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Chen L, Cai Z, Xiao D, Shi Y, Xiao Q, Liang M, Jiang Y, Huang Y, Liang F, Zhou G, Zhuang F, Wang X, Huo H, Fang L, Shao Q, He B. SENP3 Drives Abdominal Aortic Aneurysm Development by Regulating Ferroptosis via De-SUMOylation of CTH. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2414500. [PMID: 40019399 PMCID: PMC12021093 DOI: 10.1002/advs.202414500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/06/2025] [Indexed: 03/01/2025]
Abstract
Abdominal aortic aneurysm (AAA) is a high-risk inflammatory disorder. SENP3, a SUMO2/3-specific protease, is closely involved in the development of cancer. In this study, the aim is to explore the role of SENP3 in macrophages in AAA. It is found that the protein expression of SENP3 is significantly upregulated in both human and murine AAA specimens. SENP3 expression is negatively regulated by the E3 ubiquitin ligase STUB1/CHIP. Furthermore, myeloid-specific SENP3 knockout inhibited AAA formation in both AngII- and CaCl2-induced mouse models. SENP3 deficiency repressed AAA lesion macrophage infiltration and inflammatory response. Mechanistic studies identified Cystathionine Gamma-Lyase (CTH), a critical enzyme involved in hydrogen sulfide production, as a target protein of SENP3 that mediated the exacerbating effects of SENP3 on ferroptosis and inflammatory programs in macrophages. SUMO-3 modification at Lysine 361 promoted CTH protein stability, whereas de-SUMOylation by SENP3 facilitated its proteasome-dependent degradation. Most importantly, it is found that CTH inhibitor counteracted the protective effect of SENP3 deficiency on AAA. Additionally, supplementation with ATB346, a novel H2S-donating naproxen derivative, prevented AAA development in mice. These studies suggest that SENP3-mediated CTH deSUMOylation regulates macrophage ferroptosis and AAA development. The SENP3/CTH axis is therefore an important therapeutic target for aortic aneurysmal diseases.
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Affiliation(s)
- Long Chen
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Zhaohua Cai
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Danrui Xiao
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Yiping Shi
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Qingqing Xiao
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Min Liang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Yangjing Jiang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Yijie Huang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Feng Liang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Guo Zhou
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Fei Zhuang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Xia Wang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Huanhuan Huo
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Liang Fang
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Qin Shao
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
| | - Ben He
- Department of CardiologyShanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai200030China
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Hayes JA, Lunger AW, Sharma AS, Fernez MT, Koppes AN, Koppes R, Woolston BM. Engineered bacteria titrate hydrogen sulfide and induce concentration-dependent effects on host in a gut microphysiological system. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.16.538950. [PMID: 37293009 PMCID: PMC10245736 DOI: 10.1101/2023.05.16.538950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Hydrogen sulfide (H2S) is a gaseous microbial metabolite whose role in gut diseases is debated, largely due to the difficulty in controlling its concentration and the use of non-representative model systems in previous work. Here, we engineered E. coli to titrate H2S controllably across the physiological range in a gut microphysiological system (chip) supportive of the co-culture of microbes and host cells. The chip was designed to maintain H2S gas tension and enable visualization of co-culture in real-time with confocal microscopy. Engineered strains colonized the chip and were metabolically active for two days, during which they produced H2S across a sixteen-fold range and induced changes in host gene expression and metabolism in an H2S concentration-dependent manner. These results validate a novel platform for studying the mechanisms underlying microbe-host interactions, by enabling experiments that are infeasible with current animal and in vitro models.
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Affiliation(s)
- Justin A. Hayes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
| | - Anna W. Lunger
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
| | - Aayushi S. Sharma
- Department of Mechanical and Industrial Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
- Department of Bioengineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
| | - Matthew T. Fernez
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
| | - Abigail N. Koppes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
- Department of Bioengineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
| | - Ryan Koppes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
| | - Benjamin M. Woolston
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
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Qiu H, Wang W, Hu K, Liu W, Pan S, Lv Q, Xu G, Yu Q. EuHD1 protects against inflammatory injury driven by NLRP3 inflammasome. Int Immunopharmacol 2023; 115:109712. [PMID: 37724954 DOI: 10.1016/j.intimp.2023.109712] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/19/2022] [Accepted: 01/06/2023] [Indexed: 01/21/2023]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) possessing anti-inflammatory, analgesic and antipyretic activities, are widely used in the treatment of osteoarthritis, rheumatism and rheumatoid arthritis. However, its long-term or large use will cause serious gastrointestinal injury or cardiovascular adverse reactions, which limits its clinical application. We have synthesized a new class of NSAIDs, EuHD1, which can release hydrogen sulfide and have better gastrointestinal safety. However, the anti-inflammatory molecular mechanism of the drug is still unclear. In this paper, we explored the mechanism of EuHD1 on NLRP3 inflammasome and its effects on acute lung injury and acute liver injury in mice. In vitro results demonstrated that EuHD1 inhibited macrophage pyroptosis and LDH release induced by LPS combined with ATP. In addition, EuHD1 blocked NLRP3 inflammasome activation and suppressed following Caspase-1 activation and secretion of mature IL-1β. EuHD1 restrained intracellular ROS production and the formation of ASC oligomers, which inhibited the assembly and activation of NLRP3 inflammasome. In vivo results further showed that EuHD1 alleviated LPS-induced acute lung injury in mice, and inhibited the production of mature IL-1β and Caspase-1 (p20). Besides, EuHD1 improved D-GalN/LPS-induced acute liver injury, and inhibited SOD/MDA levels and oxidative stress injury, and blocked the activation of NLRP3 inflammasome. In summary, we found that EuHD1 inhibits the assembly and activation of NLRP3 inflammasome through restraining the production of ROS and the formation of ASC oligomers, and has therapeutic effects on acute lung injury and liver injury in mice, indicating that EuHD1 has the potential to treat NLRP3 inflammasome-related diseases.
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Affiliation(s)
- Huanhuan Qiu
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, China
| | - Wei Wang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, China
| | - Kejun Hu
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Wangwang Liu
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Shumin Pan
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Qi Lv
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Guanglin Xu
- College of Life Science, Nanjing Normal University, Nanjing, China; Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
| | - Qingfeng Yu
- School of Science, China Pharmaceutical University, Nanjing, China.
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Xu J, Lv Q, Pan S, Qiu H, Liao Y, Zhou M, Li W, Li C, Zhang P, Li Y, Xu G, Yu Q. M378 exhibits anti-inflammatory activities through NLRP3 signaling pathway. Eur J Pharmacol 2022; 933:175261. [PMID: 36100126 DOI: 10.1016/j.ejphar.2022.175261] [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: 12/23/2021] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 11/03/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used drugs due to their values in attenuating pain, fever and inflammation. Unfortunately, conspicuous adverse effects, such as gastrointestinal (GI) damage and/or cardiovascular events have impeded their application in clinic. M378 is a novel hydrogen sulfide-releasing NSAIDs with uncompromised potency and negligible toxicity compared to the existing NSAIDs. However, its anti-inflammatory activity and mechanism are still an enigma. Here we investigated the effect of M378 on the NLRP3 inflammasome signaling pathway and addressed the underlying molecular mechanism. Our data in vitro showed that M378 dose-dependently inhibited the cleavage of Caspase-1 and the secretion of active IL-1β and blocked NLRP3-dependent pyroptosis in LPS-primed J774A.1 macrophages. Furthermore, M378 remarkably inhibited upstream ASC oligomerization and ROS production regarding the process of NLRP3 inflammasome assembly. Our data in vivo demonstrated that M378 protected mice from acute liver injury, reducing the levels of ALT/AST and IL-1β and improving hepatic pathological damages. Immunoblot analysis revealed that M378 inhibited the expressions of Caspase-1 and IL-1β in liver tissues of ALI mice. We also showed that M378 alleviated IL-1β secretion and peritoneal neutrophils infiltration in MSU-elicited acute peritonitis mice. In conclusion, M378 exerted its anti-inflammatory effect both in vitro and in vivo and its mechanisms are at least connected to its inhibitory performance on the generation of ASC oligomers and ROS production. These findings give an insight. into the molecular mechanism of hydrogen sulfide-releasing NSAIDs and support a potent therapeutic role of M378 in the treatment of NLRP3-driven inflammatory diseases.
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Affiliation(s)
- Jinling Xu
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Qi Lv
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Shumin Pan
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Huanhuan Qiu
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, China
| | - Yu Liao
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, China
| | - Ming Zhou
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Weijie Li
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Caiyan Li
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Pan Zhang
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Yujian Li
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Guanglin Xu
- College of Life Science, Nanjing Normal University, Nanjing, China; Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
| | - Qingfeng Yu
- School of Science, China Pharmaceutical University, Nanjing, China.
