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Alzokaky AA, Saber SK, Zaki MO. The reno-protective effect of Empagliflozin against carbon tetrachloride (CCl4)-induced nephrotoxicity in mice halting JNK/MKK4/NRF2/NF-KB pathway. Food Chem Toxicol 2025; 201:115439. [PMID: 40204264 DOI: 10.1016/j.fct.2025.115439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/12/2025] [Accepted: 04/07/2025] [Indexed: 04/11/2025]
Abstract
AIM This study designed to evaluate the reno-protective effects of Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, against carbon tetrachloride (CCl4)-induced nephrotoxicity in mice targeting JNK/MKK4/NRF2/NF-KB pathway. METHODS Male albino mice were given EMPA (10 mg/kg, orally) for 4 weeks prior to a single i.p. injection of 10 % CCl4 (20 ml/kg). Mice were sacrificed 48 h post CCl4 injection. KEY FINDINGS EMPA attenuated CCl4-induced renal injury, as reflected by a decrease in serum urea and creatinine levels, also preserved the histological integrity of kidney tissue. Theses reno-protective effects of EMPA can be mainly due to its 1. Antioxidant, (↑CAT, ↑SOD, ↑Nrf-2 and ↑ARE), 2. Anti-inflammatory (↓NF-κB and ↓TNF-α) and 3. Anti-apoptotic (↓Caspase-3) proprieties. EMPA also inhibited JNK/MKK4 signaling pathway, which plays a critical role in kidney damage. CONCLUSION These finding confirm the reno-protective effect of EMPA with a modulatory impact on JNK/MKK4/Nrf2/NF-κB signaling network; suggesting its therapeutic utility to minimize acute kidney injury (AKI) in clinical setting in the future.
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Affiliation(s)
- Amany A Alzokaky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Shimaa K Saber
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Mennatallah O Zaki
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
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Eddin LB, Meeran MFN, Subramanya SB, Jha NK, Ojha S. Therapeutic potential of agents targeting cannabinoid type 2 receptors in organ fibrosis. Pharmacol Res Perspect 2024; 12:e1219. [PMID: 39425446 PMCID: PMC11489134 DOI: 10.1002/prp2.1219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/08/2024] [Accepted: 04/24/2024] [Indexed: 10/21/2024] Open
Abstract
The endocannabinoid system has garnered attention as a potential therapeutic target in a range of pathological disorders. Cannabinoid receptors type 2 (CB2) are a class of G protein-coupled receptors responsible for transmitting intracellular signals triggered by both endogenous and exogenous cannabinoids, including those derived from plants (phytocannabinoids) or manufactured synthetically (synthetic cannabinoids). Recent recognition of the role of CB2 receptors in fibrosis has fueled interest in therapeutic targeting of CB2 receptors in fibrosis. Fibrosis is characterized by the alteration of the typical cellular composition within the tissue parenchyma, resulting from exposure to diverse etiological factors. The pivotal function of CB2 agonists has been widely recognized in the regulation of inflammation, fibrogenesis, and various other biological pathologies. The modulation of CB2 receptors, whether by enhancing their expression or activating their function, has the potential to provide benefits in numerous conditions, particularly by avoiding any associated adverse effects on the central nervous system. The sufficient activation of CB2 receptors resulted in the complete suppression of gene expression related to transforming growth factor β1 and its subsequent fibrogenic response. Multiple reports have also indicated the diverse functions that CB2 agonists possess in mitigating chronic inflammation and subsequent fibrosis development in various types of tissues. While currently in the preclinical stage, the advancement of CB2 compounds has garnered significant attention within the realm of drug discovery. This review presents a comprehensive synthesis of various independent experimental studies elucidating the pivotal role of identified natural and synthetic CB2 agonists in the pathophysiology of organ fibrosis, specifically in the cardiac, hepatic, and renal systems.
