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Xu J, Peng WR, Zhang D, Sun HX, Li L, Sun F, Gu ZC, Lin HW. Marine sponge-derived alkaloid ameliorates DSS-induced IBD via inhibiting IL-6 expression through modulating JAK2-STAT3-SOCS3 pathway. Int Immunopharmacol 2024; 129:111576. [PMID: 38350353 DOI: 10.1016/j.intimp.2024.111576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/05/2024] [Accepted: 01/18/2024] [Indexed: 02/15/2024]
Abstract
Cyanogramide (AC14), a novel alkaloid, isolated from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus. However, the exact role of AC14 in inflammatory bowel disease (IBD) is poorly understood. Our results demonstrated that AC14 exhibited significant inhibition of IL-6 release in THP-1 cells and a "Caco-2/THP-1" coculture system after stimulation with LPS for 24 h. However, no significant effect on TNF-α production was observed. Furthermore, in 2.5 % DSS-induced colitis mice, AC14 treatment led to improvement in body weight, colon length, and intestine mucosal barrier integrity. AC14 also suppressed serum IL-6 production and modulated dysregulated microbiota in the mice. Mechanistically, AC14 was found to inhibit the phosphorylation of Janus kinase (JAK) 2 and signal transducers and activators of transcription (STAT) 3, while simultaneously elevating the expression of suppressor of cytokine signaling (SOCS) 3, both in vivo and in vitro. These findings suggest that AC14 exerts its suppressive effects on IL-6 production in DSS-induced IBD mice through the JAK2-STAT3-SOCS3 signaling pathway. Our study highlights the potential of AC14 as a therapeutic agent for the treatment of IBD.
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Affiliation(s)
- Jing Xu
- School of Medicine, Tongji University, Shanghai 200092, People's Republic of China; Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China
| | - Wen-Rui Peng
- Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Die Zhang
- Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China
| | - Hong-Xin Sun
- Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China
| | - Lei Li
- Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China
| | - Fan Sun
- Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
| | - Zhi-Chun Gu
- Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
| | - Hou-Wen Lin
- School of Medicine, Tongji University, Shanghai 200092, People's Republic of China; Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
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Voshagh Q, Anoshiravani A, Karimpour A, Goodarzi G, Tehrani SS, Tabatabaei‐Malazy O, Panahi G. Investigating the association between the tissue expression of miRNA-101, JAK2/STAT3 with TNF-α, IL-6, IL-1β, and IL-10 cytokines in the ulcerative colitis patients. Immun Inflamm Dis 2024; 12:e1224. [PMID: 38517042 PMCID: PMC10958669 DOI: 10.1002/iid3.1224] [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: 09/04/2023] [Revised: 02/28/2024] [Accepted: 03/11/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by numerous factors, such as immune system dysfunction and genetic factors. MicroRNAs (miRNAs) play a crucial role in UC pathogenesis, particularly via the JAK-STAT pathway. Our aim was to investigate the association between miRNA-101 and JAK2-STAT3 signaling pathway with inflammatory cytokines in UC patients. METHODS We enrolled 35 UC patients and 35 healthy individuals as the control group, referred to Shariati Hospital, Tehran, Iran. Patients were diagnosed based on clinical, laboratory, histological, and colonoscopy criteria. RNA and protein extracted from tissue samples. Real-time PCR was used to assess the expression levels of miRNA-101, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10 genes, while western blot was employed to measure levels of P-STAT3, total STAT3, and JAK2 proteins. RESULTS Expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 significantly increased, while the expression of IL-10 significantly decreased in the case group versus controls. Additionally, miRNA-101 expression was significantly higher in UC patients. A significant correlation between miRNA-101 and IL-6 expression was observed, indicating their relationship and possible impact on cell signaling pathways, JAK2-STAT3. No significant changes were observed in phosphorylated and total STAT3 and JAK2 protein expression. CONCLUSION This study provides evidence of increased miRNA-101 expression in UC tissue, suggesting a potential correlation between miRNA-101 and IL-6 expression and their involvement in the JAK2-STAT3 pathway. The study confirms alterations in UC patients' pro-inflammatory cytokines and anti-inflammatory IL-10. However, further investigations are needed to understand the exact role of miRNA-101 in UC pathogenesis fully.
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Affiliation(s)
- Qazaleh Voshagh
- Department of Clinical Biochemistry, School of MedicineTehran University of Medical SciencesTehranIran
| | - Amir Anoshiravani
- Digestive Disease Research Center, Digestive Disease Research InstituteTehran University of Medical SciencesTehranIran
| | - Amin Karimpour
- Department of Clinical Biochemistry, School of MedicineTehran University of Medical SciencesTehranIran
| | - Golnaz Goodarzi
- Department of Pathobiology and Laboratory Sciences, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Sadra Samavarchi Tehrani
- Endocrine Research Center, Institute of Endocrinology and MetabolismIran University of Medical ScienceTehranIran
| | - Ozra Tabatabaei‐Malazy
- Non‐Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences InstituteTehran University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran
| | - Ghodratollah Panahi
- Department of Clinical Biochemistry, School of MedicineTehran University of Medical SciencesTehranIran
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Hao Y, Jiang L, Han D, Si D, Sun Z, Wu Z, Dai Z. Limosilactobacillus mucosae and Lactobacillus amylovorus Protect Against Experimental Colitis via Upregulation of Colonic 5-Hydroxytryptamine Receptor 4 and Transforming Growth Factor-β2. J Nutr 2023; 153:2512-2522. [PMID: 37356501 DOI: 10.1016/j.tjnut.2023.06.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/16/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023] Open
Abstract
BACKGROUND Limosilactobacillusmucosae (LM) exerts anti-inflammatory and health-promoting effects. However, its role in the modulation of gut serotonin or 5-hydroxytryptamine (5-HT) metabolism and 5-HT receptors (HTRs) in inflammation requires further investigation. OBJECTIVES We compared LM with Lactobacillus amylovorus (LA) for the regulation of 5-HT, HTRs, inflammatory mediators, and their correlations in the colon of mice with experimental colitis. METHODS Male C57BL/6 mice were randomly assigned to 6 groups: control (Con), LM, LA, dextran sodium sulfate (DSS), and DSS with pre-administration of LM (+LM) or LA (+LA). After 7 d of DSS treatment, mice were killed to analyze the expression of inflammatory mediators, HTRs, and concentrations of 5-HT and microbial metabolites in the colon. RESULTS LM was more effective than LA in alleviating DSS-induced colonic inflammation. Compared with mice in the DSS group, mice receiving DSS + LM or DSS + LA treatment had lower (P < 0.05) colonic mRNA expression of proinflammatory cytokines. DSS + LM treatment had lower mRNA expression of Il1b, Tnfa, and Ccl3, an abundance of p-STAT3, and greater expression of Tgfb2 and Htr4 in the colon (P < 0.05). The expression of inflammatory mediators (including Tgfb-1) was positively correlated (P < 0.05) with 5-HT and Htr2a and negatively correlated (P < 0.05) with Htr4. However, the expression of Tgfb-2 showed reversed correlations with the 5-HT and HTRs described above. Patterns for these correlations were different for LM and LA. Mice receiving the DSS + LM treatment had greater (P < 0.05) concentrations of acetate and valerate and lower (P < 0.05) concentrations of indole-3-acetic acid in the cecal and colonic contents. CONCLUSIONS LM showed greater efficacy than LA in alleviating DSS-induced colonic inflammation. The coordinated regulation of transforming growth factor-β subtypes and serotonin receptors in the colon may be one of the most important mechanisms underlying the probiotic effects of lactobacilli in gut inflammation.
