|
1
|
Salem MB, El-Lakkany NM, Hammam OA, Seif el-Din SH. Bacillus clausii spores maintain gut homeostasis in murine ulcerative colitis via modulating microbiota, apoptosis, and the TXNIP/NLRP3 inflammasome cascade. Toxicol Rep 2025; 14:101858. [PMID: 39802600 PMCID: PMC11721221 DOI: 10.1016/j.toxrep.2024.101858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/04/2024] [Accepted: 12/08/2024] [Indexed: 01/16/2025] Open
Abstract
Ulcerative colitis (UC), a persistent immune-mediated disorder lacking effective treatment, is distinguished by gut microbiota dysbiosis, abnormal activation of the NLRP3 inflammasome pathway, and apoptosis. Despite growing attention to these factors, understanding their significance in UC pathogenesis remains a challenge. The present study explores the potential therapeutic impact of Bacillus clausii (Bc) spores in a murine UC model induced by drinking 4 % (w/v) dextran sulfate sodium (DSS) in C57BL/6 mice. Subsequently, the DSS-induced mice were orally administered either Bc at varying concentrations (105 and 1010 Colony forming unit, CFU) or sulfasalazine (SSZ) at a dosage of 200 mg/kg for 7 days. The disease-specific activity index (DAI) was calculated daily utilizing parameters such as body weight, diarrhea, and bloody stool. Changes in fecal Firmicutes and Bacteroidetes abundance, colonic TXNIP and NLRP3 contents, as well as colonic caspase-1, IL-1β, Bax, and Bcl-2 expression, were investigated. Additionally, markers related to oxidative stress and inflammation, histopathological changes and caspase-3 immunohistochemistry testing were conducted. DSS-treated mice had significantly higher DAI scores compared to controls, indicating severe colitis. However, SSZ treatment or Bc (105 CFU) dramatically lowered DAI scores, with the highest Bc dosage (1010 CFU) producing the greatest improvement. Furthermore, Bc (1010 CFU) substantially (p < 0.05) boosted fecal Firmicutes while decreased Bacteroidetes, indicating reversal of gut dysbiosis. Bc effectively reduced colonic oxidative stress and inflammation by replenishing GSH and catalase and modulating the NF-κB, Nrf2/HO-1, and TXNIP/NLRP3 pathways. Additionally, Bc (1010 CFU) exhibited histologically almost normal mucosa, with maintained architecture and reduced apoptosis, as seen by normalization of Bcl2 and Bax with decreased caspase-3. Collectively, these findings point to the potential usefulness of Bc spores in preventing and treating DSS-induced colitis, positioning them as a promising candidate for UC management.
Collapse
Affiliation(s)
- Maha B. Salem
- Pharmcology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | | | - Olfat A. Hammam
- Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | | |
Collapse
|
|
2
|
Ma J, Wang FY, Tang XD. Involvement of the NLRP3/IL-1β pathway in activation and effector functions of γδT17 cells in patients with ulcerative colitis. World J Gastroenterol 2025; 31:98174. [PMID: 40182600 PMCID: PMC11962846 DOI: 10.3748/wjg.v31.i12.98174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/29/2024] [Accepted: 12/23/2024] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND The interleukin-17 (IL-17) mediated aberrant immune-inflammatory response plays a paramount role in ulcerative colitis (UC). γδT17 cells are one of the critical sources of IL-17, but the role they play in UC remains under debate. AIM To clarify the role of γδT17 cells in patients with mild-to-moderate UC. METHODS A single-centre observational pragmatic study was conducted on patients with UC who attended the outpatient and inpatient departments of Xiyuan Hospital of the China Academy of Traditional Chinese Medicine from September 2020 to December 2022. The research population consisted of two groups of adult patients. The first group consisted of healthy volunteers with no significant abnormalities on colonoscopy, and the other group consisted of patients with mild-to-moderate ulcerative colitis. Serum samples from healthy volunteers and patients with UC were collected for the detection of relevant inflammatory factors. Moreover, five colon mucosa samples were randomly selected from each group for testing and analyses. RESULTS An increased number of γδT17 cells and hyperactivation of the NLR family pyrin domain containing 3/IL-1β signaling pathway were observed in colonic mucosal tissues from patients with UC. CONCLUSION Hyperactivation of the NLR family pyrin domain containing 3/IL-1β signaling pathway promotes the activation of γδT17 cells in colonic mucosal tissues of patients with UC.
Collapse
Affiliation(s)
- Jing Ma
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Feng-Yun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xu-Dong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| |
Collapse
|
|
3
|
Maeda T, Shirakami Y, Taguchi D, Miwa T, Kubota M, Sakai H, Ibuka T, Mori K, Tomita H, Shimizu M. Glyburide Suppresses Inflammation-Related Colorectal Tumorigenesis Through Inhibition of NLRP3 Inflammasome. Int J Mol Sci 2024; 25:11640. [PMID: 39519191 PMCID: PMC11546087 DOI: 10.3390/ijms252111640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 10/26/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Colorectal cancer represents one of the most serious complications of inflammatory bowel disease. The NLRP3 inflammasome plays a pivotal role in the onset and progression of inflammatory bowel disease and is also implicated in colorectal cancer. This study aimed to investigate whether NLRP3 deficiency or glyburide, a sulfonylurea used for diabetes management and known as an NLRP3 inhibitor, could suppress colitis and its related colorectal tumorigenesis. Mice were divided into three groups: a control group, a glyburide group, and an NLRP3-deficient group. We investigated acute colitis and inflammation-related tumor models using azoxymethane and dextran sodium sulfate. In the colitis model, the colonic inflammation grade was significantly increased in NLRP3-deficient mice but not in mice administered glyburide. In the colorectal carcinogenesis model, fewer colorectal tumors were observed in both NLRP3-deficient and glyburide-treated groups. Additionally, a reduction in the expression levels of inflammatory cytokine genes was detected in the colonic mucosa of the mice of these groups. These findings suggest that NLRP3 deficiency may exacerbate acute colitis, while pharmacological inhibition, as well as deficiency of NLRP3, suppresses colitis-related tumorigenesis, presumably due to the attenuation of chronic inflammation in the colorectum. Glyburide holds promise as a potential chemopreventive agent for colitis-related colorectal cancer.
