoikis of surface colonocytes without affecting the crypt architecture. The increase in epithelial permeability induced by Rictor ablation produces a mild inflammatory response in the colonic mucosa, but minimally affects the development/establishment of colitis. The data identify a previously unknown mechanism by which rictor/mTORC2 signaling regulates apoptosis/anoikis in intestinal epithelial cells during colitis and clarify its role in the maintenance of the intestinal epithelial barrier.
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Affiliation(s)
- Felipe Castro-Martinez
- Departments of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Aurora Candelario-Martinez
- Departments of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Maria R Encarnacion-Garcia
- Departments of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Zayda Piedra-Quintero
- Department of Molecular Biomedicine, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Raul Bonilla-Moreno
- Department of Molecular Biomedicine, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Abigail Betanzos
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Rocio Perez-Orozco
- Medicine Program for the Teaching and Development of Scientific Research in Iztacala (MEDICI Program), Faculty of Advanced Studies Iztacala, National Autonomous University of Mexico, Mexico-City, Mexico
| | - Maria A Hernandez-Cueto
- Central Laboratory of Epidemiology, Mexican. Institute of Social Security, Mexico-City, Mexico
| | - Jose E Muñoz-Medina
- Central Laboratory of Epidemiology, Mexican. Institute of Social Security, Mexico-City, Mexico
| | - Genaro Patiño-Lopez
- Laboratory of Research in Immunology and Proteomics, Federico Gómez Children's Hospital of Mexico, Mexico-City, Mexico
| | - Michael Schnoor
- Department of Molecular Biomedicine, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico
| | - Nicolas Villegas-Sepulveda
- Department of Molecular Biomedicine, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico.
| | - Porfirio Nava
- Departments of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies- National Polytechnic Institute (CINVESTAV-IPN), Mexico-City, Mexico.
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13
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Krajewska JB, Włodarczyk J, Jacenik D, Kordek R, Taciak P, Szczepaniak R, Fichna J. New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation-Proof of Concept Based on In Vitro and In Vivo Studies. Int J Mol Sci 2021; 22:ijms22063121. [PMID: 33803793 PMCID: PMC8003307 DOI: 10.3390/ijms22063121] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/13/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are at the top of the worldwide rankings for gastrointestinal diseases as regards occurrence, yet efficient and side-effect-free treatments are currently unavailable. In the current study, we proposed a new concept for anti-inflammatory treatment based on gold (III) complexes. A new gold (III) complex TGS 121 was designed and screened in the in vitro studies using a mouse macrophage cell line, RAW264.7, and in vivo, in the dextran sulphate sodium (DSS)-induced mouse model of colitis. Physicochemical studies showed that TGS 121 was highly water-soluble; it was stable in water, blood, and lymph, and impervious to sunlight. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, the complex showed a potent anti-inflammatory profile, as evidenced in neutral red uptake and Griess tests. In the DSS-induced mouse model of colitis, the complex administered in two doses (1.68 μg/kg, intragastrically, and 16.8 μg/kg, intragastrically, once daily) produced a significant (* p < 0.05) anti-inflammatory effect, as shown by macroscopic score. The mechanism of action of TGS 121 was related to the enzymatic and non-enzymatic antioxidant system; moreover, TGS 121 induced changes in the tight junction complexes expression in the intestinal wall. This is the first study proving that gold (III) complexes may have therapeutic potential in the treatment of IBD.
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Affiliation(s)
- Julia B. Krajewska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (J.B.K.); (J.W.)
| | - Jakub Włodarczyk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (J.B.K.); (J.W.)
| | - Damian Jacenik
- Department of Cytobiochemistry, University of Lodz, 90-236 Lodz, Poland;
| | - Radzisław Kordek
- Department of Pathology, Faculty of Medicine, 92-213 Lodz, Poland;
| | - Przemysław Taciak
- Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland;
| | | | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (J.B.K.); (J.W.)
- Correspondence:
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14
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Takagi T, Naito Y, Higashimura Y, Uchiyama K, Okayama T, Mizushima K, Katada K, Kamada K, Ishikawa T, Itoh Y. Rectal administration of carbon monoxide inhibits the development of intestinal inflammation and promotes intestinal wound healing via the activation of the Rho-kinase pathway in rats. Nitric Oxide 2021; 107:19-30. [PMID: 33340673 DOI: 10.1016/j.niox.2020.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 12/12/2020] [Accepted: 12/14/2020] [Indexed: 11/24/2022]
Abstract
The inhalation of carbon monoxide (CO) gas and the administration of CO-releasing molecules were shown to inhibit the development of intestinal inflammation in a murine colitis model. However, it remains unclear whether CO promotes intestinal wound healing. Herein, we aimed to evaluate the therapeutic effects of the topical application of CO-saturated saline enemas on intestinal inflammation and elucidate the underlying mechanism. Acute colitis was induced with trinitrobenzene sulfonic acid (TNBS) in male Wistar rats. A CO-saturated solution was prepared via bubbling 50% CO gas into saline and was rectally administrated twice a day after colitis induction; rats were sacrificed 3 or 7 days after induction for the study of the acute or healing phases, respectively. The distal colon was isolated, and ulcerated lesions were measured. In vitro wound healing assays were also employed to determine the mechanism underlying rat intestinal epithelial cell restitution after CO treatment. CO solution rectal administration ameliorated acute TNBS-induced colonic ulceration and accelerated ulcer healing without elevating serum CO levels. The increase in thiobarbituric acid-reactive substances and myeloperoxidase activity after induction of acute TNBS colitis was also significantly inhibited after CO treatment. Moreover, the wound healing assays revealed that the CO-saturated medium enhanced rat intestinal epithelial cell migration via the activation of Rho-kinase. In addition, the activation of Rho-kinase in response to CO treatment was confirmed in the inflamed colonic tissue. Therefore, the rectal administration of a CO-saturated solution protects the intestinal mucosa from inflammation and accelerates colonic ulcer healing through enhanced epithelial cell restitution. CO may thus represent a novel therapeutic agent for the treatment of inflammatory bowel disease.
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Affiliation(s)
- Tomohisa Takagi
- Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan; Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yasuki Higashimura
- Department of Food Science, Ishikawa Prefectural University, Nonoichi, 921-8836, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Tetsuya Okayama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Kazuhiro Katada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Kazuhiro Kamada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
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15
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Chang CWT, Takemoto JY, Chang PE, AlFindee MN, Lin YY. Effects of Mesobiliverdin IXα-Enriched Microalgae Feed on Gut Health and Microbiota of Broilers. Front Vet Sci 2021; 7:586813. [PMID: 33553275 PMCID: PMC7854538 DOI: 10.3389/fvets.2020.586813] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 12/22/2020] [Indexed: 11/13/2022] Open
Abstract
Gut inflammatory bowel diseases (IBDs) links to animal medicinal feed and antibiotic-resistance are fueling major economic impacts in the agricultural livestock industry. New animal feeds that promote livestock gut health and control of IBDs without antibiotics are needed. This study investigates the effects of mesobiliverdin IXα (MBV)-enriched microalgae spirulina extracts on the growth performance, blood parameters, intestinal morphology, and gut microbiota of broilers. A total of 288 1-day-old broiler chicks (Arbor Acres) were randomly allotted to six dietary treatments (4 pens/treatment and 12 birds/pen). The dietary treatments comprised a basal diet as control (CON), basal diet plus 0.05 and 0.1% microalgae extract as low and high dose, respectively (SP1 and SP2), basal diet plus 0.05 and 0.1% MBV-enriched microalgae extract as low and high dose, respectively (MBV-SP1 and MBV-SP2), and basal diet plus 0.1% amoxicillin (AMX). All treated animals showed no significant differences in live weight, average daily gain, and feed efficiency compared to control animals. Histological examination showed that AMX treatment decreased the villi lengths of the duodenum and ileum below control villi length (P < 0.05) while MBV-SP1 and particularly MBV-SP2 increased villi lengths in the duodenum, jejunum, and ileum above AMX -treatment lengths (P < 0.05). The Firmicutes/Bacteroidetes ratio increased in the cecum of broilers fed AMX (P < 0.05) while SP2, MBV-SP1, and MBV-SP2-fed animals showed (in order) increasing ratios up to the AMX level. The abundance of bacterial species of the genus Lactobacillus increased in MBV-SP1 and MBV-SP2-fed groups including a striking increase in Lactobacillus salivarius abundance with MBV-SP2 (P < 0.05). Feeding MBV-SP1 and MBV-SP2 decreased the level of pro-inflammatory cytokine IL-6 in plasma of broilers to a greater extent than SP1 and SP2. These results reveal that MBV-enriched microalgae extracts improve the intestinal health and beneficial microflora composition of broilers.