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Affiliation(s)
- Youling Hao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Lili Jiang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Dandan Han
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Dayong Si
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zhiyuan Sun
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China.
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Liu J, Zong C, Yu X, Ding Y, Chang B, Wang R, Sang L. Alanyl-Glutamine (Ala-Gln) Ameliorates Dextran Sulfate Sodium (DSS)-Induced Acute Colitis by Regulating the Gut Microbiota, PI3K-Akt/NF-κB/STAT3 Signaling, and Associated Pulmonary Injury. ACS Infect Dis 2023; 9:979-992. [PMID: 36917734 DOI: 10.1021/acsinfecdis.3c00014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
The aim of this study was to investigate the protective effect of alanyl-glutamine (Ala-Gln) on acute colitis complicated by pulmonary injury induced by dextran sulfate sodium (DSS) in C57BL/6 mice. The results showed that Ala-Gln intervention alleviated weight loss, the disease activity index (DAI), colon shortening, and pathological injury and regulated the absolute number of CD4+T-cell subsets in mesenteric lymph nodes (MLNs). In addition, Ala-Gln intervention significantly ameliorated the composition of the gut microbiota in mice with DSS- induced acute colitis, significantly decreasing the relative abundance of Desulfovibrionaceae and increasing the abundances of Gastranaerophilales, Clostridia-vadinBB60, and Alistipes. Moreover, Ala-Gln treatment significantly inhibited the activation of the PI3K-Akt/NF-κB/STAT3 inflammatory signaling pathways in the colon of mice with DSS-induced acute colitis. Notably, Ala-Gln intervention also alleviated the pulmonary injury as well as the imbalance in levels of CD4+T-cell subsets in pulmonary tissue in mice with DSS-induced acute colitis. In conclusion, Ala-Gln alleviates DSS-induced acute colitis by regulating the gut microflora and PI3K-Akt/NF-κB/STAT3 signaling pathways, as well as by alleviating accompanying pulmonary injury.
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Affiliation(s)
- Jing Liu
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Chengguo Zong
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Xin Yu
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Yan Ding
- Clinical Laboratory, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006 Liaoning, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang 110001, Liaoning, China
| | - Ruoyu Wang
- Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian 110006, Liaoning, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian 116001, Liaoning, China
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang 110022, Liaoning, China
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Ma S, Xu L, Chen L, Sun X, Hu F, Gong Y, Yang R, Li J, Wang Q, Huang S, Zhou H, Wang J. Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury. Biochem Pharmacol 2022; 203:115165. [PMID: 35803318 DOI: 10.1016/j.bcp.2022.115165] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/15/2022] [Accepted: 06/28/2022] [Indexed: 11/15/2022]
Abstract
Necrotizing enterocolitis (NEC), an acute intestinal inflammatory disease of premature infants, is one of the leading causes of death in neonates. Effective measures for clinical treatment are limited and there is a pressing need in searching for new therapeutic strategies. Jumonji domain-containing protein D3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase plays a proinflammatory role in sepsis and neuroinflammation. However, whether JMJD3 is involved in the pathogenesis of NEC has not been elucidated. Here we report that overexpressed JMJD3 was revealed in the intestine of NEC patients by bioinformatic analysis. Moreover, upregulated JMJD3 and suppressed H3K27me3 were detected in both NEC patients and neonatal mice subjected to experimental NEC. Importantly, administration of GSK-J4, a specific JMJD3 inhibitor, rescued neonatal mice from NEC-associated lethality by suppressing proinflammatory response with attenuated IL-6, TNF-α, and MCP-1 levels and ameliorating intestinal injury with reversed claudin-1, occludin, and E-cadherin expression. Remarkably, administration of GSK-J4 attenuated intestinal injury by inhibiting activation of intestinal necroptosis in NEC mice. Administration of GSK-J4 regulated intestinal inflammation via NF-κB and JAK2/STAT3 pathway. These results indicate that JMJD3 is involved in the development of NEC and inhibition of JMJD3 overexpression by mean of GSK-J4 could be a potential therapeutic approach in the prevention and treatment of NEC.
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Affiliation(s)
- Shurong Ma
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Lingqi Xu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Lulu Chen
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Xu Sun
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Fangjie Hu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Yuan Gong
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Randong Yang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Jing Li
- Department of Surgery, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Qian Wang
- Department of Anesthesiology, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Shungen Huang
- Department of Surgery, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Huiting Zhou
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China.
| | - Jian Wang
- Department of Surgery, Children's Hospital of Soochow University, Suzhou 215025, China.
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Jiang Q, Li W, Zhu X, Yu L, Lu Z, Liu Y, Ma B, Cheng L. Estrogen receptor β alleviates inflammatory lesions in a rat model of inflammatory bowel disease via down-regulating P2X7R expression in macrophages. Int J Biochem Cell Biol 2021; 139:106068. [PMID: 34464722 DOI: 10.1016/j.biocel.2021.106068] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 07/25/2021] [Accepted: 08/19/2021] [Indexed: 02/08/2023]
Abstract
Estrogen receptor beta (ERβ) agonists could inhibit inflammation in animal models of inflammatory bowel disease (IBD). However, the mechanism underlying such effect and the potential role of P2 × 7 receptor (P2X7R) remains unclear. In the present study, we examined whether the effect of ERβ activation in IBD rats was related to P2X7R. Overexpression of ERβ using a recombinant lentivirus in IBD rats improved the IBD-like symptoms, including weight loss, disease activity index (DAI) scores, and inflammatory responses. ERβ agonists DPN and ERB-041 attenuated P2X7R expression in macrophages from colitis rats and in a murine macrophage cell line (RAW264.7) in response to either lipopolysaccharide (LPS) or adenosine triphosphate (ATP). DPN and ERB-041 also blocked increased production of TNF-α, IL-6, and IL-1β in the rectocolon of colitis rats. The two ERβ agonists reversed LPS- and ATP-induced up-regulation of P2X7R and its downstream proteins, including NLRP3, ASC, caspase-1, and pro-IL-1β, in RAW264.7 cells. Also, in both the rectocolon of colitis rats and RAW264.7 cells, ERβ agonists reversed the up-regulation of extracellular regulated protein kinases (ERK), the Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3), but not up-regulation of serine threonine kinase or cAMP-response element binding protein (CREB). Blockade of JAK2 or STAT3 phosphorylation significantly reduced the ability of DPN to down-regulate P2X7R expression and the ability of ERB-041 and DPN to inhibit IL-1β release from RAW264.7 cells. We found that ERβ and P2X7R co-localized in the macrophages of rat rectocolon and in RAW264.7 cells. Deletion of macrophages from colitis rats with clodronate abolished the inhibitory effect of DPN. These results suggest that ERβ plays an important anti-inflammatory role in IBD rats by down-regulating P2X7R expression and inhibiting IL-1β release from macrophages through the JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Qian Jiang
- Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China.
| | - Wenxin Li
- Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China.
| | - Xu Zhu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China.
| | - Lihua Yu
- Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Zhanying Lu
- Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Yuchen Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China
| | - Bei Ma
- Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China.
| | - Liming Cheng
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China.
