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Long Y, Li Y, Ma Z, Xie Y, Zhao H, Zhang M, Liu R. Epimedii Folium and Ligustri Lucidi Fructus synergistically delay renal aging through AMPK/ULK1/Bcl2L13-mediated mitophagy. JOURNAL OF ETHNOPHARMACOLOGY 2025; 346:119668. [PMID: 40122318 DOI: 10.1016/j.jep.2025.119668] [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: 01/03/2025] [Revised: 02/19/2025] [Accepted: 03/20/2025] [Indexed: 03/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The root of aging is attributed to kidney essence insufficiency and gradual loss of kidney function. The combination of Epimedii Folium and Ligustri Lucidi Fructus (ELL) is traditionally recognized to tonify kidney yin and yang and has significant efficacy in delaying aging and aging-related diseases, but little is known about the exact mechanism. AIM OF THE STUDY The research focuses on the mechanism of delaying renal aging by which ELL regulates mitophagy through serine/threonine kinase AMP-activated protein kinase (AMPK)/UNC-51- like autophagy activating kinase 1 (ULK1)/B-cell lymphoma-2-like protein 13 (Bcl2L13) in vivo. MATERIALS AND METHODS We employed a rat model of natural aging, using rats of different ages as dynamic controls, and a natural aging mouse model to evaluate the effects of ELL on delaying renal aging via AMPK/ULK1/Bcl2L13. The assessment included renal histopathology, oxidative stress, cell senescence, mitochondrial dynamics, mitophagy, and the AMPK/ULK1/Bcl2L13 signaling pathway. In the aging rat model, network pharmacology and proteomics were combined to dissect the renal aging process, and a Multilayer Perceptron (MLP) -artificial neural networks (ANN) model was used to evaluate the effects of ELL comprehensively. In the aging mouse model, the AMPK inhibitor dorsomorphin was applied to assess whether the AMPK signaling pathway was involved in ELL-induced mitophagy. RESULTS Compared with the young rats, the kidney exhibited signs of degenerative pathologies and increased oxidative stress in 17-month-old rats. A thorough analysis identified the mitochondrial protein Bcl2L13 as a crucial biomarker associated with renal aging. The AMPK/ULK1/Bcl2L13 pathway significantly regulated mitochondrial function and mitophagy, which were potential mechanisms underlying renal aging. In contrast to aged rats, the renal pathological changes and cell senescence in rats treated with ELL were significantly mitigated, the antioxidant capacity, mitochondrial dynamics, and mitophagy were improved, and the expression of AMPK/ULK1/Bcl2L13 was upregulated. After the application of AMPK inhibitor dorsomorphin, the effects of ELL were reversed. It appears that ELL modulates the AMPK/ULK1/Bcl2L13 signaling pathway, and upregulates mitophagy to potentially decelerate renal aging. CONCLUSIONS The findings indicate that aging kidneys display mitochondrial dysfunction, disorganization of mitochondria, and a decrease in mitophagy. Concurrently, ELL significantly regulates mitochondrial dynamics and mitophagy via AMPK/ULK1/Bcl2L13. This regulation helps mitigate mitochondrial dysfunction, suggesting ELL as a promising herbal remedy for delaying renal aging and age-related kidney diseases.
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Affiliation(s)
- Yuting Long
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Yuman Li
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Zaina Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Yonghao Xie
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Hui Zhao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China; Beijing Key Lab of Traditional Chinese Medicine Collateral Disease Theory Research, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, China
| | - Minyu Zhang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China; Beijing Key Lab of Traditional Chinese Medicine Collateral Disease Theory Research, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, China.
| | - Renhui Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China; Beijing Key Lab of Traditional Chinese Medicine Collateral Disease Theory Research, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, China.