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Affiliation(s)
- Cheng-Wei T Chang
- Department of Chemistry and Biochemistry, Utah State University, Logan, UT, United States
| | - Jon Y Takemoto
- Department of Biology, Utah State University, Logan, UT, United States
| | - Pei-En Chang
- Institute of Biotechnology, National Taiwan University, Taipei City, Taiwan
| | - Madher N AlFindee
- Department of Chemistry and Biochemistry, Utah State University, Logan, UT, United States
| | - Yuan-Yu Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei City, Taiwan
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16
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Hanscom M, Loane DJ, Aubretch T, Leser J, Molesworth K, Hedgekar N, Ritzel RM, Abulwerdi G, Shea-Donohue T, Faden AI. Acute colitis during chronic experimental traumatic brain injury in mice induces dysautonomia and persistent extraintestinal, systemic, and CNS inflammation with exacerbated neurological deficits. J Neuroinflammation 2021; 18:24. [PMID: 33461596 PMCID: PMC7814749 DOI: 10.1186/s12974-020-02067-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Disruptions of brain-gut axis have been implicated in the progression of a variety of gastrointestinal (GI) disorders and central nervous system (CNS) diseases and injuries, including traumatic brain injury (TBI). TBI is a chronic disease process characterized by persistent secondary injury processes which can be exacerbated by subsequent challenges. Enteric pathogen infection during chronic TBI worsened cortical lesion volume; however, the pathophysiological mechanisms underlying the damaging effects of enteric challenge during chronic TBI remain unknown. This preclinical study examined the effect of intestinal inflammation during chronic TBI on associated neurobehavioral and neuropathological outcomes, systemic inflammation, and dysautonomia. METHODS Dextran sodium sulfate (DSS) was administered to adult male C57BL/6NCrl mice 28 days following craniotomy (Sham) or TBI for 7 days to induce intestinal inflammation, followed by a return to normal drinking water for an additional 7 to 28 days for recovery; uninjured animals (Naïve) served as an additional control group. Behavioral testing was carried out prior to, during, and following DSS administration to assess changes in motor and cognitive function, social behavior, and mood. Electrocardiography was performed to examine autonomic balance. Brains were collected for histological and molecular analyses of injury lesion, neurodegeneration, and neuroinflammation. Blood, colons, spleens, mesenteric lymph nodes (mLNs), and thymus were collected for morphometric analyses and/or immune characterization by flow cytometry. RESULTS Intestinal inflammation 28 days after craniotomy or TBI persistently induced, or exacerbated, respectively, deficits in fine motor coordination, cognition, social behavior, and anxiety-like behavior. Behavioral changes were associated with an induction, or exacerbation, of hippocampal neuronal cell loss and microglial activation in Sham and TBI mice administered DSS, respectively. Acute DSS administration resulted in a sustained systemic immune response with increases in myeloid cells in blood and spleen, as well as myeloid cells and lymphocytes in mesenteric lymph nodes. Dysautonomia was also induced in Sham and TBI mice administered DSS, with increased sympathetic tone beginning during DSS administration and persisting through the first recovery week. CONCLUSION Intestinal inflammation during chronic experimental TBI causes a sustained systemic immune response and altered autonomic balance that are associated with microglial activation, increased neurodegeneration, and persistent neurological deficits.
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Affiliation(s)
- Marie Hanscom
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA.
| | - David J Loane
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
| | - Taryn Aubretch
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Jenna Leser
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Kara Molesworth
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Nivedita Hedgekar
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Rodney M Ritzel
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Gelareh Abulwerdi
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Terez Shea-Donohue
- Division of Translational Radiation Sciences (DTRS), Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
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17
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Nishino K, Nishida A, Inatomi O, Imai T, Kume S, Kawahara M, Maegawa H, Andoh A. Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis. J Clin Biochem Nutr 2020; 68:156-163. [PMID: 33879967 DOI: 10.3164/jcbn.20-90] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 06/17/2020] [Indexed: 12/11/2022] Open
Abstract
Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific Atg5 gene deficient mice (Atg5 ΔIEC mice) were generated by cross of Atg5-floxed mice (Atg5 fl/fl ) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5 ΔIEC mice compared to control Atg5 fl/fl mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS-treated Atg5 ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5 ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1α.
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Affiliation(s)
- Kyohei Nishino
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Takayuki Imai
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Shinji Kume
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Masahiro Kawahara
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Hiroshi Maegawa
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan
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18
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Zannoni A, Pietra M, Gaspardo A, Accorsi PA, Barone M, Turroni S, Laghi L, Zhu C, Brigidi P, Forni M. Non-invasive Assessment of Fecal Stress Biomarkers in Hunting Dogs During Exercise and at Rest. Front Vet Sci 2020; 7:126. [PMID: 32373631 PMCID: PMC7186473 DOI: 10.3389/fvets.2020.00126] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/19/2020] [Indexed: 12/16/2022] Open
Abstract
Intense exercise causes to organisms to have oxidative stress and inflammation at the gastrointestinal (GI) level. The reduction in intestinal blood flow and the exercise-linked thermal damage to the intestinal mucosa can cause intestinal barrier disruption, followed by an inflammatory response. Furthermore, the adaptation to exercise may affect the gut microbiota and the metabolome of the biofluids. The aim of the present research was to evaluate the presence of a GI derangement in hunting dogs through a non-invasive sampling as a consequence of a period of intense exercise in comparison with samples collected at rest. The study included nine dogs that underwent the same training regime for hunting wild boar. In order to counterbalance physiological variations, multiple-day replicates were collected and pooled at each experimental point for each dog. The samples were collected immediately at rest before the training (T0), after 60 days of training (T1), after 60 days of hunting wild boar (T2), and finally, at 60 days of rest after hunting (T3). A number of potential stress markers were evaluated: fecal cortisol metabolites (FCMs) as a major indicator of altered physiological states, immunoglobulin A (IgA) as an indicator of intestinal immune protection, and total antioxidant activity [total antioxidant capacity (TAC)]. Since stool samples contain exfoliated cells, we investigated also the presence of some transcripts involved in GI permeability [occludin (OCLN), protease-activated receptor-2 (PAR-2)] and in the inflammatory mechanism [interleukin (IL)-8, IL-6, IL-1b, tumor necrosis factor alpha (TNFα), calprotectin (CALP), heme oxygenase-1 (HO-1)]. Finally, the metabolome and the microbiota profiles were analyzed. No variation in FCM and IgA content and no differences in OCLN and CALP gene expression between rest and training were observed. On the contrary, an increase in PAR-2 and HO-1 transcripts, a reduction in total antioxidant activity, and a different profile of microbiota and metabolomics data were observed. Collectively, the data in the present study indicated that physical exercise in our model could be considered a mild stressor stimulus.
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Affiliation(s)
- Augusta Zannoni
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.,Health Sciences and Technologies-Interdepartmental Center for Industrial Research (CIRI-SDV), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Marco Pietra
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Alba Gaspardo
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Pier Attilio Accorsi
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Monica Barone
- Unit of Microbial Ecology of Health, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Silvia Turroni
- Unit of Microbial Ecology of Health, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.,Interdepartmental Centre for Agri-Food Industrial Research, University of Bologna, Bologna, Italy
| | - Luca Laghi
- Interdepartmental Centre for Agri-Food Industrial Research, University of Bologna, Bologna, Italy.,Department of Agro-Food Science and Technology, Centre of Foodomics, University of Bologna, Cesena, Italy
| | - Chenglin Zhu
- Department of Agro-Food Science and Technology, Centre of Foodomics, University of Bologna, Cesena, Italy
| | - Patrizia Brigidi
- Unit of Microbial Ecology of Health, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.,Interdepartmental Centre for Agri-Food Industrial Research, University of Bologna, Bologna, Italy
| | - Monica Forni
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.,Health Sciences and Technologies-Interdepartmental Center for Industrial Research (CIRI-SDV), Alma Mater Studiorum-University of Bologna, Bologna, Italy
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19
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Van Dingenen J, Pieters L, Van Nuffel E, Lefebvre RA. Hemin reduces postoperative ileus in a heme oxygenase 1-dependent manner while dimethyl fumarate does without heme oxygenase 1-induction. Neurogastroenterol Motil 2020; 32:e13624. [PMID: 31121086 DOI: 10.1111/nmo.13624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 03/28/2019] [Accepted: 04/26/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Postoperative ileus (POI), the impairment of gastrointestinal motility after abdominal surgery, is mainly due to intestinal muscular inflammation. Carbon monoxide (CO)-releasing compounds were shown to exert an anti-inflammatory effect in murine POI partially through induction of heme oxygenase-1 (HO-1). The influence of hemin and dimethyl fumarate (DMF), currently used for multiple sclerosis (MS), was therefore tested in murine POI. METHODS C57BL/6J mice were anesthetized and after laparotomy, POI was induced via intestinal manipulation (IM). Animals were treated with either 30 mg kg-1 hemin intraperitoneally (ip), 30 mg kg-1 DMF ip, or 100 mg kg-1 intragastrically (ig) 24 hours before IM. Intestinal transit was assessed 24 hours postoperatively and mucosa-free muscularis or whole segments of the small intestine were stored for later analysis. Intestinal HO-1 protein expression was studied at 6, 12, and 24 hours after administration of hemin or DMF in non-manipulated mice. KEY RESULTS Pretreatment with hemin and DMF, both ig and ip, prevented the delayed transit seen after IM. Concomitantly, both hemin and DMF significantly reduced the increased interleukin-6 levels and the elevated leukocyte infiltration in the muscularis. Hemin but not DMF caused a significant increase in intestinal HO-1 protein expression and co-administration of the HO-1 inhibitor chromium mesoporphyrin abolished the protective effects of hemin on POI; DMF reduced the IM-induced activation of NF-κB and ERK 1/2. CONCLUSIONS AND INFERENCES Both hemin and DMF improve the delayed transit and inflammation seen in murine POI, but only hemin does so in a HO-1-dependent manner.
