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Ahmed ZSO, Khan E, Elias N, Elshebiny A, Dou Q. Updated Review on Natural Polyphenols: Molecular Mechanisms, Biological Effects, and Clinical Applications for Cancer Management. Biomolecules 2025; 15:629. [PMID: 40427522 DOI: 10.3390/biom15050629] [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: 03/10/2025] [Revised: 04/21/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025] Open
Abstract
Polyphenols, naturally occurring compounds found exclusively in plants, have gained significant attention for their potential in cancer prevention and treatment. These compounds are known for their antioxidant properties and are abundant in various plant-based foods, such as vegetables, fruits, grains, and beverages. Recent studies have highlighted the broad spectrum of health benefits of polyphenols, including their antiviral, anti-inflammatory, and anticancer properties. In addition, these naturally derived compounds are increasingly important for drug discovery due to their high molecular diversity and novel biofunctionalities. This review provides an in-depth analysis of the current research and knowledge on the potential use of dietary polyphenols as bioactive compounds for the prevention and treatment of various cancers. This review aims to provide valuable insights into the mechanisms underlying the anticancer properties of phenolic compounds in both laboratory and clinical settings. Furthermore, this review highlights the positive clinical outcomes associated with the use of polyphenols as anticancer agents and offers guidance for future research to advance this promising field.
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Affiliation(s)
- Zainab Sabry Othman Ahmed
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt
- Department of Anatomy and Histology, Faculty of Veterinary Medicine, King Salman International University, Ras Sudr 46612, Egypt
| | - Elyas Khan
- Departments of Oncology, Pharmacology and Pathology School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Nathan Elias
- Departments of Oncology, Pharmacology and Pathology School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Alhussein Elshebiny
- Departments of Oncology, Pharmacology and Pathology School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Qingping Dou
- Departments of Oncology, Pharmacology and Pathology School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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Zhu S, Chen X, Sun L, Li X, Chen Y, Li L, Suo X, Xu C, Ji M, Wang J, Wang H, Zhang L, Meng X, Huang C, Li J. N6-Methyladenosine modification of circDcbld2 in Kupffer cells promotes hepatic fibrosis via targeting miR-144-3p/Et-1 axis. Acta Pharm Sin B 2024. [DOI: 10.1016/j.apsb.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
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Niu C, Zhang J, Okolo PI. The possible pathogenesis of liver fibrosis: therapeutic potential of natural polyphenols. Pharmacol Rep 2024; 76:944-961. [PMID: 39162986 DOI: 10.1007/s43440-024-00638-w] [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: 03/13/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/21/2024]
Abstract
Liver fibrosis is the formation of a fibrous scar resulting from chronic liver injury, independently from etiology. Although many of the mechanical details remain unknown, activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Extracellular mechanisms such as apoptotic bodies, paracrine stimuli, inflammation, and oxidative stress are critical in activating HSCs. The potential for liver fibrosis to reverse after removing the causative agent has heightened interest in developing antifibrotic therapies. Polyphenols, the secondary plant metabolites, have gained attention because of their health-beneficial properties, including well-recognized antioxidant and anti-inflammatory activities, in the setting of liver fibrosis. In this review, we present an overview of the mechanisms underlying liver fibrosis with a specific focus on the activation of resident HSCs. We highlight the therapeutic potential and promising role of natural polyphenols to mitigate liver fibrosis pathogenesis, focusing on HSCs activation. We also discuss the translational gap from preclinical findings to clinical treatments involved in natural polyphenols in liver fibrosis.
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Affiliation(s)
- Chengu Niu
- Internal medicine residency program, Rochester General Hospital, 1425 Portland Avenue, Rochester, NY, 14621, USA.
| | - Jing Zhang
- Rainier Springs Behavioral Health Hospital, 2805 NE 129th St, Vancouver, WA, 98686, USA
| | - Patrick I Okolo
- Division of Gastroenterology, Rochester General Hospital, Rochester, NY, 14621, USA
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Wenbo Z, Jianwei H, Hua L, Lei T, Guijuan C, Mengfei T. The potential of flavonoids in hepatic fibrosis: A comprehensive review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155932. [PMID: 39146877 DOI: 10.1016/j.phymed.2024.155932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND Hepatic fibrosis is a pathophysiological process of extracellular matrix abnormal deposition induced by multiple pathogenic factors. Currently, there is still a lack of effective and non-toxic drugs for treating fibrosis in clinic. Flavonoids are polyphenolic compounds synthesized in plants and modern pharmacological studies confirmed flavonoids exhibit potent hepatoprotective effect. PURPOSE Summarize literature to elaborate the mechanism of HF and evaluate the potential of flavonoids in HF, aiming to provide a new perspective for future research. METHODS The literatures about hepatic fibrosis and flavonoids are collected via a series of scientific search engines including Google Scholar, Elsevier, PubMed, CNKI, WanFang, SciFinder and Web of Science database. The key words are "flavonoids", "hepatic fibrosis", "pharmacokinetic", "toxicity", "pathogenesis" "traditional Chinese medicine" and "mechanism" as well as combination application. RESULTS Phytochemical and pharmacological studies revealed that about 86 natural flavonoids extracted from Chinese herbal medicines possess significantly anti-fibrosis effect and the mechanisms maybe through anti-inflammatory, antioxidant, inhibiting hepatic stellate cells activation and clearing activated hepatic stellate cells. CONCLUSIONS This review summarizes the flavonoids which are effective in HF and the mechanisms in vivo and in vitro. However, fewer studies are focused on the pharmacokinetics of flavonoids in HF model and most studies are limited to preclinical studies, therefore there is no reliable data from clinical trials for the development of new drugs. Further in-depth research related it can be conducted to improve the bioavailability of flavonoids and serve the development of new drugs.
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Affiliation(s)
- Zhu Wenbo
- Faculty of Chinese Medicine, Jiangsu College of Nursing, Huaian 223001, China.
| | - Han Jianwei
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150000, China
| | - Liu Hua
- NHC Key Laboratory of Birth Defect for Research and Prevention (Hunan Provincial Maternal and Child Health Care Hospital), Changsha, Hunan 410008, China
| | - Tang Lei
- Faculty of Chinese Medicine, Jiangsu College of Nursing, Huaian 223001, China
| | - Chen Guijuan
- Faculty of Chinese Medicine, Jiangsu College of Nursing, Huaian 223001, China
| | - Tian Mengfei
- Faculty of Chinese Medicine, Jiangsu College of Nursing, Huaian 223001, China
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Ciceu A, Fenyvesi F, Hermenean A, Ardelean S, Dumitra S, Puticiu M. Advancements in Plant-Based Therapeutics for Hepatic Fibrosis: Molecular Mechanisms and Nanoparticulate Drug Delivery Systems. Int J Mol Sci 2024; 25:9346. [PMID: 39273295 PMCID: PMC11394827 DOI: 10.3390/ijms25179346] [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: 08/05/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages and high costs. As such, there is an urgent need for effective therapeutic strategies. This review focuses on the potential of plant-based therapeutics, particularly polyphenols, phenolic acids, and flavonoids, in treating hepatic fibrosis. These compounds have demonstrated anti-fibrotic activities through various signaling pathways, including TGF-β/Smad, AMPK/mTOR, Wnt/β-catenin, NF-κB, PI3K/AKT/mTOR, and hedgehog pathways. Additionally, this review highlights the advancements in nanoparticulate drug delivery systems that enhance the pharmacokinetics, bioavailability, and therapeutic efficacy of these bioactive compounds. Methodologically, this review synthesizes findings from recent studies, providing a comprehensive analysis of the mechanisms and benefits of these plant-based treatments. The integration of novel drug delivery systems with plant-based therapeutics holds significant promise for developing effective treatments for hepatic fibrosis.
