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• W2600704889 abstract "Research Article27 March 2017Open Access Transparent process Niacin ameliorates ulcerative colitis via prostaglandin D2-mediated D prostanoid receptor 1 activation Juanjuan Li Juanjuan Li Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Deping Kong Deping Kong Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Qi Wang Qi Wang Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wei Wu Wei Wu Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yanping Tang Yanping Tang Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Tingting Bai Tingting Bai Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Liang Guo Liang Guo Department of Breast Surgery, Breast Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Search for more papers by this author Lumin Wei Lumin Wei Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Qianqian Zhang Qianqian Zhang Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yu Yu Yu Yu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yuting Qian Yuting Qian Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Shengkai Zuo Shengkai Zuo Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Guizhu Liu Guizhu Liu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Qian Liu Qian Liu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Sheng Wu Sheng Wu Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi Zang Yi Zang Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Qian Zhu Qian Zhu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Daile Jia Daile Jia Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yuanyang Wang Yuanyang Wang Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China Search for more papers by this author Weiyan Yao Weiyan Yao Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yong Ji Yong Ji The Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, Jiangsu, China Search for more papers by this author Huiyong Yin Huiyong Yin Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Masataka Nakamura Masataka Nakamura Human Gene Sciences Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan Search for more papers by this author Michael Lazarus Michael Lazarus International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Ibaraki, Japan Search for more papers by this author Richard M Breyer Richard M Breyer Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Search for more papers by this author Lifu Wang Corresponding Author Lifu Wang [email protected] orcid.org/0000-0001-5172-9932 Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Ying Yu Corresponding Author Ying Yu [email protected] [email protected] orcid.org/0000-0002-6476-1752 Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China Search for more papers by this author Juanjuan Li Juanjuan Li Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Deping Kong Deping Kong Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Qi Wang Qi Wang Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Wei Wu Wei Wu Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yanping Tang Yanping Tang Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Tingting Bai Tingting Bai Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Liang Guo Liang Guo Department of Breast Surgery, Breast Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Search for more papers by this author Lumin Wei Lumin Wei Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Qianqian Zhang Qianqian Zhang Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yu Yu Yu Yu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yuting Qian Yuting Qian Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Shengkai Zuo Shengkai Zuo Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Guizhu Liu Guizhu Liu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Qian Liu Qian Liu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Sheng Wu Sheng Wu Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yi Zang Yi Zang Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Qian Zhu Qian Zhu Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Daile Jia Daile Jia Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yuanyang Wang Yuanyang Wang Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China Search for more papers by this author Weiyan Yao Weiyan Yao Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Yong Ji Yong Ji The Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, Jiangsu, China Search for more papers by this author Huiyong Yin Huiyong Yin Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Masataka Nakamura Masataka Nakamura Human Gene Sciences Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan Search for more papers by this author Michael Lazarus Michael Lazarus International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Ibaraki, Japan Search for more papers by this author Richard M Breyer Richard M Breyer Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Search for more papers by this author Lifu Wang Corresponding Author Lifu Wang [email protected] orcid.org/0000-0001-5172-9932 Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Ying Yu Corresponding Author Ying Yu [email protected] [email