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Affiliation(s)
- Jonas Van Dingenen
- Department of Basic and Applied Medical Sciences, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium
| | - Leen Pieters
- Department of Human Structure and Repair, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium
| | - Elien Van Nuffel
- Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Romain A Lefebvre
- Department of Basic and Applied Medical Sciences, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium
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20
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Lee GR, Shaefi S, Otterbein LE. HO-1 and CD39: It Takes Two to Protect the Realm. Front Immunol 2019; 10:1765. [PMID: 31402920 PMCID: PMC6676250 DOI: 10.3389/fimmu.2019.01765] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/11/2019] [Indexed: 12/20/2022] Open
Abstract
Cellular protective mechanisms exist to ensure survival of the cells and are a fundamental feature of all cells that is necessary for adapting to changes in the environment. Indeed, evolution has ensured that each cell is equipped with multiple overlapping families of genes that safeguard against pathogens, injury, stress, and dysfunctional metabolic processes. Two of the better-known enzymatic systems, conserved through all species, include the heme oxygenases (HO-1/HO-2), and the ectonucleotidases (CD39/73). Each of these systems generates critical bioactive products that regulate the cellular response to a stressor. Absence of these molecules results in the cell being extremely predisposed to collapse and, in most cases, results in the death of the cell. Recent reports have begun to link these two metabolic pathways, and what were once exclusively stand-alone are now being found to be intimately interrelated and do so through their innate ability to generate bioactive products including adenosine, carbon monoxide, and bilirubin. These simple small molecules elicit profound cellular physiologic responses that impact a number of innate immune responses, and participate in the regulation of inflammation and tissue repair. Collectively these enzymes are linked not only because of the mitochondria being the source of their substrates, but perhaps more importantly, because of the impact of their products on specific cellular responses. This review will provide a synopsis of the current state of the field regarding how these systems are linked and how they are now being leveraged as therapeutic modalities in the clinic.
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Affiliation(s)
- Ghee Rye Lee
- Departments of Surgery and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Shahzad Shaefi
- Departments of Surgery and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Leo E Otterbein
- Departments of Surgery and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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21
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Affiliation(s)
- Jon Y. Takemoto
- Department of BiologyUtah State University, Logan Utah 84322-5305 U.S.A
| | - Cheng‐Wei T. Chang
- Department of Chemistry and BiochemistryUtah State University Logan, Utah 84322-0300 U.S.A
| | - Dong Chen
- Department of Biological EngineeringUtah State University Logan, Utah 843122 U.S.A
| | - Garrett Hinton
- Department of BiologyUtah State University Logan, Utah 84322-5305 U.S.A
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22
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Takagi T, Naito Y, Mizushima K, Hirai Y, Harusato A, Okayama T, Katada K, Kamada K, Uchiyama K, Handa O, Ishikawa T, Itoh Y. Heme oxygenase-1 prevents murine intestinal inflammation. J Clin Biochem Nutr 2018. [PMID: 30487665 DOI: 10.3164/jcbn.17.133] [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: 11/22/2022] Open
Abstract
Heme oxygenases (HOs) are rate-limiting enzymes catabolizing heme to biliverdin, ferrous iron, and carbon monoxide, and of the three HO isoforms identified, HO-1 plays a protective role against inflammatory processes. In this study, we investigated the possible role of HO-1 in intestinal inflammation. Acute colitis was induced in male C57BL/6 (wild-type) and homozygous BTB and CNC homolog 1 (Bach1)-deficient mice, which show high HO-1 expression in the colonic mucosa, using dextran sodium sulfate. The disease activity index, myeloperoxidase activity, and inflammatory cytokines in the colonic mucosa were evaluated 7 days after dextran sodium sulfate-dependent colitis induction. We also evaluated the impact of HO-1 inhibition using zinc protoporphyrin IX (25 mg/kg i.p., daily). After dextran sodium sulfate administration, HO-1 mRNA and protein expression increased in a time-dependent manner. Disease activity index score, myeloperoxidase activity, and colonic production of TNF-α and IFN-γ were increased after dextran sodium sulfate administration, and co-administration of zinc protoporphyrin IX enhanced their increase. In addition, disease activity index in Bach1-deficient was significantly lower after dextran sodium sulfate administration than that in wild type mice. These results indicate that HO-1 plays a protective role against dextran sodium sulfate-induced intestinal inflammation, possibly by regulating pro-inflammatory cytokines in intestinal tissues.
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Affiliation(s)
- Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.,Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yasuko Hirai
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Akihito Harusato
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tetsuya Okayama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazhuhiro Katada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuhiro Kamada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Osamu Handa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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23
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Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Andoh A. Ameliorating effects of bortezomib, a proteasome inhibitor, on development of dextran sulfate sodium-induced murine colitis. J Clin Biochem Nutr 2018; 63:217-223. [PMID: 30487672 PMCID: PMC6252295 DOI: 10.3164/jcbn.18-42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 01/25/2023] Open
Abstract
We examined the effect of bortezomib, a proteasome inhibitor, on the development of dextran sulfate sodium (DSS)-induced colitis in mice. DSS-colitis was induced by the administration of 3% DSS in water in C57BL/6J mice. Bortezomib was intraperitoneally administered daily for 9 days from the start of DSS. Ubiquitination of IκBα was evaluated by immunoblot. Bortezomib significantly ameliorated DSS-induced body weight loss and reduced the disease activity. The translocation of NF-κBp65 into the nucleus was markedly suppressed in the DSS + bortezomib group compared to the DSS group, but this difference was not detected in submucosal tissue. Ubiquitinated IκBα in the cytoplasm of colon epithelial cells was increased in the DSS + bortezomib group compared to the DSS group. In HT-29 cells, bortezomib blocked tumor necrosis factor-α (TNF-α)-induced nuclear translocation of NF-κB and this was accompanied by an increase in ubiquitinated IκBα in the cytoplasm. The mRNA expression of inflammatory mediators in colonic epithelial cells was significantly reduced by the treatment of bortezomib. Bortezomib inhibited the nuclear translocation of NF-κB in colonic epithelial cells by suppressing the degradation of IκBα and contributed to an improvement in DSS colitis. Our study suggests that bortezomib may be a new treatment option for IBD.
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Affiliation(s)
- Shigeki Sakai
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Masashi Ohno
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Shigeki Bamba
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Mitsushige Sugimoto
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Masahiro Kawahara
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
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24
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Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Andoh A. Astaxanthin, a xanthophyll carotenoid, prevents development of dextran sulphate sodium-induced murine colitis. J Clin Biochem Nutr 2018; 64:66-72. [PMID: 30705514 PMCID: PMC6348411 DOI: 10.3164/jcbn.18-47] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 05/11/2018] [Indexed: 12/11/2022] Open
Abstract
Astaxanthin is a xanthophyll carotenoid, which possesses strong scavenging effect on reactive oxygen species. In this study, we examined the effect of astaxanthin on dextran sulfate sodium (DSS)-induced colitis in mice. Experimental colitis was induced by the oral administration of 4% w/v DSS in tap water in C57BL/6J mice. Astaxanthin was mixed with a normal rodent diet (0.02 or 0.04%). Astaxanthin significantly ameliorated DSS-induced body weight loss and reduced the disease activity index. The ameliorating effects was observed in a dose-dependent manner. Immunochemical analyses showed that astaxanthin markedly suppressed DSS-induced histological inflammatory changes (inflammatory cell infiltration, edematous changes and goblet cell depletion). Plasma levels of malondialdehyde and 8-hydroxy-2-deoxyguanosine were significantly reduced by the administration of 0.04% astaxanthin. Astaxanthin significantly suppressed the mucosal mRNA expression of IL-1β, IL-6, TNF-α, IL-36α and IL-36γ. Astaxanthin blocked the DSS-induced translocation of NF-κB p65 and AP-1 (c-Jun) into the nucleus of mucosal epithelial cells, and also suppressed DSS-induced mucosal activation of MAPKs (ERK1/2, p38 and JNK). In conclusion, astaxanthin prevented the development of DSS-induced colitis via the direct suppression of NF-κB, AP-1 and MAPK activation. These findings suggest that astaxanthin is a novel candidate as a therapeutic option for the treatment of inflammatory bowel disease.