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Affiliation(s)
- Alina Ciceu
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Ferenc Fenyvesi
- Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary
| | - Anca Hermenean
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Simona Ardelean
- Faculty of Pharmacy, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Simona Dumitra
- Faculty of Medicine, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
| | - Monica Puticiu
- Faculty of Medicine, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania
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Xue Y, Zhu W, Qiao F, Yang Y, Qiu J, Zou C, Gao Y, Zhang X, Li M, Shang Z, Gao Y, Huang L. Ba-Qi-Rougan formula alleviates hepatic fibrosis by suppressing hepatic stellate cell activation via the MSMP/CCR2/PI3K pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 329:118169. [PMID: 38621463 DOI: 10.1016/j.jep.2024.118169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 04/03/2024] [Accepted: 04/07/2024] [Indexed: 04/17/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Ba-Qi-Rougan formula (BQRGF) is a traditional and effective compound prescription from Traditional Chinese Medicine (TCM) utilized in treating hepatic fibrosis (HF). AIM OF THE STUDY We aimed to evaluate the therapeutic efficacy of BQRGF on HF and explore the underlying mechanisms of action. MATERIALS AND METHODS UPLC-Q-TOF-MS technology was employed to identify the material basis of BQRGF. Mice with carbon tetrachloride (CCl4)-induced HF received BQRGF at three doses (3.87, 7.74, and 15.48 g/kg per day). We examined serum and liver biochemical indicators and liver histology to assess the therapeutic impact. Primary mouse cells were isolated and utilized for experimental analysis. MSMP expression levels were examined in vitro and in vivo experimental models, including human and mouse tissue. Furthermore, lentivirus and small interfering RNA (siRNA) transfections were employed to manipulate microseminoprotein (MSMP) expression in LO2 cells (human normal liver cells). These manipulated LO2 cells were then co-cultured with LX2 human hepatic stellate cells (HSCs). Through the modulation of MSMP expression in co-cultured cells, administering recombinant MSMP (rMSMP) with or without BQRGF-medicated serum, and using specific pathway inhibitors or agonists in LX2 cells, we elucidated the underlying mechanisms. RESULTS A total of 48 compounds were identified from BQRGF, with 12 compounds being absorbed into the bloodstream and 9 compounds being absorbed into the liver. Four weeks of BQRGF treatment in the HF mouse model led to significant improvements in biochemical and molecular assays and histopathology, particularly in the medium and high-dose groups. These improvements included a reduction in the level of liver injury and fibrosis-related factors. MSMP levels were elevated in human and mouse fibrotic liver tissues, and this increase was mitigated in HF mice treated with BQRGF. Moreover, primary cells and co-culture studies revealed that BQRGF reduced MSMP expression, decreased the expression of the hepatic stellate cell (HSC) activation markers, and suppressed critical phosphorylated protein levels in the CCR2/PI3K/AKT pathway. These findings were further validated using CCR2/PI3K/AKT signaling inhibitors and agonists in MSMP-activated LX2 cells. CONCLUSIONS Collectively, our results suggest that BQRGF combats HF by diminishing MSMP levels and inhibiting MSMP-induced HSC activation through the CCR2/PI3K/AKT pathway.
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Affiliation(s)
- Yan Xue
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Wanchun Zhu
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Fengjie Qiao
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yilan Yang
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Jiaohao Qiu
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Chen Zou
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yating Gao
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xin Zhang
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Man Li
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Zhi Shang
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yueqiu Gao
- Laboratory of Cellular Immunity, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lingying Huang
- Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Yin NN, Chen X, Sun YY, Yang L, Zhang YF, Niu XN, Song H, Huang C, Li J. PSTPIP2 protects against alcoholic liver injury and invokes STAT3-mediated suppression of apoptosis. Biochem Pharmacol 2024; 225:116334. [PMID: 38824967 DOI: 10.1016/j.bcp.2024.116334] [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: 03/08/2024] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/04/2024]
Abstract
Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.
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Affiliation(s)
- Na-Na Yin
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Department of Pharmacology, The Traditional Chinese Medicine Hospital of Huoshan County, Luan 237200, Anhui, China
| | - Xin Chen
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ying-Yin Sun
- Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lei Yang
- Department of Pharmacology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei 230601, Anhui, China
| | - Ya-Fei Zhang
- Department of Pharmacology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei 230601, Anhui, China
| | - Xue-Ni Niu
- Department of Pharmacology, Infection Hospital of Anhui Provincial Hospital, Hefei Infectious Disease Hospital, Hefei 230601, Anhui, China
| | - Heng Song
- Office of Huoshan Vocational School, Luan 237200, Anhui, China
| | - Cheng Huang
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Jun Li
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China.
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Zhao B, Liu K, Liu X, Li Q, Li Z, Xi J, Xie F, Li X. Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis. Phytother Res 2024; 38:3122-3145. [PMID: 38613172 DOI: 10.1002/ptr.8193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 02/28/2024] [Accepted: 03/10/2024] [Indexed: 04/14/2024]
Abstract
Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.
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Affiliation(s)
- Bolin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kai Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhibei Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingjing Xi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Xie
- Hospital of Chengdu University of Traditional Chinese Medicine 610032, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Ji Z, Deng W, Chen D, Liu Z, Shen Y, Dai J, Zhou H, Zhang M, Xu H, Dai B. Recent understanding of the mechanisms of the biological activities of hesperidin and hesperetin and their therapeutic effects on diseases. Heliyon 2024; 10:e26862. [PMID: 38486739 PMCID: PMC10937595 DOI: 10.1016/j.heliyon.2024.e26862] [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: 07/02/2023] [Revised: 02/19/2024] [Accepted: 02/21/2024] [Indexed: 03/17/2024] Open
Abstract
Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in lemon, sweet orange, bitter orange, clementine. Hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory, antioxidant, antitumor and antibacterial potential. Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as bone diseases, cardiovascular diseases, neurological diseases, respiratory diseases, digestive diseases, urinary tract diseases. This review provides a comprehensive overview of the biological activities of hesperidin and hesperetin, their therapeutic potential in various diseases and their associated molecular mechanisms. This article also discusses future considerations for the clinical applications of hesperidin and hesperetin.