Collapse
Affiliation(s)
- Toshihide Maeda
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Daisuke Taguchi
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Takao Miwa
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Masaya Kubota
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Hiroyasu Sakai
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Takashi Ibuka
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Kosuke Mori
- Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
| |
Collapse
|
|
4
|
Cho YH, Park JE. Anti-Inflammatory and Autophagy Activation Effects of 7-Methylsulfonylheptyl Isothiocyanate Could Suppress Skin Aging: In Vitro Evidence. Antioxidants (Basel) 2024; 13:1282. [PMID: 39594424 PMCID: PMC11591029 DOI: 10.3390/antiox13111282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 11/28/2024] Open
Abstract
Skin inflammation, characterized by redness, swelling, and discomfort, is exacerbated by oxidative stress, where compounds like 7-methylsulfonylheptyl isothiocyanate (7-MSI) from cruciferous plants exhibit promising antioxidant and anti-inflammatory properties, though their effects on skin aging and underlying mechanisms involving the NLRP3 inflammasome and autophagy are not fully elucidated. NLRP3 is a crucial inflammasome involved in regulating inflammatory responses, and our study addresses its activation and associated physiological effects. Using biochemical assays such as ELISA, RT-qPCR, Western blotting, confocal microscopy, and RNA interference, we evaluated 7-MSI's impact on cytokine production, protein expression, and genetic regulation in Raw 264.7 and RAW-ASC cells. 7-MSI significantly reduced TNF-α, IL-1β, IL-6, COX-2, and PGE transcription levels in LPS-stimulated Raw 264.7 cells, indicating potent anti-inflammatory effects. It also inhibited NF-κB signaling and NLRP3 inflammasome activity, demonstrating its role in preventing the nuclear translocation of NF-κB and reducing caspase-1 and IL-1β production. In terms of autophagy, 7-MSI enhanced the expression of Beclin-1, LC3, and Atg12 while reducing phospho-mTOR levels, suggesting an activation of autophagy. Moreover, it effectively decreased ROS production induced by LPS. The interaction between autophagy and inflammasome regulation was further confirmed through experiments showing that interference with autophagy-related genes altered the effects of 7-MSI on cytokine production. Collectively, this study demonstrates that 7-MSI promotes autophagy, including ROS removal, and to suppress inflammation, we suggest the potential use of 7-MSI as a skin care and disease treatment agent.
Collapse
Affiliation(s)
- Yeong Hee Cho
- Department of Biomedical Science, College of Natural Sciences and Public Health and Safety, Chosun University, Gwangju 61452, Republic of Korea;
- Department of Agricultural Biology, National Institute of Agricultural Sciences, RDA, Wanju-gun 55365, Republic of Korea
| | - Jung Eun Park
- Department of Biomedical Science, College of Natural Sciences and Public Health and Safety, Chosun University, Gwangju 61452, Republic of Korea;
- BK21-Four Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea
| |
Collapse
|
|
5
|
Dadkhah M, Sharifi M. The NLRP3 inflammasome: Mechanisms of activation, regulation, and role in diseases. Int Rev Immunol 2024; 44:98-111. [PMID: 39402899 DOI: 10.1080/08830185.2024.2415688] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/09/2024] [Accepted: 10/05/2024] [Indexed: 02/22/2025]
Abstract
Because of numerous stress signals, intracellular protein complexes are called inflammasomes. They function as catalysts for the proteolytic transformation of pro-interleukin into the active form of interleukin. Inflammasomes can promote a type of cell death process known as pyroptosis. The NLRP3 inflammasome, comprised of the NLRP3 protein, procaspase-1, and ASC, tightly regulates inflammation. The NLRP3 inflammasome is activated by a variety of stimuli, and several molecular and cellular events, such as ion influx, mitochondrial dysfunction, reactive oxygen species production, and lysosomal damage have been shown to trigger its activation. Inflammation plays a major role in almost all types of human diseases. The NLRP3 inflammasome has been the most widely studied and plays an important pathogenic role in various inflammatory pathologies. This review briefly presents the basic features of NLRP3 inflammasome and their mechanisms of activation and regulation. In addition, recent studies report the role of NLRP3 inflammasome in several diseases have been summarized.
Collapse
Affiliation(s)
- Mina Dadkhah
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
6
|
Malicevic U, Rai V, Skrbic R, Agrawal DK. NLRP3 Inflammasome and Gut Dysbiosis Linking Diabetes Mellitus and Inflammatory Bowel Disease. ARCHIVES OF INTERNAL MEDICINE RESEARCH 2024; 7:200-218. [PMID: 39328924 PMCID: PMC11426418 DOI: 10.26502/aimr.0178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Abstract
Diabetes mellitus and inflammatory bowel disease are chronic conditions with significant overlap in their pathophysiology, primarily driven by chronic inflammation. Both diseases are characterized by an aberrant immune response and disrupted homeostasis in various tissues. However, it remains unclear which disease develops first, and which one contributes to the other. Diabetes mellitus increases the risk of inflammatory bowel disease and inflammatory bowel disease may increase the risk of developing diabetes. This review focuses on comprehensively discussing the factors commonly contributing to the pathogenesis of diabetes mellitus and inflammatory bowel disease to draw a relationship between them and the possibility of targeting common factors to attenuate the incidence of one if the other is present. A key player in the intersection of diabetes mellitus and inflammatory bowel disease is the NLRP3 inflammasome, which regulates the production of pro-inflammatory cytokines leading to prolonged inflammation and tissue damage. Additionally, toll-like receptors via sensing microbial components contribute to diabetes mellitus and inflammatory bowel disease by initiating inflammatory responses. Gut dysbiosis, a common link in both diseases, further intensifies inflammation and metabolic dysfunction. Alterations in gut microbiota composition affect intestinal permeability and immune modulation, perpetuating a vicious cycle of inflammation and disease progression by changing protein expression. The overlap in the underlying inflammatory mechanisms has led to the potential of targeting mediators of chronic inflammation using anti-inflammatory drugs and biologics that benefit both conditions or attenuate the incidence of one in the presence of the other.