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Affiliation(s)
- Shigeki Sakai
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Masashi Ohno
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Shigeki Bamba
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Mitsushige Sugimoto
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Masahiro Kawahara
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
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25
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Takagi T, Naito Y, Mizushima K, Hirai Y, Harusato A, Okayama T, Katada K, Kamada K, Uchiyama K, Handa O, Ishikawa T, Itoh Y. Heme oxygenase-1 prevents murine intestinal inflammation. J Clin Biochem Nutr 2018; 63:169-174. [PMID: 30487665 PMCID: PMC6252298 DOI: 10.3164/jcbn.17-133] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 04/17/2018] [Indexed: 12/20/2022] Open
Abstract
Heme oxygenases (HOs) are rate-limiting enzymes catabolizing heme to biliverdin, ferrous iron, and carbon monoxide, and of the three HO isoforms identified, HO-1 plays a protective role against inflammatory processes. In this study, we investigated the possible role of HO-1 in intestinal inflammation. Acute colitis was induced in male C57BL/6 (wild-type) and homozygous BTB and CNC homolog 1 (Bach1)-deficient mice, which show high HO-1 expression in the colonic mucosa, using dextran sodium sulfate. The disease activity index, myeloperoxidase activity, and inflammatory cytokines in the colonic mucosa were evaluated 7 days after dextran sodium sulfate-dependent colitis induction. We also evaluated the impact of HO-1 inhibition using zinc protoporphyrin IX (25 mg/kg i.p., daily). After dextran sodium sulfate administration, HO-1 mRNA and protein expression increased in a time-dependent manner. Disease activity index score, myeloperoxidase activity, and colonic production of TNF-α and IFN-γ were increased after dextran sodium sulfate administration, and co-administration of zinc protoporphyrin IX enhanced their increase. In addition, disease activity index in Bach1-deficient was significantly lower after dextran sodium sulfate administration than that in wild type mice. These results indicate that HO-1 plays a protective role against dextran sodium sulfate-induced intestinal inflammation, possibly by regulating pro-inflammatory cytokines in intestinal tissues.
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Affiliation(s)
- Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.,Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yasuko Hirai
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Akihito Harusato
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tetsuya Okayama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazhuhiro Katada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuhiro Kamada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Osamu Handa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Ohno M, Nishida A, Sugitani Y, Nishino K, Inatomi O, Sugimoto M, Kawahara M, Andoh A. Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells. PLoS One 2017; 12:e0185999. [PMID: 28985227 PMCID: PMC5630155 DOI: 10.1371/journal.pone.0185999] [Citation(s) in RCA: 140] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 09/22/2017] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND AND AIMS Curcumin is a hydrophobic polyphenol derived from turmeric, a traditional Indian spice. Curcumin exhibits various biological functions, but its clinical application is limited due to its poor absorbability after oral administration. A newly developed nanoparticle curcumin shows improved absorbability in vivo. In this study, we examined the effects of nanoparticle curcumin (named Theracurmin) on experimental colitis in mice. METHODS BALB/c mice were fed with 3% dextran sulfate sodium (DSS) in water. Mucosal cytokine expression and lymphocyte subpopulation were analyzed by real-time PCR and flow cytometry, respectively. The profile of the gut microbiota was analyzed by real-time PCR. RESULTS Treatment with nanoparticle curcumin significantly attenuated body weight loss, disease activity index, histological colitis score and significantly improved mucosal permeability. Immunoblot analysis showed that NF-κB activation in colonic epithelial cells was significantly suppressed by treatment with nanoparticle curcumin. Mucosal mRNA expression of inflammatory mediators was significantly suppressed by treatment with nanoparticle curcumin. Treatment with nanoparticle curcumin increased the abundance of butyrate-producing bacteria and fecal butyrate level. This was accompanied by increased expansion of CD4+ Foxp3+ regulatory T cells and CD103+ CD8α- regulatory dendritic cells in the colonic mucosa. CONCLUSIONS Treatment with nanoparticle curcumin suppressed the development of DSS-induced colitis potentially via modulation of gut microbial structure. These responses were associated with induction of mucosal immune cells with regulatory properties. Nanoparticle curcumin is one of the promising candidates as a therapeutic option for the treatment of IBD.
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Affiliation(s)
- Masashi Ohno
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Yoshihiko Sugitani
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Kyohei Nishino
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | | | - Masahiro Kawahara
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
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Sturm C, Wagner AE. Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways. Int J Mol Sci 2017; 18:E1890. [PMID: 28862664 PMCID: PMC5618539 DOI: 10.3390/ijms18091890] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/22/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
A high consumption of vegetables belonging to the Brassicaceae family has been related to a lower incidence of chronic diseases including different kinds of cancer. These beneficial effects of, e.g., broccoli, cabbage or rocket (arugula) intake have been mainly dedicated to the sulfur-containing glucosinolates (GLSs)-secondary plant compounds nearly exclusively present in Brassicaceae-and in particular to their bioactive breakdown products including isothiocyanates (ITCs). Overall, the current literature indicate that selected Brassica-derived ITCs exhibit health-promoting effects in vitro, as well as in laboratory mice in vivo. Some studies suggest anti-carcinogenic and anti-inflammatory properties for ITCs which may be communicated through an activation of the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) that controls the expression of antioxidant and phase II enzymes. Furthermore, it has been shown that ITCs are able to significantly ameliorate a severe inflammatory phenotype in colitic mice in vivo. As there are studies available suggesting an epigenetic mode of action for Brassica-derived phytochemicals, the conduction of further studies would be recommendable to investigate if the beneficial effects of these compounds also persist during an irregular consumption pattern.
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Affiliation(s)
- Christine Sturm
- Institute of Nutritional Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
| | - Anika E Wagner
- Institute of Nutritional Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
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28
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Zhou JA, Jiang M, Yang X, Liu Y, Guo J, Zheng J, Qu Y, Song Y, Li R, Qin X, Wang X. Unconjugated bilirubin ameliorates the inflammation and digestive protease increase in TNBS-induced colitis. Mol Med Rep 2017; 16:1779-1784. [PMID: 28656252 PMCID: PMC5562003 DOI: 10.3892/mmr.2017.6825] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 05/31/2017] [Indexed: 12/12/2022] Open
Abstract
The authors previously demonstrated that unconjugated bilirubin (UCB) may inhibit the activities of various digestive proteases, including trypsin and chymotrypsin. The digestive proteases in the lower gut are important in the pathogenesis of inflammatory bowel diseases. The effects of UCB on the inflammation and levels of digestive proteases in feces of rats with colitis have not yet been revealed. The present study investigated the effect of UCB on the inflammatory status and levels of trypsin and chymotrypsin in the feces of rats with trinitrobenzenesulfonic acid (TNBS)‑induced colitis. The data indicated that treatment with TNBS resulted in a marked reduction in weight gain, which was significantly alleviated in UCB‑treated rats. Furthermore, UCB treatment alleviated the inflammation induced by TNBS, detected via macroscopic damage and microscopic inflammation scores, and pro‑inflammatory markers including myeloperoxidase (MPO), tumor necrosis factor (TNF)‑α and interleukin (IL)‑1β. Furthermore, rats with colitis demonstrated significant increases in fecal trypsin and chymotrypsin levels, whereas UCB treatment significantly alleviated these increases. A significant positive correlation was additionally revealed among the pro‑inflammatory markers (MPO, TNF‑α and IL‑1β) and fecal digestive proteases (trypsin and chymotrypsin) in colitis. The results of the present study demonstrated that UCB ameliorated the inflammation and digestive protease increase in TNBS-induced colitis.