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Affiliation(s)
| | | | - Dong Chen
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Zhidong Liu
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Yucheng Shen
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Jiuming Dai
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Hai Zhou
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Miao Zhang
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Hucheng Xu
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
| | - Bin Dai
- Binhai County People's Hospital, No.148, Middle Fudong Road, Dongkan Town, Binhai County, Yancheng City, 224500, China
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Sun LJ, Chen X, Zhu S, Xu JJ, Li XF, Diao SX, Yang YL, Liu JY, Wang JN, Sun YY, Huang C, Meng XM, Wang H, Lv XW, Li J. Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2. Acta Pharmacol Sin 2024; 45:354-365. [PMID: 37845343 PMCID: PMC10789727 DOI: 10.1038/s41401-023-01171-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/14/2023] [Indexed: 10/18/2023]
Abstract
Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 μM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.
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Affiliation(s)
- Li-Jiao Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Jin-Jin Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Xiao-Feng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Shao-Xi Diao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Ying-Li Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Jin-Yu Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Ying-Yin Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Hua Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
- Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China.
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11
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He C, Wang W, Wei G, Wang Y, Wei Y, Wang J, Zhang Z. Sodium alginate combined with oxymatrine ameliorates CCl 4-induced chemical hepatic fibrosis in mice. Int Immunopharmacol 2023; 125:111144. [PMID: 37922569 DOI: 10.1016/j.intimp.2023.111144] [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: 09/17/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023]
Abstract
Hepatic fibrosis (HF) is a challenging clinical problem. Both sodium alginate (SA) and oxymatrine (OM) can be used to treat HF; however, the influence of viscosity on the therapeutic efficacy of sodium alginate is currently unknown. This study used a CCl4-induced HF mouse model to screen the specifications and doses of SA and investigate its therapeutic effects on HF in combination with OM. Sodium alginate of different viscosities ameliorated HF in mice, with 232 mPa·s SA delivered at a dose of 100 mg/kg showing remarkable therapeutic effect, characterized by reduced aspartate transaminase/alanine transaminase levels, reduced expression of α-SMA, collagen I, and other related genes, and increased abundance of beneficial intestinal probiotics such as Lactococcus and Blautia. The combination treatment further improved other related indices and increased the abundance of Phascolarctobacterium and Oscillospiraceae. These results suggest that the oral administration of SA may improve HF via the "gut-liver axis" based on the gut microbiota and has potential clinical applications.
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Affiliation(s)
- Chen He
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Wenjing Wang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Guoli Wei
- Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu 211200, China
| | - Yuqing Wang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Yingjie Wei
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China
| | - Jing Wang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China.
| | - Zhenhai Zhang
- State Key Laboratory of Oral Drug Delivery Systems of Chinese Materia Medica, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu 210028, China.
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12
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Ma M, Chen L, Tang Z, Song Z, Kong X. Hepatoprotective effect of total flavonoids from Carthamus tinctorius L. leaves against carbon tetrachloride-induced chronic liver injury in mice. Fitoterapia 2023; 171:105605. [PMID: 37437698 DOI: 10.1016/j.fitote.2023.105605] [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: 04/20/2023] [Revised: 07/07/2023] [Accepted: 07/08/2023] [Indexed: 07/14/2023]
Abstract
Carthamus tinctorius L. leaves, a waste product after Carthami flos production, are rich in flavonoids. Total flavonoids from C. tinctorius L. leaves (TFCTLL) exhibited the protective effect on acute liver injury in mice in previous studies. The aim of the present study was to evaluate the hepatoprotective effect of TFCTLL on chronic liver injury (CLI) and investigate the underlying mechanism. The chemical components of TFCTLL were identified by UPLC-Q-TOF/MS, and their migration into blood was evaluated. The protective effect of TFCTLL on CLI was evaluated by antioxidative and anti-inflammatory experiments in vitro, network pharmacology and a carbon tetrachloride (CCl4)-induced CLI mouse model. We indentified 18 chemical components in the TFCTLL samples and 4 components in plasma. TFCTLL showed significant anti-inflammatory activity and antioxidant capacity in vitro and in vivo. TFCTLL administration prominently improved the liver function and structure, decreased the mRNA expression levels of TLR2, TLR3, TLR4, NF-κB p65, IRF3, AKT1, TRIF, PI3K, MyD88, IL-1β and TNF-α and inhibited the protein expression and nuclear translocation of NF-κB p65 in mice with CLI. The molecular docking results showed that components in plasma had high binding affinity for the targets TLR4, PI3K and AKT1. Therefore, TFCTLL has a protective effect against CCl4-induced CLI, and the underlying mechanisms may be related to antioxidation, anti-inflammation and modulation of the TLRs/NF-κB and PI3K/AKT pathways.
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Affiliation(s)
- Mengge Ma
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, 712083, Xianyang, Shaanxi, PR China
| | - Lin Chen
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, 712083, Xianyang, Shaanxi, PR China.
| | - Zhishu Tang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, 712083, Xianyang, Shaanxi, PR China; China Academy of Chinese Medical Sciences, 100700 Beijing, PR China.
| | - Zhongxing Song
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, 712083, Xianyang, Shaanxi, PR China
| | - Xin Kong
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, 712083, Xianyang, Shaanxi, PR China
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13
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Wang W, Qu L, Cui Z, Lu F, Li L, Liu F. Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:16174-16183. [PMID: 37870747 DOI: 10.1021/acs.jafc.3c06816] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Misfolding and subsequent fibrillogenesis of α-synuclein (αSN) significantly influence the development of Parkinson's disease (PD). This study reports the inhibitory effect of citrus flavonoid hesperetin (Hst) on αSN fibrillation. Based on thioflavin T fluorometry and atomic force microscopy studies, Hst inhibited αSN fibrillation by interfering with initial nucleation and slowing the elongation rate. Furthermore, the inhibitory effect was concentration-dependent with a half-maximal inhibitory concentration of 24.4 μM. Cytotoxicity experiments showed that 100 μM Hst significantly reduced the cytotoxicity of αSN aggregates and maintained 98.4% cell activity. In addition, Hst disassembled the preprepared αSN fibrils into smaller and less-toxic aggregates. Excitingly, supplementation with 100 μM Hst inhibited the accumulation of 36.3% αSN in NL5901 and restored the amyloid-induced reduction in NL5901 lipid abundance, extending the mean lifespan of NL5901 to 23 d. These findings could support the use of Hst as a dietary supplement to regulate αSN fibrillation and prevent the development of PD.