Collapse
Affiliation(s)
- Ugljesa Malicevic
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
- Departments of Pathophysiology, Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
| | - Ranko Skrbic
- Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
- Departments of Pathophysiology, Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
| |
Collapse
|
|
7
|
Zhang W, Zou M, Fu J, Xu Y, Zhu Y. Autophagy: A potential target for natural products in the treatment of ulcerative colitis. Biomed Pharmacother 2024; 176:116891. [PMID: 38865850 DOI: 10.1016/j.biopha.2024.116891] [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: 01/24/2024] [Revised: 05/16/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the mucosa of the colon and rectum. UC is characterized by recurrent episodes, often necessitating lifelong medication use, imposing a significant burden on patients. Current conventional and advanced treatments for UC have the disadvantages of insufficient efficiency, susceptibility to drug resistance, and notable adverse effects. Therefore, developing effective and safe drugs has become an urgent need. Autophagy is an intracellular degradation process that plays an important role in intestinal homeostasis. Emerging evidence suggests that aberrant autophagy is involved in the development of UC, and modulating autophagy can effectively alleviate experimental colitis. A growing number of studies have established that autophagy can interplay with endoplasmic reticulum stress, gut microbiota, apoptosis, and the NLRP3 inflammasome, all of which contribute to the pathogenesis of UC. In addition, a variety of intestinal epithelial cells, including absorptive cells, goblet cells, and Paneth cells, as well as other cell types like neutrophils, antigen-presenting cells, and stem cells in the gut, mediate the development of UC through autophagy. To date, many studies have found that natural products hold the potential to exert therapeutic effects on UC by regulating autophagy. This review focuses on the possible effects and pharmacological mechanisms of natural products to alleviate UC with autophagy as a potential target in recent years, aiming to provide a basis for new drug development.
Collapse
Affiliation(s)
- Wei Zhang
- The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Menglong Zou
- The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jia Fu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
| | - Ying Zhu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
| |
Collapse
|
|
8
|
Yeh JJ, Liw PX, Wong YS, Kao HM, Lee CH, Lin CL, Kao CH. The effect of colchicine on cancer risk in patients with immune-mediated inflammatory diseases: a time-dependent study based on the Taiwan's National Health Insurance Research Database. Eur J Med Res 2024; 29:245. [PMID: 38649928 PMCID: PMC11034118 DOI: 10.1186/s40001-024-01836-1] [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: 12/22/2023] [Accepted: 04/10/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND To determine the effect of colchicine on cancer risk in patients with the immune-mediated inflammatory diseases (IMIDs)-related to colchicine use. METHODS This is a time-dependent propensity-matched general population study based on the National Health Insurance Research Database (NHIRD) of Taiwan. We identified the IMIDs patients (n = 111,644) newly diagnosed between 2000 and 2012 based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)-274,712, 135, 136.1, 279.49, 518.3, 287.0, 696.0, 696.1, 696.8, 420, 429.4, 710.0, 710.1, 710.3, 710.4, 714.0, 720, 55.0, 55.1, 55.9, 556. INCLUSION CRITERIA aged ≧ 20 years, if a patient had at least these disease diagnosis requirements within 1 year of follow-up, and, these patients had at least two outpatient visits or an inpatient visit. After propensity-matched according to age, sex, comorbidities, medications and index date, the IMIDs patients enter into colchicine users (N = 16,026) and colchicine nonusers (N = 16,026). Furthermore, time-dependent Cox models were used to analyze cancer risk in propensity-matched colchicine users compared with the nonusers. The cumulative cancer incidence was analyzed using Cox proportional regression analysis. We calculated adjusted hazard ratios (aHRs) and their 95% confidence intervals (95% CIs) for cancer after adjusting for sex, age, comorbidities, and use of medicine including acetylcysteine, medication for smoking cessation such as nicotine replacement medicines (the nicotine patch) and pill medicines (varenicline), anti-inflammatory drugs and immunosuppressant drugs. RESULTS Comparing the colchicine nonusers, all cancer risk were mildly attenuated, the (aHR (95% CI)) of all cancer is (0.84 (0.55, 0.99)). Meanwhile, the colchicine users were associated with the lower incidence of the colorectal cancer, the (aHRs (95% CI)) is (0.22 (0.19, 0.89)). Those aged < 65 years and male/female having the colchicine users were associated with lower risk the colorectal cancer also. Moreover, the colchicine > 20 days use with the lower aHR for colorectal cancer. CONCLUSION Colchicine was associated with the lower aHR of the all cancer and colorectal cancer formation in patients with the IMIDs.
Collapse
Affiliation(s)
- Jun-Jun Yeh
- Department of Family Medicine, Chest Medicine, Geriatric Medicine and Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
| | - Pei-Xuan Liw
- Department of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Yi-Sin Wong
- Department of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Husan-Min Kao
- Department of Geriatric Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Chia-Hsun Lee
- Department of Medical Education, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Cheng-Li Lin
- College of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung, 404, Taiwan.
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan.