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Gupta R, Sahu M, Tripathi R, Ambasta RK, Kumar P. Protein S-sulfhydration: Unraveling the prospective of hydrogen sulfide in the brain, vasculature and neurological manifestations. Ageing Res Rev 2022; 76:101579. [PMID: 35124235 DOI: 10.1016/j.arr.2022.101579] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/30/2022] [Accepted: 02/01/2022] [Indexed: 02/08/2023]
Abstract
Hydrogen sulfide (H2S) and hydrogen polysulfides (H2Sn) are essential regulatory signaling molecules generated by the entire body, including the central nervous system. Researchers have focused on the classical H2S signaling from the past several decades, whereas the last decade has shown the emergence of H2S-induced protein S-sulfhydration signaling as a potential therapeutic approach. Cysteine S-persulfidation is a critical paradigm of post-translational modification in the process of H2S signaling. Additionally, studies have shown the cross-relationship between S-sulfhydration and other cysteine-induced post-translational modifications, namely nitrosylation and carbonylation. In the central nervous system, S-sulfhydration is involved in the cytoprotection through various signaling pathways, viz. inflammatory response, oxidative stress, endoplasmic reticulum stress, atherosclerosis, thrombosis, and angiogenesis. Further, studies have demonstrated H2S-induced S-sulfhydration in regulating different biological processes, such as mitochondrial integrity, calcium homeostasis, blood-brain permeability, cerebral blood flow, and long-term potentiation. Thus, protein S-sulfhydration becomes a crucial regulatory molecule in cerebrovascular and neurodegenerative diseases. Herein, we first described the generation of intracellular H2S followed by the application of H2S in the regulation of cerebral blood flow and blood-brain permeability. Further, we described the involvement of S-sulfhydration in different biological and cellular functions, such as inflammatory response, mitochondrial integrity, calcium imbalance, and oxidative stress. Moreover, we highlighted the importance of S-sulfhydration in cerebrovascular and neurodegenerative diseases.
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Głowacka U, Magierowska K, Wójcik D, Hankus J, Szetela M, Cieszkowski J, Korbut E, Danielak A, Surmiak M, Chmura A, Wallace JL, Magierowski M. Microbiome Profile and Molecular Pathways Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroidal Anti-Inflammatory Drug (ATB-352): Insight into Possible Safer Polypharmacy. Antioxid Redox Signal 2022; 36:189-210. [PMID: 33678013 DOI: 10.1089/ars.2020.8240] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aims: Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (H2S) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel H2S-releasing derivative of ketoprofen (ATB-352) versus classic ketoprofen and the molecular mechanisms of their activity after chronic treatment in experimental animal models. Results: Ketoprofen (10 mg/kg/day) administered intragastrically for 7 days in contrast with ATB-352 (14 mg/kg/day) reduced mucosal H2S content inducing GI damage with significantly increased injury score, altered intestinal microbiome profile, and modulation of more than 50% of 36 investigated molecular sensors (e.g., mammalian target of rapamycin or suppressor of cytokine signaling 3 [SOCS3]). Polypharmacy with aspirin (10 mg/kg/day) enhanced ketoprofen toxicity not affecting GI safety of ATB-352. Omeprazole (20 mg/kg/day) decreased ketoprofen-induced injury to the level of ATB-352 alone. Both compounds combined or not with aspirin or omeprazole maintained the ability to inhibit cyclooxygenase (COX) activity manifested by decreased prostaglandin production. Innovation and Conclusions: Ketoprofen-induced H2S-production decrease and intestinal microbiome profile alterations lead to GI toxicity observed on macro-/microscopic and molecular levels. Ketoprofen but not ATB-352 requires concomitant treatment with omeprazole to eliminate GI adverse effects. ATB-352 applied alone or in a polypharmacy setting with aspirin effectively inhibited COX and maintained GI safety due to H2S-release. Neither compound affected DNA oxidation in the GI mucosa, but ATB-352 had lower impact on molecular oxidative/inflammatory response pathways and intestinal microbiome. The GI safety of ATB-352 could be due to the involvement of heme oxygenase 1 and SOCS3 pathway activation. Antioxid. Redox Signal. 36, 189-210.
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Affiliation(s)
- Urszula Głowacka
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | | | - Dagmara Wójcik
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Jerzy Hankus
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow, Poland
| | - Małgorzata Szetela
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Jakub Cieszkowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Edyta Korbut
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Aleksandra Danielak
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.,Department of Internal Medicine, Jagiellonian University Medical College, Cracow, Poland
| | - Anna Chmura
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada
| | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
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Jiang M, Lv K. Ameliorative efficacy of oxypaeoniflorin, a traditional chinese medicine monomer against adjuvant-induced arthritic inflammation and pain. Pharmacogn Mag 2022. [DOI: 10.4103/pm.pm_571_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Ahlawat S, Shankar A, Vandna, Mohan H, Sharma KK. Yersinia enterocolitica and Lactobacillus fermentum induces differential cellular and behavioral responses during diclofenac biotransformation in rat gut. Toxicol Appl Pharmacol 2021; 431:115741. [PMID: 34619158 DOI: 10.1016/j.taap.2021.115741] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce small-intestinal injuries through inhibition of prostaglandin synthesis. Gut has an important role in building and maintaining the barriers to avoid the luminal gut microbiota from invading the host, and cytoskeleton plays a crucial role in the maintenance of cellular barrier. The recent advances suggest a bi-directional interaction between the drugs and gut microbiota, where gut microbes can metabolize the drugs, and in response drugs can alter the composition of gut microbiota. In the present study, we evaluated the effect of diclofenac on rat gut, when co-administrated with either Yersinia enterocolitica strain 8081 (an enteropathogen) or Lactobacillus fermentum strain 9338 (a probiotic). The LC-MS/MS based label-free quantitation of rat gut proteins revealed 51.38% up-regulated, 48.62% down-regulated in diclofenac-Y. enterocolitica strain 8081 (D*Y), and 74.31% up-regulated, 25.69% down-regulated in diclofenac-L. fermentum strain 9338 (D*L) experiments. The identified proteins belonged to cytoskeleton, metabolism, heme biosynthesis and binding, stress response, apoptosis and redox homeostasis, immune and inflammatory response, and detoxification and antioxidant defence. Further, the histopathological and biochemical analysis indicated more pronounced histological alterations and oxidative stress (enhanced malonaldehyde and altered antioxidant levels) in D*Y rats than D*L rats, compared to control rats. Elevated plus maze (EPM) test performed to determine the behavioral changes, suggested increased anxiety in D*Y rats than D*L rats, compared to control rats. These results together suggest the differential role of either bacterium in biotransformation of diclofenac, and inflammatory and cellular redox response.
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Affiliation(s)
- Shruti Ahlawat
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana, India; Presently at SGT University, Gurgaon-Badli Road Chandu, Budhera, Gurugram 122505, Haryana, India
| | - Akshay Shankar
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Vandna
- Department of Medical Biotechnology, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Hari Mohan
- Department of Medical Biotechnology, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Krishna Kant Sharma
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana, India.
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Luo Y, Zhu LP, Lei Y, Zhao JW, Wang BM, Chen X. Research progress of non-steroidal anti-inflammatory drug-induced small intestinal injury. Shijie Huaren Xiaohua Zazhi 2021; 29:1191-1200. [DOI: 10.11569/wcjd.v29.i20.1191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely around the world because of their anti-inflammatory, analgesic, and antiplatelet activity. However, long-term application of NSAIDs can lead to complications. Previously, the clinical attention was dedicated to the NSAID-induced upper gastrointestinal complications. Recently, the detection rate of small intestinal damage related to NSAIDs has increased due to the wide use of endoscopes such as capsule endoscopy and double-balloon colonoscopy. Although the majority of patients have no significant symptoms, there are still a small percentage of patients who develop obvious symptoms or complicated ulcers that require therapeutic intervention. Despite significant advances in our understanding of NSAIDs, the treatment modality and regimen for NSAID-induced small intestinal damage have remained relatively unclear. This article will provide a comprehensive overview of NSAID-induced small intestinal damage with regard to the epidemiology, clinical manifestations, diagnosis, risk factors, pathogenesis, and treatment, in order to provide informative evidence for clinical practice.
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Affiliation(s)
- Yang Luo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Lan-Ping Zhu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yue Lei
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jing-Wen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Malvidin Protects against and Repairs Peptic Ulcers in Mice by Alleviating Oxidative Stress and Inflammation. Nutrients 2021; 13:nu13103312. [PMID: 34684313 PMCID: PMC8537945 DOI: 10.3390/nu13103312] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022] Open
Abstract
Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg−1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.
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11
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Danielak A, Wallace JL, Brzozowski T, Magierowski M. Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology. Front Pharmacol 2021; 12:657457. [PMID: 33995080 PMCID: PMC8116801 DOI: 10.3389/fphar.2021.657457] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H2S and CO, a novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms.