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Affiliation(s)
- Lujain Bader Eddin
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
| | - M. F. Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
| | - Sandeep B. Subramanya
- Department of Physiology, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
| | - Niraj Kumar Jha
- Centre for Global Health Research, Saveetha Medical CollegeSaveetha Institute of Medical and Technical Sciences, Saveetha UniversityChennaiIndia
- School of Bioengineering & BiosciencesLovely Professional UniversityPhagwaraIndia
- Department of Biotechnology, School of Applied & Life Sciences (SALS)Uttaranchal UniversityDehradunIndia
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
- Zayed Bin Sultan Center for Health SciencesUnited Arab Emirates UniversityAl AinUAE
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Li Y, Deng X, Tan X, Li Q, Yu Z, Wu W, Ma X, Zeng J, Wang X. Protective role of curcumin in disease progression from non-alcoholic fatty liver disease to hepatocellular carcinoma: a meta-analysis. Front Pharmacol 2024; 15:1343193. [PMID: 38313314 PMCID: PMC10834658 DOI: 10.3389/fphar.2024.1343193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 01/04/2024] [Indexed: 02/06/2024] Open
Abstract
Background: Pathological progression from non-alcoholic fatty liver disease (NAFLD) to liver fibrosis (LF) to hepatocellular carcinoma (HCC) is a common dynamic state in many patients. Curcumin, a dietary supplement derived from the turmeric family, is expected to specifically inhibit the development of this progression. However, there is a lack of convincing evidence. Methods: The studies published until June 2023 were searched in PubMed, Web of Science, Embase, and the Cochrane Library databases. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) approach was used to evaluate the certainty of evidence. StataSE (version 15.1) and Origin 2021 software programs were used to analyze the critical indicators. Results: Fifty-two studies involving 792 animals were included, and three disease models were reported. Curcumin demonstrates a significant improvement in key indicators across the stages of NAFLD, liver fibrosis, and HCC. We conducted a detailed analysis of common inflammatory markers IL-1β, IL-6, and TNF-α, which traverse the entire disease process. The research results reveal that curcumin effectively hinders disease progression at each stage by suppressing inflammation. Curcumin exerted hepatoprotective effects in the dose range from 100 to 400 mg/kg and treatment duration from 4 to 10 weeks. The mechanistic analysis reveals that curcumin primarily exerts its hepatoprotective effects by modulating multiple signaling pathways, including TLR4/NF-κB, Keap1/Nrf2, Bax/Bcl-2/Caspase 3, and TGF-β/Smad3. Conclusion: In summary, curcumin has shown promising therapeutic effects during the overall progression of NAFLD-LF-HCC. It inhibited the pathological progression by synergistic mechanisms related to multiple pathways, including anti-inflammatory, antioxidant, and apoptosis regulation.
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Affiliation(s)
- Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiyue Tan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qianrong Li
- Department of Obstetrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhi Yu
- Department of Obstetrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenbin Wu
- Health Care Office of the Service Bureau of Agency for Offices Administration of the Central Military Commission, Beijing, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyin Wang
- Department of Obstetrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Ma J, Vaishnani DK, Mansi, Zeng J, Xie Z, Jin X, Zhang H, Wut Yi Hla K, Ying F. Novel Curcumin Analogue L6H4 in Treating Liver Fibrosis and Type 2 Diabetes. Diabetes Metab Syndr Obes 2023; 16:2639-2650. [PMID: 37667770 PMCID: PMC10475286 DOI: 10.2147/dmso.s425038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/22/2023] [Indexed: 09/06/2023] Open
Abstract
Purpose The objective of this study was to evaluate the therapeutic efficacy of the curcumin analogue L6H4 in attenuating liver fibrosis and alleviating insulin resistance in streptozotocin-induced diabetic rats. Methods Male Sprague-Dawley rats were fed a high-fat diet to induce insulin resistance, followed by streptozotocin injection to induce diabetes. The rats were then treated with L6H4 for eight weeks. Body weight, metabolic parameters, liver function, and liver histopathology were evaluated. Immunohistochemistry was performed to assess the expression of TGF-β1, TIMP-2, and MMP-2 in liver tissues. Statistical analysis was conducted using one-way ANOVA and Spearman rank correlation test. Results L6H4 treatment effectively reversed the weight gain associated with a high-fat diet and improved metabolic parameters in diabetic rats. Liver function markers, such as ALT and AST, were reduced after L6H4 treatment. Histological analysis showed improved liver morphology and reduced fibrosis in L6H4-treated rats. Electron microscopy revealed improved ultrastructural features of hepatocytes. Immunohistochemistry demonstrated downregulation of TGF-β1 and TIMP-2 expression and restoration of MMP-2 expression in the liver tissue of L6H4-treated rats. Correlation analysis showed a significant positive correlation between TGF-β1 and TIMP-2 expression. Conclusion The findings suggest that L6H4 has therapeutic potential in attenuating liver fibrosis and alleviating insulin resistance in streptozotocin-induced diabetic rats. The hepatoprotective effect of L6H4 may be attributed to its anti-inflammatory properties and its ability to target molecules involved in fibrosis. Further research is warranted to explore the potential of L6H4 as a treatment option for nonalcoholic fatty liver disease and type 2 diabetes.