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
- Artificial Intelligence Center, China Medical University Hospital, Taichung, Taiwan.
| |
Collapse
|
|
9
|
Tao Y, Wang L, Ye X, Qian X, Pan D, Dong X, Jiang Q, Hu P. Huang Qin decoction increases SLC6A4 expression and blocks the NFκB-mediated NLRP3/Caspase1/GSDMD pathway to disrupt colitis-associated carcinogenesis. Funct Integr Genomics 2024; 24:55. [PMID: 38467948 PMCID: PMC10927794 DOI: 10.1007/s10142-024-01334-x] [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: 11/29/2023] [Revised: 01/23/2024] [Accepted: 03/04/2024] [Indexed: 03/13/2024]
Abstract
Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated carcinogenesis (CAC) are still unclear. Therefore, we aimed to determine the beneficial effects of HQD on CAC in mice and to reveal the underlying mechanism involved. AOM/DSS was used to induce CAC in mice, and the effects of HQD on tumorigenesis in mice were examined (with mesalazine serving as a positive control). Mesalazine or HQD treatment alleviated body weight loss and decreased the disease activity index in mice induced by AOM/DSS. Mesalazine or HQD treatment also suppressed the shortening of colon tissue length, the number of tumors, and the infiltration of inflammatory cells. The genes targeted by HQD were predicted and verified, followed by knockout experiments. Elevated SLC6A4 and inhibited serotonin production and inflammation were observed in HQD-treated mice. HQD inhibited the NFκB and NLRP3/caspase1/GSDMD pathways. The therapeutic effect of HQD was diminished in SLC6A4-deficient AOM/DSS mice. Additionally, the downregulation of SLC6A4 mitigated the inhibitory effect of HQD-containing serum on MODE-K cell pyroptosis. Our findings suggest that SLC6A4 is a pivotal regulator of HQD-alleviated CAC via its modulation of the NLRP3/caspase1/GSDMD pathway.
Collapse
Affiliation(s)
- Yili Tao
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Lai Wang
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Xiaofeng Ye
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Xin Qian
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Danye Pan
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Xiaoyu Dong
- Department of Gastroenterology, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Qian Jiang
- Digestive Disease Diagnosis and Treatment Center of Integrated Traditional Chinese and Western Medicine, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China
| | - Po Hu
- Department of Pulmonary Diseases, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, Jiangsu, P.R. China.
| |
Collapse
|
|
10
|
Cheng X, Chen J, Guo X, Cao H, Zhang C, Hu G, Zhuang Y. Disrupting the gut microbiota/metabolites axis by Di-(2-ethylhexyl) phthalate drives intestinal inflammation via AhR/NF-κB pathway in mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 343:123232. [PMID: 38171427 DOI: 10.1016/j.envpol.2023.123232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/19/2023] [Accepted: 12/24/2023] [Indexed: 01/05/2024]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer known for its environmental endocrine-disrupting properties, posing potential risks to various organs. However, the precise impact of DEHP on intestinal health and its contribution to the initiation of intestinal inflammation remains elucidated. This study aims to investigate the underlying mechanisms of DEHP-induced intestinal inflammation in mice, specifically focusing on the complex interplay between the gut microbiota-metabolite axis and associated pathophysiological alterations. Our findings showed that DEHP-induced damage of multiple organs systemically, as indicated by abnormal liver and kidney biochemical markers, along with a disrupted ileum morphology. Additionally, DEHP exposure disrupted gut barrier function, causing intestinal inflammation characterized by bacterial translocation and alterations in defense and inflammation-related gene expressions. Moreover, 16S rRNA analysis suggested that DEHP-induced gut microbial remodeling is characterized by an upregulation of detrimental bacteria (Erysipelotrichaceae) and a downregulation of beneficial bacteria (Muribaculaceae, Ruminococcaceae, and Lachnospiraceae). Metabolomics analysis revealed DEHP perturbed gut metabolic homeostasis, particularly affecting the degradation of aromatic compounds, which generated an aberrant activation of the AhR and NF-κB, subsequently causing intestinal inflammation. Consequently, our results elucidate the mechanistic link between disrupted gut microbiota and metabolome and the initiation of DEHP-induced intestinal inflammation, mediated through the AhR/NF-κB signaling pathway.
Collapse
Affiliation(s)
- Xinyi Cheng
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China
| | - Jinyan Chen
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China
| | - Xiaoquan Guo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China
| | - Yu Zhuang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang, 330045, Jiangxi, PR China.
| |
Collapse
|
|
11
|
Kim ME, Lee JS. Molecular Foundations of Inflammatory Diseases: Insights into Inflammation and Inflammasomes. Curr Issues Mol Biol 2024; 46:469-484. [PMID: 38248332 PMCID: PMC10813887 DOI: 10.3390/cimb46010030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 12/25/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
Inflammatory diseases are a global health problem affecting millions of people with a wide range of conditions. These diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), osteoarthritis (OA), gout, and diabetes, impose a significant burden on patients and healthcare systems. A complicated interaction between genetic variables, environmental stimuli, and dysregulated immune responses shows the complex biological foundation of various diseases. This review focuses on the molecular mechanisms underlying inflammatory diseases, including the function of inflammasomes and inflammation. We investigate the impact of environmental and genetic factors on the progression of inflammatory diseases, explore the connection between inflammation and inflammasome activation, and examine the incidence of various inflammatory diseases in relation to inflammasomes.
Collapse
Affiliation(s)
| | - Jun Sik Lee
- Department of Biological Science, Immunology Research Lab & BK21-Four Educational Research Group for Age-Associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea;
| |
Collapse
|
|
12
|
Klughammer B, Piali L, Nica A, Nagel S, Bailey L, Jochum C, Ignatenko S, Bläuer A, Danilin S, Gulati P, Hayward J, Scepanovic P, Zhang JD, Bhosale S, Chong CF, Christ A. A randomized, double-blind phase 1b study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of the NLRP3 inhibitor selnoflast in patients with moderate to severe active ulcerative colitis. Clin Transl Med 2023; 13:e1471. [PMID: 37962000 PMCID: PMC10644327 DOI: 10.1002/ctm2.1471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/24/2023] [Accepted: 10/28/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND The NLRP3 inflammasome drives release of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo-controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast. METHODS Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL-1β inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated. RESULTS Selnoflast was well-tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post-dose. Mean plasma concentrations stayed above the IL-1β IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 μg/mL and 2.66 μg/mL, respectively). At steady state, post-dose selnoflast concentrations in sigmoid colon (5-20 μg/g) were above the IC90 . Production of IL-1β was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL-18 levels. There were no meaningful differences in the expression of an IL-1-related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers. CONCLUSIONS Selnoflast was safe and well-tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL-1β IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL-1β in tissue. TRIAL REGISTRATION ISRCTN16847938.