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Affiliation(s)
- Aleksandra Danielak
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
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12
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Oncel S, Gupta R, Wang Q, Basson MD. ZINC40099027 Promotes Gastric Mucosal Repair in Ongoing Aspirin-Associated Gastric Injury by Activating Focal Adhesion Kinase. Cells 2021; 10:908. [PMID: 33920786 PMCID: PMC8071155 DOI: 10.3390/cells10040908] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/06/2021] [Accepted: 04/13/2021] [Indexed: 12/23/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs cause gastric ulcers and gastritis. No drug that treats GI injury directly stimulates mucosal healing. ZINC40099027 (ZN27) activates focal adhesion kinase (FAK) and heals acute indomethacin-induced small bowel injury. We investigated the efficacy of ZN27 in rat and human gastric epithelial cells and ongoing aspirin-associated gastric injury. ZN27 (10 nM) stimulated FAK activation and wound closure in rat and human gastric cell lines. C57BL/6J mice were treated with 300 mg/kg/day aspirin for five days to induce ongoing gastric injury. One day after the initial injury, mice received 900 µg/kg/6 h ZN27, 10 mg/kg/day omeprazole, or 900 µg/kg/6 h ZN27 plus 10 mg/kg/day omeprazole. Like omeprazole, ZN27 reduced gastric injury vs. vehicle controls. ZN27-treated mice displayed better gastric architecture, with thicker mucosa and less hyperemia, inflammation, and submucosal edema, and lost less weight than vehicle controls. Gastric pH, serum creatinine, serum alanine aminotransferase (ALT), and renal and hepatic histology were unaffected by ZN27. Blinded scoring of pFAK-Y-397 immunoreactivity at the edge of ZN27-treated lesions demonstrated increased FAK activation, compared to vehicle-treated lesions, confirming target activation in vivo. These results suggest that ZN27 ameliorates ongoing aspirin-associated gastric mucosal injury by a pathway involving FAK activation. ZN27-derivatives may be useful to promote gastric mucosal repair.
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Affiliation(s)
- Sema Oncel
- Department of Biomedical Sciences, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA;
| | - Rashmi Gupta
- Department of Surgery, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA; (R.G.); (Q.W.)
| | - Qinggang Wang
- Department of Surgery, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA; (R.G.); (Q.W.)
| | - Marc D. Basson
- Department of Biomedical Sciences, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA;
- Department of Surgery, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA; (R.G.); (Q.W.)
- Department of Pathology, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA
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13
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Fening NY. Novel NSAIDs. SOUTHERN AFRICAN JOURNAL OF ANAESTHESIA AND ANALGESIA 2020. [DOI: 10.36303/sajaa.2020.26.6.s3.2536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most commonly used drugs to relieve a multitude of pain symptoms.F They are readily available and used extensively. There is a lot of concern about their adverse side effects namely cardiovascular (CV) and gastrointestinal (GI) side effects. It is important to have a good grasp of the pharmacology of these drugs in order to use them safely and effectively. NSAIDs work by inhibiting the cyclooxygenase (COX) enzyme system responsible for production of prostaglandins. Prostaglandins mediate pain inflammation and temperature regulation in the body. NSAIDS can be divided into selective and non-selective types. Three isoforms of COX have been identified COX-1, COX-2 and COX-3. Selective NSAIDs act on these isoforms. COX-1 is anti-inflammatory, COX-2 pro-inflammatory and COX-3, a variant of COX-1, does not produce prostaglandins. The CV side effects of these drugs can be wide ranging and include a rise in blood pressure (BP) and a higher risk of thromboembolic events. Patients also suffer from peptic ulcer disease or bleeding in the stomach as a result of their use. NSAIDs can cause liver and kidney toxicity and should be used with caution in patients with bleeding tendencies. New NSAIDs on the market include; lornoxicam (xefo®), meloxicam (coxflam®), celecoxib (celebrex®), parecoxib (rayzon®) and etoricoxib (arcoxia®). New ways of delivering NSAIDs to the body with minimal or no side effects are being researched. Novel technology in this field includes nano formulated NSAIDs; indomethacin (tivorbex®) and dicofenac (zorvolex), prodrugs and multi action drugs; cyclooxygenase inhibiting nitric oxide donors and hydrogen sulphide releasing drugs. Further exciting innovations are in the pipeline that could change the face of how we use these drugs. Until then they must be used with careful consideration and only if the benefits of use outweigh the risks.
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Bonvicini F, Pagnotta E, Punzo A, Calabria D, Simoni P, Mirasoli M, Passerini N, Bertoni S, Ugolini L, Lazzeri L, Gentilomi GA, Caliceti C, Roda A. Effect of Lactobacillus acidophilus Fermented Broths Enriched with Eruca sativa Seed Extracts on Intestinal Barrier and Inflammation in a Co-Culture System of an Enterohemorrhagic Escherichia coli and Human Intestinal Cells. Nutrients 2020; 12:nu12103064. [PMID: 33036498 PMCID: PMC7600469 DOI: 10.3390/nu12103064] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/02/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022] Open
Abstract
Lactic acid bacteria (LAB) “fermentates” confer a beneficial effect on intestinal function. However, the ability of new fermentations to improve LAB broth activity in preventing pathogen-induced intestinal inflammation and barrier dysfunction has not yet been studied. The objective of this study was to determine if broths of LAB fermented with Eruca sativa or Barbarea verna seed extracts prevent gut barrier dysfunction and interleukin-8 (CXCL8) release in vitro in human intestinal Caco-2 cells infected with enterohemorrhagic Escherichia coli (EHEC) O157:H7. LAB broths were assayed for their effects on EHEC growth and on Caco-2 viability; thereafter, their biological properties were analysed in a co-culture system consisting of EHEC and Caco-2 cells. Caco-2 cells infected with EHEC significantly increased CXCL8 release, and decreased Trans-Epithelial Electrical Resistance (TEER), a barrier-integrity marker. Notably, when Caco-2 cells were treated with LAB broth enriched with E. sativa seed extract and thereafter infected, both CXCL8 expression and epithelial dysfunction reduced compared to in untreated cells. These results underline the beneficial effect of broths from LAB fermented with E. sativa seed extracts in gut barrier and inflammation after EHEC infection and reveal that these LAB broths can be used as functional bioactive compounds to regulate intestinal function.
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Affiliation(s)
- Francesca Bonvicini
- Department of Pharmacy and Biotechnology—FABIT, University of Bologna, 40126 Bologna, Italy; (F.B.); (N.P.); (S.B.); (G.A.G.)
| | - Eleonora Pagnotta
- CREA-Council for Agricultural Research and Economics, Research Centre for Cereal and Industrial Crops, via di Corticella 133, 40128 Bologna, Italy; (E.P.); (L.U.); (L.L.)
| | - Angela Punzo
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy; (A.P.); (D.C.); (M.M.); (A.R.)
| | - Donato Calabria
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy; (A.P.); (D.C.); (M.M.); (A.R.)
| | - Patrizia Simoni
- Department of Medical and Surgical Sciences—DIMEC, University of Bologna, 40126 Bologna, Italy;
| | - Mara Mirasoli
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy; (A.P.); (D.C.); (M.M.); (A.R.)
| | - Nadia Passerini
- Department of Pharmacy and Biotechnology—FABIT, University of Bologna, 40126 Bologna, Italy; (F.B.); (N.P.); (S.B.); (G.A.G.)
| | - Serena Bertoni
- Department of Pharmacy and Biotechnology—FABIT, University of Bologna, 40126 Bologna, Italy; (F.B.); (N.P.); (S.B.); (G.A.G.)
| | - Luisa Ugolini
- CREA-Council for Agricultural Research and Economics, Research Centre for Cereal and Industrial Crops, via di Corticella 133, 40128 Bologna, Italy; (E.P.); (L.U.); (L.L.)
| | - Luca Lazzeri
- CREA-Council for Agricultural Research and Economics, Research Centre for Cereal and Industrial Crops, via di Corticella 133, 40128 Bologna, Italy; (E.P.); (L.U.); (L.L.)
| | - Giovanna Angela Gentilomi
- Department of Pharmacy and Biotechnology—FABIT, University of Bologna, 40126 Bologna, Italy; (F.B.); (N.P.); (S.B.); (G.A.G.)
| | - Cristiana Caliceti
- Department of Biomedical and Neuromotor Sciences—DIBINEM, University of Bologna, 40126 Bologna, Italy
- Istituto Nazionale Biosistemi e Biostrutture—INBB, 00136 Rome, Italy
- Correspondence:
| | - Aldo Roda
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy; (A.P.); (D.C.); (M.M.); (A.R.)