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Zhang Z, Xue Z, Yang H, Zhao F, Liu C, Chen J, Lu S, Zou Z, Zhou Y, Zhang X. Differential effects of EPA and DHA on DSS-induced colitis in mice and possible mechanisms involved. Food Funct 2021; 12:1803-1817. [PMID: 33523066 DOI: 10.1039/d0fo02308f] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The anti-inflammatory effect of n-3 PUFAs has been widely documented. Emerging evidence suggests that the main component of n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects in ulcerative colitis (UC). It was aimed to clarify their differential effects in UC. METHODS Eight-week-old male C57BL/6J mice were randomly divided into 7 groups, namely control, UC model, salicylazosulfapyridine (SASP), low-dose DHA, high-dose DHA, low-dose EPA, and high-dose EPA. DHA, EPA and SASP treatment groups were orally treated accordingly for 9 weeks. During the 5th to 9th week the control group was given distilled water, while other groups were given distilled water with 2% dextran sodium sulfate (DSS) to induce UC. Body weight loss, diarrhea, and stool bleeding were recorded to calculate the disease activity index (DAI). The level of tight junction proteins Claudin-1 and Occludin, and cytokines including TNF-α, IL-6, and IL-1β as well as inflammatory cell markers such as MPO, F4/80, and MCP-1 in the intestinal epithelium were measured using western blotting. Activation of IL-6/STAT3 and NLRP3/IL-1β inflammatory pathways was also assessed. Levels of proliferation-related proteins of the Wnt/β-catenin pathway with c-myc, Cyclin-D1, and PCNA were detected. RESULTS EPA, superior to DHA, significantly attenuated DSS-induced colitis evidenced by reduced DAI scores, cytokine production and inflammatory cell infiltration. Mechanically, EPA triggered a marked up-regulation of Claudin-1 and Occludin with down-regulation of their up-stream Akt and ERK. EPA also inhibited NLRP3/IL-1β and IL-6/STAT3 inflammatory pathways and up-regulated the Wnt/β-catenin pathway. CONCLUSIONS EPA is more suitable to be used for the treatment of UC than DHA.
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Affiliation(s)
- Zhuangwei Zhang
- Institute of Preventative Medicine and Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo University, Ningbo, 315211 Zhejiang, China. and Department of Nutrition, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310000 Zhejiang, China
| | - Zhe Xue
- Institute of Preventative Medicine and Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo University, Ningbo, 315211 Zhejiang, China.
| | - Haitao Yang
- Department of Pathology, Mingzhou Hospital of Zhejiang University, Ningbo, 315040 Zhejiang, China
| | - Feng Zhao
- Institute of Nutrition and Health, Qingdao University, 266071 Qingdao, China
| | - Chundi Liu
- Central South University, Changsha, 410083 Hunan, China
| | - Jiahui Chen
- Institute of Preventative Medicine and Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo University, Ningbo, 315211 Zhejiang, China.
| | - Songtao Lu
- Institute of Preventative Medicine and Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo University, Ningbo, 315211 Zhejiang, China.
| | - Zuquan Zou
- Institute of Preventative Medicine and Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo University, Ningbo, 315211 Zhejiang, China.
| | - Yuping Zhou
- Department of Gastroenterology, Affiliated Hospital of Medical School of Ningbo University, Ningbo, 315040 Zhejiang, China
| | - Xiaohong Zhang
- Institute of Preventative Medicine and Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo University, Ningbo, 315211 Zhejiang, China.
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Abstract
The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.
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Phytochemicals Targeting JAK-STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models. Molecules 2021; 26:molecules26092824. [PMID: 34068714 PMCID: PMC8126249 DOI: 10.3390/molecules26092824] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn’s disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK–STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK–STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK–STAT pathways are potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical agents for the treatment of IBD.
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Chalikonda G, Lee H, Sheik A, Huh YS. Targeting key transcriptional factor STAT3 in colorectal cancer. Mol Cell Biochem 2021; 476:3219-3228. [PMID: 33866491 DOI: 10.1007/s11010-021-04156-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 04/02/2021] [Indexed: 12/22/2022]
Abstract
In developed countries, colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of malignant-related deaths. CRC is treatable cancer when diagnosed early; however, diagnosis at the advanced stage is associated with a poor prognosis. Although chemotherapy is generally very promising, STAT3 protein which is overexpressed and persistently activated in CRC cells is observed to be the major contributor of chemoresistance development. It has been shown to play a prominent and pathogenic role in CRC initiation, progression, and metastasis. While over the past few years, research has been focused on STAT3 which is expressed at the center of various oncogenic pathways. This review is a discussion of the oncogenic role of STAT3 in CRC and potential therapeutic STAT3 inhibitors and analogs used to control and treat CRC.
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Affiliation(s)
| | - Hoomin Lee
- NanoBio High-Tech Materials Research Center, Department of Biological Engineering, Inha University, Incheon, 22212, Republic of Korea
| | - Aliya Sheik
- NanoBio High-Tech Materials Research Center, Department of Biological Engineering, Inha University, Incheon, 22212, Republic of Korea.
| | - Yun Suk Huh
- NanoBio High-Tech Materials Research Center, Department of Biological Engineering, Inha University, Incheon, 22212, Republic of Korea.
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Shiah JV, Grandis JR, Johnson DE. Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides. Mol Cancer Ther 2021; 20:219-228. [PMID: 33203730 PMCID: PMC7888537 DOI: 10.1158/1535-7163.mct-20-0599] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/09/2020] [Accepted: 11/02/2020] [Indexed: 11/16/2022]
Abstract
STAT3 has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of antitumor immunity. Given the ubiquity of dysregulated STAT3 activity in cancer, it has long been considered a highly attractive target for the development of anticancer therapies. Efforts to target STAT3, however, have proven to be especially challenging, perhaps owing to the fact that transcription factors lack targetable enzymatic activity and have historically been considered "undruggable." Small-molecule inhibitors targeting STAT3 have been limited by insufficient selectivity and potency. More recently, therapeutic approaches that selectively target STAT3 protein for degradation have been developed, offering novel strategies that do not rely on inhibition of upstream pathways or direct competitive inhibition of the STAT3 protein. Here, we review these emerging approaches, including the development of STAT3 proteolysis targeting chimera agents, as well as preclinical and clinical studies of chemically stabilized antisense molecules, such as the clinical agent AZD9150. These therapeutic strategies may robustly reduce the cellular activity of oncogenic STAT3 and overcome the historical limitations of less selective small molecules.
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Affiliation(s)
- Jamie V Shiah
- Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, California
| | - Jennifer R Grandis
- Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, California
| | - Daniel E Johnson
- Department of Otolaryngology - Head and Neck Surgery, University of California at San Francisco, San Francisco, California.