Collapse
|
|
13
|
Sun HX, Zhu Y. Progress on Regulation of NLRP3 Inflammasome by Chinese Medicine in Treatment of Ulcerative Colitis. Chin J Integr Med 2023:10.1007/s11655-023-3551-1. [PMID: 37148482 DOI: 10.1007/s11655-023-3551-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2022] [Indexed: 05/08/2023]
Abstract
Ulcerative colitis (UC) is a chronic, non-specific intestinal disease that not only affects the quality of life of patients and their families but also increases the risk of colorectal cancer. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is an important component of inflammatory response system, and its activation induces an inflammatory cascade response that is involved in the development and progression of UC by releasing inflammatory cytokines, damaging intestinal epithelial cells, and disrupting the intestinal mucosal barrier. Chinese medicine (CM) plays a vital role in the prevention and treatment of UC and is able to regulate NLRP3 inflammasome. Many experimental studies on the regulation of NLRP3 inflammasome mediated by CM have been carried out, demonstrating that CM formulae with main effects of clearing heat, detoxifying toxicity, drying dampness, and activating blood circulation. Flavonoids and phenylpropanoids can effectively regulate NLRP3 inflammasome. Other active components of CM can interfere with the process of NLRP3 inflammasome assembly and activation, leading to a reduction in inflammation and UC symptoms. However, the reports are relatively scattered and lack systematic reviews. This paper reviews the latest findings regarding the NLRP3 inflammasome activation-related pathways associated with UC and the potential of CM in treating UC through modulation of NLRP3 inflammasome. The purpose of this review is to explore the possible pathological mechanisms of UC and suggest new directions for development of therapeutic tools.
Collapse
Affiliation(s)
- Hao-Xian Sun
- Department of Gastroenterology, the First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Ying Zhu
- Department of Gastroenterology, the First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China.
| |
Collapse
|
|
14
|
Li X, Zhao C, Li C, Zhang M, Xie Y, Feng F, Yao W, Wang N. Detection and analysis of lung microbiota in mice with lung cancer lacking the NLRP3 gene. Biochem Biophys Res Commun 2023; 639:117-125. [PMID: 36481355 DOI: 10.1016/j.bbrc.2022.11.059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 11/18/2022] [Indexed: 11/27/2022]
Abstract
To explore whether the lung microbiota have changed in the process of NLRP3 inflammasome promoting cancer, we constructed a murine lung cancer model using tracheal instillation of benzo(a)pyrene and an equal volume of tricaprylin, and characterized lung microbiota in bronchoalveolar lavage fluid from 24 SPF wild-type and NLRP3 gene knockout (NLRP3-/-) C57BL/6 mice. 16SrDNA sequencing was used to analyze the changes in the microbiota. The wild-type and the NLRP3-/- lung cancer group had statistically significant differences in tumor formation rate, tumor number, and tumor size. At the phylum and the genus level, the relative abundance of Proteobacteria and Sphingomonas were the highest in each group respectively. Simpson (P = 0.002) and Shannon (P = 0.008) indexes showed that the diversity of microbiota in the lung cancer group was lower than that in the control group under the NLRP3-/- background. According to the ANOSIM and MRPP analysis, there was a difference between the NLRP3-/- lung cancer group and the NLRP3-/- control group (P < 0.05). The knockout of the NLRP3 gene caused changes in the lung microbiota of mice. There may be a regulatory relationship between the NLRP3 inflammasome and the lung microbiota, which affects the occurrence and development of lung cancer.
Collapse
Affiliation(s)
- Xinyan Li
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Congcong Zhao
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Chao Li
- President's Office, Shandong Cancer Hospital, Jinan, 250117, China
| | - Mengmeng Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Yuanchen Xie
- Henan Red Cross Blood Center, Zhengzhou, 450053, China
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Wu Yao
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
| | - Na Wang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
| |
Collapse
|
|
15
|
Yu L, Zhang MM, Hou JG. Molecular and cellular pathways in colorectal cancer: apoptosis, autophagy and inflammation as key players. Scand J Gastroenterol 2022; 57:1279-1290. [PMID: 35732586 DOI: 10.1080/00365521.2022.2088247] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal carcinogenesis (CRC) is one of the most aggressive forms of cancer, particularly in developing countries. It accounts for the second and third-highest reason for cancer-induced lethality in women and men respectively. CRC involves genetic and epigenetic modifications in colonic epithelium, leading to colon adenocarcinoma. The current review highlights the pathogenic mechanisms and multifactorial etiology of CRC, influenced by apoptosis, inflammation, and autophagy pathways. METHODS We have carried out a selective literature review on mechanisms contributing to the pathogenesis of CRC. RESULTS Resistance to senescence and apoptosis of the mesenchymal cells, which play a key role in intestinal organogenesis, morphogenesis and homeostasis, appears important for sporadic CRC. Additionally, inflammation-associated tumorigenesis is a key incident in CRC, supported by immune disruptors, adaptive and innate immune traits, environmental factors, etc. involving oxidative stress, DNA damage and epigenetic modulations. The self-digesting mechanism, autophagy, also plays a twin role in CRC through the participation of LC3/LC3-II, Beclin-1, ATG5, other autophagy proteins, and Inflammatory Bowel Disease (IBD) susceptibility genes. It facilitates the promotion of effective surveillance pathways and stimulates the generation of malignant tumor cells. The autophagy and apoptotic pathways undergo synergistic or antagonistic interactions in CRC and bear a critical association with IBD that results from the pro-neoplastic effects of persistent intestinal inflammation. Conversely, pro-inflammatory factors stimulate tumor growth and angiogenesis and inhibit apoptosis, suppressing anti-tumor activities. CONCLUSION Hence, research attempts for the development of potential therapies for CRC are in progress, primarily based on combinatorial approaches targeting apoptosis, inflammation, and autophagy.