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Wei Y, Tu J, Ji L, Wang R, Zhou R, Lei X, Hu L, Huang H. Icariin inhibition of NLRP3 mediated Leydig cell pyroptosis and insulin resistance ameliorates spermatogenesis disorders in obese mice. Int Immunopharmacol 2025; 151:114280. [PMID: 40007375 DOI: 10.1016/j.intimp.2025.114280] [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: 10/07/2024] [Revised: 12/26/2024] [Accepted: 02/08/2025] [Indexed: 02/27/2025]
Abstract
Obesity, characterized by excessive body fat accumulation due to energy metabolism imbalance, has emerged as a significant risk factor for male infertility. Icariin (ICA), a principal constituent of Epimedium, has demonstrated potential in improving obesity and enhancing testicular spermatogenesis. This study aimed to elucidate the role and underlying mechanisms of ICA in mitigating obesity-induced male infertility through the suppression of inflammation and insulin resistance. Utilizing a high-fat diet (HFD)-induced obese mouse model, we investigated ICA's effects on pyroptosis, insulin resistance, and cell-related genes and proteins, such as Caspase-1, NLRP3, IL-1β, IL-18, and GSDMD. Our in vitro studies on TM3 cells confirmed that ICA could ameliorate inflammation and pyroptosis induced by LPS + Nig and insulin resistance induced by insulin. We discovered that ICA significantly attenuated body weight changes, pyroptosis, insulin resistance, and testicular spermatogenic dysfunction induced by HFD. Moreover, ICA effectively mitigated inflammation and pyroptosis in TM3 cells induced by LPS + Nig and insulin resistance. The study concluded that by addressing the underlying mechanisms, ICA holds promise as a treatment for obesity-related male infertility through inflammation, insulin resistance, and metabolic dysfunction. The study calls for further investigation of the molecular mechanisms and clinical applicability of ICA, particularly with regard to its potential to alter the gut microbiota, which may contribute to improved metabolic and reproductive health. This study reveals that ICA suppresses NLRP3 inflammasome-activated pyroptosis and insulin resistance, reduces inflammatory mediator expression, enhances insulin sensitivity, promotes testosterone synthesis and secretion, restores testicular interstitial cell function, and ameliorates testicular spermatogenesis in obese mice.
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Affiliation(s)
- Yanhong Wei
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, No. 3, Longyuan Road, Qingxiu District, Nanning City, Guangxi 530000, China; Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Department of Obstetrics and Gynecology, Department of Reproductive Medicine Center, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
| | - Jian Tu
- Hunan Province Innovative Training Base for Medical Postgraduates, Hengyang Medical School, University of South China and Yueyang Women & Children's Medical Center, Hengyang and Yueyang, Hunan 421000, China.
| | - Lin Ji
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, No. 3, Longyuan Road, Qingxiu District, Nanning City, Guangxi 530000, China.
| | - Rutong Wang
- Hunan Province Innovative Training Base for Medical Postgraduates, Hengyang Medical School, University of South China and Yueyang Women & Children's Medical Center, Hengyang and Yueyang, Hunan 421000, China.
| | - Runtang Zhou
- Hunan Province Innovative Training Base for Medical Postgraduates, Hengyang Medical School, University of South China and Yueyang Women & Children's Medical Center, Hengyang and Yueyang, Hunan 421000, China.
| | - Xiaocan Lei
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Department of Obstetrics and Gynecology, Department of Reproductive Medicine Center, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China; Hunan Province Innovative Training Base for Medical Postgraduates, Hengyang Medical School, University of South China and Yueyang Women & Children's Medical Center, Hengyang and Yueyang, Hunan 421000, China.
| | - Linlin Hu
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Department of Obstetrics and Gynecology, Department of Reproductive Medicine Center, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
| | - Hua Huang
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, No. 3, Longyuan Road, Qingxiu District, Nanning City, Guangxi 530000, China.
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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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Luo P, An Y, He J, Xing X, Zhang Q, Liu X, Chen Y, Yuan H, Chen J, Wong YK, Huang J, Gong Z, Du Q, Xiao W, Wang J. Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma. Cancer Lett 2024; 587:216621. [PMID: 38242198 DOI: 10.1016/j.canlet.2024.216621] [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: 11/04/2023] [Revised: 12/15/2023] [Accepted: 01/04/2024] [Indexed: 01/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is among the deadliest malignancies worldwide and still a pressing clinical problem. Icaritin, a natural compound obtained from the Epimedium genus plant, has garnered significant attention as a potential therapeutic drug for HCC therapies. Mitophagy plays a crucial role in mitochondrial quality control through efficiently eliminating damaged mitochondria. However, the specific mechanisms of the interplay between mitophagy and apoptosis in HCC is still unclear. We aimed to explore the cross-talk between icaritin-induced mitophagy and apoptosis in HCC cells and investigate its potential mechanisms. Firstly, we confirmed that icaritin inhibits proliferation and migration while inducing mitochondrial damage and reactive oxygen species (ROS) production in HCC cells. Secondly, based on proteomics analysis, we discovered that icaritin inhibits the growth of tumor cells and disrupts their mitochondrial homeostasis through the regulation of both mitophagy and apoptosis. Thirdly, icaritin causes mitophagy mediated by PINK1-Parkin signaling via regulating feedforward loop. Furthermore, knockdown of PINK1/Parkin leads to inhibition of mitophagy, which promotes cell death induced by icaritin in HCC cells. Finally, autophagy/mitophagy inhibitors remarkably enhance icaritin-induced cell death and anticancer efficacy. Collectively, our findings reveal that icaritin suppresses growth, proliferation and migration of HCC cell through induction of mitophagy and apoptosis, while inhibition of mitophagy significantly increased the anti-cancer and pro-apoptotic effects of icaritin, indicating that targeting autophagy or mitophagy is a novel approach to overcome drug resistance and enhance anticancer therapies.