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Affiliation(s)
- Jin-An Zhou
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Mingshan Jiang
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xinguang Yang
- Department of Biochemistry and Molecular Biology, Daqing Branch of Harbin Medical University, Daqing, Heilongjiang 163319, P.R. China
| | - Yuanli Liu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Junyu Guo
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Jiadong Zheng
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Yilin Qu
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Yu Song
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Rongyan Li
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xiaofa Qin
- GI Biopharma Inc., Westfield, NJ 07090, USA
| | - Xiuhong Wang
- Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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29
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Marelli G, Erreni M, Anselmo A, Taverniti V, Guglielmetti S, Mantovani A, Allavena P. Heme-oxygenase-1 Production by Intestinal CX3CR1 + Macrophages Helps to Resolve Inflammation and Prevents Carcinogenesis. Cancer Res 2017; 77:4472-4485. [PMID: 28619710 DOI: 10.1158/0008-5472.can-16-2501] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 02/01/2017] [Accepted: 06/06/2017] [Indexed: 11/16/2022]
Abstract
CX3CR1+ macrophages in the intestinal lamina propria contribute to gut homeostasis through the immunomodulatory interleukin IL10, but there is little knowledge on how these cells or the CX3CR1 receptor may affect colorectal carcinogenesis. In this study, we show that CX3CR1-deficient mice fail to resolve gut inflammation despite high production of IL10 and have increased colitis and adenomatous polyps in chemical and genetic models of colon carcinogenesis. Mechanistically, CX3CL1-mediated engagement of the CX3CR1 receptor induced upregulation of heme-oxygenase-1 (HMOX-1), an antioxidant and anti-inflammatory enzyme. CX3CR1-deficient mice exhibited significantly lower expression of HMOX-1 in their adenomatous colon tissues. Combining LPS and CX3CL1 displayed a strong synergistic effect in vitro, but HMOX-1 levels were significantly lower in KO macrophages. Cohousing of wild-type and CX3CR1-/- mice during the AOM/DSS treatment attenuated disease severity in CX3CR1-/- mice, indicating the importance of the microbiome, but did not fully reinstate HMOX-1 levels and did not abolish polyp formation. In contrast, pharmacologic induction of HMOX-1 in vivo by cobalt protoporphyrin-IX treatment eradicated intestinal inflammation and fully protected KO mice from carcinogenesis. Taken together, our results establish an essential role for the receptor CX3CR1 in gut macrophages in resolving inflammation in the intestine, where it helps protects against colitis-associated cancer by regulating HMOX-1 expression. Cancer Res; 77(16); 4472-85. ©2017 AACR.
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Affiliation(s)
- Giulia Marelli
- Departement of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, Via Manzoni, Rozzano, Milano, Italy.
| | - Marco Erreni
- Departement of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, Via Manzoni, Rozzano, Milano, Italy
| | - Achille Anselmo
- Departement of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, Via Manzoni, Rozzano, Milano, Italy
| | - Valentina Taverniti
- Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Food Microbiology and Bioprocesses, Università degli Studi di Milano, Milano, Italy
| | - Simone Guglielmetti
- Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Food Microbiology and Bioprocesses, Università degli Studi di Milano, Milano, Italy
| | - Alberto Mantovani
- Departement of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, Via Manzoni, Rozzano, Milano, Italy.,Humanitas University, Rozzano, Milano, Italy
| | - Paola Allavena
- Departement of Immunology and Inflammation, IRCCS-Humanitas Clinical and Research Center, Via Manzoni, Rozzano, Milano, Italy. .,Humanitas University, Rozzano, Milano, Italy
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30
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Mitani T, Yoshioka Y, Furuyashiki T, Yamashita Y, Shirai Y, Ashida H. Enzymatically synthesized glycogen inhibits colitis through decreasing oxidative stress. Free Radic Biol Med 2017; 106:355-367. [PMID: 28257879 DOI: 10.1016/j.freeradbiomed.2017.02.048] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 02/17/2017] [Accepted: 02/27/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases are a group of chronic inflammation conditions of the gastrointestinal tract. Disruption of the mucosal immune response causes accumulation of oxidative stress, resulting in the induction of inflammatory bowel disease. In this study, we investigated the effect of enzymatically synthesized glycogen (ESG), which is produced from starch, on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in C57BL/6 mice. Oral administration of ESG suppressed DSS- and TNBS-induced shortening of large intestine in female mice and significant decreased DSS-induced oxidative stress and TNBS-induced pro-inflammatory cytokine expression in the large intestine. ESG increase in the expression levels of heme oxygenase-1 (HO-1) and NF-E2-related factor-2 (Nrf2), a transcription factor for HO-1 expressed in the large intestine. Furthermore, ESG-induced HO-1 and Nrf2 were expressed mainly in intestinal macrophages. ESG is considered to be metabolized to resistant glycogen (RG) during digestion with α-amylase in vivo. In mouse macrophage RAW264.7 cells, RG, but not ESG decreased 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced reactive oxygen species (ROS). Knockdown of Nrf2 inhibited RG-induced HO-1 expression and negated the decrease in AAPH-induced ROS brought about by RG. RG up-regulated the protein stability of Nrf2 to decrease the formation of Nrf2-Keap1 complexes. RG-induced phosphorylation of Nrf2 at Ser40 was suppressed by ERK1/2 and JNK inhibitors. Our data indicate that ESG, digested with α-amylase to RG, suppresses DSS- and TNBS-induced colitis by increasing the expression of HO-1 in the large intestine of mice. Furthermore, we demonstrate that RG induces HO-1 expression by promoting phosphorylation of Nrf2 at Ser40 through activation of the ERK1/2 and JNK cascade in macrophages.
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Affiliation(s)
- Takakazu Mitani
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan; Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 6578501, Japan
| | - Yasukiyo Yoshioka
- Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 6578501, Japan
| | | | - Yoko Yamashita
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan
| | - Yasuhito Shirai
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan
| | - Hitoshi Ashida
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan.
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31
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Zhang Z, Song Y, Zhang Z, Li D, Zhu H, Liang R, Gu Y, Pang Y, Qi J, Wu H, Wang J. Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice. J Cereb Blood Flow Metab 2017; 37:25-38. [PMID: 27317654 PMCID: PMC5363754 DOI: 10.1177/0271678x16655814] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 05/12/2016] [Accepted: 05/25/2016] [Indexed: 12/22/2022]
Abstract
Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. Heme oxygenase-1 (HO-1), the key enzyme in heme degradation, is highly expressed after ICH, but its role is still unclear. In this study, we used an HO-1 inducer and inhibitor to test the role of HO-1 in different stages of ICH in vivo and in vitro. In the early stage of ICH, high HO-1 expression worsened the outcomes of mice subjected to the collagenase-induced ICH model. HO-1 increased brain edema, white matter damage, neuronal death, and neurobehavioral deficits. Furthermore, elevated HO-1 increased inflammation, oxidative stress, matrix metalloproteinase-9/2 activity, and iron deposition. In the later stage of ICH, long-term induction of HO-1 increased hematoma absorption, angiogenesis, and recovery of neurologic function. We conclude that HO-1 activation mediates early brain damage after ICH but promotes neurologic function recovery in the later stage of ICH.
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Affiliation(s)
- Zhen Zhang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Yuejia Song
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Ze Zhang
- Department of Urology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Danyang Li
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Hong Zhu
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Rui Liang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Yunhe Gu
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Yuxin Pang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Jiping Qi
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - He Wu
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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32
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Zhang H, Shi Z, Ma XP, Liu HR, Hu L, Wu HG. Effect of moxibustion on expressions of HO-1 and MCP-3 protein in colon of rats with Crohn’s disease. JOURNAL OF ACUPUNCTURE AND TUINA SCIENCE 2016. [DOI: 10.1007/s11726-016-0953-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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33
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Basdeo SA, Campbell NK, Sullivan LM, Flood B, Creagh EM, Mantle TJ, Fletcher JM, Dunne A. Suppression of human alloreactive T cells by linear tetrapyrroles; relevance for transplantation. Transl Res 2016; 178:81-94.e2. [PMID: 27497182 DOI: 10.1016/j.trsl.2016.07.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 06/16/2016] [Accepted: 07/13/2016] [Indexed: 12/15/2022]
Abstract
The main limitation to successful transplantation is the antigraft response developed by the recipient immune system, and the adverse side effects of immunosuppressive agents which are associated with significant toxicity and counter indications such as infection and cancer. Furthermore, immunosuppressants do little to prevent ischemia-reperfusion injury during the transplantation procedure itself hence there is a growing need to develop novel immunosuppressive drugs specifically aimed at prolonging graft survival. Linear tetrapyrroles derived from the breakdown of mammalian heme have been shown in numerous studies to play a protective role in allograft transplantation and ischemia-reperfusion injury; however, commercial sources of these products have not been approved for use in humans. Plants and algae produce equivalent linear tetrapyrroles called bilins that serve as chromophores in light-sensing. One such marine-derived tetrapyrrole, phycocyanobilin (PCB), shows significant structural similarity to mammalian biliverdin (BV) and may prove to be a safer alternative for use in the clinic if it can exert direct effects on human immune cells. Using a mixed lymphocyte reaction, we quantified the allogeneic responses of recipient cells to donor cells and found that PCB, like BV, effectively suppressed proliferation and proinflammatory cytokine production. In addition, we found that BV and PCB can directly downregulate the proinflammatory responses of both innate dendritic cells and adaptive T cells. We therefore propose that PCB may be an effective therapeutic drug in the clinical setting of transplantation and may also have wider applications in regulating inappropriate inflammation.