Collapse
Affiliation(s)
- Lei Yu
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Miao-Miao Zhang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Ji-Guang Hou
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
16
|
Zhang T, Zhang B, Tian W, Wang F, Zhang J, Ma X, Wei Y, Tang X. Research trends in ulcerative colitis: A bibliometric and visualized study from 2011 to 2021. Front Pharmacol 2022; 13:951004. [PMID: 36199683 PMCID: PMC9529236 DOI: 10.3389/fphar.2022.951004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/19/2022] [Indexed: 12/07/2022] Open
Abstract
Background: Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease with repeated relapses and remissions. Despite decades of effort, numerous aspects, including the initiating event and pathogenesis of UC, still remain ambiguous, which requires ongoing investigation. Given the mass of publications on UC, there are multidimensional challenges to evaluating the scientific impact of relevant work and identifying the current foci of the multifaceted disease. Accordingly, herein, we aim to assess the global growth of UC research production, analyze patterns of research areas, and evaluate trends in this area. Methods: The Web of Science Core Collection of Clarivate Analytics was searched for articles related to UC published from 2011 to 2021. Microsoft Office Excel 2019 was used to visualize the number of publications over time. Knowledge maps were generated using CiteSpace and VOSviewer to analyze collaborations among countries, institutions, and authors and to present the journey of UC research as well as to reveal the current foci of UC research. Results: A total of 5,088 publications were evaluated in the present study. China had the most publications (1,099, 22.5%). Univ Calif San Diego was the most productive institution (126, 2.48%). William J Sandborn published the greatest number of articles (100, 1.97%). Toshifumi Hibi was the most influential author in the field with a betweenness centrality of 0.53. Inflammatory bowel diseases was identified as the most prolific journal (379, 7.45%). Gastroenterology was the most co-cited journal (3,730, 4.02%). “Vedolizumab,” “tofacitinib,” “Faecalibacterium prausnitzii,” “fecal microbiota transplantation (FMT),” “toll-like receptor 4,” and “nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome” were considered the hot topics. Conclusion: In UC research, manuscripts that had high impacts on the scientific community provided an evidence base. UC therapy has entered the era of personalized and precision therapy. As research on FMT, anti-integrin antibodies, Janus kinase inhibitors, and anti-tumor necrosis factor drugs continues to grow, their use in the clinical setting may also expand.
Collapse
Affiliation(s)
- Tai Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Beihua Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Wende Tian
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Jiaqi Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Xiangxue Ma
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Yuchen Wei
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Xudong Tang
- China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Xudong Tang,
| |
Collapse
|
|
17
|
Ma X, Di Q, Li X, Zhao X, Zhang R, Xiao Y, Li X, Wu H, Tang H, Quan J, Wu Z, Xiao W, Chen W. Munronoid I Ameliorates DSS-Induced Mouse Colitis by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis Via Modulation of NLRP3. Front Immunol 2022; 13:853194. [PMID: 35865528 PMCID: PMC9296101 DOI: 10.3389/fimmu.2022.853194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/07/2022] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are increasingly common diseases characterized by chronic and relapsing inflammation of the gastrointestinal tract. NLRP3 might be a crucial regulator of the homeostatic balance of the intestine, but its upregulation leads to pyroptosis. Munronoid I is extracted and purified from Munronia sinica, which has shown an anti-inflammatory effect, but the efficacy of Munronoid I in IBD remains unproven. In this study, we attempted to determine the effect of Munronoid I on NLRP3 to regulate the inflammasome activation and pyroptosis in IBD. Our data demonstrated that Munronoid I treatment attenuated DSS-induced body weight loss, pathological injury of the colon, the production of IL-1β and IL-18, and the expression of pyroptosis-associated proteins in colon tissue in mice. Moreover, Munronoid I inhibited LPS/ATP-induced pyroptosis in mouse peritoneal macrophages, MODE-K cells, and DSS-induced pyroptosis in mouse colonic epithelial cells, and decreased the release of inflammatory cytokines IL-1β and IL-18 in mouse peritoneal macrophages. Mechanically, Munronoid I could suppress the NLRP3 inflammasome activation and pyroptosis by promoting the K48-linked ubiquitination and NLRP3 degradation. It is suggested that Munronoid I might be a potential therapeutic candidate for IBD.