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12
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Salas A, Hernandez-Rocha C, Duijvestein M, Faubion W, McGovern D, Vermeire S, Vetrano S, Vande Casteele N. JAK-STAT pathway targeting for the treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:323-337. [PMID: 32203403 DOI: 10.1038/s41575-020-0273-0] [Citation(s) in RCA: 412] [Impact Index Per Article: 82.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/06/2020] [Indexed: 02/07/2023]
Abstract
Cytokines are involved in intestinal homeostasis and pathological processes associated with inflammatory bowel disease (IBD). The biological effects of cytokines, including several involved in the pathology of Crohn's disease and ulcerative colitis, occur as a result of receptor-mediated signalling through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) DNA-binding families of proteins. Although therapies targeting cytokines have revolutionized IBD therapy, they have historically targeted individual cytokines, and an unmet medical need exists for patients who do not respond to or lose response to these treatments. Several small-molecule inhibitors of JAKs that have the potential to affect multiple pro-inflammatory cytokine-dependent pathways are in clinical development for the treatment of IBD, with one agent, tofacitinib, already approved for ulcerative colitis and several other agents with demonstrated efficacy in early phase trials. This Review describes the current understanding of JAK-STAT signalling in intestinal homeostasis and disease and the rationale for targeting this pathway as a treatment for IBD. The available evidence for the efficacy, safety and pharmacokinetics of JAK inhibitors in IBD as well as the potential approaches to optimize treatment with these agents, such as localized delivery or combination therapy, are also discussed.
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Affiliation(s)
- Azucena Salas
- Department of Gastroenterology, IDIBAPS, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Cristian Hernandez-Rocha
- Zane Cohen Center for Digestive Diseases, Mount Sinai Hospital Inflammatory Bowel Disease Group, Toronto, Ontario, Canada
| | - Marjolijn Duijvestein
- Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - William Faubion
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, MI, USA
| | - Dermot McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Severine Vermeire
- Department of Gastroenterology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Laboratory of Immunology in Gastroenterology, Humanitas Clinical and Research Center IRCCS, Milan, Italy
| | - Niels Vande Casteele
- Robarts Clinical Trials, London, ON, Canada. .,Department of Medicine, University of California San Diego, La Jolla, CA, USA.
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13
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Yang C, Merlin D. Nanoparticle-Mediated Drug Delivery Systems For The Treatment Of IBD: Current Perspectives. Int J Nanomedicine 2019; 14:8875-8889. [PMID: 32009785 PMCID: PMC6859086 DOI: 10.2147/ijn.s210315] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 10/19/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD), which mainly consists of Crohn’s disease and ulcerative colitis, is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The traditional treatment strategies relied on frequent administration of high dosages of medications, including antibiotics, non-steroidal anti-inflammatory drugs, biologics, and immunomodulators, with the goal of reducing inflammation. Some of these medications were effective in alleviating the early-stage inflammatory symptoms, but their long-term efficacies were compromised by the accumulation of toxicities. Recently, nanoparticle (NP)-based drugs have been widely studied for their potential to solve such problems. Various mechanisms/strategies, including size-, charge-, pH-, pressure-, degradation-, ligand-receptor-, and microbiome- dependent drug delivery systems, have been exploited in preclinical studies. A certain number of NP delivery systems have sought to target drugs to the inflamed intestine. Although several NP-based drugs have entered clinical trials for the treatment of IBD, most have failed due to premature drug release, weak targeting ability, and the high immune toxicity of some of the synthetic nanomaterials that have been used to fabricate the NPs. Therefore, there is still a need for rationally designed and stable NP drug delivery system that can specifically target drugs to the disease site, prolong the drug’s residence time, and minimize systemic side effects. This review will analyze the current state of the art in NP-mediated drug delivery for IBD treatment. We will focus on topics such as deliverable targets (at the tissue or cellular level) for treating inflammation; the target-homing NP materials that can interact with such targets; and the major administration routes for treating IBD. These discussions will integrate notable trends in the research and development of IBD medications, including multi-responsive NP-mediated delivery and naturally-derived targeting NPs. Finally, current challenges and future directions will be presented in the hopes of advancing the study of NP-mediated strategies for treating IBD.
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Affiliation(s)
- Chunhua Yang
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group, Georgia State University, Atlanta, GA 30302, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group, Georgia State University, Atlanta, GA 30302, USA.,Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA
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Fang W, Zhu S, Niu Z, Yin Y. The protective effect of syringic acid on dextran sulfate sodium‐induced experimental colitis in BALB/c mice. Drug Dev Res 2019; 80:731-740. [PMID: 31313354 DOI: 10.1002/ddr.21524] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 01/31/2019] [Accepted: 02/05/2019] [Indexed: 01/19/2023]
Affiliation(s)
- Wenhui Fang
- Anorectal of Traditional Chinese MedicineShandong Provincial Hospital Affiliated to Shandong University Jinan Shandong Province China
| | - Shihong Zhu
- Department of Obstetrics and GynecologyFeicheng People's Hospital Taian Shandong Province China
| | - Zhongbao Niu
- Department of Traditional Chinese MedicineShandong Provincial Hospital Affiliated to Shandong University Jinan Shandong Province China
| | - Yuti Yin
- Anorectal of Traditional Chinese MedicineShandong Provincial Hospital Affiliated to Shandong University Jinan Shandong Province China
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15
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Selim AO, Gouda ZA, Selim SA. An experimental study of a rat model of emphysema induced by cigarette smoke exposure and the effect of Survanta therapy. Ann Anat 2017; 211:69-77. [DOI: 10.1016/j.aanat.2016.12.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 12/18/2016] [Accepted: 12/19/2016] [Indexed: 12/26/2022]
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16
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Qin Z, Wan JJ, Sun Y, Wu T, Wang PY, Du P, Su DF, Yang Y, Liu X. Nicotine protects against DSS colitis through regulating microRNA-124 and STAT3. J Mol Med (Berl) 2016; 95:221-233. [PMID: 27709266 DOI: 10.1007/s00109-016-1473-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 07/19/2016] [Accepted: 09/08/2016] [Indexed: 01/15/2023]
Abstract
Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis, the underlying mechanisms remain not well understood. Our previous finding that nicotine inhibits inflammatory responses through inducing miR-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine against UC. Our present study found that miR-124 expression is upregulated in colon tissues from UC patients and DSS colitis mice. Nicotine treatment further augmented miR-124 expression in lymphocytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice, both in infiltrated lymphocytes and epithelial cells. Moreover, knockdown of miR-124 significantly diminished the beneficial effect of nicotine on murine colitis and IL-6-treated Caco-2 colon epithelial cells. Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6 treated Caco-2 cells and Jurkat human T lymphocytes, in which miR-124 knockdown led to increased activation of STAT3. Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine's protective effect in this model. These data indicate that nicotine exerts its protective action in UC through inducing miR-124 and inhibiting STAT3, and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC. KEY MESSAGE Nicotine upregulates miR-124 expression in ulcerative colon tissues and cells. MiR-124 is required for the protective role of nicotine in DSS colitis mice and epithelial cells. The protective effect of nicotine in murine DSS colitis depends on blocking STAT3 activation. MiR-124 mediates the inhibitory role of nicotine on STAT3/p-STAT3. Targeting miR-124 and STAT3 represents a novel approach for treating ulcerative colitis.
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Affiliation(s)
- Zhen Qin
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Jing-Jing Wan
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Yang Sun
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Tingyu Wu
- Department of Colorectal Surgery, Xinhua hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200095, People's Republic of China
| | - Peng-Yuan Wang
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200095, People's Republic of China
| | - Ding-Feng Su
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
| | - Yili Yang
- Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, 215123, People's Republic of China.
| | - Xia Liu
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
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Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer. Vaccines (Basel) 2016; 4:vaccines4010005. [PMID: 26938566 PMCID: PMC4810057 DOI: 10.3390/vaccines4010005] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/19/2016] [Accepted: 02/25/2016] [Indexed: 12/12/2022] Open
Abstract
Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling.