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Affiliation(s)
- Wenqian Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Lili Qu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Zhan Cui
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Fuping Lu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Li Li
- College of Science, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Fufeng Liu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
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14
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Taheri A, Mobaser SE, Golpour P, Nourbakhsh M, Tavakoli-Yaraki M, Yarahmadi S, Nourbakhsh M. Hesperetin attenuates the expression of markers of adipose tissue fibrosis in pre-adipocytes. BMC Complement Med Ther 2023; 23:315. [PMID: 37697354 PMCID: PMC10496229 DOI: 10.1186/s12906-023-04152-z] [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: 03/12/2023] [Accepted: 09/04/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Excessive extracellular matrix (ECM) deposition in adipose tissue is a hallmark of fibrosis, leading to disrupted adipose tissue homeostasis and metabolic dysfunction. Hesperetin, a flavonoid compound, has shown promising anti-inflammatory, anti-obesity and anti-diabetic properties. Therefore, we investigated the anti-fibrotic effects of hesperetin, through targeting ECM components and matrix metalloproteinase enzymes. METHODS 3T3-L1 cells were cultured in DMEM, containing 10% FBS and 1% penicillin/streptomycin. Cells were treated with a range of hesperetin concentrations, and the cell viability was determined using MTT assay. Subsequently, the expression of genes encoding collagen VI, osteopontin, matrix metalloproteinase-2 (Mmp-2) and Mmp-9 was analyzed using specific primers and real-time PCR technique. To evaluate protein levels of collagen VI and osteopontin, Western blotting was performed. RESULTS Hesperetin affected the viability of 3T3-L1 adipocytes with IC50 of 447.4 µM, 339.2 µM and 258.8 µM (24 h, 48 and 72 h, respectively). Hesperetin significantly reduced the gene and protein expression of both collagen VI and osteopontin in 3T3-L1 pre-adipocytes, in a time- and dose-dependent manner. Hesperetin was also able to cause a remarkable decline in gene expression of Mmp2 and Mmp9. CONCLUSION Hesperetin could potently reduce the production of markers of adipose tissue fibrosis and might be considered a potential anti-fibrotic compound in obesity. Thus, hesperetin has the potency to be used for the treatment of obesity-associated fibrosis.
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Affiliation(s)
- Alemeh Taheri
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran
| | - Samira Ezzati Mobaser
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Pegah Golpour
- Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mona Nourbakhsh
- Hazrat Aliasghar Children Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran
| | - Sahar Yarahmadi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran
| | - Mitra Nourbakhsh
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran.
- Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran.
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15
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Chen X, Zhu S, Li HD, Wang JN, Sun LJ, Xu JJ, Hui YR, Li XF, Li LY, Zhao YX, Suo XG, Xu CH, Ji ML, Sun YY, Huang C, Meng XM, Zhang L, Lv XW, Ye DQ, Li J. N 6-methyladenosine-modified circIRF2, identified by YTHDF2, suppresses liver fibrosis via facilitating FOXO3 nuclear translocation. Int J Biol Macromol 2023; 248:125811. [PMID: 37467831 DOI: 10.1016/j.ijbiomac.2023.125811] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/17/2023] [Accepted: 06/28/2023] [Indexed: 07/21/2023]
Abstract
Circular RNA (circRNA) has been implicated in liver fibrosis and modulated by multiple elusive molecular mechanisms, while the effects of N6-methyladenosine (m6A) modification on circRNA are still elusive. Herein, we identify circIRF2 from our circRNA sequencing data, which decreased in liver fibrogenesis stage and restored in resolution stage, indicating that dysregulated circIRF2 may be closely associated with liver fibrosis. Gain/loss-of-function analysis was performed to evaluate the effects of circIRF2 on liver fibrosis at both the fibrogenesis and resolution in vivo. Ectopic expression of circIRF2 attenuated liver fibrogenesis and HSCs activation at the fibrogenesis stage, whereas downregulation of circIRF2 impaired mouse liver injury repair and inflammation resolution. Mechanistically, YTHDF2 recognized m6A-modified circIRF2 and diminished circIRF2 stability, partly accounting for the decreased circIRF2 in liver fibrosis. Microarray was applied to investigate miRNAs regulated by circIRF2, our data elucidate cytoplasmic circIRF2 may directly harbor miR-29b-1-5p and competitively relieve its inhibitory effect on FOXO3, inducing FOXO3 nuclear translocation and accumulation. Clinically, circIRF2 downregulation was prevalent in liver fibrosis patients compared with healthy individuals. In summary, our findings offer a novel insight into m6A modification-mediated regulation of circRNA and suggest that circIRF2 may be an exploitable prognostic marker and/or therapeutic target for liver fibrosis.
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Affiliation(s)
- Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China; Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Hai-Di Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Li-Jiao Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Jin-Jin Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ya-Ru Hui
- Department of Graduate Student Affairs, Anhui Medical University, Hefei 230032, China
| | - Xiao-Feng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Liang-Yun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Yu-Xin Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Xiao-Guo Suo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Chuan-Hui Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ming-Lu Ji
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ying-Yin Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Lei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
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16
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Li Y, Lu Y, Nian M, Sheng Q, Zhang C, Han C, Dou X, Ding Y. Therapeutic potential and mechanism of Chinese herbal medicines in treating fibrotic liver disease. Chin J Nat Med 2023; 21:643-657. [PMID: 37777315 DOI: 10.1016/s1875-5364(23)60443-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Indexed: 10/02/2023]
Abstract
Liver fibrosis is a pathological condition characterized by replacement of normal liver tissue with scar tissue, and also the leading cause of liver-related death worldwide. During the treatment of liver fibrosis, in addition to antiviral therapy or removal of inducers, there remains a lack of specific and effective treatment strategies. For thousands of years, Chinese herbal medicines (CHMs) have been widely used to treat liver fibrosis in clinical setting. CHMs are effective for liver fibrosis, though its mechanisms of action are unclear. In recent years, many studies have attempted to determine the possible mechanisms of action of CHMs in treating liver fibrosis. There have been substantial improvements in the experimental investigation of CHMs which have greatly promoted the understanding of anti-liver fibrosis mechanisms. In this review, the role of CHMs in the treatment of liver fibrosis is described, based on studies over the past decade, which has addressed the various mechanisms and signaling pathways that mediate therapeutic efficacy. Among them, inhibition of stellate cell activation is identified as the most common mechanism. This article provides insights into the research direction of CHMs, in order to expand its clinical application range and improve its effectiveness.
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Affiliation(s)
- Yanwei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Yunrui Lu
- Liaoning University of Traditional Chinese Medicine, Shenyang 110000, China
| | - Mozuo Nian
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Qiuju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110000, China.
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17
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Wang Z, Sun P, Zhao T, Cao J, Liu Y, Khan A, Zhou W, Cheng G. E Se tea extract ameliorates CCl 4 induced liver fibrosis via regulating Nrf2/NF-κB/TGF-β1/Smad pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 115:154854. [PMID: 37156058 DOI: 10.1016/j.phymed.2023.154854] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/26/2023] [Accepted: 05/02/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Liver fibrosis is a crucial progress to deteriorate liver disease. E Se tea (ES) is an ethnic herbal tea in China that has various biological activities for human beings. However, the traditional application on the treatment of liver disease is not studied. PURPOSE This study is firstly performed to explore the chemical constituents of ES extract together with its anti-hepatic fibrosis effect and potential mechanism on CCl4 treated mice. STUDY DESIGN AND METHODS The chemical constituents of ethanol-aqueous extract from ES (ESE) were analyzed by UPLC-ESI-MS/MS. The anti-hepatic fibrosis effect of ESE was determined by measuring ALT and AST activities, antioxidative indexes, inflammatory cytokines and collagen protein levels on CCl4 treated mice. Moreover, H&E, Masson staining and immunohistochemical analysis were performed for evaluating the protective effect of ESE on histopathological changes of liver tissues. RESULTS UHPLCHRESI-MS/MS analysis showed that the ESE was rich in flavonoids such as phlorizin, phloretin, quercetin and hyperoside. ESE could significantly reduce the plasma AST and ALT activities. The cytokines (IL-6, TNF-α, IL-1β) expressions were inhibited after ESE administration via suppressing NF-κB pathway. In addition, ESE could decrease MDA accumulation for alleviating CCl4 induced liver oxidative stress via regulating Nrf2 pathway to promote the expressions of antioxidant enzymes (SOD, HO-1, CAT and NQO1). Moreover, ESE could inhibit the expressions of TGF-β1, Smad2, α-SMA, and collagens Ⅰ and III proteins, thereby effectively alleviate the liver fibrosis. CONCLUSION This study demonstrated that ESE could alleviate liver fibrosis through enhancing antioxidant and anti-inflammatory abilities by Nrf2/NF-κB pathway and reducing deposition of liver fibrosis via suppressing TGF-β/Smad pathway.