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Affiliation(s)
- Jun Ma
- Department of Pathology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
| | - Deep K Vaishnani
- School of International Studies, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Mansi
- School of International Studies, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Jing Zeng
- School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Zhenwen Xie
- School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Xuanchen Jin
- School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Haixia Zhang
- School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Khaing Wut Yi Hla
- School of International Studies, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325035, People’s Republic of China
| | - Furong Ying
- Department of Clinical Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China
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Gan Z, Zhang W, Arslan M, Hu X, Zhang X, Li Z, Shi J, Zou X. Ratiometric Fluorescent Metal-Organic Framework Biosensor for Ultrasensitive Detection of Acrylamide. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:10065-10074. [PMID: 35939824 DOI: 10.1021/acs.jafc.2c04756] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Acrylamide is a neurotoxin and carcinogen that forms during the thermal processing of food, inflicting irreversible harm to human health. Herein, a ratiometric fluorescence biosensor based on a 6-carboxyfluorescein-labeled aptamer (FAM-ssDNA) and porphyrin metal-organic framework (PCN-224) was developed. PCN-224 exhibits strong adsorption capacity for FAM-ssDNA and also quenches the fluorescence of FAM-ssDNA via fluorescence resonance energy transfer and photoinduced electron transfer. FAM-ssDNA hybridizes with complementary DNA to form double-stranded DNA (FAM-dsDNA), which is liberated from the PCN-224 surface, resulting in fluorescence recovery. However, the intrinsic fluorescence of the ligand remains unchanged. Acrylamide can create an adduct with FAM-ssDNA and inhibit the hybridization of FAM-dsDNA, thus realizing ratiometric sensing of acrylamide. The proposed biosensor displays excellent detection performance from 10 nM∼0.5 mM with a limit of detection of 1.9 nM. In conclusion, a fabricated biosensor was successfully applied to detect acrylamide in thermally processed food, and the results were consistent with those of high-performance liquid chromatography.
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Affiliation(s)
- Ziyu Gan
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Wen Zhang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Muhammad Arslan
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Xuetao Hu
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Xinai Zhang
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Zhihua Li
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Jiyong Shi
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
| | - Xiaobo Zou
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing (Jiangsu Education Department), Zhenjiang 212013, China
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Tan S, Liu H, Ke B, Jiang J, Wu B. The peripheral CB 1 receptor antagonist JD5037 attenuates liver fibrosis via a CB 1 receptor/β-arrestin1/Akt pathway. Br J Pharmacol 2020; 177:2830-2847. [PMID: 32017042 DOI: 10.1111/bph.15010] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 12/31/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND PURPOSE Liver fibrosis is a serious cause of morbidity and mortality worldwide and has no adequate treatment. Accumulating evidence suggests that cannabinoid CB1 receptors regulate a variety of physiological and pathological processes in the liver, and blockage of CB1 receptor signalling shows promise as a new therapy for several liver diseases. The aim of this study was to investigate the potential therapeutic effects of CB1 receptors and a peripheral CB1 receptor antagonist JD5037 in liver fibrogenesis. EXPERIMENTAL APPROACH Liver samples from both humans and mouse models were investigated. The peripheral CB1 receptor antagonist JD5037, β-arr1 wild type (β-arr1-WT) and β-arr1 knockout (β-arr1-KO) littermate models, and primary hepatic stellate cells (HSCs) were also used. The mechanisms underlying CB1 receptor-regulated HSCs activation in fibrosis and the therapeutic potential of JD5037 were further analysed. KEY RESULTS CB1 receptors were induced in samples from patients with liver fibrosis and from mouse models. These receptors promoted activation of HSCs in liver fibrosis via recruiting β-arrestin1 and Akt signalling, while blockage of CB1 receptors with JD5037 attenuated CB1 receptor-regulated HSCs activation and liver fibrosis by suppressing β-arrestin1/Akt signalling. CONCLUSIONS AND IMPLICATIONS CB1 receptors promote the activation of HSCs and liver fibrosis via the β-arrestin1/Akt signalling pathway. The peripheral CB1 receptor antagonist JD5037 blocked this pathway, the activation of HSCs and liver fibrosis. This compound and the associated pathway may be a novel approach to the treatment of liver fibrosis.