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18
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Furtek SL, Backos DS, Matheson CJ, Reigan P. Strategies and Approaches of Targeting STAT3 for Cancer Treatment. ACS Chem Biol 2016; 11:308-18. [PMID: 26730496 DOI: 10.1021/acschembio.5b00945] [Citation(s) in RCA: 303] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates the expression of genes related to cell cycle, cell survival, and immune response associated with cancer progression and malignancy in a number of cancer types. Once activated, STAT3 forms a homodimer and translocates to the nucleus where it binds DNA promoting the translation of target genes associated with antiapoptosis, angiogenesis, and invasion/migration. In normal cells, levels of activated STAT3 remain transient; however, STAT3 remains constitutively active in approximately 70% of human solid tumors. The pivotal role of STAT3 in tumor progression has promoted a campaign in drug discovery to identify small molecules that disrupt the function of STAT3. A range of approaches have been used to identify novel small molecule inhibitors of STAT3, including high-throughput screening of chemical libraries, computational-based virtual screening, and fragment-based design strategies. The most common approaches in targeting STAT3 activity are either via the inhibition of tyrosine kinases capable of phosphorylating and thereby activating STAT3 or by preventing the formation of functional STAT3 dimers through disruption of the SH2 domains. However, the targeting of the STAT3 DNA-binding domain and disruption of binding of STAT3 to its DNA promoter have not been thoroughly examined, mainly due to the lack of adequate assay systems. This review summarizes the development of STAT3 inhibitors organized by the approach used to inhibit STAT3, the current inhibitors of each class, and the assay systems used to evaluate STAT3 inhibition and offers an insight into future approaches for small molecule STAT3 inhibitor development.
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Affiliation(s)
- Steffanie L. Furtek
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States
| | - Donald S. Backos
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States
| | - Christopher J. Matheson
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States
| | - Philip Reigan
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States
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Takedatsu H, Mitsuyama K, Torimura T. Nanomedicine and drug delivery strategies for treatment of inflammatory bowel disease. World J Gastroenterol 2015; 21:11343-52. [PMID: 26525603 PMCID: PMC4616210 DOI: 10.3748/wjg.v21.i40.11343] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 05/28/2015] [Accepted: 08/29/2015] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease and ulcerative colitis are two important categories of human inflammatory bowel disease (IBD). Because the precise mechanisms of the inflammation and immune responses in IBD have not been fully elucidated, the treatment of IBD primarily aims to inhibit the pathogenic factors of the inflammatory cascade. Inconsistencies exist regarding the response and side effects of the drugs that are currently used to treat IBD. Recent studies have suggested that the use of nanomedicine might be advantageous for the treatment of intestinal inflammation because nano-sized molecules can effectively penetrate epithelial and inflammatory cells. We reviewed nanomedicine treatments, such as the use of small interfering RNAs, antisense oligonucleotides, and anti-inflammatory molecules with delivery systems in experimental colitis models and clinical trials for IBD based on a systematic search. The efficacy and usefulness of the treatments reviewed in this manuscript have been demonstrated in experimental colitis models and clinical trials using various types of nanomedicine. Nanomedicine is expected to become a new therapeutic approach to the treatment of IBD.
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Pandurangan AK, Mohebali N, Esa NM, Looi CY, Ismail S, Saadatdoust Z. Gallic acid suppresses inflammation in dextran sodium sulfate-induced colitis in mice: Possible mechanisms. Int Immunopharmacol 2015; 28:1034-43. [PMID: 26319951 DOI: 10.1016/j.intimp.2015.08.019] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 08/08/2015] [Accepted: 08/14/2015] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel diseases (IBD) encompass at least two forms of intestinal inflammation: Crohn's disease and ulcerative colitis (UC). Both conditions are chronic and inflammatory disorders in the gastrointestinal tract, with an increasing prevalence being associated with the industrialization of nations and in developing countries. Patients with these disorders are 10 to 20 times more likely to develop cancer of the colon. The aim of this study was to characterize the effects of a naturally occurring polyphenol, gallic acid (GA), in an experimental murine model of UC. A significant blunting of weight loss and clinical symptoms was observed in dextran sodium sulfate (DSS)-exposed, GA-treated mice compared with control mice. This effect was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity, and a decrease in the expression of inflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and pro-inflammatory cytokines. In addition, GA reduced the activation and nuclear accumulation of p-STAT3(Y705), preventing the degradation of the inhibitory protein IκB and inhibiting of the nuclear translocation of p65-NF-κB in colonic mucosa. These findings suggest that GA exerts potentially clinically useful anti-inflammatory effects mediated through the suppression of p65-NF-κB and IL-6/p-STAT3(Y705) activation.
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Affiliation(s)
- Ashok Kumar Pandurangan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia; Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nooshin Mohebali
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Norhaizan Mohd Esa
- Department of Nutrition and Dietetics, Faculty of Medicine and Health sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia; Laboratory of Molecular Medicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
| | - Chung Yeng Looi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Salmiah Ismail
- Laboratory of Molecular Medicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Zeinab Saadatdoust
- Department of Nutrition and Dietetics, Faculty of Medicine and Health sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
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Kilic T, Parlakpinar H, Taslidere E, Yildiz S, Polat A, Vardi N, Colak C, Ermis H. Protective and Therapeutic Effect of Apocynin on Bleomycin-Induced Lung Fibrosis in Rats. Inflammation 2014; 38:1166-80. [DOI: 10.1007/s10753-014-0081-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening. Methods 2014; 71:38-43. [PMID: 25160651 DOI: 10.1016/j.ymeth.2014.07.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 07/19/2014] [Accepted: 07/21/2014] [Indexed: 12/16/2022] Open
Abstract
STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with comparable potency to the well-known STAT3 inhibitor S3I-201. A fluorescence polarization assay revealed that compound 1 targeted the SH2 domain of STAT3. Furthermore, compound 1 inhibited STAT3 phosphorylation in cells without affecting the total expression of STAT3. This study also validates the use of pharmacophore modeling to identify inhibitors of protein-protein interactions.