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Affiliation(s)
- Piao Luo
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yehai An
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, China
| | - Jingqian He
- The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Xuefeng Xing
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Qian Zhang
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xueying Liu
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China
| | - Yu Chen
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Haitao Yuan
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China
| | - Junhui Chen
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China
| | - Yin-Kwan Wong
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China
| | - Jingnan Huang
- Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China
| | - Zipeng Gong
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, China.
| | - Qingfeng Du
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Wei Xiao
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Jigang Wang
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China; Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China; State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, China; Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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Lei SS, Huang XW, Li LZ, Wang XP, Zhang Y, Li B, Shou D. Explorating the mechanism of Epimedii folium-Rhizoma drynariae herbal pair promoted bone defects healing through network pharmacology and experimental studies. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117329. [PMID: 37879510 DOI: 10.1016/j.jep.2023.117329] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 10/05/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bone defects are difficult to treat and have a high incidence of nonunion. The Epimedii folium-Rhizoma drynariae herbal pair (EDP) is a traditional Chinese medicine (TCM) used for treating bone diseases. However, the mechanisms by which EDP promotes osteogenesis or bone formation remain largely unclear. AIM OF THE STUDY This study aimed to investigate the mechanism of EDP promoted bone formation in bone defects using network pharmacology and experiments. MATERIALS AND METHODS The chemical components of EDP were analyzed by UHPLC-MS. The hub target and pathway enrichment analysis was conducted using molecular docking or network pharmacology. The pharmacological actions of EDP were determined by μCT and histopathology examination using a bone defect rat model. The effects of EDP on the mRNA expression of Bmp2, Smad2/5, Runx2, and Alp genes were measured by RT-PCR, while changes in the protein expressions of BMP2, COL1A1, SPP1, ALP, and RUNX2in the tibia tissues of the rats in response to EDP were analyzed by immunohistochemical staining or Western blot. We also performed cell viability assays, Alizarin Red and ALP staining assays, and RT-PCR to better understand how EDP affected osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RESULTS Identified 14 key compounds and 47 hub targets of EDP that may be involved in promoting osteogenesis to repair bone defects. And the BMP/Smad/Runx2 pathway was likely the key pathway through which EDP promoted bone defects repairing. The results of in vivo rat experiments indicated that EDP effectively promoted tibia repair in the model rats and activated the BMP/Smad/Runx2 pathway in the tibia tissue, with upregulating Bmp2, Bmpr1α, Smad2/5, Runx2, and Alp genes, and increased the protein expression of BMP2, COL1A1, RUNX2, and ALP. In vitro, EDP was found to increase the proliferation, differentiation, and mineralization in BMSCs- and also up-regulated the expression of key genes in the BMP/Smad/Runx2 pathway. CONCLUSION This study highlighted the ability of EDP to promote the osteogenic differentiation to enable bone repair by activating the BMP/Smad/Runx2 pathway.
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Affiliation(s)
- Shan Shan Lei
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China
| | - Xiao Wen Huang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China
| | - Lin Zi Li
- Jingmen Central Hospital, 448000, Jingmen, China
| | - Xu Ping Wang
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China
| | - Yang Zhang
- Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310053, China
| | - Bo Li
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang 310007, China.
| | - Dan Shou
- Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
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Wang Y, Wang G, Liu Y, Yang F, Zhang H, Kong Y. Icaritin inhibits endometrial carcinoma cells by suppressing O-GlcNAcylation of FOXC1. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 120:155062. [PMID: 37683586 DOI: 10.1016/j.phymed.2023.155062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 08/25/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023]
Abstract
BACKGROUND Icaritin has a wide range of pharmacological activities, including significant an-titumor activity. However, the mechanism of action of icaritin in endometrial cancer (UCEC) remains unknown. FOX proteins are a highly conserved transcription factor superfamily that play important roles in epithelial cell differentiation, tumor metastasis, angiogenesis, and cell cycle regulation. FOXC1 is an important member of the FOX protein family. FOXC1 is aberrantly expressed in endometrial cancer and may play a role in the migration and invasion of endometrial cancer; however, its mechanism of action has not yet been reported. O-GlcNAc glycosylation is a common post-translational modification. In endometrial cancer, high levels of O-GlcNAcylation promote cell proliferation, migration, and invasion. Cancer development is often accompanied by O-GlcNAc modification of proteins; however, O-GlcNAc modification of the transcription factor FOXC1 has not been reported to date. PURPOSE To investigate the inhibitory effects of icaritin on RL95-2 and Ishikawa endometrial cancer cells in vitro and in vivo and to elucidate the possible molecular mechanisms. METHODS/STUDY DESIGN CCK8, colony formation, migration, and invasion assays were used to determine the inhibitory effects of icaritin on endometrial cancer cells in vitro. Cell cycle regulation was assayed by flow cytometry. Protein levels were measured based on western blotting. The level of FOXC1 expression in endometrial cancer tissues was determined by immunohistochemistry. To assess whether icaritin also has activity in vivo, its effect on tumor xenografts was evaluated. RESULTS Immunohistochemical analysis of clinical samples revealed that FOXC1 expression was significantly higher in endometrial cancer tissues than in normal tissues. Downregulation of FOXC1 inhibited the proliferative, colony formation, migration, and invasive abilities of RL95-2 and Ishikawa endometrial cancer cells. Icaritin inhibited the proliferation, colony formation, migration, and invasion of endometrial cancer cells and blocked the cell cycle in S phase. Icaritin affected O-GlcNAc modification of FOXC1 and thus the stability of FOXC1, which subsequently triggered the inhibition of endometrial cancer cell proliferation. CONCLUSION The anti-endometrial cancer effect of icaritin is related to the inhibition of abnormal O-GlcNAc modification of FOXC1, which may provide an important theoretical foundation for the use of icaritin against endometrial cancer.
