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Luo Y, Sun S, Zhang Y, Liu S, Zeng H, Li JE, Huang J, Fang L, Yang S, Yu P, Liu J. Effects of Oltipraz on the Glycolipid Metabolism and the Nrf2/HO-1 Pathway in Type 2 Diabetic Mice. Drug Des Devel Ther 2024; 18:5685-5700. [PMID: 39654602 PMCID: PMC11626977 DOI: 10.2147/dddt.s485729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 11/26/2024] [Indexed: 12/12/2024] Open
Abstract
Purpose Oltipraz has various applications, including for treating cancer, liver fibrosis, and cirrhosis. However, its role in regulating metabolic processes, inflammation, oxidative stress, and insulin resistance in STZ-induced T2DM remains unclear. Hence, a comprehensive understanding of how oltipraz ameliorates diabetes, particularly inflammation and oxidative stress, is imperative. Methods The negative control (NC), T2DM model (T2DM), and T2DM models treated with oltipraz (OLTI) and metformin (MET) were constructed. The RNA sequencing (RNA-Seq) was performed on the pancreatic tissues. H&E staining was conducted on the liver and pancreatic tissues. The intraperitoneal glucose tolerance test (IPGTT), blood glucose and lipids, inflammatory factors, and oxidative stress indexes were measured. qPCR and Western blotting examined the nuclear factor erythroid-derived 2-like 2 (Nrf2)/ hemoglobin-1 (HO-1) signaling pathway, cell apoptosis-related genes, and Reg3g levels. Immunofluorescence (IF) analysis of the pancreas was performed to measure insulin secretion. Results A total of 256 DEGs were identified in OLTI_vs_T2DM, and they were mainly enriched in circadian rhythm, cAMP, AMPK, insulin, and MAPK signaling pathways. Moreover, Reg3g exhibits reduced expression in T2DM_vs_NC, and elevated expression in OLTI_vs_T2DM, yet remains unchanged in MET_vs_T2DM. OLTI reduced fasting blood glucose and alleviated T2DM-induced weight loss. It improved blood glucose and insulin resistance, decreased blood lipid metabolism, reduced inflammation and oxidative stress through the Nrf2/HO-1 signaling pathway, mitigated pancreatic and liver tissue injury, and enhanced pancreatic β-cell insulin secretion. OLTI exhibited anti-apoptosis effects in T2DM. Moreover, OLTI exhibits superior antioxidant activity than metformin. Conclusion In summary, OLTI improves blood glucose and insulin resistance, decreases blood lipid metabolism, reduces inflammation and apoptosis, suppresses oxidative stress through the Nrf2/HO-1 signaling pathway, mitigates pancreatic and liver tissue injury, and enhances pancreatic β-cell insulin secretion, thereby mitigating T2DM symptoms. Moreover, Reg3g could be an important target for OLTI treatment of T2DM.
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Affiliation(s)
- Yunfei Luo
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Shaohua Sun
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
- Department of Metabolism and Endocrinology, XinSteel Center Hospital, Xinyu, Jiangxi, 338000, People’s Republic of China
| | - Yuying Zhang
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Shuang Liu
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Haixia Zeng
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - jin-E Li
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Jiadian Huang
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Lixuan Fang
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Shiqi Yang
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Peng Yu
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Jianping Liu
- Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
- Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, Jiangxi, 330031, People’s Republic of China
- Branch of National Clinical Research Center for Metabolic Diseases, Nanchang, Jiangxi, 330031, People’s Republic of China
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Park JS, Rustamov N, Roh YS. The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases. Antioxidants (Basel) 2023; 12:1928. [PMID: 38001781 PMCID: PMC10669501 DOI: 10.3390/antiox12111928] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Chronic liver disease (CLD) affects a significant portion of the global population, leading to a substantial number of deaths each year. Distinct forms like non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD), though they have different etiologies, highlight shared pathologies rooted in oxidative stress. Central to liver metabolism, mitochondria are essential for ATP production, gluconeogenesis, fatty acid oxidation, and heme synthesis. However, in diseases like NAFLD, ALD, and liver fibrosis, mitochondrial function is compromised by inflammatory cytokines, hepatotoxins, and metabolic irregularities. This dysfunction, especially electron leakage, exacerbates the production of reactive oxygen species (ROS), augmenting liver damage. Amidst this, nuclear factor erythroid 2-related factor 2 (NRF2) emerges as a cellular protector. It not only counters oxidative stress by regulating antioxidant genes but also maintains mitochondrial health by overseeing autophagy and biogenesis. The synergy between NRF2 modulation and mitochondrial function introduces new therapeutic potentials for CLD, focusing on preserving mitochondrial integrity against oxidative threats. This review delves into the intricate role of oxidative stress in CLD, shedding light on innovative strategies for its prevention and treatment, especially through the modulation of the NRF2 and mitochondrial pathways.