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Affiliation(s)
- Zhengxuan Wang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China
| | - Pengzhen Sun
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China
| | - Tianrui Zhao
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China
| | - Jianxin Cao
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China
| | - Yaping Liu
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China
| | - Afsar Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan
| | - Wenbing Zhou
- Yunnan Tobacco Company, Yuxi Branch, Yuxi, 653100, China.
| | - Guiguang Cheng
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
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Shan L, Wang F, Zhai D, Meng X, Liu J, Lv X. Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis. Biomed Pharmacother 2023; 161:114472. [PMID: 37002573 DOI: 10.1016/j.biopha.2023.114472] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/20/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Liver fibrosis is the common consequence of various chronic liver injuries and is mainly characterized by the imbalance between the production and degradation of extracellular matrix, which leads to the accumulation of interstitial collagen and other matrix components. Matrix metalloproteinases (MMPs) and their specific inhibitors, that is, tissue inhibitors of metalloproteinases (TIMPs), play a crucial role in collagen synthesis and lysis. Previous in vivo and in vitro studies of our laboratory found repressing extracellular matrix (ECM) accumulation by restoring the balance between MMPs and TIMPs can alleviate liver fibrosis. We conducted a review of articles published in PubMed and Science Direct in the last decade until February 1, 2023, which were searched for using these words "MMPs/TIMPs" and "Hepatic Fibrosis." Through a literature review, this article reviews the experimental studies of liver fibrosis based on MMPs/TIMPs, summarizes the components that may exert an anti-liver fibrosis effect by affecting the expression or activity of MMPs/TIMPs, and attempts to clarify the mechanism of MMPs/TIMPs in regulating collagen homeostasis, so as to provide support for the development of anti-liver fibrosis drugs. We found the MMP-TIMP-ECM interaction can result in better understanding of the pathogenesis and progression of hepatic fibrosis from a different angle, and targeting this interaction may be a promising therapeutic strategy for hepatic fibrosis. Additionally, we summarized and analyzed the drugs that have been found to reduce liver fibrosis by changing the ratio of MMPs/TIMPs, including medicine natural products.
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Affiliation(s)
- Liang Shan
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, China; The Key Laboratory of Major Autoimmune Diseases, Hefei 230032, Anhui, China
| | - Fengling Wang
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
| | - Dandan Zhai
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
| | - Xiangyun Meng
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China
| | - Jianjun Liu
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, China.
| | - Xiongwen Lv
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230032, China; The Key Laboratory of Major Autoimmune Diseases, Hefei 230032, Anhui, China.
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Du C, Dong J, Wang Q, Xu C, Feng S, Feng R, Lv X, Li J, Zhang L, Huang C, Ma T. Hastatoside attenuatescarbon tetrachloride-induced liver fibrosis by targeting glycogen synthase kinase-3β. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 109:154585. [PMID: 36610117 DOI: 10.1016/j.phymed.2022.154585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 11/11/2022] [Accepted: 12/04/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Hastatoside is an iridoid glycoside extracted from the herb, Verbena officinalis, that exerts various pharmacological effects, including anti-inflammatory, sleep-promoting, and analgesic effects. However, only a few studies have reported the efficacy of hastatoside in liver fibrosis. Liver fibrosis is a pathophysiological process, and its persistence can seriously affect the quality of life and well-being of the patients. HYPOTHESIS/PURPOSE This study aimed to investigate the role of hastatoside on liver fibrosis and its possible underlying mechanisms. METHODS C57BL/6 J mice with carbon tetrachloride (CCl4)-induced hepatic fibrosis were used as the in vivo models. Histological features of the liver were observed using Masson's trichrome and hematoxylin-eosin staining. Alanine aminotransferase and aspartate aminotransferase levels and the hepatic fibrosis indices (type 3 procollagen, laminin, and hyaluronic acid) were measured using corresponding assay kits. LX-2 human hepatic stellate cells (HSCs) stimulated with the transforming growth factor β1 were used as the vitro models. Transfection of the glycogen synthase kinase (GSK)-3β small interfering RNA (siRNA) and β-catenin plasmids was also performed in vitro. Protein levels of GSK-3β, phospho-GSK-3β (Ser 9), α-smooth muscle actin, collagen type I alpha 1, c-Myc, cyclin D1, and β-catenin were determined via western blotting. Moreover, the p-GSK-3β:GSK-3β ratio was calculated to determine the GSK-3β activity. RESULTS Hastatoside prevented CCl4-induced liver injury and histological damage. It inhibited the upregulation of α-SMA and Col1α1 levels in a CCl4-induced mouse hepatic fibrosis model. In vitro, hastatoside inhibited the proliferation and activation of HSCs by decreasing the expression levels of cyclin D1 and c-Myc and the proportion of LX-2 cells activated in the G0/G1 phase. Molecular docking results showed that hastatoside bound to GSK-3β. Hastatoside significantly increased the GSK-3β activity and inhibited the downstream effector expression of β-catenin. CONCLUSION These findings suggest that hastatoside can bind to GSK-3β and promote its activity, while inhibiting the GSK-3β downstream effector expression of β-catenin, thereby inhibiting the activation and proliferation of HSCs, which further prevents the development of liver fibrosis. These results provide innovative insights into the underlying liver fibrosis. Moreover, hastatoside is a potential anti-fibrosis monomer that can potentially be used for the treatment of liver fibrosis.
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Affiliation(s)
- Changlin Du
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Jiahui Dong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Qi Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Chuanting Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Shiqi Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Rui Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Xiongwen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China
| | - Lei Zhang
- Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China.
| | - Taotao Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China.