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Affiliation(s)
- Yufei Wang
- Institute of Neurology, General Hospital of Shenyang Military Command, Shenyang, Liaoning 110016, China
| | - Gang Wang
- Dalian Medical University, Lvshun South Road #9, Dalian, Liaoning 116044, China
| | - Yingping Liu
- Dalian Medical University, Lvshun South Road #9, Dalian, Liaoning 116044, China
| | - Fangyu Yang
- Institute of Neurology, General Hospital of Shenyang Military Command, Shenyang, Liaoning 110016, China
| | - Hongshuo Zhang
- Dalian Medical University, Lvshun South Road #9, Dalian, Liaoning 116044, China.
| | - Ying Kong
- Dalian Medical University, Lvshun South Road #9, Dalian, Liaoning 116044, China.
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Ma Y, Zhao C, Hu H, Yin S. Liver protecting effects and molecular mechanisms of icariin and its metabolites. PHYTOCHEMISTRY 2023; 215:113841. [PMID: 37660725 DOI: 10.1016/j.phytochem.2023.113841] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 08/24/2023] [Accepted: 08/27/2023] [Indexed: 09/05/2023]
Abstract
As a detoxification and metabolism organ, the liver plays a vital role in human health. However, an excessive consumption of drugs and toxins, exposure to pathogenic viruses, and unhealthy living habits can lead to liver damage, which may even develop into liver cirrhosis and liver cancer. Epimedium brevicornum Maxim. is a traditional Chinese medicine and dietary supplement in which the flavonoid icariin is a main functional component. Although the protective mechanisms of icariin and its metabolites against liver injury are not yet comprehensively understood, an increasing number of studies have confirmed their liver-protective and anticancer effects. Indeed, icaritin, one of the metabolites of icariin, is currently utilized as an active component of an anti-cancer drug. This paper presents a review of the molecular mechanisms through which icariin and its metabolites actively protect against the occurrence and development of liver injury, and, thus, provides a comprehensive reference for further research and their application in liver protection.
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Affiliation(s)
- Yurong Ma
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
| | - Chong Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
| | - Hongbo Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
| | - Shutao Yin
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
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Huong NT, Son NT. Icaritin: A phytomolecule with enormous pharmacological values. PHYTOCHEMISTRY 2023:113772. [PMID: 37356700 DOI: 10.1016/j.phytochem.2023.113772] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 05/24/2023] [Accepted: 06/10/2023] [Indexed: 06/27/2023]
Abstract
Pharmacological studies on flavonoids have always drawn much interest for many years. Icaritin (ICT), a representative flavone containing an 8-prenyl group, is a principal compound detected in medicinal plants of the genus Epimedum, the family Berberidaceae. Experimental results in the phytochemistry and pharmacology of this molecule are abundant now, but a deep overview has not been carried out. The goal of this review is to provide an insight into the natural observation, biosynthesis, biotransformation, synthesis, pharmacology, and pharmacokinetics of prenyl flavone ICT. The relevant data on ICT was collected from bibliographic sources, like Google Scholar, Web of Science, Sci-Finder, and various published journals. "Icaritin" alone or in combination is the main keyword to seek for references, and references have been updated till now. ICT is among the characteristic phytomolecules of Epimedum plants. Bacteria monitored its biosynthesis and biotransformation, while this agent was rapidly synthesized from phloroglucinol by microwave-assistance Claisen rearrangement. ICT is a potential agent in numerous in vitro and in vivo pharmacological records, which demonstrated its role in cancer treatments via apoptotic-related mechanisms. It also brings in various health benefits since it reduced harmful effects on the liver, lung, heart, bone, blood, and skin, and improved immune responses. Pharmacokinetic outcomes indicated that its metabolic pathway involved hydration, hydroxylation, dehydrogenation, glycosylation, and glucuronidation. Molecule mechanisms of action at a cellular level are predominant, but clinical studies are expected to get more. Structure-activity relationship records seem insufficient, and the studies on nano-combined approaches to improve its soluble property in living bodied medium are needed.