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Affiliation(s)
| | | | - Yoon-Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Republic of Korea; (J.-S.P.); (N.R.)
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Polat EC, Bozkurt M, Ozcan L, Sonmez K, Ozturk Gurgen H, Danis E, Otunctemur A. Effect of Oltipraz on urethral healing: An experimental study. Prog Urol 2023; 33:555-561. [PMID: 37385830 DOI: 10.1016/j.purol.2023.06.001] [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: 05/01/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND We aimed to examine the oral and topical effect of Oltipraz (OPZ) on fibrosis and healing after urethra injury in a rat model. METHODS In all, 33 adult Sprague-Dawley rats were divided randomly into 5 different groups: sham, urethral injury group (UI), oral Oltipraz treatment group for 14 days after urethral injury (UI+oOPZ), intraurethral Oltipraz treatment group for 14 days after urethral injury (UI+iOPZ) and only intraurethral Oltipraz treatment for 14 days without urethral injury (sham+iOPZ). Pediatric urethrotome blade was used to create the urethral injury model for the injury groups (UI, UI+oOPZ and UI+iOPZ). After 14 days of treatment, all rats were sacrificed after penectomy under general anesthesia. Urethral tissue was evaluated histopathologically for congestion, inflammatory cell infiltration and spongiofibrosis, and immunohistochemically for transforming growth factor Beta-1 (TBF) and vascular endothelial growth factor receptor2 (VEGFR2). RESULTS The congestion score was not statistically significantly different between the groups. Spongiofibrosis was distinctive in UI group and OPZ given groups. Inflammation and spongiofibrosis score were statistically significantly higher in the sham+iOPZ group compared to the sham group (P<0.05). VEGFR2 and TGF Beta-1 scores were statistically significantly higher in the sham+iOPZ group compared to the sham group (P<0.05). We did not find beneficial effect of OPZ on urethral healing. We found the harmful effect of intraurethral administration of OPZ in the group without urethral injury in compared to sham. CONCLUSIONS According to our results, we cannot suggest OPZ in the treatment of urethral injury. Future studies in this area are needed.
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Affiliation(s)
- E C Polat
- Department of Urology, University of Health Sciences, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey.
| | - M Bozkurt
- Department of Urology, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey.
| | - L Ozcan
- Department of Urology, University of Health Sciences, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey
| | - K Sonmez
- Department of Pathology, Faculty of Veterinary Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - H Ozturk Gurgen
- Department of Pathology, Faculty of Veterinary Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - E Danis
- Department of Urology, University of Health Sciences, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey
| | - A Otunctemur
- Department of Urology, University of Health Sciences, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey
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Garbuzenko DV. Current strategies for targeted therapy of liver fibrosis. BULLETIN OF SIBERIAN MEDICINE 2022; 21:154-165. [DOI: 10.20538/1682-0363-2022-3-154-165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver fibrosis (LF) is an unfavorable event in the natural course of chronic liver diseases (CLD), therefore, early implementation and widespread use of antifibrotic therapy methods is a pressing issue in hepatology. The aim of the review was to describe current approaches to targeted therapy of LF.PubMed database, Google Scholar search engine, Cochrane Database of Systematic Reviews, eLIBRARY.RU scientific electronic library, as well as reference lists of articles were used to search for scientific articles. The publications that corresponded to the aim of the study were selected for the period from 1998 to 2021 by the terms “liver fibrosis”, “pathogenesis”, and “treatment”. Inclusion criteria were restricted to targeted therapy of LF.Despite the growing evidence for reversibility of LF, there are currently no effective or clinically approved regimens for its specific therapy. However, taking into account the relevance of the issue, scientific research in this area is necessary. Multiple drugs with a good safety profile have been studied, which, though intended for other purposes, can have a positive effect on LF. In addition, a number of innovative approaches that differ from pharmacotherapy inspire optimism about finding a solution to this problem. It is obvious that studies focused on well-characterized groups of patients with confirmed histologic, elastography, clinical, and radiological parameters are required. This is a challenging task, since the key point will be stratification of risk based on ethnicity, etiology, and clinical status, and very large samples will be required for a reliable assessment. Nevertheless, the solution will increase efficiency of treatment for patients with CLD, improve their prognosis and quality of life, and significantly reduce the need for liver transplantation, a demand for which remains extremely high worldwide.