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Dong J, Wang H, Wu G, Zhao J, Zhang L, Zuo L, Zhu W, Gong J, Li Y, Gu L, Li J. Oral treatment with SEW2871, a sphingosine-1-phosphate type 1 receptor agonist, ameliorates experimental colitis in interleukin-10 gene deficient mice. Clin Exp Immunol 2014; 177:94-101. [PMID: 24611843 PMCID: PMC4089158 DOI: 10.1111/cei.12304] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2014] [Indexed: 12/17/2022] Open
Abstract
SEW2871, a selective sphingosine-1-phosphate type 1 receptor (S1P1) agonist, has been shown to be effective in protecting kidneys against ischaemia-reperfusion injury by reducing CD4(+) T cell infiltration in mice. However, the effects of SEW2871 on colitis remain unclear. The aim of this study was to investigate the effects of SEW2871 on established colitis in interleukin (IL)-10 gene-deficient (IL-10(-/-)) mice, a murine model of Crohn's disease (CD). SEW2871 was administered by gavage at a dose of 20 mg/kg/day for 2 weeks to IL-10(-/-) mice. Severity of colitis, serum amyloid A, tissue myeloperoxidase (MPO), T cells in blood and colon lamina propria (LP) and proinflammatory cytokine productions were evaluated. Furthermore, the phospho-signal transducer and activator of transcription (STAT)-3 (p-STAT-3) expression in lymphocytes isolated from colon LP was also assessed. The 2-week administration of SEW2871 ameliorated established colitis in IL-10(-/-) mice, associated with a reduction of serum amyloid A concentration, a decreased colon MPO concentration, a depletion of the peripheral CD4(+) CD45(+) T cells and a reduction of the homing of T cells into colon LP. Moreover, typical cytokines of T helper type 1 (Th1) and Th17 cells and p-STAT-3 expression were also suppressed by SEW2871 treatment. SEW2871 treatment ameliorates established experimental colitis in IL-10(-/-) mice, which may provide a new therapeutic approach for human CD therapy.
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Affiliation(s)
- J Dong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
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Abstract
: Ulcerative colitis (UC), an inflammatory bowel disease, affects many people across the globe, and its prevalence is increasing steadily. Inflammation and oxidative stress play a vital role in the perpetuation of inflammatory process and the subsequent DNA damage associated with the development of UC. UC induces not only local but also systemic damage, which involves the perturbation of multiple molecular pathways. Furthermore, UC leads to an increased risk of colorectal cancer, the third most common malignancy in humans. Most of the drugs used for the treatment of UC are unsatisfactory because they are generally mono-targeted, relatively ineffective and unaffordable for many people. Thus, agents that can target multiple molecular pathways and are less expensive have enormous potential to treat UC. Melatonin has beneficial effects against UC in experimental and clinical studies because of its ability to modulate several molecular pathways of inflammation, oxidative stress, fibrosis, and cellular injury. However, many novel targets are yet to be explored on which melatonin may act to exert its favorable effects in UC. It is time to explore improved intervention strategies with melatonin in UC on the basis of studies investigating different molecular targets using proteomic and genomic approaches. This review identifies various molecular targets for melatonin with the intent of providing novel strategies for combating UC and the associated extraintestinal manifestations of this debilitating disease.
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Affiliation(s)
- Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India
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XU DEKUI, YU HONGBO, YU QINGGONG, WU SIMENG, LIU DONGMEI, LIN YAN, ZHANG YING, ZHENG CHANGQING. Salvia miltiorrhiza increases the expression of transcription factor Foxp3 in experimental murine colitis. Mol Med Rep 2014; 9:1947-51. [DOI: 10.3892/mmr.2014.1986] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 02/07/2014] [Indexed: 01/30/2023] Open
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26
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Takashima T, Sakata Y, Iwakiri R, Shiraishi R, Oda Y, Inoue N, Nakayama A, Toda S, Fujimoto K. Feeding with olive oil attenuates inflammation in dextran sulfate sodium-induced colitis in rat. J Nutr Biochem 2014; 25:186-92. [DOI: 10.1016/j.jnutbio.2013.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 09/24/2013] [Accepted: 10/04/2013] [Indexed: 02/06/2023]
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27
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Liu L, Liu YL, Liu GX, Chen X, Yang K, Yang YX, Xie Q, Gan HK, Huang XL, Gan HT. Curcumin ameliorates dextran sulfate sodium-induced experimental colitis by blocking STAT3 signaling pathway. Int Immunopharmacol 2013; 17:314-20. [PMID: 23856612 DOI: 10.1016/j.intimp.2013.06.020] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 05/30/2013] [Accepted: 06/18/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Although a series of studies have shown that curcumin can exert anti-inflammatory effects in colitis by inhibiting NF-κB activation, whether these anti-inflammatory effects of curcumin are also attributed to its ability to inhibiting STAT3 pathway has never been tested in experimental colitis to date. The purpose of the study was to investigate whether curcumin could exert its therapeutic effects in experimental colitis by inhibiting STAT3 pathway. MATERIALS AND METHODS Curcumin was administered in experimental colitis induced by dextran sulfate sodium (DSS). The disease activity index (DAI) and histological score were observed. The phospho-STAT3 was assessed by western blot analysis. The DNA-binding activity of STAT3 dimers was evaluated by electrophoretic mobility shift assay (EMSA). The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β was measured by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity was determined by using MPO assay kit. RESULTS A significant improvement was observed in DAI and histological score in mice with curcumin, and the increases in phospho-STAT3 activity, DNA-binding activity of STAT3 dimers, MPO activity, IL-1β, and TNF-α expression in mice with DSS-induced colitis were significantly reduced following treatment with curcumin. CONCLUSION Curcumin exerts beneficial effects in experimental colitis by the suppression of STAT3 pathway, which may therefore provide a better understanding of the mechanism of action for curcumin in treating colitis.
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Affiliation(s)
- Liu Liu
- Department of Gastroenterology and Geriatrics Medicine, Sichuan University, Chengdu, Sichuan, China
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Arranz A, Reinsch C, Papadakis KA, Dieckmann A, Rauchhaus U, Androulidaki A, Zacharioudaki V, Margioris AN, Tsatsanis C, Panzner S. Treatment of experimental murine colitis with CD40 antisense oligonucleotides delivered in amphoteric liposomes. J Control Release 2013; 165:163-72. [PMID: 23178664 DOI: 10.1016/j.jconrel.2012.11.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 11/12/2012] [Accepted: 11/14/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS CD40-CD40L interactions appear to play an important role in the pathogenesis of experimental colitis. We tested the effect and investigated the underlying mechanism of action of systemically administered antisense oligonucleotide (ASO) targeting CD40 formulated in amphoteric liposomes (nov038/CD40). The charge characteristics of the amphoteric liposomes (anionic surface charge at physiological pH that becomes cationic at low pH), facilitate efficient sequestration of the ASO inside the liposomes at low pH and the direction of the carriers towards macrophages and dendritic cells under physiological conditions. METHODS Colitis was induced in Balb/c mice using 2,4,6-Trinitrobenzene sulphonic acid (TNBS) and treated with nov038/CD40. Disease was monitored by body weight, histology, cytokine profiling and changes in immune cell populations. CD40 expression on different cell subsets was analyzed by flow cytometry. An antigen challenge model was used to determine neoimmunity under CD40 modulation. RESULTS Administration of nov038/CD40 inhibited the development of TNBS colitis as assessed by weight loss, histology and cytokine profiles; unformulated CD40 ASO or nov038 encapsulating an unrelated ASO (nov038/SCR) were ineffective. The novel agent is potent as it completely suppressed even established colitis with a single treatment and significantly reduced T-cell activation as well as levels of pro-inflammatory mediators in serum. The inhibition of CD40 specifically occurred in macrophages, but not in B-cells. In contrast to prednisolone, standard treatment for inflammatory bowel diseases (IBD) that is effective in a single administration and involves extensive immunosuppression, nov038/CD40 did not affect the number of B- or Treg cells. Eventually, we observed a largely intact neoimmunity under conditions of a CD40 inhibition. CONCLUSIONS Administration of nov038/CD40, but neither naked CD40 ASO nor nov038/SCR, prevents the development and treats established colitis in mice. Delivery of CD40 ASO in nov038 is highly cell-specific as it selectively suppresses CD40 on macrophages, but not on B-cells; the novel agent has strong anti-inflammatory characteristics without being immunosuppressive.