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Affiliation(s)
- Nguyen Thi Huong
- Faculty of Chemical Technology, Hanoi University of Industry, Hanoi, Viet Nam
| | - Ninh The Son
- Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi, Viet Nam.
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10
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Riaz M, Khalid R, Afzal M, Anjum F, Fatima H, Zia S, Rasool G, Egbuna C, Mtewa AG, Uche CZ, Aslam MA. Phytobioactive compounds as therapeutic agents for human diseases: A review. Food Sci Nutr 2023; 11:2500-2529. [PMID: 37324906 PMCID: PMC10261751 DOI: 10.1002/fsn3.3308] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 06/17/2023] Open
Abstract
Phytobioactive compounds are plant secondary metabolites and bioactive compounds abundantly present in medicinal plants and have remarkable therapeutic potential. Oxidative stress and antibiotic resistance are major causes of present-day ailments such as diabetes, atherosclerosis, cardiovascular disorders, cancer, and inflammation. The data for this review were collected from Google Scholar, PubMed, Directory of Open Access Journals (DOAJ), and Science Direct by using keywords: "Medicinal plants, Phytobioactive compounds, Polyphenols, Alkaloids, Carotenoids etc." Several studies have reported the pharmacological and therapeutic potential of the phytobioactives. Polyphenols, alkaloids, terpenes, and polysaccharides isolated from medicinal plants showed remarkable antioxidant, anticancer, cytotoxic, anti-inflammatory, cardioprotective, hepatoprotective, immunomodulatory, neuroprotective, and antidiabetic activities. This literature review was planned to provide comprehensive insight into the biopharmacological and therapeutic potential of phytobioactive compounds. The techniques used for the extraction and isolation of phytobioactive compounds, and bioassays required for their biological activities such as antioxidant, antimicrobial, anti-inflammatory, and cytotoxic activities, have been discussed. Characterization techniques for the structural elucidation of phytobioactive compounds such as HPLC, TLC, FTIR, GC-MS/MS, and NMR have also been discussed. This review concludes that phytobioactive compounds may be used as potential alternative to synthetic compounds as therapeutic agents for the treatment of various diseases.
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Affiliation(s)
- Muhammad Riaz
- Department of Allied Health SciencesUniversity of SargodhaSargodhaPakistan
| | - Ramsha Khalid
- Department of BiochemistryUniversity of AgricultureFaisalabadPakistan
| | | | - Fozia Anjum
- Department of ChemistryGovernment College UniversityFaisalabadPakistan
| | - Hina Fatima
- Department of BiochemistryUniversity of AgricultureFaisalabadPakistan
- Department of Basic and Applied Chemistry, Faculty of Science and TechnologyUniversity of Central PunjabLahorePakistan
| | - Saadiya Zia
- Department of BiochemistryUniversity of AgricultureFaisalabadPakistan
| | - Ghulam Rasool
- Department of Allied Health SciencesUniversity of SargodhaSargodhaPakistan
| | - Chukwuebuka Egbuna
- Africa Centre of Excellence in Public Health and Toxicological Research (ACE‐PUTOR), Nutritional Biochemistry and Toxicology UnitUniversity of Port‐HarcourtPort HarcourtNigeria
| | - Andrew G. Mtewa
- Chemistry Section, Malawi Institute of TechnologyMalawi University of Science and TechnologyLimbeMalawi
| | - Chukwuemelie Zedech Uche
- Department of Medical Biochemistry and Molecular Biology, Faculty of Basic Medical SciencesUniversity of NigeriaEnuguNigeria
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11
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Lu Y, Luo Q, Jia X, Tam JP, Yang H, Shen Y, Li X. Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: Integration of herbal medicine, enzyme engineering, and nanotechnology. J Pharm Anal 2023; 13:239-254. [PMID: 37102112 PMCID: PMC10123947 DOI: 10.1016/j.jpha.2022.12.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/29/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023] Open
Abstract
Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects. Nonetheless, both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content, poor bioavailability, and unfavorable in vivo delivery efficiency. Recently, various strategies, including enzyme engineering and nanotechnology, have been developed to increase productivity and activity, improve delivery efficiency, and enhance therapeutic effects of epimedium flavonoids. In this review, the structure-activity relationship of epimedium flavonoids is described. Then, enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed. The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized. Finally, the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.