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Yu HX, Feng Z, Lin W, Yang K, Liu RQ, Li JQ, Liu XY, Pei M, Yang HT. Ongoing Clinical Trials in Aging-Related Tissue Fibrosis and New Findings Related to AhR Pathways. Aging Dis 2022; 13:732-752. [PMID: 35656117 PMCID: PMC9116921 DOI: 10.14336/ad.2021.1105] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/05/2021] [Indexed: 11/06/2022] Open
Abstract
Fibrosis is a pathological manifestation of wound healing that replaces dead/damaged tissue with collagen-rich scar tissue to maintain homeostasis, and complications from fibrosis contribute to nearly half of all deaths in the industrialized world. Ageing is closely associated with a progressive decline in organ function, and the prevalence of tissue fibrosis dramatically increases with age. Despite the heavy clinical and economic burden of organ fibrosis as the population ages, to date, there is a paucity of therapeutic strategies that are specifically designed to slow fibrosis. Aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that exacerbates aging phenotypes in different tissues that has been brought back into the spotlight again with economic development since AhR could interact with persistent organic pollutants derived from incomplete waste combustion. In addition, gut microbiota dysbiosis plays a pivotal role in the pathogenesis of numerous diseases, and microbiota-associated tryptophan metabolites are dedicated contributors to fibrogenesis by acting as AhR ligands. Therefore, a better understanding of the effects of tryptophan metabolites on fibrosis modulation through AhR may facilitate the exploitation of new therapeutic avenues for patients with organ fibrosis. In this review, we primarily focus on how tryptophan-derived metabolites are involved in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. Moreover, a series of ongoing clinical trials are highlighted.
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Affiliation(s)
- Hang-Xing Yu
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhe Feng
- 3Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Wei Lin
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Kang Yang
- 4Kidney Disease Treatment Center, The first affiliated hospital of Henan university of CM, Zhengzhou, Henan, China
| | - Rui-Qi Liu
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jia-Qi Li
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xin-Yue Liu
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Ming Pei
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hong-Tao Yang
- 1Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Kim MJ, Jeon JH. Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases. Int J Mol Sci 2022; 23:ijms23052846. [PMID: 35269986 PMCID: PMC8910922 DOI: 10.3390/ijms23052846] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice.
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Affiliation(s)
- Min-Ji Kim
- Department of Endocrinology in Internal Medicine, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Jae-Han Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea
- Correspondence: ; Tel.: +82-(53)-200-3182; Fax: +82-(53)-200-3155
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Yagishita Y, Gatbonton-Schwager TN, McCallum ML, Kensler TW. Current Landscape of NRF2 Biomarkers in Clinical Trials. Antioxidants (Basel) 2020; 9:antiox9080716. [PMID: 32784785 PMCID: PMC7464243 DOI: 10.3390/antiox9080716] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/02/2020] [Accepted: 08/05/2020] [Indexed: 12/12/2022] Open
Abstract
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans.
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Zhou YQ, Liu DQ, Chen SP, Chen N, Sun J, Wang XM, Cao F, Tian YK, Ye DW. Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain. Acta Pharmacol Sin 2020; 41:1041-1048. [PMID: 32203087 PMCID: PMC7470811 DOI: 10.1038/s41401-020-0394-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023]
Abstract
Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg-1· d-1, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg-1· d-1, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.