Collapse
Affiliation(s)
- Xingyu Ma
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Qianqian Di
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
| | - Xibao Zhao
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
| | - Yue Xiao
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xunwei Li
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Han Wu
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Haimei Tang
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Jiazheng Quan
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Zherui Wu
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
- *Correspondence: Weilie Xiao, ; Weilin Chen,
| | - Weilin Chen
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
- *Correspondence: Weilie Xiao, ; Weilin Chen,
| |
Collapse
|
|
18
|
Perindopril/Ambrosin Combination Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice: Crosstalk between Toll-like Receptor 4, the Pro-Inflammatory Pathways, and SIRT1/PPAR-γ Signaling. Pharmaceuticals (Basel) 2022; 15:ph15050600. [PMID: 35631426 PMCID: PMC9143999 DOI: 10.3390/ph15050600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/02/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
Colitis is one of the inflammatory states that affect the intestinal wall and may even predispose to malignancy due to chronic irritation. Although the etiology of colitis is not yet fully explored, a combination of genetic and environmental factors is strongly incriminated. Perindopril is an angiotensin-converting enzyme inhibitor that is used for the management of a wide range of cardiovascular diseases. Ambrosin is a sesquiterpene lactone that was proven to have beneficial effects in disorders characterized by inflammatory nature. The objective of this study is to make a comparison between the effects of perindopril or ambrosin on dextran sulfate sodium (DSS)-induced colitis in mice and to explore the effect of their combination. The present findings indicate that each ambrosin or perindopril alone or in combination is able to ameliorate oxidative stress and suppress the proinflammatory pathways in the colonic tissues of DSS-treated mice via mechanisms related to toll-like receptor 4/nuclear factor kappa B signaling and modulation of peroxisome proliferator-activated receptor gamma/sirtuin-1 levels. In addition, each ambrosin or perindopril alone or in combination inhibits apoptosis and augments the mediators of autophagy in DSS-treated mice. These effects are reflected in the amelioration of the histopathological and electron microscopic changes in the colonic tissues. Interestingly, the most remarkable effects are those encountered with the perindopril/ambrosin combination compared to the groups treated with each of these agents alone. In conclusion, the perindopril/ambrosin combination might represent an effective modality for mitigation of the pathogenic events and the clinical sequelae of colitis.
Collapse
|
|
19
|
Kasti AN, Synodinou KD, Pyrousis IA, Nikolaki MD, Triantafyllou KD. Probiotics Regulating Inflammation via NLRP3 Inflammasome Modulation: A Potential Therapeutic Approach for COVID-19. Microorganisms 2021; 9:2376. [PMID: 34835501 PMCID: PMC8624812 DOI: 10.3390/microorganisms9112376] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 12/21/2022] Open
Abstract
Inflammasomes are cytoplasmic multiprotein complexes formed by the host's immune system as a response to microbial infection and cellular damage. Many studies have revealed various regulators of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, while it has been recently shown that NLRP3 is implicated in COVID-19 pathogenesis. At the same time, probiotics counteract the inflammatory process and modulate cytokine release, thus influencing both innate and adaptive immune systems. Herein, we review the immunomodulatory potential of probiotics on the assembly of NLRP3 inflammasome, as well as the pathophysiological mechanisms supporting the use of probiotic bacteria for SARS-CoV-2 infection management, presenting evidence from preclinical studies of the last decade: in vivo, ex vivo, and mixed trials. Data show that probiotics intake is related to NLRP3 inflammasome attenuation and lower levels of inflammation markers, highlighting the beneficial effects of probiotics on inflammatory conditions. Currently, none of the ongoing clinical trials evaluating the effectiveness of probiotics intake in humans with COVID-19 has been completed. However, evidence from preclinical studies indicates that probiotics may block virus invasion and replication through their metabolites, bacteriocins, and their ability to block Angiotensin-Converting Enzyme 2 (ACE2), and by stimulating the immune response through NLRP3 inflammasome regulation. In this review, the beneficial effects of probiotics in the inflammatory process through NLRP3 inflammasome attenuation are presented. Furthermore, probiotics may target SARS-CoV-2 both by blocking virus invasion and replication and by stimulating the immune response through NLRP3 inflammasome regulation. Heterogeneity of the results-due to, among others, different bacterial strains and their metabolites, forms, dosage, and experimental designs-indicates the need for more extensive research.
Collapse
Affiliation(s)
- Arezina N. Kasti
- Department of Nutrition and Dietetics, Attikon University General Hospital, 12462 Athens, Greece; (A.N.K.); (K.D.S.); (I.A.P.); (M.D.N.)
| | - Kalliopi D. Synodinou
- Department of Nutrition and Dietetics, Attikon University General Hospital, 12462 Athens, Greece; (A.N.K.); (K.D.S.); (I.A.P.); (M.D.N.)
| | - Ioannis A. Pyrousis
- Department of Nutrition and Dietetics, Attikon University General Hospital, 12462 Athens, Greece; (A.N.K.); (K.D.S.); (I.A.P.); (M.D.N.)
- Medical School, University of Patras, 26504 Patras, Greece
| | - Maroulla D. Nikolaki
- Department of Nutrition and Dietetics, Attikon University General Hospital, 12462 Athens, Greece; (A.N.K.); (K.D.S.); (I.A.P.); (M.D.N.)
| | - Konstantinos D. Triantafyllou
- Hepatogastroenterology Unit, 2nd Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University General Hospital, 12462 Athens, Greece
| |
Collapse
|
|
20
|
Saber S, Abd El-Fattah EE, Yahya G, Gobba NA, Maghmomeh AO, Khodir AE, Mourad AAE, Saad AS, Mohammed HG, Nouh NA, Shata A, Amin NA, Abou El-Rous M, Girgis S, El-Ahwany E, Khalaf EM, El-Kott AF, El-Baz AM. A Novel Combination Therapy Using Rosuvastatin and Lactobacillus Combats Dextran Sodium Sulfate-Induced Colitis in High-Fat Diet-Fed Rats by Targeting the TXNIP/NLRP3 Interaction and Influencing Gut Microbiome Composition. Pharmaceuticals (Basel) 2021; 14:ph14040341. [PMID: 33917884 PMCID: PMC8068273 DOI: 10.3390/ph14040341] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/31/2021] [Accepted: 04/06/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammasome targeting and controlling dysbiosis are promising therapeutic approaches to control ulcerative colitis. This report is the first to investigate the mechanisms underlying the coloprotective effects of rosuvastatin and Lactobacillus and their combined therapy on dextran sodium sulfate (DSS)-induced colitis in high-fat diet (HFD)-fed rats. Our results demonstrate the aggravation of intestinal inflammation as a consequence of an HFD following DSS administration. An association between dyslipidemia, LDL oxidation, CD36 expression, ROS generation, thioredoxin-interacting protein (TXNIP) upregulation, and NLRP3 inflammasome activation was demonstrated by DSS exposure in HFD-fed rats. We demonstrated that rosuvastatin/Lactobacillus significantly suppressed the DSS/HFD-induced increase in colon weight/length ratio, DAI, MDI, and myeloperoxidase, as well as corrected dysbiosis and improved histological characteristics. Additionally, caspase-1 activity and IL-1β-driven pyroptotic activity was significantly reduced. Rosuvastatin/Lactobacillus showed prominent anti-inflammatory effects as revealed by the IL-10/IL-12 ratio and the levels of TNF-α and IL-6. These latter effects may be attributed to the inhibition of phosphorylation-induced activation of NF-κB and a concomitant reduction in the expression of NLRP3, pro-IL-1β, and pro-IL-18. Furthermore, rosuvastatin/Lactobacillus reduced Ox-LDL-induced TXNIP and attenuated the inflammatory response by inhibiting NLRP3 inflammasome assembly. To conclude, rosuvastatin/Lactobacillus offers a safe and effective strategy for the management of ulcerative colitis.