- Istituto Nazionale Biosistemi e Biostrutture—INBB, 00136 Rome, Italy
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Wallace JL, Nagy P, Feener TD, Allain T, Ditrói T, Vaughan DJ, Muscara MN, de Nucci G, Buret AG. A proof-of-concept, Phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide-releasing anti-inflammatory drug. Br J Pharmacol 2020; 177:769-777. [PMID: 30834513 PMCID: PMC7024706 DOI: 10.1111/bph.14641] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 02/07/2019] [Accepted: 02/16/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE ATB-346 is a hydrogen sulfide (H2 S)-releasing anti-inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti-inflammatory effects. In humans, ATB-346 (250 mg once daily) was found to inhibit COX to the same extent as naproxen (550 mg twice daily). EXPERIMENTAL APPROACH Two hundred forty-four healthy volunteers completed a 2-week, double-blind study, taking either ATB-346 (250 mg once daily) or naproxen (550 mg twice daily), with upper GI ulceration being examined endoscopically. KEY RESULTS Forty-two per cent of the subjects taking naproxen developed at least one ulcer (≥3-mm diameter), while only 3% of the subjects taking ATB-346 developed at least one ulcer. The two drugs produced comparable and substantial (>94%) suppression of COX activity. Subjects in the naproxen group developed more ulcers per subject than ATB-346-treated subjects and a greater incidence of larger ulcers (≥5-mm diameter). The incidence of dyspepsia, abdominal pain, gastro-oesophageal reflux, and nausea was lower with ATB-346 than with naproxen. Subjects treated with ATB-346 had significantly higher plasma levels of H2 S than those treated with naproxen. CONCLUSIONS AND IMPLICATIONS This Phase 2B study provides unequivocal evidence for a marked reduction of GI toxicity of the H2 S-releasing analgesic/anti-inflammatory drug, ATB-346, as compared to the conventional dose of naproxen that produced equivalent suppression of COX. LINKED ARTICLES This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
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Affiliation(s)
- John L. Wallace
- Department of Physiology and PharmacologyUniversity of CalgaryCalgaryABCanada
- Antibe Therapeutics Inc.TorontoONCanada
| | - Peter Nagy
- National Institute of OncologyBudapestHungary
- Department of Medicine, Faculty of MedicineUniversity of DebrecenDebrecenHungary
| | - Troy D. Feener
- Department of Biological SciencesUniversity of CalgaryCalgaryABCanada
| | - Thibault Allain
- Department of Biological SciencesUniversity of CalgaryCalgaryABCanada
| | | | | | | | | | - Andre G. Buret
- National Institute of OncologyBudapestHungary
- Department of Medicine, Faculty of MedicineUniversity of DebrecenDebrecenHungary
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16
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Human disorders associated with inflammation and the evolving role of natural products to overcome. Eur J Med Chem 2019; 179:272-309. [PMID: 31255927 DOI: 10.1016/j.ejmech.2019.06.034] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 06/12/2019] [Indexed: 12/11/2022]
Abstract
Inflammation is a biological function which triggered after the mechanical tissue disruption or from the responses by the incidence of physical, chemical or biological negotiator in body. These responses are essential act provided by the immune system during infection and tissue injury to maintain normal tissue homeostasis. Inflammation is a quite complicated process at molecular level with the involvement of several proinflammatory expressions. Several health problems are associated with prolonged inflammation, which effects nearly all major to minor diseases. The molecular and epidemiological studies jagged that the inflammation is closely associated with several disorders with their specific targets. It would be great achievement for human health around the world to overcome on inflammation. Mostly used anti-inflammatory drugs are at high risk of side effects and also expensive. Hence, the plant-based formulations gained a wide acceptance by the public and medical experts to treat it. Due to extensive dispersal, chemical diversity and systematically established biological potentials of natural products have induced renewed awareness as a gifted source for medications. However, today's urgent need to search for cheaper, more potent and safe anti-inflammatory medications to overcome on current situation. The goal of this review to compile an update on inflammation, associated diseases, molecular targets, inflammatory mediators and role of natural products. The entire text concise the involvement of various cytokines in pathogenesis of various human disorders. This assignment discussed about 321 natural products with their promising anti-inflammatory potential discovered during January 2009 to December 2018 with 262 citations.
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17
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García-Rayado G, Navarro M, Lanas A. NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs. Expert Rev Clin Pharmacol 2018; 11:1031-1043. [DOI: 10.1080/17512433.2018.1516143] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Guillermo García-Rayado
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- IIS Aragón, Zaragoza, Spain
| | - Mercedes Navarro
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- IIS Aragón, Zaragoza, Spain
| | - Angel Lanas
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- IIS Aragón, Zaragoza, Spain
- CIBERehd, Madrid, Spain
- University of Zaragoza, Zaragoza, Spain
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18
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Zhu LP, Zhao JW, Chen X, Wang BM. Proton pump inhibitor usage and nonsteroidal anti-inflammatory drugs-associated small intestinal injury: How to balance risks and benefits. Shijie Huaren Xiaohua Zazhi 2018; 26:1334-1339. [DOI: 10.11569/wcjd.v26.i22.1334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases and can effectively prevent upper gastrointestinal damage associated with nonsteroidal anti-inflammatory drugs (NSAIDs). However, recent studies have shown that PPIs cannot protect from NSAIDs-associated small bowel injury, and may even aggravate intestinal injury by altering the intestinal flora. This article will discuss the risks associated with the combined use of NSAIDs and PPIs, as well as how to balance risks and benefits of PPIs treatment, and provide a brief review of strategies for the prevention of NSAIDs-associated small bowel injury.
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Affiliation(s)
- Lan-Ping Zhu
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Jing-Wen Zhao
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, General Hospital of Tianjin Medical University, Tianjin 300052, China
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19
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Wallace JL, Vaughan D, Dicay M, MacNaughton WK, de Nucci G. Hydrogen Sulfide-Releasing Therapeutics: Translation to the Clinic. Antioxid Redox Signal 2018; 28:1533-1540. [PMID: 28388861 DOI: 10.1089/ars.2017.7068] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
SIGNIFICANCE Shortly after the discovery of the role of hydrogen sulfide (H2S) in many physiological and pathological processes, attempts were made to develop novel pharmaceuticals that may be of benefit for treatment or prevention of a wide range of disorders. The promise of H2S-based therapeutics is now being demonstrated in clinical trials. Recent Advances: H2S-releasing drugs, such as SG1002 for cardiovascular disorders, and ATB-346 for arthritis, have progressed into clinical trials and have shown considerable promise. Some older drugs, such as zofenopril, have now been recognized to produce at least some of the beneficial effects through release of H2S. CRITICAL ISSUES There remains a need to better understand the underlying mechanisms for some of the observed effects of H2S-releasing drugs in a clinical setting, such as the marked increase in analgesic potency that has been observed with ATB-346. FUTURE DIRECTIONS The proof-of-concept clinical studies reviewed herein pave the way for examination, in a clinical setting, of several other potential applications of H2S-based drugs in a wide range of disorders, including diabetes, hypertension, and cancer chemoprevention. Antioxid. Redox Signal. 28, 1533-1540.
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Affiliation(s)
- John L Wallace
- 1 Department of Physiology and Pharmacology, University of Calgary , Calgary, Canada .,2 Antibe Therapeutics, Inc. , Toronto, Canada .,3 Universidade Camilo Castelo Branco , Department of Medicine, Fernandopolis, Brazil
| | | | - Michael Dicay
- 1 Department of Physiology and Pharmacology, University of Calgary , Calgary, Canada
| | - Wallace K MacNaughton
- 1 Department of Physiology and Pharmacology, University of Calgary , Calgary, Canada
| | - Gilberto de Nucci
- 3 Universidade Camilo Castelo Branco , Department of Medicine, Fernandopolis, Brazil
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20
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Sub-chronic toxicological studies of transition metal complexes of naproxen on sprague-dawley rats. ALEXANDRIA JOURNAL OF MEDICINE 2017. [DOI: 10.1016/j.ajme.2016.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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21
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Szabo C, Papapetropoulos A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H 2S Levels: H 2S Donors and H 2S Biosynthesis Inhibitors. Pharmacol Rev 2017; 69:497-564. [PMID: 28978633 PMCID: PMC5629631 DOI: 10.1124/pr.117.014050] [Citation(s) in RCA: 304] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Affiliation(s)
- Csaba Szabo
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
| | - Andreas Papapetropoulos
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas (C.S.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece (A.P.); and Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (A.P.)
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22
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Wallace JL, Ianaro A, de Nucci G. Gaseous Mediators in Gastrointestinal Mucosal Defense and Injury. Dig Dis Sci 2017; 62:2223-2230. [PMID: 28733867 DOI: 10.1007/s10620-017-4681-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 07/11/2017] [Indexed: 12/26/2022]
Abstract
Of the numerous gaseous substances that can act as signaling molecules, the best characterized are nitric oxide, carbon monoxide and hydrogen sulfide. Contributions of each of these low molecular weight substances, alone or in combination, to maintenance of gastrointestinal mucosal integrity have been established. There is considerable overlap in the actions of these gases in modulating mucosal defense and responses to injury, and in some instances they act in a cooperative manner. Each also play important roles in regulating inflammatory and repair processes throughout the gastrointestinal tract. In recent years, significant progress has been made in the development of novel anti-inflammatory and cytoprotective drugs that exploit the beneficial activities of one or more of these gaseous mediators.
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Affiliation(s)
- John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. .,Department of Medicine, Universidade Camilo Castelo Branco, Fernandopolis, SP, Brazil.
| | - Angela Ianaro
- Department of Experimental Pharmacology, University of Naples, Naples, Italy
| | - Gilberto de Nucci
- Department of Medicine, Universidade Camilo Castelo Branco, Fernandopolis, SP, Brazil
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23
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H2S confers colonoprotection against TNBS-induced colitis by HO-1 upregulation in rats. Inflammopharmacology 2017; 26:479-489. [DOI: 10.1007/s10787-017-0382-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/22/2017] [Indexed: 12/31/2022]
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Utzeri E, Usai P. Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease. World J Gastroenterol 2017; 23:3954-3963. [PMID: 28652650 PMCID: PMC5473116 DOI: 10.3748/wjg.v23.i22.3954] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/19/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of non-alcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.