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Chen X, Zhu S, Chen SY, Wang JN, Sun LJ, Tao SM, Li XF, Li HD, Sun YY, Xu CH, Suo XG, Ji ML, Huang C, Meng XM, Li J. miR-301a-3p promotes hepatic stellate cells activation and liver fibrogenesis via regulating PTEN/PDGFR-β. Int Immunopharmacol 2022; 110:109034. [PMID: 35834952 DOI: 10.1016/j.intimp.2022.109034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/26/2022] [Accepted: 07/04/2022] [Indexed: 12/20/2022]
Abstract
Hepatic fibrosis is an essential pathology of multiple chronicliverdiseases. The aim of this study was to investigate the role of miR-301a-3p in hepatic fibrosis. We found that miR-301a-3p was upregulated in hepatic fibrosis patients and in culture-activated human hepatic stellate cells (HSCs). Interestingly, miR-301a-3p expression was increased in hepatic fibrosis progression mice while decreased in hepatic fibrosis recovery mice, indicating that miR-301a-3p may participate in the hepatic fibrosis pathology. Functionally, the effects of miR-301a-3p both on hepatic fibrosis progression and regression were assessed in vivo. Inhibiting miR-301a-3p amelioratedmouse liver fibrogenesis and collagen deposition and suppressed HSC activation and fibrogenic factor expression. Whereas, in hepatic fibrosis regression, upregulating miR-301a-3p impaired mouse hepatic fibrosis recovery by inducing HSC activation and triggering inflammation. Consistently, gain-of-function and loss-of-function analysis of miR-301a-3p were performed to evaluate its effects on human HSCs LX-2 cell. We found that suppressing miR-301a-3p inhibited LX-2 cell activation and proliferation, and induced LX-2 cell apoptosis, accompaniedby decreased fibrotic mediators expression. Collectively, these findings suggest miR-301a-3p drives liver fibrogenesis and HSC activation in hepatic fibrosis. Mechanistically, we demonstrated miR-301a-3p binds directly to phosphatase and tensin homolog (PTEN) by luciferase reporter analysis, pull-down, and RIP assay. Indicating that miR-301a-3p plays a critical rolein promotingliverfibrogenesis viamodulating the PTEN/platelet derived growth factor β (PDGFR-β) pathway. In conclusion, our findings demonstrate that miR-301a-3p expression is closely correlated with hepatic fibrosis pathology, and that enhancing miR-301a-3p maintains the HSC profibrogenic phenotype, triggers inflammatoryresponses, promotes fibrogenic factor production, and further exacerbates liver fibrogenesis. These findings suggest that miR-301a-3p may serve as a promising diagnostic and prognosis biomarker for hepatic fibrosis treatment.
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Affiliation(s)
- Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Si-Yu Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Li-Jiao Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Shan-Min Tao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xiao-Feng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Hai-Di Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Ying-Yin Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Chuan-Hui Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Xiao-Guo Suo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ming-Lu Ji
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The KeyLaboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
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Zhu S, Chen X, Chen SY, Wang A, Wu S, Wu YY, Cheng M, Xu JJ, Li XF, Huang C, Li J. Hesperetin derivative decreases CCl 4 -induced hepatic fibrosis by Ptch1-dependent mechanisms. J Biochem Mol Toxicol 2022; 36:e23149. [PMID: 35712856 DOI: 10.1002/jbt.23149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 03/05/2022] [Accepted: 05/30/2022] [Indexed: 11/08/2022]
Abstract
Hepatic fibrosis (HF), a continuous wound-healing response of the liver to repeated injuries, is characterized by abnormal extracellular matrix (ECM) accumulation. Hepatic stellate cells (HSCs) are considered a major cell type for ECM production. However, recent evidence indicates the lack of effective treatments for HF. Hesperetin, a Traditional Chinese Medicine monomer, has been isolated from the fruit peel of Citrusaurantium L. (Rutaceae). Growing evidence suggests the partial function of hesperetin in HF treatment. A hesperetin derivative (HD) was synthesized in our laboratory to increase the bioavailability and the water solubility of hesperetin. In this study, we detected the functions of HD in a mouse model of CCl4 -induced HF and transforming growth factor-β1-stimulated HSC-T6 cells, in vivo and in vitro. HD reduced histological damage and CCl4 -induced HF. Moreover, HD interference was associated with the activation of indicators in HSC-T6 cells, showing that HD is involved in HSCs activation in HF. Mechanistically, the Hedgehog pathway is involved in the HD treatment of HF, and HD may attenuate the aberrant expression of patched1. In conclusion, the studies indicate that HD may function as a potential antifibrotic Traditional Chinese Medicine monomer in HF therapy.
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Affiliation(s)
- Sai Zhu
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Xin Chen
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Si-Yu Chen
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Ao Wang
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Sha Wu
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Yuan-Yuan Wu
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Miao Cheng
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Jin-Jin Xu
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Xiao-Feng Li
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China
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O-alkyl and o-benzyl hesperetin derivative-1L attenuates inflammation and protects against alcoholic liver injury via inhibition of BRD2-NF-κB signaling pathway. Toxicology 2022; 466:153087. [PMID: 34974135 DOI: 10.1016/j.tox.2021.153087] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/21/2021] [Accepted: 12/27/2021] [Indexed: 01/09/2023]
Abstract
Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl4-induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6-8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro. Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease.
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Li JJ, Jiang HC, Wang A, Bu FT, Jia PC, Zhu S, Zhu L, Huang C, Li J. Hesperetin derivative-16 attenuates CCl 4-induced inflammation and liver fibrosis by activating AMPK/SIRT3 pathway. Eur J Pharmacol 2022; 915:174530. [PMID: 34902361 DOI: 10.1016/j.ejphar.2021.174530] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 09/20/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022]
Abstract
Liver fibrosis, a chronic inflammatory healing reaction, progresses to hepatocirrhosis without effective intervention. Hesperetin derivative (HD-16), a monomer compound derived from hesperitin, exerts anti-inflammatory and hepatoprotective effects against a spectrum of liver diseases. However, the anti-fibrotic potential of HD-16 in liver fibrosis and its underlying mechanism have not yet been elucidated. In this study, we investigated the anti-fibrotic effect of HD-16 on mouse liver fibrosis induced by CCl4 and on LX-2 cells (human immortalized HSCs) stimulated by TGF-β1, in vivo and in vitro. HD-16 exerted an anti-fibrotic effect via regulation of the AMPK/SIRT3 pathway. Pharmacodynamic results showed that HD-16 alleviated the degree of injury and inflammation in CCl4-induced mouse liver fibrosis. Consistently, HD-16 also effectively inhibited the expression of α-SMA, Col1α1, Col3α1, and TIMP-1 in TGF-β1-activated LX-2 cells. Mechanistically, HD-16 promoted SIRT3 expression and activity in fibrotic liver and activated LX-2 cells. Furthermore, SIRT3 depletion attenuated the anti-fibrotic effects of HD-16. Intriguingly, HD-16 increased AMPK phosphorylation, whereas inhibition of SIRT3 expression did not affect AMPK phosphorylation. In contrast, AMPK silencing suppressed SIRT3 expression, suggesting that SIRT3 is a downstream target of AMPK in liver fibrosis. Overall, HD-16 attenuated CCl4-induced liver inflammation and fibrosis by activating the AMPK/SIRT3 pathway, and HD-16 may be a potential anti-fibrotic compound in the treatment of liver fibrosis.