protected] orcid.org/0000-0002-6476-1752 Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China Search for more papers by this author Author Information Juanjuan Li1,2,‡, Deping Kong2,‡, Qi Wang1,‡, Wei Wu1,‡, Yanping Tang1, Tingting Bai1, Liang Guo3,4, Lumin Wei1,2, Qianqian Zhang2, Yu Yu2, Yuting Qian1, Shengkai Zuo2, Guizhu Liu2, Qian Liu2, Sheng Wu1, Yi Zang1, Qian Zhu2, Daile Jia2, Yuanyang Wang5, Weiyan Yao1, Yong Ji6, Huiyong Yin2, Masataka Nakamura7, Michael Lazarus8, Richard M Breyer9,10, Lifu Wang *,1 and Ying Yu *,*,2,5 1Department of Gastroenterology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 3Department of Breast Surgery, Breast Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China 4Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 5Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China 6The Key Laboratory of Cardiovascular Disease and Molecular Intervention, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, Jiangsu, China 7Human Gene Sciences Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan 8International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Ibaraki, Japan 9Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA 10Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA ‡These authors contributed equally to this work *Corresponding author. Tel: +86 021 64370045 665290; Fax: +86 021 66295266; E-mail: [email protected] *Corresponding author. Tel: +86 21 54920970; E-mails: [email protected]; [email protected] EMBO Mol Med (2017)9:571-588https://doi.org/10.15252/emmm.201606987 Correction(s) for this article Niacin ameliorates ulcerative colitis via prostaglandin D2-mediated D prostanoid receptor 1 activation07 December 2020 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro-inflammatory gene expression of macrophages. Moreover, treatment with niacin-containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS-induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation. Synopsis Niacin, an ancient lipid-lowering drug that elicits a strong flushing response through release of prostaglandin (PG) D2. Niacin improves experimentally induced ulcerative colitis in mice and humans through the activation of PGD2/DP1 axis. Niacin increases PGD2 release in both mice and humans. Niacin confers protection against DSS/TNBS-induced colitis in mice through DP1-mediated inhibition of vascular leakage, suppression of colonic epithelium apoptosis, and reduction of pro-inflammatory cytokine secretion. Retention enema treatment containing niacin effectively promotes clinical remission and mucosal healing in patients with moderately active UC. Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by recurrent episodes of active disease, which commonly affects the colon, the rectum, or both simultaneously. Histologically, it displays chronic inflammatory alterations limited to the mucosa and submucosa with cryptitis and crypt abscesses (Danese & Fiocchi, 2011). Despite UC-related mortality being low, its morbidity remains high and 10–20% of affected individuals undergo colectomy. Although the UC etiology is largely unknown, accumulated evidence supports an interaction between genetic predisposition and microbial/environmental factors that trigger pro-colitogenic perturbations of the host–commensal relationship and an aberrant mucosal immune response (Khor et al, 2011). Genome-wide association studies (GWAS) have identified 47 genetic susceptibility loci for UC, 28 of which are shared between Crohn's disease (CD) and UC (Franke et al, 2010; Anderson et al, 2011). Indeed, these risk loci implicated in IBD are involved in different key signal pathways which are essential for intestinal homeostasis, such as epithelial restitution, barrier function, innate and adaptive immune regulation, microbial defense, cellular stress, and metabolism (Khor et al, 2011). Moreover, vascular injury including dilated vessels and increased vascular permeability also contributes to the inflammatory disorder of colonic mucosa in UC patients (Deng et al, 2013). Niacin (nicotinic acid) is also known as vitamin B3 and serves as a precursor for coenzymes such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are essential for living cells. Niacin has been used for more than five decades to treat dyslipidemia, because it reduces low-density lipoprotein cholesterol (LDLc), very low-density lipoprotein cholesterol (VLDLc), and triglycerides (TGs), and elevates high-density lipoprotein cholesterol (HDLc) (Song & FitzGerald, 2013). The orphan G-protein-coupled receptor GPR109A, also known as hydroxycarboxylic acid 2 (HCA2) in mice, and as HM74A in humans, can be activated by niacin (Wise et al, 2003). The beneficial effect of niacin on free fatty acid and TGs is mediated by GPR109A suppression of lipolysis; however, the effects on HDLc and LDLc are not mediated by the GPR109A receptor (Bodor & Offermanns, 2008). GPR109A expression is markedly upregulated in macrophages upon inflammatory stimulation (Feingold et al, 2014). Moreover, emerging evidence demonstrated that niacin displays multiple anti-inflammatory properties through GPR109A receptor activation (Holzhauser et al, 2011; Digby et al, 2012; Godin et