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25
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Grösch S, Niederberger E, Geisslinger G. Investigational drugs targeting the prostaglandin E2 signaling pathway for the treatment of inflammatory pain. Expert Opin Investig Drugs 2017; 26:51-61. [PMID: 27841017 DOI: 10.1080/13543784.2017.1260544] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Non-steroidal anti-inflammatory drugs (NSAID) are the most commonly used drugs for the treatment of pain, inflammation and fever. Although they are effective for a huge number of users, their analgesic properties are not sufficient for several patients and the occurrence of side effects still constitutes a big challenge during long term therapy. Areas covered: This review gives an overview about the first and second generations of NSAIDs (COX1/2 non-selective, COX-2 selective), and their main side effects which gave still an urgent need for safer drugs and for the establishment of novel treatment strategies (improved safety, tolerability, patient convenience). The current developments of a possible third generation NSAID class comprise changes in the formulation of already approved drugs, combination therapies, dual cyclooxygenase-lipoxygenase inhibitors, NO- and H2S-releasing NSAIDs, prostaglandin synthase inhibitors and EP receptor modulators, respectively. Literature search has been done with PubMed NCBI. Expert opinion: Currently, there is no newly developed drug that is superior to the already approved selective and non-selective NSAIDs. Several novel approaches show promising analgesic efficacy but side effects are still an important problem. Solutions might be constituted by combination therapies allowing administration of lower drug doses or by individualized therapies targeting molecules apart from COX, respectively.
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Affiliation(s)
- Sabine Grösch
- a Pharmazentrum frankfurt/ZAFES , Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt , Frankfurt am Main , Germany
| | - Ellen Niederberger
- a Pharmazentrum frankfurt/ZAFES , Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt , Frankfurt am Main , Germany
| | - Gerd Geisslinger
- a Pharmazentrum frankfurt/ZAFES , Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt , Frankfurt am Main , Germany
- b Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group for Translational Medicine & Pharmacology (TMP) , Frankfurt/Main , Germany
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Pereira-Leite C, Nunes C, Jamal SK, Cuccovia IM, Reis S. Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety. Med Res Rev 2016; 37:802-859. [PMID: 28005273 DOI: 10.1002/med.21424] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/27/2016] [Accepted: 10/05/2016] [Indexed: 01/01/2023]
Abstract
The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.
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Affiliation(s)
- Catarina Pereira-Leite
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.,Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Cláudia Nunes
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Sarah K Jamal
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Iolanda M Cuccovia
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Salette Reis
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
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27
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Functional and Molecular Insights of Hydrogen Sulfide Signaling and Protein Sulfhydration. J Mol Biol 2016; 429:543-561. [PMID: 28013031 DOI: 10.1016/j.jmb.2016.12.015] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 12/08/2016] [Accepted: 12/12/2016] [Indexed: 12/23/2022]
Abstract
Hydrogen sulfide (H2S), a novel gasotransmitter, is endogenously synthesized by multiple enzymes that are differentially expressed in the peripheral tissues and central nervous systems. H2S regulates a wide range of physiological processes, namely cardiovascular, neuronal, immune, respiratory, gastrointestinal, liver, and endocrine systems, by influencing cellular signaling pathways and sulfhydration of target proteins. This review focuses on the recent progress made in H2S signaling that affects mechanistic and functional aspects of several biological processes such as autophagy, inflammation, proliferation and differentiation of stem cell, cell survival/death, and cellular metabolism under both physiological and pathological conditions. Moreover, we highlighted the cross-talk between nitric oxide and H2S in several bilogical contexts.
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28
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Sukul A, Poddar SK, Saha SK, Das SC. Synthesis and characterization of cobalt and manganese complexes of indomethacin and comparative study of local analgesic, anti-inflammatory, and anti-ulcerogenic properties. RUSS J GEN CHEM+ 2016. [DOI: 10.1134/s1070363216080260] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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29
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Singh DP, Borse SP, Nivsarkar M. Clinical importance of nonsteroidal anti-inflammatory drug enteropathy: the relevance of tumor necrosis factor as a promising target. Transl Res 2016; 175:76-91. [PMID: 27083387 DOI: 10.1016/j.trsl.2016.03.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/18/2016] [Accepted: 03/21/2016] [Indexed: 12/13/2022]
Abstract
The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enteropathy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo.
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Affiliation(s)
- Devendra Pratap Singh
- Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Ahmedabad, Gujarat, India; Registered Ph.D Scholar (External) at Institute of Pharmacy, NIRMA University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India
| | - Swapnil P Borse
- Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Ahmedabad, Gujarat, India; Registered Ph.D Scholar (External) at Institute of Pharmacy, NIRMA University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, India
| | - Manish Nivsarkar
- Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej, Ahmedabad, Gujarat, India.
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30
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Ianaro A, Cirino G, Wallace JL. Hydrogen sulfide-releasing anti-inflammatory drugs for chemoprevention and treatment of cancer. Pharmacol Res 2016; 111:652-658. [PMID: 27475881 DOI: 10.1016/j.phrs.2016.07.041] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 07/05/2016] [Accepted: 07/26/2016] [Indexed: 02/07/2023]
Abstract
For many years it has been recognized that inhibition of cyclooxygenase enzymes is effective in reducing the incidence of many types of cancer, but the adverse effects of these drug, particularly in the gastrointestinal and cardiovascular systems, limits their utility. Recently developed hydrogen sulfide-releasing anti-inflammatory drugs may be a promising option for cancer chemoprevention. In this paper we review evidence suggesting that these novel compounds are effective in a range of animal models of various types of cancer, while exhibiting greatly reduced toxicity relative to currently marketed non-steroidal anti-inflammatory drugs. Some of the possible mechanisms of action of hydrogen sulfide-releasing anti-inflammatory drugs are also discussed.
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Affiliation(s)
- Angela Ianaro
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy; Faculty of Medicine, Universidade Camilo Castelo Branco, São Paulo, SP, Brazil
| | - John L Wallace
- Faculty of Medicine, Universidade Camilo Castelo Branco, São Paulo, SP, Brazil; Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.
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31
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Abstract
Non-steroidal anti-inflammatory drug (NSAID) use increases the risk of gastrointestinal complications such as ulcers or bleeding. The presence of factors like advanced age, history of peptic ulcer, Helicobacter pylori infection and the use of anticoagulants or antiplatelet agents increase this risk further. COX-2 inhibitors and antisecretory drugs, particularly proton pump inhibitors, help to minimize the risk of gastrointestinal complications in high-risk patients. This review presents a practical approach to the prevention and treatment of NSAID-associated peptic ulcer disease and examines the new advances in the rational use of NSAIDs.
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Affiliation(s)
- Luigi Melcarne
- a Unidad de Gastroenterología, Servicio de Digestivo , Corporació Sanitària Parc Taulí , Sabadell , Spain
| | - Pilar García-Iglesias
- a Unidad de Gastroenterología, Servicio de Digestivo , Corporació Sanitària Parc Taulí , Sabadell , Spain
| | - Xavier Calvet
- a Unidad de Gastroenterología, Servicio de Digestivo , Corporació Sanitària Parc Taulí , Sabadell , Spain.,b Departament de Medicina , Universitat Autònoma de Barcelona , Sabadell , Spain.,c CIBERehd , Instituto Carlos III , Madrid , Spain
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32
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Mayo SA, Song YK, Cruz MR, Phan TM, Singh KV, Garsin DA, Murray BE, Dial EJ, Lichtenberger LM. Indomethacin injury to the rat small intestine is dependent upon biliary secretion and is associated with overgrowth of enterococci. Physiol Rep 2016; 4:e12725. [PMID: 27033447 PMCID: PMC4814884 DOI: 10.14814/phy2.12725] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 01/21/2016] [Accepted: 02/06/2016] [Indexed: 12/14/2022] Open
Abstract
NSAIDuse is limited due to the drugs' toxicity to the gastrointestinal mucosa, an action incompletely understood. Lower gut injury induced byNSAIDs is dependent on bile secretion and is reported to increase the growth of a number of bacterial species, including an enterococcal species,Enterococcus faecalis This study examined the relationships between indomethacin (INDO)-induced intestinal injury/bleeding, small bowel overgrowth (SBO) and dissemination of enterococci, and the contribution of bile secretion to these pathological responses. Rats received either a sham operation (SO) or bile duct ligation (BDL) prior to administration of two daily subcutaneous doses of saline orINDO, and 24 h later, biopsies of ileum and liver were collected for plating on selective bacterial media. Fecal hemoglobin (Hb) and blood hematocrit (Hct) were measured to assess intestinal bleeding. Of the four treatment groups, onlySO/INDOrats experienced a significant 10- to 30-fold increase in fecal Hb and reduction in Hct, indicating thatBDLattenuatedINDO-induced intestinal injury/bleeding. Ileal enterococcal colony-forming units were significantly increased (500- to 1000-fold) inSO/INDOrats. Of all groups, only theSO/INDOrats demonstrated gut injury, and this was associated with enterococcal overgrowth of the gut and dissemination to the liver. We also demonstrated thatINDO-induced intestinal injury andE. faecalisovergrowth was independent of the route of administration of the drug, as similar findings were observed in rats orally dosed with theNSAID Bile secretion plays an important role inINDO-induced gut injury and appears to support enterococcal overgrowth of the intestine.NSAID-induced enterococcalSBOmay be involved either as a compensatory response to gut injury or with the pathogenic process itself and the subsequent development of sepsis.