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Affiliation(s)
- Ya-Qun Zhou
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dai-Qiang Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shu-Ping Chen
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Nan Chen
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia Sun
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiao-Mei Wang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fei Cao
- Department of Psychiatry, UMKC School of Medicine, Kansas City, MO, 64108, USA
| | - Yu-Ke Tian
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Da-Wei Ye
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Polat EC, Besiroglu H, Ozcan L, Otunctemur A, Eruyar AT, Somay A, Ozbay N, Cekmen M, Eraldemir C, Ozbek E. Beneficial effects of Oltipraz, nuclear factor - erythroid - 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model. Int Braz J Urol 2019; 44:1243-1251. [PMID: 30130014 PMCID: PMC6442183 DOI: 10.1590/s1677-5538.ibju.2018.0232] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Introduction: We investigated whether Oltipraz (OPZ) attenuated renal fibrosis in a unilateral ureteral obstruction (UUO) rat model. Materials and Methods: We randomly divided 32 rats into four groups, each consisting of eight animals as follows: Rats in group 1 underwent a sham operation and received no treatment. Rats in group 2 underwent a sham operation and received OPZ. Rats in group 3 underwent unilateral ureteral ligation and received no treatment. Group 4 rats were subjected to unilateral ureteral ligation plus OPZ administration. Transforming growth factor beta-1 (TGF-β1), E-cadherin, nitric oxide (NO) and hydroxyproline levels were measured. Histopathological and immunohistochemical examinations were carried out. Results: TGF-β1, NO and E-cadherin levels in the UUO group were significantly higher than the sham group and these values were significantly different in treated groups compared to the UUO group. In rats treated with UUO + OPZ, despite the presence of mild tubular degeneration and less severe tubular necrosis, glomeruli maintained a better morphology when compared to the UUO group. Expressions of α-SMA in immunohistochemistry showed that the staining positivity decreased in the tubules of the OPZ-treated group. Conclusions: While the precise mechanism of action remains unknown, our results demonstrated that OPZ exerted a protective role in the UUO-mediated renal fibrosis rat model highlighting a promising therapeutic potency of Nrf2-activators for alleviating the detrimental effects of unilateral obstruction in kidneys.
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Affiliation(s)
- Emre Can Polat
- Department of Urology, Okmeydani Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Huseyin Besiroglu
- Department of Urology, Catalca Ilyas Cokay State Hospital, Istanbul, Turkey
| | - Levent Ozcan
- Department of Urology, Derince Training and Research Hospital, University of Health Sciences, Kocaeli, Turkey
| | - Alper Otunctemur
- Department of Urology, Okmeydani Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Ahmet Tugrul Eruyar
- Department of Pathology, Derince Training and Research Hospital, University of Health Sciences, Kocaeli, Turkey
| | - Adnan Somay
- Department of Pathology, Fatih Sultan Mehmet Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nurver Ozbay
- Department of Pathology, Fatih Sultan Mehmet Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Mustafa Cekmen
- Department of Biochemistry, Istanbul Medeniyet University, Istanbul, Turkey
| | - Ceyla Eraldemir
- Department of Biochemistry, Kocaeli University, Kocaeli, Turkey
| | - Emin Ozbek
- Department of Urology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
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Abstract
The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.
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Affiliation(s)
- Qin M Chen
- Department of Pharmacology, College of Medicine, University of Arizona , Tucson, Arizona
| | - Anthony J Maltagliati
- Department of Pharmacology, College of Medicine, University of Arizona , Tucson, Arizona
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Ramachandran P, Henderson NC. Antifibrotics in chronic liver disease: tractable targets and translational challenges. Lancet Gastroenterol Hepatol 2016; 1:328-340. [PMID: 28404203 DOI: 10.1016/s2468-1253(16)30110-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/22/2016] [Accepted: 07/26/2016] [Indexed: 12/30/2022]
Abstract
Chronic liver disease prevalence is increasing globally. Iterative liver damage, secondary to any cause of liver injury, results in progressive fibrosis, disrupted hepatic architecture, and aberrant regeneration, which are defining characteristics of liver cirrhosis. Liver transplantation is an effective treatment for end-stage liver disease; however, demand greatly outweighs donor organ supply, and in many parts of the world liver transplantation is unavailable. Hence, effective antifibrotic therapies are urgently required. In the past decade, rapid progress has been made in our understanding of the pathophysiology of liver fibrosis and a large number of potential cellular and molecular antifibrotic targets have been identified. This has led to numerous clinical trials of antifibrotic agents in patients with chronic liver disease. However, none of these have resulted in a robust and reproducible effect on fibrosis. It is therefore imperative that the ongoing translational challenges are addressed, to convert scientific discoveries into potent antifibrotics and enable bridging of the translational gap between putative therapeutic targets and effective treatments for patients with chronic liver disease.