al, 2012; Zandi-Nejad et al, 2013; Zhou et al, 2014). Thus, the potential therapeutic efficacy of niacin on patients with UC warrants further clinical investigation. One unpleasant side effect caused by niacin is cutaneous flushing. Niacin stimulates prostaglandin D2 (PGD2) release in both mice and humans (Hanson et al, 2010; Song & FitzGerald, 2013), which plays a central role in the niacin-induced flushing. Low-dose aspirin could depress niacin-evoked PGD2 release and reduce the associated flushing (Cefali et al, 2007; Song & FitzGerald, 2013). PGD2 promotes the niacin-evoked flushing through its specific D prostanoid receptor 1 (DP1). Blockade of DP1 receptor completely inhibits niacin-induced vasodilation in mice and humans without affecting its effects on lipid metabolism (Cheng et al, 2006; Paolini et al, 2008; Maccubbin et al, 2009). In addition, PGD2 mediates active resolution of inflammation through DP1 receptor (Rajakariar et al, 2007; Kong et al, 2016). Interestingly, marked elevation of PGD2 production was observed in inflamed colon tissues from both UC patients and experimental colitis murine models (Ajuebor et al, 2000; Vong et al, 2010), which is associated with long-term remission in humans (Vong et al, 2010). Yet, it remains to be determined whether niacin-mediated protection against UC depends on PGD2 production. In this study, we investigated the therapeutic effect of niacin on colitis both in mice and in patients with moderately active UC. We found that niacin shows anti-inflammatory and anti-apoptotic properties through downregulation of colonic inflammatory cytokine levels, suppression of vascular permeability, and inhibition of colonic epithelium apoptosis by activation of DP1 receptor in macrophages, endothelial cells, and colonic epithelium. Furthermore, treatment with retention enema containing niacin effectively promoted clinical remission and mucosal healing in patients with moderately active UC. Results Niacin boosts PGD2 generation in mice To explore whether niacin protects against inflammatory bowel diseases (IBDs) through releasing PGD2, we first examined niacin-induced PGD2 production in colon tissues and urinary secretion of PGD2 metabolites- 11,15-Dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) from DSS-induced colitis mouse model by using mass spectrometry analysis. Indeed, PGD2 production in homogenized colons and urinary tetranor PGDM was markedly elevated by niacin administration in DSS-challenged mice in a dose-dependent manner (Fig 1A and B). In addition, niacin treatment induced PGF2α product in colon tissues (Fig EV1A) and increased urinary metabolites of PGE2, PGI2, and PGF2α (Fig EV1B) in DSS-challenged mice, indicating niacin may upregulate PG biosynthesis pathway. Accordingly, we observed niacin treatment upregulated cytosolic phospholipase A2 (cPLA2), COX-2, and hematopoietic PGD synthase (hPGDS) in peritoneal macrophages (Fig 1C–E). However, niacin had no markedly influence on specialized pro-resolving mediators (SPMs) in colon tissues from DSS-challenged mice, such as lipoxin (LX) A4, resolvin (Rv) E1 (Fig EV1C). Figure 1. Niacin induces PGD2 secretion in DSS-challenged mice A. Mass spectrometry analysis of PGD2 production in colons from niacin-treated mice after DSS challenge. B. Mass spectrometry analysis of urinary PGD2 metabolites (PGDM) from niacin-treated mice after DSS challenge. PGDM, 11,15-dioxo-9 alpha-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid. C–E. Real-time PCR analysis of cPLA2, COX-1, COX-2, and hPGDS expression in peritoneal macrophage treated with niacin. Data information: Data are shown as mean ± SEM. Data are representative of at least two independent experiments. Statistical significance was determined using unpaired Student's t-tests. (A) #P < 0.05, ##P < 0.01 vs. vehicle; vehicle, n = 6; niacin 300 mg/kg, n = 5; niacin 600 mg/kg, n = 7. (B) #P < 0.05, ##P < 0.01 vs. vehicle; n = 6. (C–E) #P < 0.05 vs. vehicle; n = 4. Download figure Download PowerPoint Click here to expand this figure. Figure EV1. Effect of niacin on PG, RvE1, and LXA4 production in mice after DSS challenge Mass spectrometry analysis of PG production in colons from niacin (600 mg/kg)-treated mice after DSS challenge. Vehicle, n = 6; niacin 600 mg/kg, n = 7. Measurement of urinary metabolite of PGs in niacin (600 mg/kg)-treated mice. PGEM, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid; PGIM, 2,3-dinor-6-keto-PGF1α; TxM, 2,3-dinor-TxB2; PGFM, 13,14-dihydro-15-keto-PGF2α. n = 6. Mass spectrometry analysis of RvE1 and LXA4 production in colons from niacin (600 mg/kg)-treated mice after DSS challenge. n = 6. Data information: Data are shown as mean ± SEM. Data are representative of at least two independent experiments. Statistical significance was determined using unpaired Student's t-tests. (A) ##P < 0.01. (B) #P < 0.05, ##P < 0.01. Download figure Download PowerPoint Disruption of DP1 receptor deteriorates both DSS- and TNBS-induced colitis in mice PGD2 specifically binds and activates two distinct D prostanoid receptors DP1 and DP2. Next, we investigated the effects of PGD2 receptor deficiency on development of DSS- or TNBS-induced colitis in