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Affiliation(s)
- Siwei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bilun Ke
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
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A Synthetic Curcuminoid Analog, (2 E,6 E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone, Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Increasing miR-146a. Molecules 2020; 25:molecules25040920. [PMID: 32092902 PMCID: PMC7070912 DOI: 10.3390/molecules25040920] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 02/08/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023] Open
Abstract
The impairment in diabetic wound healing represents a significant clinical problem, with no efficient targeted treatments for these wound disorders. Curcumin is well confirmed to improve diabetic wound healing, however, its low bioavailability and poor solubility severely limit its clinical application. This study aims to provide the pharmacological basis for the use of (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66). The results showed that topically applied C66 improved cutaneous wound healing in vivo. Further studies showed that C66 treatment increased the level of microRNA-146a (miR-146a) in the wounds in streptozotocin (STZ)-induced diabetic mice, downregulated the expression of interleukin-1 receptor-associated kinase 1 (IRAK1) and phosphorylated nuclear factor-κB (NF-κB) p65 subunit (p-p65) (both p < 0.05), and suppressed the mRNA expression of inflammation-related cytokines, tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6). The in vitro data obtained in human umbilical vein endothelial cells (HUVECs) showed that C66 could reverse high glucose (HG)-induced NF-κB activation due to upregulation of miR-146a expression, which matched the in vivo findings. In conclusion, the present study indicates that C66 exerts anti-inflammation activity and accelerates skin wound healing of diabetic mice, probably via increasing miR-146a and inhibiting the NF-κB-mediated inflammation pathway. Therefore, C66 may be a promising alternative for the treatment of diabetic wounds.
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Yu Y, Sun J, Wang R, Liu J, Wang P, Wang C. Curcumin Management of Myocardial Fibrosis and its Mechanisms of Action: A Review. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:1675-1710. [PMID: 31786946 DOI: 10.1142/s0192415x19500861] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myocardial fibrosis is implicated as a leading risk factor for heart failure, arrhythmia, and sudden death after cardiac injury, as the excessive interstitial extracellular matrix impedes heart contraction and electrical conduction. Complicated mechanisms involving oxidative stress, pro-inflammatory cytokines, chemokine families, NLRP3 inflammasomes, growth factors, and non-coding RNAs participate in cardiac fibrogenesis and make it difficult to designate specific and effective therapies. Oriental herbs have been popular for thousands of years in the health care of Asian residents, due to their multi-targeted, multi-faceted approaches and their multi-functional effects in fighting difficult and complicated diseases, including cardiovascular disorders such as myocardial fibrosis. Curcumin, a natural polyphenol and yellow pigment obtained from the spice turmeric, was found to have strong anti-oxidant and anti-inflammatory properties. Increasing evidence has shown that curcumin can be used to prevent and treat myocardial fibrosis, when the myocardium suffers pathological pro-fibrotic changes in vivo and in vitro. The present review focuses on recent studies elucidating the mechanisms of curcumin in treating different pathologic conditions, including ischemia, hypoxia/reoxygenation, pressure or volume overload, and hyperglycemia or high-fat-induced cardiac fibrosis. Novel analogs such as C66, B2BrBC, Y20, and J17 have been designed to maximize the therapeutic potentials of curcumin. These optimized curcumin analogs with improved bioavailability and pharmacokinetic profiles need to be clinically verified before curcumin could be recommended for the treatment of myocardial fibrosis.