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Affiliation(s)
- Juan-Juan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - He-Chun Jiang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The First Affiliated Hospital of USTC Anhui Provincial Hospital, China
| | - Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Fang-Tian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Lin Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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Sohel M, Sultana H, Sultana T, Al Amin M, Aktar S, Ali MC, Rahim ZB, Hossain MA, Al Mamun A, Amin MN, Dash R. Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review. Heliyon 2022; 8:e08815. [PMID: 35128104 PMCID: PMC8810372 DOI: 10.1016/j.heliyon.2022.e08815] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/23/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cancer has become a significant concern in the medical sector with increasing disease complexity. Although some available conventional treatments are still a blessing for cancer patients, short-and long-term adverse effects and poor efficiency make it more difficult to treat cancer patients, demonstrating the need for new potent and selective anticancer drugs. In search of potent anticancer agents, naturally occurring compounds have always been admired due to their structural diversity, where Hesperetin (HSP) may be one of the potent candidates. PURPOSE We aimed to summarize all sources, pharmacological properties, anticancer activities of HSP against numerous cancers types through targeting multiple pathological processes, mechanism of HSP on sensitizing the current anti-cancer agents and other phytochemicals, overcoming resistance pattern and determining absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox). METHODS Information was retrieved from PubMed, Science Direct, and Google Scholar based on some key points like Hesperetin, cancer name, anticancer resistance, nanoformulation, and ADME/Tox was determined by in silico approaches. RESULT HSP is a phytoestrogen present in citrus fruits in a high concentration (several hundred mg/kg) and exhibited anti-cancer activities through interfering at several pathways. HSP can suppress tumor formation by targeting several cellular proteins such as cell cycle regulatory, apoptosis, metastatic, tyrosine kinase, growth factor receptor, estrogen metabolism, and antioxidant-related protein.HSP has shown remarkable synergistic properties in combination therapy and has been reported to overcome multidrug cancer resistance drugs, leading to an improved defensive mechanism. These anticancer activities of HSP may be due to proper structural chemistry. CONCLUSION Overall, HSP showed potential anticancer activities against all cancer and possess better pharmacokinetic properties. So this phytochemical alone or combination with other agents can be an effective alternative drug for cancer treatment.
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Affiliation(s)
- Md Sohel
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Habiba Sultana
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Tayeba Sultana
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Md. Al Amin
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Suraiya Aktar
- Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi, Bangladesh
| | - Md. Chayan Ali
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia 7003, Bangladesh
| | - Zahed Bin Rahim
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Md. Arju Hossain
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Abdullah Al Mamun
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Mohammad Nurul Amin
- Department of Pharmacy, Atish Dipankar University of Science and Technology, Dhaka 1230, Bangladesh
- Pratyasha Health Biomedical Research Center, Dhaka 1230 Bangladesh
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
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25
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Zhu S, Chen X, Wang JN, Xu JJ, Wang A, Li JJ, Wu S, Wu YY, Li XF, Huang C, Li J. Circular RNA circUbe2k promotes hepatic fibrosis via sponging miR-149-5p/TGF-β2 axis. FASEB J 2021; 35:e21622. [PMID: 33982351 DOI: 10.1096/fj.202002738r] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/25/2021] [Accepted: 04/12/2021] [Indexed: 12/12/2022]
Abstract
Abundant regulatory genes and complex circuits involving non-coding RNAs (ncRNAs) monitor the formation and development of hepatic fibrosis (HF). Circular RNAs (circRNAs) are a class of RNAs generated from protein coding genes by back-splicing, playing crucial roles in various pathological processes, including HF. However, little is known about mechanisms of action of circRNAs, let alone in HF. In this study, we found circUbe2k enhanced in CCl4 -induced HF mice and LX-2 cells stimulated with TGF-β1, regulating the development of HF. Restraining the expression of circUbe2k inhibited α-SMA and Col1α1 expression in CCl4 -induced HF mice and in LX-2 cells stimulated with TGF-β1. Furthermore, inhibiting circUbe2k expression reduced hepatic stellate cells (HSCs) activation and proliferation in vivo and in vitro. Mechanistically, we demonstrated a direct interaction between circUbe2k and miR-149-5p, which results in the modulation of TGF-β2 expressions. Together, circUbe2k may act as a "catalyst" of HSCs activation and HF through the circUbe2k/miR-149-5p/TGF-β2 axis. Our results provide unprecedented evidence for a significant role for circUbe2k to serve as a potential biomarker for HF therapy.
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Affiliation(s)
- Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jin-Jin Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Juan-Juan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Sha Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yuan-Yuan Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Feng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China.,School of Pharmacy, Anhui Medical University, Hefei, China
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26
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Arroyave-Ospina JC, Wu Z, Geng Y, Moshage H. Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy. Antioxidants (Basel) 2021; 10:antiox10020174. [PMID: 33530432 PMCID: PMC7911109 DOI: 10.3390/antiox10020174] [Citation(s) in RCA: 282] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress (OxS) is considered a major factor in the pathophysiology of inflammatory chronic liver diseases, including non-alcoholic liver disease (NAFLD). Chronic impairment of lipid metabolism is closely related to alterations of the oxidant/antioxidant balance, which affect metabolism-related organelles, leading to cellular lipotoxicity, lipid peroxidation, chronic endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Increased OxS also triggers hepatocytes stress pathways, leading to inflammation and fibrogenesis, contributing to the progression of non-alcoholic steatohepatitis (NASH). The antioxidant response, regulated by the Nrf2/ARE pathway, is a key component in this process and counteracts oxidative stress-induced damage, contributing to the restoration of normal lipid metabolism. Therefore, modulation of the antioxidant response emerges as an interesting target to prevent NAFLD development and progression. This review highlights the link between disturbed lipid metabolism and oxidative stress in the context of NAFLD. In addition, emerging potential therapies based on antioxidant effects and their likely molecular targets are discussed.
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27
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Liu H, Lv C, Lu J. Panax ginseng C. A. Meyer as a potential therapeutic agent for organ fibrosis disease. Chin Med 2020; 15:124. [PMID: 33292321 PMCID: PMC7683279 DOI: 10.1186/s13020-020-00400-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022] Open
Abstract
Background Ginseng (Panax ginseng C. A. Meyer), a representative Chinese herbal medicine, can improve the body’s antioxidant and anti-inflammatory capacity. Recently, scientists have shifted emphasis towards the initial stages of different malignant diseases—corresponding organ fibrosis and explored the essential role of P. ginseng in the treatment of fibrotic diseases. Main body In the first instance, the review generalizes the molecular mechanisms and common therapeutic methods of fibrosis. Next, due to the convenience and safety of individual medication, the research progress of ginseng extract and formulas in treating liver fibrosis, pulmonary fibrosis, myocardial fibrosis, and renal fibrosis has been systematically summarized. Finally, we describe active ingredients isolated from P. ginseng for their outstanding anti-fibrotic properties and further reveal the potential therapeutic prospect and limitations of P. ginseng in fibrotic diseases. Conclusions P. ginseng can be regarded as a valuable herbal medicine against fibrous tissue proliferation. Ginseng extract, derived formulas and monomers can inhibit the abundant deposition of extracellular matrix which caused by repeated damage and provide protection for fibrotic organs. Although the molecular mechanisms such as transforming growth factor β signal transduction have been confirmed, future studies should still focus on exploring the underlying mechanisms of P. ginseng in treating fibrotic disease including the therapeutic targets of synergistic action of multiple components in P. ginseng. Moreover, it is also necessary to carry out clinical trial to evaluate the feasibility of P. ginseng in combination with common fibrosis drugs.