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Affiliation(s)
- A Arranz
- Department of Clinical Chemistry, University of Crete Medical School, Crete, Greece
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Beneficial effect of shikonin on experimental colitis induced by dextran sulfate sodium in BALB/c mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:271606. [PMID: 23346196 PMCID: PMC3549420 DOI: 10.1155/2012/271606] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 12/03/2012] [Indexed: 12/19/2022]
Abstract
The naphthoquinone shikonin, a major component of the root of Lithospermum erythrorhizon, now is studied as an anti-inflammatory agent in the treatment of ulcerative colitis (UC). Acute UC was induced in Balb/C mice by oral administration of 5% dextran sodium sulfate (DSS). The disease activity index was evaluated, and a histologic study was carried out. Orally administered shikonin reduces induced UC in a dose-dependent manner, preventing the shortening of the colorectum and decreasing weight loss by 5% while improving the appearance of feces and preventing bloody stools. The disease activity index score was much lower in shikonin-treated mice than in the colitic group, as well as the myeloperoxidase activity. The expression of cyclooxygenase-2 was reduced by 75%, activation of NF-κB was reduced by 44%, and that of pSTAT-3 by 47%, as well as TNF-α, IL-1β, and IL-6 production. Similar results were obtained in primary macrophages culture. This is the first report of shikonin's ability to attenuate acute UC induced by DSS. Shikonin acts by blocking the activation of two major targets: NF-κB and STAT-3, and thus constitutes a promising potential therapeutic agent for the management of the inflammatory bowel disease.
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Fitzpatrick LR, Small JS, Doblhofer R, Ammendola A. Vidofludimus inhibits colonic interleukin-17 and improves hapten-induced colitis in rats by a unique dual mode of action. J Pharmacol Exp Ther 2012; 342:850-60. [PMID: 22691298 DOI: 10.1124/jpet.112.192203] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Vidofludimus (Vido) is a novel oral immunomodulatory drug that inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro. Vido inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation. Our primary goal was to evaluate the in vivo effects of Vido on IL-17 secretion and the parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. To further delineate the mechanism of action for Vido, rats were dosed concomitantly with uridine (Uri). Young Wistar rats received a 150-μl enema of either phosphate-buffered saline (PBS) or TNBS on study day 1. The ex vivo effects of Vido on 24-h colonic IL-17 secretion were determined by using colonic strips from PBS- or TNBS-treated rats. Some rats were dosed with vehicle, Vido, or Vido + Uri for 6 days. On day 6, the parameters of colitis were determined from colonic tissue. These parameters included macroscopic, histological, and transcription factor measurements, IL-17 production, and numbers of CD3+ T cells. Ex vivo Vido completely blocked IL-23 + IL-1β-stimulated secretion of IL-17 by colonic strips. In vivo Vido treatment alone most effectively reduced macroscopic and histological pathology and the numbers of CD3+ T cells. In contrast, similarly reduced nuclear signal transducer and activator of transcription 3 (STAT3) binding and IL-17 levels were observed from animals treated with Vido alone and Vido + Uri. Vido improves TNBS-induced colonic inflammation by a unique dual mode of action: 1) inhibiting expansion of colonic T lymphocytes, and 2) suppressing colonic IL-17 production, which is independent from the control of T-lymphocyte proliferation, by inhibition of STAT3 and nuclear factor-κB activation.
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Affiliation(s)
- Leo R Fitzpatrick
- Department of Pharmacology, Penn State College of Medicine, Hummelstown, PA 17036, USA.
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Debnath B, Xu S, Neamati N. Small molecule inhibitors of signal transducer and activator of transcription 3 (Stat3) protein. J Med Chem 2012; 55:6645-68. [PMID: 22650325 DOI: 10.1021/jm300207s] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Bikash Debnath
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90089, United States
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Dai YC, Tang ZP, Wang ZN, Zhang YL, He XY. Influence of Shenqing Recipe on morphology and quantity of colonic interstitial cells of Cajal in trinitrobenzene sulfonic acid induced rat colitis. ACTA ACUST UNITED AC 2011; 26:43-8. [PMID: 21496422 DOI: 10.1016/s1001-9294(11)60018-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To observe the influence of Shenqing Recipe (SQR), a kind of Traditional Chinese Medicine, on the morphology and quantity of colonic interstitial cells of Cajal (ICC) in trinitrobenzene sulfonic acid (TNBS)-induced rat colitis, and to investigate the possible mechanism of SQR in regulating intestinal dynamics. METHODS Sixty rats were randomly divided into normal control, model 1, model 2, mesalazine, and high-dose, and low-dose SQR groups with 10 rats in each group. TNBS (10 mg) dissolved in 50% ethanol was instilled into the lumen of the rat colon of the latter five groups to induce colitis. On the 4th day after administration of TNBS, each treatment group was administered one of the following formulations by enteroclysis gavage once a day for 7 days: 600 mg•kg⁻¹•d⁻¹ mesalazine, 2.4 g•kg⁻¹•d⁻¹ SQR, and 1.2 g•kg⁻¹•d⁻¹ SQR. Model 2 rats received normal saline solution. After 7 days colonic samples were collected. While the colonic samples of model 1 group were collected on the 3rd day after TNBS administered. Ultrastructure of ICC in the damaged colonic tissues was observed with transmission electron microscope. Expression of c-kit protein in colonic tissue was determined by immunohistochemical staining and Western blot. RESULTS The ultrastructure of colonic ICC in the rat model of TNBS-induced colitis showed a severe injury, and administration of SQR or mesalazine reduced the severity of injury. Similarly, the expression of c-kit protein of TNBS-induced colitis rat model was significantly decreased compared with the normal control group (P < 0.05). Treatment with SQR or mesalazine significantly increased the expression of c-kit protein compared with the administration of control formulations (P < 0.05), especially the high-dose SQR group. CONCLUSION SQR could alleviate and repair the injured ICC, and improve its quantity, which might be involved in regulating intestinal motility.