mice. Interestingly, mice with global DP1 disruption (Fig 2A) lost over 12% more weight than wild-type (WT) controls (Fig 2B), and had significantly higher DAI than WT after DSS challenge (2.33 ± 0.33 vs. 0.42 ± 0.22, P < 0.01, Fig 2C). Accordingly, DP1 deletion augmented the severity of DSS-induced colitis in mice including reduction of colon length (Fig 2D), increase of epithelial cell lost, thickening of intestinal wall, enhanced infiltration of inflammatory cells in colon tissues (Fig 2E), and increase of overall mortality (Fig 2F). Likewise, DP1−/− mice were also more vulnerable to TNBS-induced colitis (Fig EV2). However, DP2 deficiency (Satoh et al, 2006) did not influence DSS-induced colitis in mice (Fig 2A–F). Thus, activation of DP1 receptor, not DP2, protects mice against DSS/TNBS-induced colitis. Figure 2. DP1 knockout augments DSS-induced colitis in mice A. PCR analysis of tail genomic DNA from DP1−/−, DP2−/−, and WT mice. B–D. Body weight loss (B) and disease activity index (C), and colon length (D) of DP1−/−, DP2−/−, and WT mice in response to DSS challenge. Scale bar: 1 cm. E. H&E staining of histological sections in the distal colon from the mice administered with DSS for 6 days. Scale bars: 100 μm. Graphs represent overall histology score. F. Survival rates of DSS-challenged DP1−/−, DP2−/− mice, and WT controls. Data information: Data are shown as mean ± SEM. Data are representative of three independent experiments. (B–D) Statistical significance was determined using unpaired Student's t-tests. **P < 0.01 compared with WT. Left panel: WT, n = 8; DP1−/−, n = 8. Right panel: WT, n = 7; DP2−/−, n = 8. (F) Survival rate was compared using the log-rank test. *P < 0.05, compared with WT; n = 10. Download figure Download PowerPoint Click here to expand this figure. Figure EV2. DP1 deficiency augments TNBS-induced colitis in mice A. H&E staining of histological sections in the distal colon from the mice after TNBS challenge. Scale bar: 100 μm. Graphs represent overall histology score. B–D. Body weight loss (B), disease activity index (DAI, C), and colon length (D) of DP1−/− and WT mice in response to 2.5% TNBS challenge. Data information: Data are shown as mean ± SEM. Statistical significance was determined using unpaired Student's t-tests. *P < 0.05, **P < 0.01 compared with WT; n = 6. Download figure Download PowerPoint Niacin ameliorates DSS/TNBS-induced colitis in mice through DP1 receptor Treatment with niacin promotes PGD2 release in colon tissues (Fig 1A), and disruption of DP1 receptor worsens DSS/TNBS-induced colitis in mice (Figs 2 and EV2). We hypothesized niacin could improve clinical manifestation of colitis induced by DSS or TNBS. Indeed, administration of niacin (600 mg/kg by gavage, once a day, Fig 3A) markedly delayed body weight loss (7.94 ± 1.44% vs. 14.25 ± 1.03%, P < 0.01, Fig 3B), elevation of DAI (1.46 ± 0.14 vs. 2.58 ± 0.16, P < 0.01, Fig 3C), and shortening of colon length (6.26 ± 0.19 cm vs. 4.43 ± 0.27 cm, P < 0.01, Fig 3D and E) caused by DSS challenge in WT mice, and consequently reduced mortality (Fig 3F). In addition, niacin also ameliorated body weight loss and shortening of colon length caused by TNBS challenge in mice (Fig EV3). In contrast, these beneficial effects of niacin were not observed in DP1-deficient mice (Figs 3B–F and EV3). Figure 3. Niacin protects mice from DSS-induced colitis A. Protocol for niacin treatment on DSS-induced colitis in mice. B, C. Effect of niacin treatment on body weight loss (B) and disease activity index (C) of DP1−/− and WT mice in response to DSS challenge. D. Macroscopic appearance of colons from DSS-challenged mice after niacin treatment. Scale bar: 1 cm. E. Effect of niacin treatment on colon length (centimeter) of DP1−/− and WT mice in response to DSS challenge. F. Effect of niacin treatment on survival rates of DSS-challenged DP1−/− mice and WT controls. Data information: Data are representative of two independent experiments. (B, C, E) Data are shown as mean ± SEM. Statistical analysis was performed using unpaired Student's t-test. #P < 0.05, ##P < 0.01 vs. vehicle; n = 8. (F) Survival rate was compared using the log-rank test. #P < 0.05, vs. vehicle, *P < 0.05, **P < 0.01 compared with WT; WT, n = 17; DP1−/−, n = 20. Download figure Download PowerPoint Click here to expand this figure. Figure EV3. Niacin protects mice against from TNBS-induced colitis A–C. Effect of niacin treatment on body weight loss (A), disease activity index (DAI, B), and colon length (centimeter) (C) of DP1−/− and WT mice in response to 2.5% TNBS challenge. Data information: Data are shown as mean ± SEM. Statistical significance was determined using two-way ANOVA followed by a Bonferroni post hoc test. #P < 0.05, ##P < 0.01 vs. vehicle. *P < 0.05, **P < 0.01 compared with WT. WT-vehicle, n = 7; WT-niacin, n = 8; DP1−/−-vehicle, DP1−/−-niacin, n = 6. Download figure Download PowerPoint We also examined the effect of n" @default.
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• W2600704889 title "Niacin ameliorates ulcerative colitis via prostaglandin D₂‐mediated D prostanoid receptor 1 activation" @default.
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