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Affiliation(s)
- Yonghui Yu
- Department of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Jinghui Sun
- Graduate School of China Academy of Chinese Medical Science, Beijing 100700, P. R. China
| | - Ru Wang
- Graduate School of China Academy of Chinese Medical Science, Beijing 100700, P. R. China
| | - Jiangang Liu
- Center for Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100091, P. R. China
| | - Peili Wang
- Center for Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100091, P. R. China
| | - Chenglong Wang
- Center for Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100091, P. R. China
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Sugimoto N, Ishibashi H, Ueda Y, Nakamura H, Yachie A, Ohno-Shosaku T. Corticosterone inhibits the expression of cannabinoid receptor-1 and cannabinoid receptor agonist-induced decrease in cell viability in glioblastoma cells. Oncol Lett 2019; 18:1557-1563. [PMID: 31423223 DOI: 10.3892/ol.2019.10456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 05/10/2019] [Indexed: 11/06/2022] Open
Abstract
The endocannabinoid system regulates physiological and pathological conditions, including inflammation and cancer. Recently, emotional and physical stressors were observed to be involved in impairing the endocannabinoid system, which was concomitant with an increase in serum corticosteroids. However, the influence of corticosteroids on the endocannabinoid system has yet to be completely elucidated. The present study investigated the effects of corticosterone, one of the corticosteroids, on the endocannabinoid system in malignant glioblastoma cells in vitro. U-87 MG cells derived from malignant glioblastoma were subjected to corticosterone stimulation and their viability, signal transduction, and endocannabinoid-related gene expression were examined. Corticosterone decreased the mRNA and protein expressions of cyclooxygenase-2. Of note, although endocannabinoids decreased cell viability, corticosterone inhibited the cannabinoid receptor agonist-induced decrease in cell viability by downregulating the mRNA and protein expressions of cannabinoid receptor 1 (CB1) in glioblastoma cells. These results suggest that corticosteroids modify the endocannabinoid system in glioblastoma cells, and a reduction in the beneficial anti-tumor effects of endocannabinoids through downregulation of the CB1 receptor by corticosterone may promote the malignant phenotype of glioblastoma.
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Affiliation(s)
- Naotoshi Sugimoto
- Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.,Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Hiroaki Ishibashi
- Department of Oral and Maxillofacial Surgery, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan
| | - Yoshibumi Ueda
- Department of General Systems Studies, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.,AMED-PRIME, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Hiroyuki Nakamura
- Department of Public Health, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Akihiro Yachie
- Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan
| | - Takako Ohno-Shosaku
- Faculty of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-0942, Japan
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Mohammadi A, Blesso CN, Barreto GE, Banach M, Majeed M, Sahebkar A. Macrophage plasticity, polarization and function in response to curcumin, a diet-derived polyphenol, as an immunomodulatory agent. J Nutr Biochem 2019; 66:1-16. [PMID: 30660832 DOI: 10.1016/j.jnutbio.2018.12.005] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 11/04/2018] [Accepted: 12/12/2018] [Indexed: 12/19/2022]
Abstract
Monocytes and macrophages are important cells of the innate immune system that have diverse functions, including defense against invading pathogens, removal of dead cells by phagocytosis, antigen presentation in the context of MHC class I and class II molecules, and production of various pro-inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1. In addition, pro-inflammatory (M1) and anti-inflammatory (M2) macrophages clearly play important roles in the progression of several inflammatory diseases. Therefore, therapies that target macrophage polarization and function by either blocking their trafficking to sites of inflammation, or skewing M1 to M2 phenotype polarization may hold clinical promise in several inflammatory diseases. Dietary-derived polyphenols have potent natural anti-oxidative properties. Within this group of polyphenols, curcumin has been shown to suppress macrophage inflammatory responses. Curcumin significantly reduces co-stimulatory molecules and also inhibits MAPK activation and the translocation of NF-κB p65. Curcumin can also polarize/repolarize macrophages toward the M2 phenotype. Curcumin-treated macrophages have been shown to be highly efficient at antigen capture and endocytosis via the mannose receptor. These novel findings provide new perspectives for the understanding of the immunopharmacological role of curcumin, as well as its therapeutic potential for impacting macrophage polarization and function in the context of inflammation-related disease. However, the precise effects of curcumin on the migration, differentiation, polarization and immunostimulatory functions of macrophages remain unknown. Therefore, in this review, we summarized whether curcumin can influence macrophage polarization, surface molecule expression, cytokine and chemokine production and their underlying pathways in the prevention of inflammatory diseases.