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Affiliation(s)
- Yan-cheng Dai
- Department of Gastroenterology, Longhua Hospital, Shanghai, China
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Bai A, Lu N, Zeng H, Li Z, Zhou X, Chen J, Liu P, Peng Z, Guo Y. All-trans retinoic acid ameliorates trinitrobenzene sulfonic acid-induced colitis by shifting Th1 to Th2 profile. J Interferon Cytokine Res 2010; 30:399-406. [PMID: 20187766 DOI: 10.1089/jir.2009.0028] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Inflammatory bowel disease is characterized with uncontrolled immune response in inflamed mucosa, with dominance of Th1 cells. Recently, all-trans retinoic acid has been shown that can lead T-cell response by suppressing Th17 development via retinoic acid receptor (RAR), but it is still unknown whether all-trans retinoic acid can modulate Th1 response of inflammatory bowel disease. In the experiment, we investigated the effect of all-trans retinoic acid on trinitrobenzene sulfonic acid (TNBS)-induced murine colitis, and the possible mechanism. Mice were intraperitoneally treated daily with all-trans retinoic acid (the agonist of RAR-alpha) or LE135 (the antagonist of RAR-alpha) or medium, and sacrificed 6 days later. Colon was collected for histological analysis and myeloperoxidase (MPO) activity measurement. Lamina propria mononuclear cells (LPMCs) were isolated, cultured, and assayed for the expressions of T-bet and GATA-3 by the use of Western blot and for cytokine levels by the use of ELISA. All-trans retinoic acid treatment inhibited inflammatory responses as shown by lower histological inflammatory scores and MPO activity, compared with LE135 and medium groups. Furthermore, in LPMCs culture supernatants, the levels of Th1 cytokines (INF-gamma, IL-12, and TNF-alpha) were decreased while those of Th2 cytokines (IL-4 and IL-10) were increased significantly in all-trans retinoic acid-treated mice. In addition, T-bet expression in LPMCs was inhibited and GATA-3 expression was up-regulated in all-trans retinoic acidtreated mice. On the contrary, LE135 showed the reverse effects in colon inflammation and cytokine profile. By shifting Th1 to Th2 profile in inflamed mucosa, all-trans retinoic acid down-regulates inflammatory response and ameliorates acute TNBS-induced colitis, which suggests the ligand of RAR-alpha-based pharmaceutical strategies for managing inflammatory bowel disease.
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Affiliation(s)
- Aiping Bai
- Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang City, People's Republic of China.
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Li F, Zou Y, Li X. Up-regulation of signal transducer and activator of transcription-3 is associated with aggravation of ulcerative colitis. Surgeon 2010; 8:262-6. [PMID: 20709283 DOI: 10.1016/j.surge.2010.03.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Accepted: 03/28/2010] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The signal transducers and activators of transcription (STAT) family of proteins are intracellular signal transduction molecules involved in the expression of numerous proinflammatory genes in inflammatory cells. This study was executed to determine the association between the expression pattern of STAT-3 in the colonic mucosa of patients with ulcerative colitis (UC) and the progression of this disease. METHODS We carried out the real-time reverse transcription-polymerase chain reaction (RT-PCR), Western-blot analysis and immunohistochemical staining to examine the expression of STAT-3 at both mRNA and protein levels in 25 patients with UC and 10 normal controls. The association between STAT-3 expression pattern and the severity of the disease was also analyzed. RESULTS The expression of STAT-3 mRNA and protein in the ulcerated and inflamed colonic mucosa was significantly higher than that in the non-inflamed colonic mucosa (for mRNA: P = 0.001, 0.02 and for protein: P = 0.003, 0.03, respectively), but there was no statistically significant difference in the non-inflamed colonic mucosa of UC patients and normal controls (for mRNA: P = 0.062 and for protein: P = 0.063). Furthermore, immunohistochemical analysis showed that among the inactive, mild approximately moderate, and severe colonic mucosae of UC patients, the positive rates of STAT-3 expression were 60.0%, 66.7%, and 88.9%, respectively. CONCLUSION Our study provides convincing evidence for the first time that the up-regulation of STAT-3 in colonic mucosa may be associated with the progression of human UC and STAT-3 may be a potential therapeutic target for this disease.
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Affiliation(s)
- Fujun Li
- Department of digestion in Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
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Bai A, Lu N, Guo Y, Liu Z, Chen J, Peng Z. All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis. J Leukoc Biol 2009; 86:959-69. [PMID: 19477911 DOI: 10.1189/jlb.0109006] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RARalpha, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RARalpha or LE135 as the antagonist of RARalpha. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and down-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-17) but more regulatory cytokines (IL-10, TGF-beta) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.
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Affiliation(s)
- Aiping Bai
- Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang 330006, China.
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Bai A, Lu N, Guo Y, Chen J, Liu Z. Modulation of inflammatory response via alpha2-adrenoceptor blockade in acute murine colitis. Clin Exp Immunol 2009; 156:353-62. [PMID: 19250273 DOI: 10.1111/j.1365-2249.2009.03894.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by heavy production of proinflammatory cytokines such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Interactions of the autonomic nervous system with local immune cells play an important role in the development of IBD, and the balance of autonomic nerve function is broken in IBD patients with sympathetic overactivity. However, the function of catecholamines in the progress of colitis is unclear. In this study, we examined the role of catecholamines via alpha2-adrenoreceptor in acute murine colitis. The expression of tyrosine hydroxylase (TH) and dopamine b-hydroxylase (DBH), two rate-limiting enzymes in catecholamine synthesis, was detected by immunohistochemistry in murine colitis. Murine colitis was induced by dextran sodium sulphate or trinitrobenzene sulphonic acid (TNBS), and the mice were administered RX821002 or UK14304, alpha2-adrenoceptor antagonists or agonists. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, TNF-alpha and IL-1beta production and histology. Lamina propria mononuclear cells (LPMCs) from mice with TNBS colitis were cultured in the absence or presence of RX821002 or UK14304, and stimulated further by lipopolysaccharide. TH and DBH are induced in LPMCs of inflamed colon, the evidence of catecholamine synthesis during the process of colitis. RX821002 down-regulates the production of proinflammatory cytokines from LPMCs, while UK14304 leads to exacerbation of colitis. Together, our data show a critical role of catecholamines via alpha2-adrenoreceptors in the progress of acute colitis, and suggest that use of the alpha2-adrenoceptor antagonist represents a novel therapeutic approach for the management of colitis.
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Affiliation(s)
- A Bai
- Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang City, China.
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Bai A, Guo Y, Lu N. The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol 2007; 66:538-45. [PMID: 17953529 DOI: 10.1111/j.1365-3083.2007.02011.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel diseases (IBD) are characterized by proinflammatory cytokines, tissue damage and loss of neuron in inflamed mucosa, which implies the cholinergic anti-inflammatory pathway may be destroyed during the process of inflammatory response. In the study, we identified the effect of cholinergic agonist as anabaseine (AN) and nicotinic receptor antagonist as chlorisondamine diiodide (CHD) on trinitrobenzene sulfonic acid (TNBS)-induced colitis, to investigate the potential therapeutic effect of the cholinergic anti-inflammatory pathway on IBD. Experimental colitis was induced by TNBS at day 1, 10 mug AN or 1.5 mug CHD was injected i.p. to mouse right after the induction of colitis, and repeated on interval day till the mice were sacrificed at day 8. Colonic inflammation was examined by histological analysis, myeloperoxidase (MPO) activity, and the production of tumour necrosis factor (TNF)-alpha in tissue. Lamina propria mononuclear cells (LPMC) were isolated, and NF-kappaB activation was detected by western blot. The mice with colitis treated by AN showed less tissue damage, less MPO activity, less TNF-alpha production in colon, and inhibited NF-kappaB activation in LPMC, compared with those mice with colitis untreated, whereas the mice with colitis treated by CHD showed the worst tissue damage, the highest MPO activity, the highest TNF-alpha level, and enlarged NF-kappaB activation in LPMC. Agonist of the cholinergic anti-inflammatory pathway inhibits colonic inflammatory response by downregulating the production of TNF-alpha, and inhibiting NF-kappaB activation, which suggests that modulating the cholinergic anti-inflammatory pathway may be a new potential management for IBD.
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Affiliation(s)
- A Bai
- Department of Gastroenterology, the First Affiliated Hospital, Nanchang University, Nanchang City, China
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