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Affiliation(s)
- Sara A Mayo
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Ye K Song
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Melissa R Cruz
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Tri M Phan
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Kavindra V Singh
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Danielle A Garsin
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Barbara E Murray
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Elizabeth J Dial
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Lenard M Lichtenberger
- Departments of Integrative Biology & Pharmacology, Microbiology and Molecular Genetics, and Internal Medicine-Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas
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33
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A novel model for NSAID induced gastroenteropathy in rats. J Pharmacol Toxicol Methods 2016; 78:66-75. [DOI: 10.1016/j.vascn.2015.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 11/30/2015] [Accepted: 11/30/2015] [Indexed: 12/24/2022]
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34
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Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis. PLoS One 2016; 11:e0147289. [PMID: 26910063 PMCID: PMC4766010 DOI: 10.1371/journal.pone.0147289] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 01/02/2016] [Indexed: 12/21/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinal cancers, but the propensity of these drugs to cause ulcers and bleeding limits their use. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substance in the digestive system. This study explored the possibility that a H2S-releasing nonsteroidal anti-inflammatory drug (ATB-346) would be effective in a murine model of hereditary intestinal cancer (APCMin+ mouse) and investigated potential mechanisms of action via transcriptomics analysis. Daily treatment with ATB-346 was significantly more effective at preventing intestinal polyp formation than naproxen. Significant beneficial effects were seen with a treatment period of only 3–7 days, and reversal of existing polyps was observed in the colon. ATB-346, but not naproxen, significantly decreased expression of intestinal cancer-associated signaling molecules (cMyc, β-catenin). Transcriptomic analysis identified 20 genes that were up-regulated in APCMin+ mice, 18 of which were reduced to wild-type levels by one week of treatment with ATB-346. ATB-346 is a novel, gastrointestinal-sparing anti-inflammatory drug that potently and rapidly prevents and reverses the development of pre-cancerous lesions in a mouse model of hereditary intestinal tumorigenesis. These effects may be related to the combined effects of suppression of cyclooxygenase and release of H2S, and correction of most of the APCMin+-associated alterations in the transcriptome. ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GI tract and elsewhere.
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35
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Bos EM, van Goor H, Joles JA, Whiteman M, Leuvenink HGD. Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia. Br J Pharmacol 2016; 172:1479-93. [PMID: 25091411 DOI: 10.1111/bph.12869] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 06/19/2014] [Accepted: 07/27/2014] [Indexed: 12/19/2022] Open
Abstract
Hydrogen sulfide (H2 S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H2 S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia.
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Affiliation(s)
- Eelke M Bos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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36
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Gaseous mediator-based anti-inflammatory drugs. Curr Opin Pharmacol 2015; 25:1-6. [DOI: 10.1016/j.coph.2015.08.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 08/10/2015] [Indexed: 12/22/2022]
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37
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Liu CC, Fan Y, Zhang ZY. Advances in research of non-steroidal anti-inflammatory drugs induced small intestinal injury. Shijie Huaren Xiaohua Zazhi 2015; 23:5184-5189. [DOI: 10.11569/wcjd.v23.i32.5184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, anti-pyretic and analgesic properties and have been widely used in clinical practice; however, they can cause cytotoxicity in the gastrointestinal tract, especially in the intestine. The injurious effects of NSAIDs on the small intestine occur frequently and can lead to severe clinical outcomes. A multifactorial etiology is involved in the pathogenesis of these lesions. Current studies found that, in addition to the suppression of cyclooxygenase activity, several factors including enterobacterial invasion, neutrophil migration, enterohepatic cycling of NSAIDs, bile and mitochondrial injury have been implicated in the pathogenesis of these lesions. This article reviews the mechanisms and therapeutic strategies in NSAIDs induced intestinal injury.
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38
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Wallace JL, de Nucci G, Sulaieva O. Toward More GI-Friendly Anti-Inflammatory Medications. ACTA ACUST UNITED AC 2015; 13:377-85. [PMID: 26303996 DOI: 10.1007/s11938-015-0064-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OPINION STATEMENT Despite the introduction 20-30 years ago of potent inhibitors of gastric acid secretion and anti-inflammatory drugs that preferentially inhibit cyclo-oxygenase (COX)-2, the GI adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) remain a significant clinical concern and a considerable economic burden. Inhibitors of acid secretion and selective COX-2 inhibitors reduce damage only in the proximal GI tract (stomach and proximal duodenum), but NSAIDs produce injury and bleeding throughout the GI tract. The small intestinal damage caused by NSAIDs is common, difficult to diagnose, and there are no proven-effective preventative or curative therapies. There is also emerging evidence that proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs) exacerbate NSAID-induced small intestinal injury. A new approach to solve this clinical problem is to deliver an endogenous, cytoprotective "rescue molecule" together with a COX inhibitor. Hydrogen sulfide (H2S) is a naturally produced, potent protective agent in the GI tract. H2S-releasing NSAIDs have been synthesized and extensively tested in laboratory animals and humans. They exhibit improved anti-inflammatory activity over the parent NSAID, while causing negligible damage in the GI tract.
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Affiliation(s)
- John L Wallace
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada. .,Faculty of Medicine, Universidade Camilo Castelo Branco, São Paulo, SP, Brazil. .,, 15 Prince Arthur Avenue, Toronto, ON, M5R 1B2, Canada.
| | - Gilberto de Nucci
- Faculty of Medicine, Universidade Camilo Castelo Branco, São Paulo, SP, Brazil.
| | - Oksana Sulaieva
- Department of Histology, Zaporozhye State Medical University, Zaporozhye, Ukraine.
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Kodela R, Nath N, Chattopadhyay M, Nesbitt DE, Velázquez-Martínez CA, Kashfi K. Hydrogen sulfide-releasing naproxen suppresses colon cancer cell growth and inhibits NF-κB signaling. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:4873-82. [PMID: 26346117 PMCID: PMC4554424 DOI: 10.2147/dddt.s91116] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) is the second leading cause of death due to cancer and the third most common cancer in men and women in the USA. Nuclear factor kappa B (NF-κB) is known to be activated in CRC and is strongly implicated in its development and progression. Therefore, activated NF-κB constitutes a bona fide target for drug development in this type of malignancy. Many epidemiological and interventional studies have established nonsteroidal anti-inflammatory drugs (NSAIDs) as a viable chemopreventive strategy against CRC. Our previous studies have shown that several novel hydrogen sulfide-releasing NSAIDs are promising anticancer agents and are safer derivatives of NSAIDs. In this study, we examined the growth inhibitory effect of a novel H2S-releasing naproxen (HS-NAP), which has a repertoire as a cardiovascular-safe NSAID, for its effects on cell proliferation, cell cycle phase transitions, and apoptosis using HT-29 human colon cancer cells. We also investigated its effect as a chemo-preventive agent in a xenograft mouse model. HS-NAP suppressed the growth of HT-29 cells by induction of G0/G1 arrest and apoptosis and downregulated NF-κB. Tumor xenografts in mice were significantly reduced in volume. The decrease in tumor mass was associated with a reduction of cell proliferation, induction of apoptosis, and decreases in NF-κB levels in vivo. Therefore, HS-NAP demonstrates strong anticancer potential in CRC.
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Affiliation(s)
- Ravinder Kodela
- Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA
| | - Niharika Nath
- Department of Life Sciences, New York Institute of Technology, New York, NY, USA
| | - Mitali Chattopadhyay
- Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA
| | - Diandra E Nesbitt
- Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA
| | | | - Khosrow Kashfi
- Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY, USA
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40
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Abstract
There are numerous gaseous substances that can act as signaling molecules, but the best characterized of these are nitric oxide, hydrogen sulfide and carbon monoxide. Each has been shown to play important roles in many physiological and pathophysiological processes. This article is focused on the effects of these gasotransmitters in the context of inflammation. There is considerable overlap in the actions of nitric oxide, hydrogen sulfide and carbon monoxide with respect to inflammation, and these mediators appear to act primarily as anti-inflammatory substances, promoting resolution of inflammatory processes. They also have protective and pro-healing effects in some tissues, such as the gastrointestinal tract and lung. Over the past two decades, significant progress has been made in the development of novel anti-inflammatory and cytoprotective drugs that release of one or more of these gaseous mediators.