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Affiliation(s)
- Asadollah Mohammadi
- Cellular & Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, University of Western Australia, Perth, Australia.
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Lv J, Sharma A, Zhang T, Wu Y, Ding X. Pharmacological Review on Asiatic Acid and Its Derivatives: A Potential Compound. SLAS Technol 2018; 23:111-127. [PMID: 29361877 DOI: 10.1177/2472630317751840] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Natural triterpenes represent a group of pharmacologically active and structurally diverse organic compounds. The focus on these phytochemicals has been enormous in the past few years, worldwide. Asiatic acid (AA), a naturally occurring pentacyclic triterpenoid, is found mainly in the traditional medicinal herb Centella asiatica. Triterpenoid saponins, which are the primary constituents of C. asiatica, are commonly believed to be responsible for their extensive therapeutic actions. Published research work has described the molecular mechanisms underlying the various biological activities of AA and its derivatives, which vary for each chronic disease. However, a compilation of the various pharmacological properties of AA has not yet been done. Herein, we describe in detail the pharmacological properties of AA and its derivatives that inhibit multiple pathways of intracellular signaling molecules and transcription factors that are involved in the various stages of chronic diseases. Furthermore, the pharmacological activities of AA were compared with two natural compounds: curcumin and resveratrol. This review summarizes the research on AA and its derivatives and helps to provide future directions in the area of drug development.
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Affiliation(s)
- Junwei Lv
- 1 School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Alok Sharma
- 1 School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Ting Zhang
- 1 School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yuchen Wu
- 1 School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Xianting Ding
- 1 School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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13
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Xia Y, Xiao HT, Liu K, Zhang HJ, Tsang SW. Resveratrol Ameliorates the Severity of Fibrogenesis in Mice with Experimental Chronic Pancreatitis. Mol Nutr Food Res 2018; 62:e1700561. [PMID: 29148265 DOI: 10.1002/mnfr.201700561] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 10/15/2017] [Indexed: 01/18/2023]
Abstract
SCOPE Resveratrol is generally considered beneficial to health-span and longevity since this dietary stilbenoid has been scrutinized for its activating property on the "rescue gene" sirtuin-1 that promotes cellular survival under stress. In addition to its antiaging property, our previous in vitro studies revealed that resveratrol notably inhibits the production of extracellular matrix (ECM) proteins in pancreatic stellate cells (PSCs), the classic effector cells against pancreatic injury. OBJECTIVE We aim to extrapolate resveratrol intervention to the management of fibrogenesis in mice with chronic pancreatitis. METHODS AND RESULTS C57/BL6 mice are given repetitive injections of cerulein (50 μg kg-1 h-1 ) for 6 weeks for the induction of chronic pancreatitis. We demonstrate that the oral administration of resveratrol (20 mg kg-1 d-1 ) effectively attenuated PSC activation, ECM deposition, fibrogenesis, and acinar atrophy in the pancreatitic parenchyma of cerulein-induced mice, as the damage index score was improved by 45.5%. The enhanced cell survival and preserved acinar integrity by resveratrol plausibly involves a perpetuated nuclear accumulation of Mist1 and a negative modulation of the Akt and p38 MAPK pathways. CONCLUSION We suggest that resveratrol is potentially a nutraceutical for the mitigations of pancreatic fibrosis in chronic pancreatitis for which no effective therapeutic measure is currently available.