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Affiliation(s)
- Yi Lu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Qiulan Luo
- College of Fashion & Design, Jiaxing Nanhu University, Jiaxing, Zhejiang, 314001, China
| | - Xiaobin Jia
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - James P. Tam
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore, Singapore
| | - Huan Yang
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Yuping Shen
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Xin Li
- DWI-Leibniz-Institute for Interactive Materials e.V., 52056, Aachen, Germany
- Institute for Technical and Macromolecular Chemistry, RWTH Aachen University, 52074, Aachen, Germany
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12
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Li WQ, Liu WH, Qian D, Liu J, Zhou SQ, Zhang L, Peng W, Su L, Zhang H. Traditional Chinese medicine: An important source for discovering candidate agents against hepatic fibrosis. Front Pharmacol 2022; 13:962525. [PMID: 36081936 PMCID: PMC9445813 DOI: 10.3389/fphar.2022.962525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/28/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of "traditional Chinese medicine," "herbal medicine," "natural agents," "liver diseases," and "hepatic fibrosis." So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF.
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Affiliation(s)
- Wen-Qing Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Hao Liu
- Department of Pharmacy, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Die Qian
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shi-Qiong Zhou
- Hospital of Nursing, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Lei Zhang
- Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Su
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Hong Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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13
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Huang JJ, Hu HX, Lu YJ, Bao YD, Zhou JL, Huang M. Computer-Aided Design of α-L-Rhamnosidase to Increase the Synthesis Efficiency of Icariside I. Front Bioeng Biotechnol 2022; 10:926829. [PMID: 35800333 PMCID: PMC9253678 DOI: 10.3389/fbioe.2022.926829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
Icariside I, the glycosylation product of icaritin, is a novel effective anti-cancer agent with immunological anti-tumor activity. However, very limited natural icariside I content hinders its direct extraction from plants. Therefore, we employed a computer-aided protein design strategy to improve the catalytic efficiency and substrate specificity of the α-L-rhamnosidase from Thermotoga petrophila DSM 13995, to provide a highly-efficient preparation method. Several beneficial mutants were obtained by expanding the active cavity. The catalytic efficiencies of all mutants were improved 16-200-fold compared with the wild-type TpeRha. The double-point mutant DH was the best mutant and showed the highest catalytic efficiency (k cat /K M : 193.52 s-1 M-1) against icariin, which was a 209.76-fold increase compared with the wild-type TpeRha. Besides, the single-point mutant H570A showed higher substrate specificity than that of the wild-type TpeRha in hydrolysis of different substrates. This study provides enzyme design strategies and principles for the hydrolysis of rhamnosyl natural products.
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Affiliation(s)
- Jia-Jun Huang
- School of Food Science and Engineering, South China University of Technology, Guangzhou, China
- Golden Health Biotechnology Co., Ltd., Foshan, China
| | - Hao-Xuan Hu
- Golden Health Biotechnology Co., Ltd., Foshan, China
| | - Yu-Jing Lu
- Golden Health Biotechnology Co., Ltd., Foshan, China
- School of Chemical Engineering and Light Industry, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Ya-Dan Bao
- Golden Health Biotechnology Co., Ltd., Foshan, China
| | - Jin-Lin Zhou
- Golden Health Biotechnology Co., Ltd., Foshan, China
| | - Mingtao Huang
- School of Food Science and Engineering, South China University of Technology, Guangzhou, China
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14
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Tu S, Mao D, Shi M, Zhang H, Liu C, Li X, Zhao Y, Chen Y, Liu Y. Icaritin ameliorates extracellular microparticles‐induced inflammatory pre‐metastatic niche via modulating the
cGAS‐STING
signaling. Phytother Res 2022; 36:2127-2142. [PMID: 35257426 DOI: 10.1002/ptr.7433] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/27/2021] [Accepted: 11/18/2021] [Indexed: 11/09/2022]
Affiliation(s)
- Shumei Tu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Dengxuan Mao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Mengxin Shi
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Huangqin Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Congyan Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Xiaoqi Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine Nanjing China
| | - Yan Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
| | - Yuping Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine Nanjing China
- Jiangsu Province Academy of Traditional Chinese Medicine Nanjing China
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15
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Li Y, Li Y, Zhang J, Ji L, Li M, Sun X, Feng H, Yu Z, Gao Y. Current Perspective of Traditional Chinese Medicines and Active Ingredients in the Therapy of Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:41-56. [PMID: 35178363 PMCID: PMC8843800 DOI: 10.2147/jhc.s346047] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/27/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading lethal tumors worldwide, and the treatment remains a great medical challenge. Surgery and chemotherapy are current standard curative methods for patients with HCC, but the prognosis is still dismal. Based on unique medical theories and rich practical experience, traditional Chinese medicine (TCM) has been broadly employed to effectively treat HCC for a long history. Recently, systematic clinical trials have been well designed to study the efficacy of TCMs in the treatment of HCC, and the underlying antitumor mechanisms were also deeply explored. Here, we reviewed the published clinical evaluation of some commonly used TCMs in the treatment of HCC, and the related anti-HCC mechanisms through in vitro and in vivo study, promoting the modernization of TCM study in oncology for achieving a substantial reduction of HCC burden in the future.