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Affiliation(s)
- Sharee A Basdeo
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Nicole K Campbell
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Louise M Sullivan
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Brian Flood
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Emma M Creagh
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Timothy J Mantle
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Jean M Fletcher
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Aisling Dunne
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
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34
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Wegiel B, Hauser CJ, Otterbein LE. Heme as a danger molecule in pathogen recognition. Free Radic Biol Med 2015; 89:651-61. [PMID: 26456060 DOI: 10.1016/j.freeradbiomed.2015.08.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 08/08/2015] [Indexed: 01/13/2023]
Abstract
Appropriate control of redox mechanisms are critical for and effective innate immune response, which employs multiple cell types, receptors and molecules that recognize danger signals when they reach the host. Recognition of pathogen-associated pattern molecules (PAMPs) is a fundamental host survival mechanism for efficient elimination of invading pathogens and resolution of the infection and inflammation. In addition to PAMPs, eukaryotic cells contain a plethora of intracellular molecules that are normally secured within the confines of the plasma membrane, but if liberated and encountered in the extracellular milieu can provoke rapid cell activation. These are known as Alarmins or Danger-Associated Molecular Patterns (DAMPs) and can be released actively by cells or passively as a result of sterile cellular injury after trauma, ischemia, or toxin-induced cell rupture. Both PAMPs and DAMPs are recognized by a series of cognate receptors that increase the generation of free radicals and activate specific signaling pathways that result in regulation of a variety of stress response, redox sensitive genes. Multiple mediators released, as cells die include, but are not limited to ATP, hydrogen peroxide, heme, formyl peptides, DNA or mitochondria provide the second signal to amplify immune responses. In this review, we will focus on how sterile and infective stimuli activate the stress response gene heme oxygenase-1 (Hmox1, HO-1), a master gene critical to an appropriate host response that is now recognized as one with enormous therapeutic potential. HO-1 gene expression is regulated in large part by redox-sensitive proteins including but not limited to nrf2. Both PAMPs and DAMPs increase the activation of nrf2 and HO-1. Heme is a powerful pro-oxidant and as such should be qualified as a DAMP. With its degradation by HO-1a molecule of carbon monoxide (CO) is generated that in turn serves as a bioactive signaling molecule. PAMPs such as bacterial endotoxin activate HO-1, and the CO that is generated diffuses into the extracellular milieu where it interacts with bacteria, altering their behavior to increase production of ATP, which then functions as a second signal danger molecule. This two-hit cycle scenario results in efficient and effective activation of host leukocytes to attack and clear bacteria in part via enhanced reactive oxygen species generation. We discuss this intimate communication that occurs between host and bacteria and how these molecules serve as critical regulators of the acute inflammatory response, the overall redox status of the cell, and survival of the host.
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Affiliation(s)
- Barbara Wegiel
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Carl J Hauser
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Leo E Otterbein
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
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35
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Shigemori S, Watanabe T, Kudoh K, Ihara M, Nigar S, Yamamoto Y, Suda Y, Sato T, Kitazawa H, Shimosato T. Oral delivery of Lactococcus lactis that secretes bioactive heme oxygenase-1 alleviates development of acute colitis in mice. Microb Cell Fact 2015; 14:189. [PMID: 26608030 PMCID: PMC4658813 DOI: 10.1186/s12934-015-0378-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 11/06/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Mucosal delivery of therapeutic proteins using genetically modified strains of lactic acid bacteria (gmLAB) is being investigated as a new therapeutic strategy. METHODS We developed a strain of gmLAB, Lactococcus lactis NZ9000 (NZ-HO), which secretes the anti-inflammatory molecule recombinant mouse heme oxygenase-1 (rmHO-1). The effects of short-term continuous oral dosing with NZ-HO were evaluated in mice with dextran sulfate sodium (DSS)-induced acute colitis as a model of inflammatory bowel diseases (IBD). RESULTS We identified the secretion of rmHO-1 by NZ-HO. rmHO-1 was biologically active as determined with spectroscopy. Viable NZ-HO was directly delivered to the colon via oral administration, and rmHO-1 was secreted onto the colonic mucosa in mice. Acute colitis in mice was induced by free drinking of 3 % DSS in water and was accompanied by an increase in the disease activity index score and histopathological changes. Daily oral administration of NZ-HO significantly improved these colitis-associated symptoms. In addition, NZ-HO significantly increased production of the anti-inflammatory cytokine interleukin (IL)-10 and decreased the expression of pro-inflammatory cytokines such as IL-1α and IL-6 in the colon compared to a vector control strain. CONCLUSIONS Oral administration of NZ-HO alleviates DSS-induced acute colitis in mice. Our results suggest that NZ-HO may be a useful mucosal therapeutic agent for treating IBD.
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Affiliation(s)
- Suguru Shigemori
- Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. .,Research Fellow of the Japan Society for the Promotion of Science, Japan Society for the Promotion of Science (JSPS), 5-3-1, Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan.
| | - Takafumi Watanabe
- Department of Food Production Science, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan.
| | - Kai Kudoh
- Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan.
| | - Masaki Ihara
- Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. .,Department of Bioscience and Biotechnology, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. .,Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences (IBS), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan.
| | - Shireen Nigar
- Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan.
| | - Yoshinari Yamamoto
- Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan.
| | - Yoshihito Suda
- Department of Food, Agriculture and Environment, Miyagi University, 2-2-1 Hatadate, Taihaku-ku, Sendai, Miyagi, 982-0215, Japan.
| | - Takashi Sato
- Department of Internal Medicine and Clinical Immunology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
| | - Haruki Kitazawa
- Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan. .,Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan.
| | - Takeshi Shimosato
- Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. .,Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences (IBS), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. .,Department of Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan.
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Zucker SD, Vogel ME, Kindel TL, Smith DLH, Idelman G, Avissar U, Kakarlapudi G, Masnovi ME. Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase. Am J Physiol Gastrointest Liver Physiol 2015; 309:G841-54. [PMID: 26381705 PMCID: PMC4652140 DOI: 10.1152/ajpgi.00149.2014] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 08/21/2015] [Indexed: 01/31/2023]
Abstract
Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression.
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Affiliation(s)
- Stephen D. Zucker
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Megan E. Vogel
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Tammy L. Kindel
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Darcey L. H. Smith
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Gila Idelman
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Uri Avissar
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Ganesh Kakarlapudi
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
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Chang M, Xue J, Sharma V, Habtezion A. Protective role of hemeoxygenase-1 in gastrointestinal diseases. Cell Mol Life Sci 2015; 72:1161-73. [PMID: 25428780 PMCID: PMC4342274 DOI: 10.1007/s00018-014-1790-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 11/16/2014] [Accepted: 11/20/2014] [Indexed: 12/22/2022]
Abstract
Disorders and diseases of the gastrointestinal system encompass a wide array of pathogenic mechanisms as a result of genetic, infectious, neoplastic, and inflammatory conditions. Inflammatory diseases in general are rising in incidence and are emerging clinical problems in gastroenterology and hepatology. Hemeoxygenase-1 (HO-1) is a stress-inducible enzyme that has been shown to confer protection in various organ-system models. Its downstream effectors, carbon monoxide and biliverdin have also been shown to offer these beneficial effects. Many studies suggest that induction of HO-1 expression in gastrointestinal tissues and cells plays a critical role in cytoprotection and resolving inflammation as well as tissue injury. In this review, we examine the protective role of HO-1 and its downstream effectors in modulating inflammatory diseases of the upper (esophagus and stomach) and lower (small and large intestine) gastrointestinal tract, the liver, and the pancreas. Cytoprotective, anti-inflammatory, anti-proliferative, antioxidant, and anti-apoptotic activities of HO-1 make it a promising if not ideal therapeutic target for inflammatory diseases of the gastrointestinal system.
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Affiliation(s)
- Marisol Chang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Jing Xue
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Vishal Sharma
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
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Zhang L, Zhang Y, Zhong W, Di C, Lin X, Xia Z. Heme oxygenase-1 ameliorates dextran sulfate sodium-induced acute murine colitis by regulating Th17/Treg cell balance. J Biol Chem 2014; 289:26847-26858. [PMID: 25112868 DOI: 10.1074/jbc.m114.590554] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of autoimmune diseases characterized by nonspecific inflammation in the gastrointestinal tract. Recent investigations suggest that activation of Th17 cells and/or deficiency of regulatory T cells (Treg) is involved in the pathogenesis of IBD. Heme oxygenase (HO)-1 is a protein with a wide range of anti-inflammatory and immune regulatory function, which exerts significantly protective roles in various T cell-mediated diseases. In this study, we aim to explore the immunological regulation of HO-1 in the dextran sulfate sodium-induced model of experimental murine colitis. BALB/c mice were administered 4% dextran sulfate sodium orally; some mice were intraperitoneally pretreated with HO-1 inducer hemin or HO-1 inhibitor stannum protoporphyrin IX. The results show that hemin enhances the colonic expression of HO-1 and significantly ameliorates the symptoms of colitis with improved histological changes, accompanied by a decreased proportion of Th17 cells and increased number of Tregs in mesenteric lymph node and spleen. Moreover, induction of HO-1 down-regulates retinoic acid-related orphan receptor γt expression and IL-17A levels, while promoting Treg-related forkhead box p3 (Foxp3) expression and IL-10 levels in colon. Further study in vitro revealed that up-regulated HO-1 switched the naive T cells to Tregs when cultured under a Th17-inducing environment, which involved in IL-6R blockade. Therefore, HO-1 may exhibit anti-inflammatory activity in the murine model of acute experimental colitis via regulating the balance between Th17 and Treg cells, thus providing a possible novel therapeutic target in IBD.