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41
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Blackler RW, De Palma G, Manko A, Da Silva GJ, Flannigan KL, Bercik P, Surette MG, Buret AG, Wallace JL. Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID. Am J Physiol Gastrointest Liver Physiol 2015; 308:G994-1003. [PMID: 25882612 DOI: 10.1152/ajpgi.00066.2015] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The small intestine is a significant site of ulceration and bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis is poorly understood. The present study explored the roles of bile, bacteria, and enterohepatic circulation to NSAID enteropathy, using both a conventional NSAID (naproxen) and a gastrointestinal-safe naproxen derivative (ATB-346), as well as proton pump inhibitors (PPIs). Rats were treated orally with naproxen or equimolar doses of ATB-346 over a 5-day period, with or without PPI administration, and intestinal damage was quantified. The cytotoxicity of bile from the rats was evaluated in vitro. Biliary excretion of naproxen and ATB-346 was determined. The impact of the NSAIDs and of PPIs on the composition of the intestinal microbiota was examined by deep sequencing of 16s rRNA. Naproxen caused significant intestinal damage and inflammation, whereas ATB-346 did not. Naproxen, but not ATB-346, dose dependently increased the cytotoxicity of bile, and it was further increased by PPI coadministration. Whereas biliary excretion of naproxen was significant in naproxen-treated rats, it was greatly reduced in rats treated with ATB-346. The enteric microbiota of naproxen-treated rats was distinct from that in vehicle- or ATB-346-treated rats, and PPI administration caused significant intestinal dysbiosis. The increase in cytotoxicity of bile induced by naproxen and PPIs may contribute significantly to intestinal ulceration and bleeding. Some of these effects may occur secondary to significant changes in the jejunal microbiota induced by both naproxen and PPIs.
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Affiliation(s)
- Rory W. Blackler
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Giada De Palma
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Anna Manko
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - Gabriela J. Da Silva
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
- Faculty of Pharmacy and Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Kyle L. Flannigan
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Premysl Bercik
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | | | - Andre G. Buret
- Department of Biological Sciences, University of Calgary, Calgary, Alberta; and
| | - John L. Wallace
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
- Faculty of Medicine, Universidade Camilo Castelo Branco, Sao Paulo, SP, Brazil
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42
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Magierowski M, Magierowska K, Kwiecien S, Brzozowski T. Gaseous mediators nitric oxide and hydrogen sulfide in the mechanism of gastrointestinal integrity, protection and ulcer healing. Molecules 2015; 20:9099-123. [PMID: 25996214 PMCID: PMC6272495 DOI: 10.3390/molecules20059099] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 04/29/2015] [Accepted: 05/13/2015] [Indexed: 12/16/2022] Open
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2S) are known as biological messengers; they play an important role in human organism and contribute to many physiological and pathophysiological processes. NO is produced from l-arginine by constitutive NO synthase (NOS) and inducible NOS enzymatic pathways. This gaseous mediator inhibits platelet aggregation, leukocyte adhesion and contributes to the vessel homeostasis. NO is known as a vasodilatory molecule involved in control of the gastric blood flow (GBF) and the maintenance of gastric mucosal barrier integrity in either healthy gastric mucosa or that damaged by strong irritants. Biosynthesis of H2S in mammals depends upon two enzymes cystathionine-β-synthase and cystathionine γ-lyase. This gaseous mediator, similarly to NO and carbon monoxide, is involved in neuromodulation, vascular contractility and anti-inflammatory activities. For decades, H2S has been known to inhibit cytochrome c oxidase and reduce cell energy production. Nowadays it is generally considered to act through vascular smooth muscle ATP-dependent K+ channels, interacting with intracellular transcription factors and promote sulfhydration of protein cysteine moieties within the cell, but the mechanism of potential gastroprotective and ulcer healing properties of H2S has not been fully explained. The aim of this review is to compare current results of the studies concerning the role of H2S and NO in gastric mucosa protection and outline areas that may pose new opportunities for further development of novel therapeutic targets.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, Cracow 31-531, Poland.
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, Cracow 31-531, Poland.
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, Cracow 31-531, Poland.
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Cracow 31-531, Poland.
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Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter. Nat Rev Drug Discov 2015; 14:329-45. [PMID: 25849904 DOI: 10.1038/nrd4433] [Citation(s) in RCA: 626] [Impact Index Per Article: 62.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H2S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.
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NSAID enteropathy and bacteria: a complicated relationship. J Gastroenterol 2015; 50:387-93. [PMID: 25572030 DOI: 10.1007/s00535-014-1032-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 12/05/2014] [Indexed: 02/04/2023]
Abstract
The clinical significance of small intestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains under-appreciated. It occurs with greater frequency than the damage caused by these drugs in the upper gastrointestinal tract, but is much more difficult to diagnose and treat. Although the pathogenesis of NSAID enteropathy remains incompletely understood, it is clear that bacteria, bile, and the enterohepatic circulation of NSAIDs are all important factors. However, they are also interrelated with one another. Bacterial enzymes can affect the cytotoxicity of bile and are essential for enterohepatic circulation of NSAIDs. Gram-negative bacteria appear to be particularly important in the pathogenesis of NSAID enteropathy, possibly through release of endotoxin. Inhibitors of gastric acid secretion significantly aggravate NSAID enteropathy, and this effect is due to significant changes in the intestinal microbiome. Treatment with antibiotics can, in some circumstances, reduce the severity of NSAID enteropathy, but published results are inconsistent. Specific antibiotic-induced changes in the microbiota have not been causally linked to prevention of intestinal damage. Treatment with probiotics, particularly Bifidobacterium, Lactobacillus, and Faecalibacteriaum prausnitzii, has shown promising effects in animal models. Our studies suggest that these beneficial effects are due to colonization by the bacteria, rather than to products released by the bacteria.
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Magierowski M, Jasnos K, Kwiecien S, Drozdowicz D, Surmiak M, Strzalka M, Ptak-Belowska A, Wallace JL, Brzozowski T. Endogenous prostaglandins and afferent sensory nerves in gastroprotective effect of hydrogen sulfide against stress-induced gastric lesions. PLoS One 2015; 10:e0118972. [PMID: 25774496 PMCID: PMC4361614 DOI: 10.1371/journal.pone.0118972] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 01/27/2015] [Indexed: 11/25/2022] Open
Abstract
Hydrogen sulfide (H2S) plays an important role in human physiology, exerting vasodilatory, neuromodulatory and anti-inflammatory effects. H2S has been implicated in the mechanism of gastrointestinal integrity but whether this gaseous mediator can affect hemorrhagic lesions induced by stress has been little elucidated. We studied the effect of the H2S precursor L-cysteine, H2S-donor NaHS, the H2S synthesizing enzyme (CSE) activity inhibitor- D,L-propargylglycine (PAG) and the gastric H2S production by CSE/CBS/3-MST activity in water immersion and restraint stress (WRS) ulcerogenesis and the accompanying changes in gastric blood flow (GBF). The role of endogenous prostaglandins (PGs) and sensory afferent nerves releasing calcitonin gene-related peptide (CGRP) in the mechanism of gastroprotection induced by H2S was examined in capsaicin-denervated rats and those pretreated with capsazepine to inhibit activity of vanilloid receptors (VR-1). Rats were pretreated with vehicle, NaHS, the donor of H2S and or L-cysteine, the H2S precursor, with or without the concurrent treatment with 1) nonselective (indomethacin) and selective cyclooxygenase (COX)-1 (SC-560) or COX-2 (rofecoxib) inhibitors. The expression of mRNA and protein for COX-1 and COX-2 were analyzed in gastric mucosa pretreated with NaHS with or without PAG. Both NaHS and L-cysteine dose-dependently attenuated severity of WRS-induced gastric lesions and significantly increased GBF. These effects were significantly reduced by pretreatment with PAG and capsaicin denervation. NaHS increased gastric H2S production via CSE/CBS but not 3-MST activity. Inhibition of COX-1 and COX-2 activity significantly diminished NaHS- and L-cysteine-induced protection and hyperemia. NaHS increased expression of COX-1, COX-2 mRNAs and proteins and raised CGRP mRNA expression. These effects of NaHS on COX-1 and COX-2 protein contents were reversed by PAG and capsaicin denervation. We conclude that H2S exerts gastroprotection against WRS-induced gastric lesions by the mechanism involving enhancement in gastric microcirculation mediated by endogenous PGs, sensory afferent nerves releasing CGRP and the activation of VR-1 receptors.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Katarzyna Jasnos
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Danuta Drozdowicz
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Malgorzata Strzalka
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Agata Ptak-Belowska
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - John L. Wallace
- Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
- * E-mail:
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Chan FKL. Lower gastrointestinal bleeding: what have we learned from the past 3 decades? Clin Gastroenterol Hepatol 2015; 13:495-7. [PMID: 25460549 DOI: 10.1016/j.cgh.2014.11.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 11/10/2014] [Accepted: 11/10/2014] [Indexed: 02/07/2023]
Affiliation(s)
- Francis K L Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong
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Herrera BS, Coimbra LS, da Silva AR, Teixeira SA, Costa SKP, Wallace JL, Spolidorio LC, Muscara MN. The H2S-releasing naproxen derivative, ATB-346, inhibits alveolar bone loss and inflammation in rats with ligature-induced periodontitis. Med Gas Res 2015; 5:4. [PMID: 25755876 PMCID: PMC4353461 DOI: 10.1186/s13618-015-0025-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 02/14/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND In experimental periodontitis, non-steroidal antiinflammatory drugs (NSAIDs) effectively inhibit the resultant alveolar bone loss. However, their deleterious gastric effects, observed in both animals and humans, dramatically limit their long-term use. It has been proven that the addition of a hydrogen sulfide (H2S)-releasing moiety to classical NSAID structures results in antiinflammatory compounds with improved gastric safeness. In this way, we decided to compare the effects of naproxen with its H2S-releasing derivative ATB-346 on ligature-induced periodontitis in rats. METHODS Male Holtzman rats had a cotton ligature placed subgingivally around the lower right first molar during 7 days. During this period, groups of animals were daily treated with Na2S (a spontaneous H2S donor) or equimolar oral doses of naproxen (10 mg/kg) or ATB-346 (16 mg/kg). The mandibles were finally collected for histological analysis, radiographical measurements of alveolar bone loss and micro-computed tomography (μCT) analysis. Interleukin (IL)-1β, IL-6 and IL-10 were quantified in gingiva samples, and the stomachs were also collected for scoring of tissue damage and measurement of myeloperoxidase (MPO, a marker of granulocyte infiltration). RESULTS Ligature-induced bone loss was significantly inhibited by all the treatments, although only ATB-346 treatment resulted in significant inhibition of bone defect and other histological characteristics (such as flatness of the gingival epithelium, chronic inflammatory cell infiltration and loss of connective tissue in the gingival papillae). Both naproxen and ATB-346 inhibited the increase of gingival IL-1β and IL-6 secondary to periodontitis, but IL-10 was unaffected. Significant damage and increased MPO contents were only found in the stomachs of the naproxen-treated animals. CONCLUSION The H2S-releasing moiety in the ATB-346 compound not only does not impair the effects of the parent naproxen on periodontitis, but also improves bone quality and prevents the gastric mucosa damage due to prostaglandin inhibition, thus configuring a potentially new adjuvant therapy for periodontal diseases.