Collapse
Affiliation(s)
- Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
- Correspondence: (S.S.); or (A.M.E.-B.); Tel.: +2-01033124949 (S.S.); +2-01069096934 (A.M.E.-B.); Fax: +2-050-2770140 (S.S. & A.M.E.-B.)
| | - Eslam E. Abd El-Fattah
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt;
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia 44519, Egypt;
| | - Naglaa A. Gobba
- Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, Giza 12411, Egypt; or
| | - Abdalkareem Omar Maghmomeh
- Department of Biochemistry, Faculty of Pharmacy, Arab Private University for Science and Technology, Hama 1293400, Syria; or
| | - Ahmed E. Khodir
- Department of Pharmacology, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt; or
| | - Ahmed A. E. Mourad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt; (A.A.E.M.); (A.S.S.)
| | - Ahmed S. Saad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt; (A.A.E.M.); (A.S.S.)
| | | | - Nehal A. Nouh
- Department of Microbiology, Albatterjee Medical College, Jeddah 6231, Saudi Arabia;
| | - Ahmed Shata
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Noha A. Amin
- Department of Haematology, Theodor Bilharz Research Institute, Giza 12411, Egypt; or
| | - Magdy Abou El-Rous
- Department of Biochemistry, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt; or
| | - Samuel Girgis
- Department of Pharmaceutics, Faculty of Pharmacy, Alsalam University, Kafr El-Zayat 31612, Egypt;
| | - Eman El-Ahwany
- Department of Immunology, Theodor Bilharz Research Institute, Giza 12411, Egypt;
| | - Eman M. Khalaf
- Department of Microbiology and Immunology, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt;
| | - Attalla F. El-Kott
- Department of Biology, College of Science, King Khalid University, Abha 61421, Saudi Arabia;
- Department of Zoology, Faculty of Science, Damanhour University, Damanhour 22511, Egypt
| | - Ahmed M. El-Baz
- Department of Microbiology and Biotechnology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
- Correspondence: (S.S.); or (A.M.E.-B.); Tel.: +2-01033124949 (S.S.); +2-01069096934 (A.M.E.-B.); Fax: +2-050-2770140 (S.S. & A.M.E.-B.)
| |
Collapse
|
|
21
|
Xu Q, Zhou X, Strober W, Mao L. Inflammasome Regulation: Therapeutic Potential for Inflammatory Bowel Disease. Molecules 2021; 26:molecules26061725. [PMID: 33808793 PMCID: PMC8003415 DOI: 10.3390/molecules26061725] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor for the development of IBD. Inflammasomes and related cytokines play an important role in the maintenance of gut immune homeostasis, while its overactivation might induce excess immune responses and consequently cause tissue damage in the gut. Emerging studies provide evidence that some genetic abnormalities might induce enhanced NLRP3 inflammasome activation and cause colitis. In these cases, the colonic inflammation can be ameliorated by blocking NLRP3 activation or its downstream cytokine IL-1β. A number of natural products were shown to play a role in preventing colon inflammation in various experimental colitis models. On the other hand, lack of inflammasome function also causes intestinal abnormalities. Thus, an appropriate regulation of inflammasomes might be a promising therapeutic strategy for IBD intervention. This review aims at summarizing the main findings in these studies and provide an outline for further studies that might contribute to our understanding of the role of inflammasomes in the pathogenesis and therapeutic treatment of IBD.
Collapse
Affiliation(s)
- Qiuyun Xu
- Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226019, China; (Q.X.); (X.Z.)
| | - Xiaorong Zhou
- Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226019, China; (Q.X.); (X.Z.)
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Correspondence: (W.S.); (L.M.)
| | - Liming Mao
- Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226019, China; (Q.X.); (X.Z.)
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong 226019, China
- Correspondence: (W.S.); (L.M.)
| |
Collapse
|
|
22
|
Editorial of Special Issue "Regulatory Roles of Inflammasomes in Human Diseases". Int J Mol Sci 2021; 22:ijms22063008. [PMID: 33809447 PMCID: PMC7999501 DOI: 10.3390/ijms22063008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 03/15/2021] [Indexed: 12/20/2022] Open
Abstract
Inflammation is an innate immunity protecting the body from pathogens and cellular damages and comprises two steps; 1) priming (preparatory step) and triggering (activation step). The key feature of the triggering step is the activation of inflammasomes that are intracellular protein complexes consisting of pattern recognition receptors and inflammatory molecules. Inflammasomes are activated in response to various ligands, leading to the caspase-1-mediated maturation and secretion of pro-inflammatory cytokines, IL-1β and IL-18 and the gasdermin D-mediated pyroptosis, an inflammatory form of cell death. Previous studies have demonstrated that inflammasome activation is a key determinant of inflammatory responses and many human diseases; therefore, inflammasomes have been attracted much attention as critical drug targets to prevent and treat various human diseases.
Collapse
|