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Affiliation(s)
- Liya Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Yanjie Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Wenwei Zhong
- Department of Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, China
| | - Caixia Di
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Xiaoliang Lin
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Zhenwei Xia
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and.
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Babu D, Motterlini R, Lefebvre RA. CO and CO-releasing molecules (CO-RMs) in acute gastrointestinal inflammation. Br J Pharmacol 2014; 172:1557-73. [PMID: 24641722 DOI: 10.1111/bph.12632] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/30/2014] [Accepted: 02/05/2014] [Indexed: 12/13/2022] Open
Abstract
Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti-inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO-releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post-operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation.
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Affiliation(s)
- D Babu
- Heymans Institute of Pharmacology, Ghent University, Gent, Belgium
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Higashimura Y, Naito Y, Takagi T, Tanimura Y, Mizushima K, Harusato A, Fukui A, Yoriki H, Handa O, Ohnogi H, Yoshikawa T. Preventive effect of agaro-oligosaccharides on non-steroidal anti-inflammatory drug-induced small intestinal injury in mice. J Gastroenterol Hepatol 2014; 29:310-7. [PMID: 23980531 DOI: 10.1111/jgh.12373] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/07/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly used in clinical medicine, cause erosion, ulcers, and bleeding in the gastrointestinal tract. No effective agent for the prevention and treatment of small intestinal injury by NSAIDs has been established. This study investigates the effects of agaro-oligosaccharides (AGOs) on NSAID-induced small intestinal injury in mice. METHODS Mice were treated with indomethacin, an NSAID, to induce intestinal injury. The respective degrees of mucosal injury of mice that received AGO and control mice were compared. Heme oxygenase-1 (HO-1) expression using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were measured. The expression of keratinocyte chemoattractant (KC) was measured using qRT-PCR and enzyme-linked immunosorbent assay. RESULTS AGO administration induced HO-1 expression in mouse small intestinal mucosa. Induction was observed mainly in F4/80 positive macrophages. The increased ulcers score, myeloperoxidase activity, and KC expression by indomethacin were inhibited by AGO administration. Conversely, HO inhibitor cancelled AGO-mediated prevention of intestinal injury. In mouse peritoneal macrophages, AGOs enhanced HO-1 expression and suppressed lipopolysaccharide-induced KC expression. Furthermore, AGOs enhanced the expressions of alternatively activated macrophage markers arginase-1, mannose receptor-1, and chitinase 3-like 3. CONCLUSIONS Results suggest that oral administration of AGOs prevents NSAID-induced intestinal injury.
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Affiliation(s)
- Yasuki Higashimura
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan; Department of Food Factor Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
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Gibbons SJ, Verhulst PJ, Bharucha A, Farrugia G. Review article: carbon monoxide in gastrointestinal physiology and its potential in therapeutics. Aliment Pharmacol Ther 2013; 38:689-702. [PMID: 23992228 PMCID: PMC3788684 DOI: 10.1111/apt.12467] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 05/03/2013] [Accepted: 08/07/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND While carbon monoxide (CO) is a known toxin, it is now recognised that CO is also an important signalling molecule involved in physiology and pathophysiology. AIMS To summarise our current understanding of the role of endogenous CO in the regulation of gastrointestinal physiology and pathophysiology, and to potential therapeutic applications of modulating CO. METHODS This review is based on a comprehensive search of the Ovid Medline comprehensive database and supplemented by our ongoing studies evaluating the role of CO in gastrointestinal physiology and pathophysiology. RESULTS Carbon monoxide derived from haem oxygenase (HO)-2 is predominantly involved in neuromodulation and in setting the smooth muscle membrane potential, while CO derived from HO-1 has anti-inflammatory and antioxidative properties, which protect gastrointestinal smooth muscle from damage caused by injury or inflammation. Exogenous CO is being explored as a therapeutic agent in a variety of gastrointestinal disorders, including diabetic gastroparesis, post-operative ileus, organ transplantation, inflammatory bowel disease and sepsis. However, identifying the appropriate mechanism for safely delivering CO in humans is a major challenge. CONCLUSIONS Carbon monoxide is an important regulator of gastrointestinal function and protects the gastrointestinal tract against noxious injury. CO is a promising therapeutic target in conditions associated with gastrointestinal injury and inflammation. Elucidating the mechanisms by which CO works and developing safe CO delivery mechanisms are necessary to refine therapeutic strategies.
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Affiliation(s)
- S J Gibbons
- Enteric NeuroScience Program, Mayo Clinic, Rochester, MN 55905, USA
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Won HY, Jang EJ, Lee K, Oh S, Kim HK, Woo HA, Kang SW, Yu DY, Rhee SG, Hwang ES. Ablation of peroxiredoxin II attenuates experimental colitis by increasing FoxO1-induced Foxp3+ regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2013; 191:4029-37. [PMID: 24048895 DOI: 10.4049/jimmunol.1203247] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Peroxiredoxin (Prx) II is an intracellular antioxidant molecule that eliminates hydrogen peroxide, employing a high substrate-binding affinity. PrxII deficiency increases the levels of intracellular reactive oxygen species in many types of cells, which may increase reactive oxygen species-mediated inflammation. In this study, we investigated the susceptibility of PrxII knockout (KO) mice to experimentally induced colitis and the effects of PrxII on the immune system. Wild-type mice displayed pronounced weight loss, high mortality, and colon shortening after dextran sulfate sodium administration, whereas colonic inflammation was significantly attenuated in PrxII KO mice. Although macrophages were hyperactivated in PrxII KO mice, the amount of IFN-γ and IL-17 produced by CD4(+) T cells was substantially reduced. Foxp3(+) regulatory T (Treg) cells were elevated, and Foxp3 protein expression was increased in the absence of PrxII in vitro and in vivo. Restoration of PrxII into KO cells suppressed the increased Foxp3 expression. Interestingly, endogenous PrxII was inactivated through hyperoxidation during Treg cell development. Furthermore, PrxII deficiency stabilized FoxO1 expression by reducing mouse double minute 2 homolog expression and subsequently activated FoxO1-mediated Foxp3 gene transcription. PrxII overexpression, in contrast, reduced FoxO1 and Foxp3 expression. More interestingly, adoptive transfer of naive CD4(+) T cells from PrxII KO mice into immune-deficient mice attenuated T cell-induced colitis, with a reduction in mouse double minute 2 homolog expression and an increase in FoxO1 and Foxp3 expression. These results suggest that inactivation of PrxII is important for the stability of FoxO1 protein, which subsequently mediates Foxp3(+) Treg cell development, thereby attenuating colonic inflammation.
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Affiliation(s)
- Hee Yeon Won
- College of Pharmacy and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea
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Serum bilirubin may serve as a marker for increased heme oxygenase activity and inducibility in tissues--a rationale for the versatile health protection associated with elevated plasma bilirubin. Med Hypotheses 2013; 81:607-10. [PMID: 23932761 DOI: 10.1016/j.mehy.2013.07.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 07/08/2013] [Indexed: 12/17/2022]
Abstract
Unconjugated bilirubin functions intracellularly as a potent inhibitor of NADPH oxidase complexes, and albumin-bound bilirubin contributes significantly to the oxidant scavenging activity of plasma. So it is not surprising that serum levels of bilirubin have been found to correlate inversely with risk for vascular diseases and a host of other disorders. Nonetheless, recent Mendelian randomization analyses reveal that individuals who carry low expression alleles of the hepatic bilirubin conjugating enzyme UGT1A1, and hence have somewhat elevated levels of plasma bilirubin throughout life, are not at decreased risk for vascular disorders. This likely reflects the fact that, in most people, plasma levels of unconjugated, unbound bilirubin--the fraction of bilirubin capable of fluxing back into cells--are so low (near 1 nM) that they can exert only a trivial antioxidant influence on cells. In light of these findings, it is reasonable to propose that the inverse correlation of plasma bilirubin and disease risks noted in many studies often reflect the fact that elevated plasma bilirubin can serve as a marker for an increased propensity to generate bilirubin within cells. Consistent with this view, high expression alleles of the major enzymatic source of bilirubin, heme oxygenase-1 (HO-1), do associate with decreased vascular risk in the majority of studies that have addressed this issue, and increased plasma bilirubin has been reported in carriers of these alleles. Hence, the consistent reduction in vascular risk noted in people with Gilbert syndrome (traditionally defined as having serum bilirubin in excess of 20 μM) is likely attributable to an increased rate of bilirubin generation within tissues, rather than to the decreased hepatic UGT1A1 activity that characterizes this syndrome. However, there is good reason to suspect that, at some sufficiently high plasma bilirubin level--as in individuals with very intense Gilbert syndrome or in Gunn rats lacking UGT1A1 activity--the plasma bilirubin pool does indeed provide some antioxidant protection to cells. Strategies for boosting bilirubin production within cells via HO-1 induction, or for mimicking bilirubin's antioxidant activity with cyanobacterial phycobilins, may have important potential for health promotion.