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Affiliation(s)
- Bruno Schneider Herrera
- />Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil
- />Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil
| | - Leila Santana Coimbra
- />Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil
| | - Agatha Ribeiro da Silva
- />Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil
| | - Simone Aparecida Teixeira
- />Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil
| | - Soraia Katia Pereira Costa
- />Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil
| | - John Lawrence Wallace
- />Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON Canada
| | - Luis Carlos Spolidorio
- />Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University (UNESP), Araraquara, SP Brazil
| | - Marcelo Nicolas Muscara
- />Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo (USP), Sao Paulo, SP Brazil
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Zayachkivska O, Bula N, Khyrivska D, Gavrilyuk E, Wallace JL. Exposure to non-steroid anti-inflammatory drugs (NSAIDs) and suppressing hydrogen sulfide synthesis leads to altered structure and impaired function of the oesophagus and oesophagogastric junction. Inflammopharmacology 2015; 23:91-9. [PMID: 25711289 DOI: 10.1007/s10787-015-0230-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/04/2015] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The non-steroid anti-inflammatory drugs (NSAIDs) are among the drugs that can commonly cause injury in the esophagus, such as non-reflux oesophagitis, with important clinical consequences. This injury may be 'silent' and therefore often overlooked. Recently, we established that hydrogen sulfide (H2S) is a critical mediator of esophageal mucosal protection and repair. The aim of the study was to determine the effect of naproxen, the most commonly used NSAIDs, on the oesophagus and oesophagogastric junction and its relation with suppression or stimulation of endogenous H2S synthesis during naproxen-induced oesophageal injury. METHODS Rats were treated with vehicle (control) or naproxen, with or without being subjected to water immersion restricted stress (Takagi et al. Chem Pharm Bul 12:465-472, 1964). Subgroups of rats were pre-treated with an inhibitor of H2S synthesis cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS), or with the Sodium sulphide (NaHS), which spontaneously generates H2S in solution. Damage of the oesophageal mucosa and oesophagogastric junction was estimated and scored using a histological damage index. RESULTS Treatment with naproxen increased the thickness of the corneal and epithelial layers of the oesophagus, as well as producing disorganization of the muscle plate and irregular submucosal oedema. Both injury factors, stress and suppression of H2S synthesis resulted in the development of severe esophagitis and damage to the oesophagogastric junction. The damage was exacerbated by inhibitors of H2S biosynthesis, and attenuated by treatment with NaHS. CONCLUSIONS Inhibition of endogenous H2S synthesis provides a novel experimental model that can be useful in preclinical studies NSAID-related non-reflux oesophagitis. H2S contributes significantly to mucosal defence in the oesophagus.
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Affiliation(s)
- Oksana Zayachkivska
- Department of Physiology, Lviv National Medical University, 69 Pekarska str., 79010, Lviv, Ukraine,
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Amoruso A, Fresu LG, Dalli J, Miglietta D, Bardelli C, Federici Canova D, Perretti M, Brunelleschi S. Characterization of the anti-inflammatory properties of NCX 429, a dual-acting compound releasing nitric oxide and naproxen. Life Sci 2015; 126:28-36. [PMID: 25711428 DOI: 10.1016/j.lfs.2015.01.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 12/11/2014] [Accepted: 01/21/2015] [Indexed: 01/04/2023]
Abstract
AIMS Cyclooxygenase (COX)-inhibiting nitric oxide donors (CINODs) are a new class of drugs that structurally combine a COX inhibitor with a nitric oxide (NO) donating moiety. This combination reduces potential toxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) whilst maintaining the analgesic and anti-inflammatory effects. The present study was undertaken to investigate the anti-inflammatory effects of NCX 429, a naproxen-based CINOD, and to assess the additional properties of NO donation beyond those related to naproxen. MAIN METHODS We evaluated the in vitro effects of NCX 429 on oxy-radical production, phagocytosis, cytokine release, MMP-9, PPARγ expression and NF-κB activation in human monocytes/MDM and compared to naproxen. Moreover, we compared the in vivo efficacy of NCX 429 and naproxen in a murine model of peritonitis. KEY FINDINGS In all the experiments performed in vitro, NCX 429 reduced the inflammatory responses with equal or higher efficacy compared to naproxen. Moreover, in in vivo experiments, NCX 429, at the lowest dose tested, was able to significantly inhibit cell influx in response to IL-1β administration although naproxen was found to be more potent than NCX 429 at reducing PGE2 in inflammatory exudates. SIGNIFICANCE These results demonstrate that both in vitro and in vivo--in a murine model of peritonitis--NCX 429 elicits significant anti-inflammatory activity, beyond the simple COX inhibition or pure NO release. Therefore, NO donation along with COX inhibition may represent a strategy for investigating inflammatory diseases in which pain and function are not fully resolved by analgesics/anti-inflammatory drugs.
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Affiliation(s)
- Angela Amoruso
- Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy
| | - Luigia Grazia Fresu
- Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy.
| | - Jesmond Dalli
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Preoperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Louis Pasteur Avenue, Boston, MA 02115, USA
| | - Daniela Miglietta
- Nicox Research Institute, Via L. Ariosto, 20091 Bresso, Milano, Italy
| | - Claudio Bardelli
- Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy
| | - Donata Federici Canova
- The William Harvey Research Institute, Barts and The London Medical School, Charterhouse Square, London EC1M 6QB, UK
| | - Mauro Perretti
- The William Harvey Research Institute, Barts and The London Medical School, Charterhouse Square, London EC1M 6QB, UK
| | - Sandra Brunelleschi
- Department of Health Sciences, School of Medicine, University "A. Avogadro", Via Solaroli, 17-28100 Novara, Italy; Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD), Novara, Italy
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Wallace JL, Blackler RW, Chan MV, Da Silva GJ, Elsheikh W, Flannigan KL, Gamaniek I, Manko A, Wang L, Motta JP, Buret AG. Anti-inflammatory and cytoprotective actions of hydrogen sulfide: translation to therapeutics. Antioxid Redox Signal 2015; 22:398-410. [PMID: 24635322 DOI: 10.1089/ars.2014.5901] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
SIGNIFICANCE There is a rapidly expanding body of evidence for important roles of hydrogen sulfide in protecting against tissue injury, reducing inflammation, and promoting repair. There is also growing evidence that H2S can be successfully exploited in drug development. RECENT ADVANCES H2S synthesis and degradation are regulated in circumstances of inflammation and injury so as to promote repair and re-establish homeostasis. Novel H2S-releasing drugs exhibit enhanced anti-inflammatory and pro-restorative effects, while having reduced adverse effects in many tissues. CRITICAL ISSUES H2S is a pleiotropic mediator, having effects on many elements in the inflammatory cascade and promoting the resolution of inflammation and injury. It also contributes significantly to mucosal defence in the gastrointestinal tract, and in host defence against infection. There is strong evidence that novel, H2S-based therapeutics are safe and effective in animal models, and several are progressing through human trials. FUTURE DIRECTIONS A better understanding of the physiological and pathophysiological roles of H2S continues to be restrained by the lack of simple, reliable methods for measurement of H2S synthesis, and the paucity of highly selective inhibitors of enzymes that participate in endogenous H2S synthesis. On the other hand, H2S donors show promise as therapeutics for several important indications.
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Affiliation(s)
- John L Wallace
- 1 Department of Physiology & Pharmacology, University of Calgary , Calgary, Canada
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