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Affiliation(s)
- Yuyao Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yue Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jinghao Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Longshan Ji
- Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Man Li
- Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xuehua Sun
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Correspondence: Zhuo Yu; Yueqiu Gao, Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Pudong New District, Shanghai, 201203, People’s Republic of China, Tel +86 21 2025 6507, Fax +86 21 20256699, Email ;
| | - Yueqiu Gao
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
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16
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Immobilization of Thermostable β-Glucosidase and α-l-Rhamnosidase from Dictyoglomus thermophilum DSM3960 and Their Cooperated Biotransformation of Total Flavonoids Extract from Epimedium into Icaritin. Catal Letters 2021. [DOI: 10.1007/s10562-020-03522-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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17
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Madić V, Petrović A, Jušković M, Jugović D, Djordjević L, Stojanović G, Vasiljević P. Polyherbal mixture ameliorates hyperglycemia, hyperlipidemia and histopathological changes of pancreas, kidney and liver in a rat model of type 1 diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2021; 265:113210. [PMID: 32795501 DOI: 10.1016/j.jep.2020.113210] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/07/2020] [Accepted: 07/20/2020] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE One of the commonly prescribed 'anti-diabetic' polyherbal mixtures by European herbalists is made of Rubus fruticosus and Vaccinium myrtillus leaves, Potentilla erecta roots, Geum urbanum aerial parts and Phaseolus vulgaris pods. AIM OF THE STUDY This study aimed to evaluate the phytochemical composition, antioxidant capacity, potential toxicity, hypoglycemic, hypolipidemic, nephroprotective and hepatoprotective activities of this polyherbal mixture decoction. MATERIALS AND METHODS The phytochemical composition was evaluated using HPLC-UV. The antioxidant activity was assessed using the DPPH test. Potential toxicity was evaluated using the acute and sub-chronic oral toxicity method. Diabetes was induced in Wistar female rats with a single intraperitoneal injection of alloxan monohydrate (150 mg/kg). The animals whose blood glucose was >20 mmol/L for 14 consecutive days were considered diabetic. For the next 14 days, D-10 and D-20 groups were treated with the polyherbal mixture (10 and 20 g of dry plant material/kg, respectively). I and M were control groups treated with insulin glargine (13 IU/kg) and metformin (150 mg/kg), respectively. Healthy control (HC) and diabetic control (DC) groups were treated with water. The blood glucose level was measured on days 14, 21 and 28. Lipid profile analysis was done on day 28. Pancreas, kidney and liver histopathology was evaluated using the H&E and Masson's trichrome staining. The liver tissue was additionally tested for PAS-positive cells. RESULTS The HPLC-UV analysis revealed the presence of quinic, gallic and caftaric acid, arbutin, rutin, trifolin, astragalin, hyperoside, isoquercetin and quercitrin. The antioxidant activity of the extract was higher than the reference's one (p < 0.01). Treatment with the polyherbal mixture (10 and 20 g/kg) has shown no toxic effects. No major decline in blood sugar was recorded in I and M groups compared to the DC one (22.86 ± 2.58, 28.5 ± 0.42 and 27.82 ± 0.9 mmol/L, respectively). The polyherbal mixture lowered the blood glucose level to the normal value (8.64 ± 4.09, 5.26 ± 1.3 and 6.76 ± 1.54 mmol/L in D-10, D-20 and HC groups, respectively). Furthermore, it decreased the levels of total cholesterol, triglycerides, VLDL, LDL, atherogenic and cardiovascular risk indices (p < 0.001) compared to the DC group. In addition, the extract restored histopathological changes of the pancreas, kidneys and liver to the healthy animal level. CONCLUSION Treatment with the polyherbal mixture extract was more effective than the standard drugs (insulin and metformin) in the amelioration of hyperglycemia, hyperlipidemia, and histopathological changes of the pancreas, kidney and liver tissue.