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Higashimura Y, Naito Y, Takagi T, Mizushima K, Hirai Y, Harusato A, Ohnogi H, Yamaji R, Inui H, Nakano Y, Yoshikawa T. Oligosaccharides from agar inhibit murine intestinal inflammation through the induction of heme oxygenase-1 expression. J Gastroenterol 2013. [PMID: 23188093 DOI: 10.1007/s00535-012-0719-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGOs). Recently, it has been demonstrated that AGOs induce heme oxygenase-1 (HO-1) expression in macrophages and that they might lead to anti-inflammatory property. Nevertheless, the molecular mechanism of AGO-mediated HO-1 induction remains unknown, as does AGOs' ability to elicit anti-inflammatory activity in vivo. This study was undertaken to uncover the mechanism of AGO-mediated HO-1 induction and to investigate the therapeutic effect of AGOs on intestinal inflammation. METHODS Mice were treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. The respective degrees of mucosal injury of mice that had received AGO and control mice were compared. We investigated HO-1 expression using Western blotting, quantitative real-time PCR (qRT-PCR), and immunohistochemistry. The expression of tumor necrosis factor-α (TNF-α) was measured using qRT-PCR and enzyme-linked immunosorbent assay. RESULTS AGO administration induced HO-1 expression in colonic mucosa. The induction was observed mainly in F4/80 positive macrophages. Increased colonic damage and myeloperoxidase activity after TNBS treatment were inhibited by AGO administration. TNBS treatment induced TNF-α expression, and AGO administration suppressed induction. However, HO inhibitor canceled AGO-mediated amelioration of colitis. In RAW264 cells, AGOs enhanced HO-1 expression time-dependently and concentration-dependently and suppressed lipopolysaccharide-induced TNF-α expression. Furthermore, agarotetraose-mediated HO-1 induction required NF-E2-related factor 2 function and phosphorylation of c-jun N-terminal kinase. CONCLUSIONS We infer that AGO administration inhibits TNBS-induced colitis in mice through HO-1 induction in macrophages. Consequently, oral administration of AGOs might be an important therapeutic strategy for inflammatory bowel disease.
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Affiliation(s)
- Yasuki Higashimura
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Kyoto, 602-8566, Japan
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Westernized high-fat diet accelerates weight loss in dextran sulfate sodium-induced colitis in mice, which is further aggravated by supplementation of heme. J Nutr Biochem 2013; 24:1159-65. [DOI: 10.1016/j.jnutbio.2012.09.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 09/01/2012] [Accepted: 09/10/2012] [Indexed: 12/21/2022]
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Schulz S, Wong RJ, Jang KY, Kalish F, Chisholm KM, Zhao H, Vreman HJ, Sylvester KG, Stevenson DK. Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model. Am J Physiol Gastrointest Liver Physiol 2013; 304:G991-G1001. [PMID: 23578787 PMCID: PMC3680684 DOI: 10.1152/ajpgi.00363.2012] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 04/09/2013] [Indexed: 01/31/2023]
Abstract
Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.
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Affiliation(s)
- Stephanie Schulz
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Heme oxygenase 1-generated carbon monoxide and biliverdin attenuate the course of experimental necrotizing pancreatitis. Pancreas 2013; 42:265-71. [PMID: 23000891 DOI: 10.1097/mpa.0b013e318264cc8b] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The cytoprotective enzyme heme oxygenase 1 (HO-1) is highly up-regulated in acute pancreatitis (AP). In this study, we tested its metabolites as potential therapeutic agents for AP in rats. METHODS Acute necrotizing pancreatitis was induced by retrograde intraductal injection of sodium taurocholate in rats. Biliverdin hydrochloride (BV HCl) (50 μmol/kg subcutaneously), the carbon monoxide, donor methylene chloride (MC) (500 mg/kg orally), or iron-chelating desferrioxamine (DFO) (125 mg/kg subcutaneously) were administered in a therapeutic manner starting with the first dose 4 hours after taurocholate injection to mimic the effects of HO-1 metabolites. RESULTS Administration of BV HCl, MC, or DFO showed significant reduction of inflammatory activity in comparison to controls leading to lower myeloperoxidase activity in the pancreas, less edema, lower ascites volumes, and preservation of tissue integrity (P < 0.05). Administration of either BV HCl or MC markedly increased 5-day survival rate (70% and 75% vs 40%; P < 0.05), whereas DFO had no significant effect on survival (60%). When given in therapeutic manner, all 3 substances led to diminished nuclear factor κB activity in the pancreas (P < 0.05). CONCLUSIONS Therapeutic use of BV HCl and MC led to marked reduction of mortality in experimental pancreatitis. Thus, HO-1 metabolites may present a novel therapeutic approach in AP treatment.
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BTB and CNC homolog 1 (Bach1) deficiency ameliorates TNBS colitis in mice: role of M2 macrophages and heme oxygenase-1. Inflamm Bowel Dis 2013; 19:740-53. [PMID: 23446334 DOI: 10.1097/mib.0b013e3182802968] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1), which plays an important role in the protection of cells and tissues against acute and chronic inflammation. However, the role of Bach1 in the gastrointestinal mucosal defense system remains little understood. HO-1 supports the suppression of experimental colitis and localizes mainly in macrophages in colonic mucosa. This study was undertaken to elucidate the Bach1/HO-1 system's effects on the pathogenesis of experimental colitis. METHODS This study used C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice in which colonic damage was induced by the administration of an enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Subsequently, they were evaluated macroscopically, histologically, and biochemically. Peritoneal macrophages from the respective mice were isolated and analyzed. Then, wild-type mice were injected with peritoneal macrophages from the respective mice. Acute colitis was induced similarly. RESULTS TNBS-induced colitis was inhibited in Bach1-deficient mice. TNBS administration increased the expression of HO-1 messenger RNA and protein in colonic mucosa in Bach1-deficient mice. The expression of HO-1 mainly localized in F4/80-immunopositive and CD11b-immunopositive macrophages. Isolated peritoneal macrophages from Bach1-deficient mice highly expressed HO-1 and also manifested M2 macrophage markers, such as Arginase-1, Fizz-1, Ym1, and MRC1. Furthermore, TNBS-induced colitis was inhibited by the transfer of Bach1-deficient macrophages into wild-type mice. CONCLUSIONS Deficiency of Bach1 ameliorated TNBS-induced colitis. Bach1-deficient macrophages played a key role in protection against colitis. Targeting of this mechanism is applicable to cell therapy for human inflammatory bowel disease.
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Bonkovsky HL, Guo J, Hou W, Li T, Narang T, Thapar M. Porphyrin and Heme Metabolism and the Porphyrias. Compr Physiol 2013; 3:365-401. [DOI: 10.1002/cphy.c120006] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Karimi K, Kandiah N, Chau J, Bienenstock J, Forsythe P. A Lactobacillus rhamnosus strain induces a heme oxygenase dependent increase in Foxp3+ regulatory T cells. PLoS One 2012; 7:e47556. [PMID: 23077634 PMCID: PMC3471882 DOI: 10.1371/journal.pone.0047556] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 09/18/2012] [Indexed: 02/07/2023] Open
Abstract
We investigated the consequences of feeding with a Lactobacillus species on the immune environment in GALT, and the role of dendritic cells and heme oxygenase-1 in mediating these responses. Feeding with a specific strain of Lactobacillus rhamnosus induced a significant increase in CD4+CD25+Foxp3+ functional regulatory T cells in GALT. This increase was greatest in the mesenteric lymph nodes and associated with a marked decrease in TNF and IFNγ production. Dendritic cell regulatory function and HO-1 expression was also increased. The increase in Foxp3+ T cells could be prevented by treatment with a heme oxygenase inhibitor. However, neither inhibition of heme oxygenase nor blockade of IL-10 and TGFβ prevented the inhibition of inflammatory cytokine production. In conclusion Lactobacillus feeding induced a tolerogenic environment in GALT. HO-1 was critical to the enhancement of Foxp3+ regulatory T cells while additional, as yet unknown, pathways were involved in the down-regulation of inflammatory cytokine production by T cells.
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Affiliation(s)
- Khalil Karimi
- The Brain Body institute, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- * E-mail: (PF); (KK)
| | - Nalaayini Kandiah
- The Brain Body institute, McMaster University, Hamilton, Ontario, Canada
| | - Jessie Chau
- The Brain Body institute, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - John Bienenstock
- The Brain Body institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Paul Forsythe
- The Brain Body institute, McMaster University, Hamilton, Ontario, Canada
- Firestone Institute for Respiratory Health, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- * E-mail: (PF); (KK)
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