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Affiliation(s)
- Prakash Ramachandran
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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Montano-Loza AJ, Thandassery RB, Czaja AJ. Targeting Hepatic Fibrosis in Autoimmune Hepatitis. Dig Dis Sci 2016; 61:3118-3139. [PMID: 27435327 DOI: 10.1007/s10620-016-4254-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 07/11/2016] [Indexed: 02/06/2023]
Abstract
Hepatic fibrosis develops or progresses in 25 % of patients with autoimmune hepatitis despite corticosteroid therapy. Current management regimens lack reliable noninvasive methods to assess changes in hepatic fibrosis and interventions that disrupt fibrotic pathways. The goals of this review are to indicate promising noninvasive methods to monitor hepatic fibrosis in autoimmune hepatitis and identify anti-fibrotic interventions that warrant evaluation. Laboratory methods can differentiate cirrhosis from non-cirrhosis, but their accuracy in distinguishing changes in histological stage is uncertain. Radiological methods include transient elastography, acoustic radiation force impulse imaging, and magnetic resonance elastography. Methods based on ultrasonography are comparable in detecting advanced fibrosis and cirrhosis, but their performances may be compromised by hepatic inflammation and obesity. Magnetic resonance elastography has excellent performance parameters for all histological stages in diverse liver diseases, is uninfluenced by inflammatory activity or body habitus, has been superior to other radiological methods in nonalcoholic fatty liver disease, and may emerge as the preferred instrument to evaluate fibrosis in autoimmune hepatitis. Promising anti-fibrotic interventions are site- and organelle-specific agents, especially inhibitors of nicotinamide adenine dinucleotide phosphate oxidases, transforming growth factor beta, inducible nitric oxide synthase, lysyl oxidases, and C-C chemokine receptors types 2 and 5. Autoimmune hepatitis has a pro-fibrotic propensity, and noninvasive radiological methods, especially magnetic resonance elastography, and site- and organelle-specific interventions, especially selective antioxidants and inhibitors of collagen cross-linkage, may emerge to strengthen current management strategies.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Ragesh B Thandassery
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.
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Abstract
INTRODUCTION The p90 ribosomal S6 kinases (RSK) are a family of Ser/Thr protein kinases that are downstream effectors of MEK1/2-ERK1/2. Increased RSK activation is implicated in the etiology of multiple pathologies, including numerous types of cancers, cardiovascular disease, liver and lung fibrosis, and infections. AREAS COVERED The review summarizes the patent and scientific literature on small molecule modulators of RSK and their potential use as therapeutics. The patents were identified using World Intellectual Property Organization and United States Patent and Trademark Office databases. The compounds described are predominantly RSK inhibitors, but a RSK activator is also described. The majority of the inhibitors are not RSK-specific. EXPERT OPINION Based on the overwhelming evidence that RSK is involved in a number of diseases that have high mortalities it seems surprising that there are no RSK modulators that have pharmacokinetic properties suitable for in vivo use. MEK1/2 inhibitors are in the clinic, but the efficacy of these compounds appears to be limited by their side effects. We hypothesize that targeting the downstream effectors of MEK1/2, like RSK, are an untapped source of drug targets and that they will generate less side effects than MEK1/2 inhibitors because they regulate fewer effectors.
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Affiliation(s)
- Katarzyna A Ludwik
- a Department of Pathology, Microbiology & Immunology , Vanderbilt University , Nashville , TN , USA
| | - Deborah A Lannigan
- a Department of Pathology, Microbiology & Immunology , Vanderbilt University , Nashville , TN , USA.,b Department of Cancer Biology , Vanderbilt University , Nashville , TN , USA
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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89:1727-50. [PMID: 25963329 DOI: 10.1007/s00204-015-1525-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.