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Affiliation(s)
- Yixuan Xia
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Hai-Tao Xiao
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Kanglun Liu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Hong-Jie Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - Siu Wai Tsang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.,Institute of Research and Continuing Education, Hong Kong Baptist University Shenzhen Research Center, Shenzhen, China
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Fu Q, Zheng Y, Dong X, Wang L, Jiang CG. Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice. Oncotarget 2017; 8:103486-103498. [PMID: 29262578 PMCID: PMC5732744 DOI: 10.18632/oncotarget.21975] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/23/2017] [Indexed: 11/25/2022] Open
Abstract
Activation of cannabinoid receptor type 2 has been shown to have anti-fibrosis function in skin and heart. However, whether activating cannabinoid receptor type 2 inhibits pulmonary fibrosis remains elusive. Lung fibroblasts and TGF-β1 are key players in the pathogenesis of pulmonary fibrosis. In this research, we aimed to investigate the role of cannabinoid receptor type 2 in pulmonary fibrosis in vitro and in vivo. In lung fibroblasts stimulated by TGF-β1, preincubated by cannabinoid receptor type 2 agonist JWH133 not only reduced the elevated levels of collagen I and α-SMA, but also inhibited fibroblasts’ proliferation and migration. The dosage of JWH133 had no clear cytotoxic activity, and all these JWH133 effects were partially abrogated by cannabinoid receptor type 2 antagonist SR144528. In bleomycin-induced mice pulmonary fibrosis model, CT images of the lung tissue revealed an extensive ground-glass opacity, reticular pattern and fibrosis stranding. Notably, JWH133 treatment controlled the ongoing fibrotic process (showed by decreased lung density and fibrosis score). Meanwhile, lung histological results revealed that JWH133 treatment suppressed both the inflammatory response and extracellular collagen deposition. SR144528 may increase the pulmonary fibrosis, but no statistically significant difference was proved. Importantly, JWH133 reduced serum profibrotic cytokines levels of TGF-β1 and inhibited TGF-β1/Smad2 pathway in vitro and in vivo. Our research indicated that activating cannabinoid receptor type 2 by a pharmacological method might be a potential strategy for pulmonary fibrosis.
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Affiliation(s)
- Qiang Fu
- Department of Rheumatology and Immunology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yi Zheng
- Department of Rheumatology and Immunology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xin Dong
- Department of Rheumatology and Immunology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Li Wang
- Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Chun Guo Jiang
- Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Tsai ML, Tsai SP, Ho CT. Tetrahydrocurcumin attenuates carbon tetrachloride-induced hepatic fibrogenesis by inhibiting the activation and autophagy of hepatic stellate cells. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.07.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Zhang C, Tian X, Zhang K, Li GY, Wang HY, Wang JH. Protective effects of Foeniculum vulgare root bark extract against carbon tetrachloride-induced hepatic fibrosis in mice. World J Gastroenterol 2017; 23:5722-5731. [PMID: 28883697 PMCID: PMC5569286 DOI: 10.3748/wjg.v23.i31.5722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/14/2017] [Accepted: 06/12/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the protective effects of Foeniculum vulgare root bark (FVRB), a traditional Uyghur medicine, against carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice.
METHODS Mice were randomly divided into eight groups (n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected (i.p.) with 0.1% CCl4-olive oil mixture at 10 mL/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB (88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), hexadecenoic acid (HA), laminin (LN), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured. Hematoxylin-eosin (H and E) staining and Masson trichrome (MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β1 (TGF-β1), matrix metalloprotein 9 (MMP-9) and metallopeptidase inhibitor 1 (TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β1 and alpha-smooth muscle actin (α-SMA) protein expression was measured by Western blot.
RESULTS A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β1 and α-SMA detected by Western blot was decreased by FVRB treatment.
CONCLUSION Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.
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Affiliation(s)
- Cai Zhang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Xing Tian
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Ke Zhang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Guo-Yu Li
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Hang-Yu Wang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Jin-Hui Wang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
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