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Affiliation(s)
- Hao Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China
| | - Chongning Lv
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.,Liaoning Provincial Key Laboratory of TCM Resources Conservation and Development, Shenyang Pharmaceutical University, Shenyang, 110006, PR China
| | - Jincai Lu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110006, PR China. .,Liaoning Provincial Key Laboratory of TCM Resources Conservation and Development, Shenyang Pharmaceutical University, Shenyang, 110006, PR China.
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28
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Siddiqui SS, Rahman S, Rupasinghe HV, Vazhappilly CG. Dietary Flavonoids in p53-Mediated Immune Dysfunctions Linking to Cancer Prevention. Biomedicines 2020; 8:biomedicines8080286. [PMID: 32823757 PMCID: PMC7460013 DOI: 10.3390/biomedicines8080286] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/03/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022] Open
Abstract
The p53 protein plays a central role in mediating immune functioning and determines the fate of the cells. Its role as a tumor suppressor, and in transcriptional regulation and cytokine activity under stress conditions, is well defined. The wild type (WT) p53 functions as a guardian for the genome, while the mutant p53 has oncogenic roles. One of the ways that p53 combats carcinogenesis is by reducing inflammation. WT p53 functions as an anti-inflammatory molecule via cross-talk activity with multiple immunological pathways, such as the major histocompatibility complex I (MHCI) associated pathway, toll-like receptors (TLRs), and immune checkpoints. Due to the multifarious roles of p53 in cancer, it is a potent target for cancer immunotherapy. Plant flavonoids have been gaining recognition over the last two decades to use as a potential therapeutic regimen in ameliorating diseases. Recent studies have shown the ability of flavonoids to suppress chronic inflammation, specifically by modulating p53 responses. Further, the anti-oxidant Keap1/Nrf2/ARE pathway could play a crucial role in mitigating oxidative stress, leading to a reduction of chronic inflammation linked to the prevention of cancer. This review aims to discuss the pharmacological properties of plant flavonoids in response to various oxidative stresses and immune dysfunctions and analyzes the cross-talk between flavonoid-rich dietary intake for potential disease prevention.
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Affiliation(s)
- Shoib Sarwar Siddiqui
- Department of Biotechnology, American University of Ras Al Khaimah, Ras Al Khaimah PO Box 10021, UAE;
| | - Sofia Rahman
- School of Natural Sciences and Mathematics, The University of Texas at Dallas, Richardson, TX 75080, USA;
| | - H.P. Vasantha Rupasinghe
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada;
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Cijo George Vazhappilly
- Department of Biotechnology, American University of Ras Al Khaimah, Ras Al Khaimah PO Box 10021, UAE;
- Correspondence:
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29
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Yang YR, Bu FT, Yang Y, Li H, Huang C, Meng XM, Zhang L, Lv XW, Li J. LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway. Mol Immunol 2020; 126:31-39. [PMID: 32745796 DOI: 10.1016/j.molimm.2020.07.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/23/2020] [Accepted: 07/08/2020] [Indexed: 12/17/2022]
Abstract
Activated hepatic stellate cells (HSCs) are the major cell type involved in the deposition of extracellular matrix (ECM) during the development of hepatic fibrosis. In this study, we revealed that left-right determination factor 2 (LEFTY2), one of the proteins belonging to the transforming growth factor-β (TGF-β) protein superfamily, was remarkedly decreased in human hepatic fibrosis tissues and in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. In addition, TGF-β1 treatment markedly reduced the level of LEFTY2 in HSCs. Importantly, overexpression of LEFTY2 suppressed the activation and proliferation of HSCs. LEFTY2 inhibited the expression of TGF-β1-induced fibrosis-associated genes (α-SMA and COL1a1) in human (LX-2) and rat (HSC-T6) HSC cell lines in vitro. Mechanistically, we demonstrated, for the first time, the role of LEFTY2 in inhibiting TGF-β1/Smad3 signaling, suggesting that there is a mutual antagonism between LEFTY2 and TGF-β1/Smad3 signaling during liver fibrosis. Similarly, we observed that LEFTY2 has a negative effect on its downstream genes, including c-MYC, CDK4, and cyclin D1, in liver fibrosis. Collectively, our data strongly indicated that LEFTY2 plays an important role in controlling the proliferation and activation of HSCs in the progression of liver fibrosis and this could be a potential therapeutic target for its treatment.
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Affiliation(s)
- Ya-Ru Yang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; Department of Clinical Pharmacology, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China
| | - Fang-Tian Bu
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Yang Yang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Hao Li
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Xiao-Ming Meng
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Xiong-Wen Lv
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
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30
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Fu X, Qie J, Fu Q, Chen J, Jin Y, Ding Z. miR-20a-5p/TGFBR2 Axis Affects Pro-inflammatory Macrophages and Aggravates Liver Fibrosis. Front Oncol 2020; 10:107. [PMID: 32117757 PMCID: PMC7031347 DOI: 10.3389/fonc.2020.00107] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 01/21/2020] [Indexed: 12/25/2022] Open
Abstract
Combined inhibition of programmed death-ligand 1 (PD-L1) and transforming growth factor-β (TGF-β) displayed additive anti-tumor response in a subgroup of cancer patients, highlighting the importance of understanding the multifaceted roles of TGF-β in immunity and fibrosis. In the present research, we show that TGF-β signaling pathway, controlled by miR-20a-5p and transforming growth factor-β receptor 2 (TGFBR2), alters the inflammation and fibrosis processes in liver. We performed integrated analysis of differently expressed miRNA (DEM) associated with liver fibrosis and screened miR-20a-5p out as a key regulator in inflammation-driven liver fibrosis. We subsequently conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the genes targeted by miR-20a-5p. And the result showed that 12 target genes were significantly enriched in TGF-β signaling pathway. Further study showed that miR-20a-5p was down-regulated and involved in inflammation during liver fibrosis in human and mouse samples, indicating that miR-20a-5p and inflammation are functionally linked during liver fibrosis progression. To uncover the underlying pro-inflammatory mechanism of miR-20a-5p in liver fibrosis, we selected and verified TGFBR2, which is a key functional receptor in TGF-β signaling pathway, as a direct target gene of miR-20a-5p. The downregulation of miR-20a-5p in liver fibrosis resulted in TGFBR2-activated TGF-β signaling pathway, followed by the activation of macrophage and extracellular matrix (ECM) production by hepatic stellate cell (HSC). Our results identify the miR-20a-5p/TGFBR2 axis as a key regulator of TGF-β signaling, and highlight the critical role of miR-20a-5p in the development of liver fibrosis.
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Affiliation(s)
- Xiutao Fu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jingbo Qie
- Minhang Hospital and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qingchun Fu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jiafeng Chen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yinpeng Jin
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Zhenbin Ding
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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