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Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20:2515-32. [PMID: 24627588 PMCID: PMC3949261 DOI: 10.3748/wjg.v20.i10.2515] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
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Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:385-406. [PMID: 24387318 DOI: 10.1111/apt.12592] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 11/29/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Shimozono R, Asaoka Y, Yoshizawa Y, Aoki T, Noda H, Yamada M, Kaino M, Mochizuki H. Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol Pharmacol 2013; 84:62-70. [PMID: 23592516 DOI: 10.1124/mol.112.084269] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 (nuclear factor-erythroid-2-related factor 2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH. To test this hypothesis, we used two chemically distinct types of Nrf2 activator. One is the thiol-reactive agent oltipraz (OPZ), a typical Nrf2 activator, and the other is a novel biaryl urea compound, termed NK-252 (1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea). NK-252 exhibits a greater Nrf2-activating potential than OPZ. Furthermore, in vitro binding studies revealed that NK-252 interacts with the domain containing the Nrf2-binding site of Keap1, whereas OPZ does not. This finding indicates that NK-252 is more potent than OPZ due to its unique mechanism of action. For in vivo animal model studies, we used rats on a choline-deficient L-amino acid-defined (CDAA) diet, which demonstrate pathologic findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histologic abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2 activators with independent mechanisms of action, we show that, in a rat model of NASH, the activation of Nrf2 is responsible for the antifibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis.
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Affiliation(s)
- Rieko Shimozono
- Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan.
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Zenkov NK, Menshchikova EB, Tkachev VO. Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target. BIOCHEMISTRY (MOSCOW) 2013; 78:19-36. [DOI: 10.1134/s0006297913010033] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Magesh S, Chen Y, Hu L. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 2012; 32:687-726. [PMID: 22549716 DOI: 10.1002/med.21257] [Citation(s) in RCA: 631] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic, and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, overactivation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.
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Affiliation(s)
- Sadagopan Magesh
- Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
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Jacob C, Battaglia E, Burkholz T, Peng D, Bagrel D, Montenarh M. Control of oxidative posttranslational cysteine modifications: from intricate chemistry to widespread biological and medical applications. Chem Res Toxicol 2011; 25:588-604. [PMID: 22106817 DOI: 10.1021/tx200342b] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Cysteine residues in proteins and enzymes often fulfill rather important roles, particularly in the context of cellular signaling, protein-protein interactions, substrate and metal binding, and catalysis. At the same time, some of the most active cysteine residues are also quite sensitive toward (oxidative) modification. S-Thiolation, S-nitrosation, and disulfide bond and sulfenic acid formation are processes which occur frequently inside the cell and regulate the function and activity of many proteins and enzymes. During oxidative stress, such modifications trigger, among others, antioxidant responses and cell death. The unique combination of nonredox function on the one hand and participation in redox signaling and control on the other has placed many cysteine proteins at the center of drug design and pesticide development. Research during the past decade has identified a range of chemically rather interesting, biologically very active substances that are able to modify cysteine residues in such proteins with huge efficiency, yet also considerable selectivity. These agents are often based on natural products and range from simple disulfides to complex polysulfanes, tetrahydrothienopyridines, α,β -unsaturated disulfides, thiuramdisulfides, and 1,2-dithiole-3-thiones. At the same time, inhibition of enzymes responsible for posttranslational cysteine modifications (and their removal) has become an important area of innovative drug research. Such investigations into the control of the cellular thiolstat by thiol-selective agents cross many disciplines and are often far from trivial.
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Affiliation(s)
- Claus Jacob
- Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany.
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Cohen-Naftaly M, Friedman SL. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol 2011; 4:391-417. [PMID: 22043231 PMCID: PMC3187682 DOI: 10.1177/1756283x11413002] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Fibrosis accumulation is a dynamic process resulting from a wound-healing response to acute or chronic liver injury of all causes. The cascade starts with hepatocyte necrosis and apoptosis, which instigate inflammatory signaling by chemokines and cytokines, recruitment of immune cell populations, and activation of fibrogenic cells, culminating in the deposition of extracellular matrix. These key elements, along with pathways of transcriptional and epigenetic regulation, represent fertile therapeutic targets. New therapies include drugs specifically designed as antifibrotics, as well as drugs already available with well-established safety profiles, whose mechanism of action may also be antifibrotic. At the same time, the development of noninvasive fibrogenic markers, and techniques (e.g. fibroscan), as well as combined scoring systems incorporating serum and clinical features will allow improved assessment of therapy response. In aggregate, the advances in the elucidation of the biology of fibrosis, combined with improved technologies for assessment will provide a comprehensive framework for design of antifibrotics and their analysis in well-designed clinical trials. These efforts may ultimately yield success in halting the progression of, or reversing, liver fibrosis.
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Affiliation(s)
| | - Scott L. Friedman
- Fishberg Professor of Medicine, Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70C, New York, NY 10029-6574, USA
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