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Affiliation(s)
- Višnja Madić
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Aleksandra Petrović
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Marina Jušković
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Dragana Jugović
- Laboratory for Cytogenetics and Immunology, Clinical Center of Niš, Bulevar Dr. Zorana Đinđića 48, 18000, Niš, Serbia.
| | - Ljubiša Djordjević
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Gordana Stojanović
- Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Perica Vasiljević
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
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18
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Icaritin Inhibits Skin Fibrosis through Regulating AMPK and Wnt/β-catenin Signaling. Cell Biochem Biophys 2020; 79:231-238. [PMID: 33125640 DOI: 10.1007/s12013-020-00952-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2020] [Indexed: 10/23/2022]
Abstract
Skin fibrosis is one of the major features of scleroderma. WNT/β-catenin signaling is associated with the progression of skin fibrosis. In this study, we aimed to determine the effect of icaritin (IT), a natural compound, on scleroderma-related skin fibrosis and its mechanisms. We found that IT could reduce the expression of COL1A1, COL1A2, COL3A1, CTGF, and α-SMA in human foreskin fibroblasts (HFF-1 cells), scleroderma skin fibroblasts (SSF cells), and TGF-β-induced HFF-1 cells. Wnt/β-catenin signaling was shown to be suppressed by IT. Additionally, IT activated AMPK signaling in HFF-1 cells. In conclusion, IT has an anti-skin fibrotic effect through activation of AMPK signaling and inhibition of WNT/β-catenin signaling. Our findings indicate the potential role of IT in the treatment of scleroderma and provide novel insight for the selection of drug therapy for scleroderma.
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19
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Yu Z, Guo J, Hu M, Gao Y, Huang L. Icaritin Exacerbates Mitophagy and Synergizes with Doxorubicin to Induce Immunogenic Cell Death in Hepatocellular Carcinoma. ACS NANO 2020; 14:4816-4828. [PMID: 32188241 DOI: 10.1021/acsnano.0c00708] [Citation(s) in RCA: 266] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Hepatocellular carcinoma (HCC) resistant to both chemotherapy and immunotherapy is among the deadliest malignancies. Doxorubicin widely used in transarterial chemotherapy in HCC can induce immunogenic cell death (ICD), but the resulting immunogenicity is still weak. We aim to seek a strategy for improving the efficacy of ICD in HCC based on an immunoregulatory drug called icaritin. Icaritin induced mitophagy and apoptosis to provoke ICD both in mouse Hepa1-6 and human Huh7 HCC cells. A combination of icaritin and doxorubicin with a molar ratio of 1:2 played a synergistic role in ICD induction. The poly lactic-co-glycolic acid (PLGA)-polyethylene glycol (PEG)-aminoethyl anisamide (AEAA) nanoparticle (NP) targeted codelivery of icaritin and doxorubicin remodeled the immunosuppressive tumor microenvironment and triggered a robust immune memory response, which efficiently improved anti-HCC effect at an early stage in mouse HCC model. In addition, the combo PLGA-PEG-AEAA NP together with lenvatinib significantly prolonged survival time of mice at the advanced stage of HCC. Collectively, our findings reveal an anti-HCC mechanism of icaritin on mitophagy and provide an effective immune-based therapeutic strategy for HCC.
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Affiliation(s)
- Zhuo Yu
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Department of Liver Disease, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jianfeng Guo
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
| | - Mengying Hu
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Leaf Huang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
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20
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Shan L, Liu Z, Ci L, Shuai C, Lv X, Li J. Research progress on the anti-hepatic fibrosis action and mechanism of natural products. Int Immunopharmacol 2019; 75:105765. [PMID: 31336335 DOI: 10.1016/j.intimp.2019.105765] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 07/15/2019] [Indexed: 12/15/2022]
Abstract
Hepatic fibrosis is the most common pathological feature of most chronic liver diseases, and its continuous deterioration gradually develops into liver cirrhosis and eventually leads to liver cancer. At present, there are many kinds of drugs used to treat liver fibrosis. However, Western drugs tend to only target single genes/proteins and induce many adverse reactions. Most of the mechanisms and active ingredients of traditional Chinese medicine (TCM) are not clear, and there is a lack of unified diagnosis and treatment standards. Natural products, which are characterized by structural diversity, low toxicity, and origination from a wide range of sources, have unique advantages and great potential in anti-liver fibrosis. This article summarizes the work done over the previous decade, on the active ingredients in natural products that are reported to have anti-hepatic fibrosis effects. The effective anti-hepatic fibrosis ingredients identified can be generally divided into flavonoids, saponins, polysaccharides and alkaloids. Mechanisms of anti-liver fibrosis include inhibition of liver inflammation, anti-lipid peroxidation injury, inhibition of the activation and proliferation of hepatic stellate cells (HSCs), modulation of the synthesis and secretion of pro-fibrosis factors, and regulation of the synthesis and degradation of the extracellular matrix (ECM). This review provides suggestions for the development of anti-hepatic fibrosis drugs.
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Affiliation(s)
- Liang Shan
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key laboratory of Anti-inflammatory and Immune medicines, Ministry of Education Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Zhenni Liu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key laboratory of Anti-inflammatory and Immune medicines, Ministry of Education Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Leilei Ci
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key laboratory of Anti-inflammatory and Immune medicines, Ministry of Education Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Chen Shuai
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key laboratory of Anti-inflammatory and Immune medicines, Ministry of Education Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiongwen Lv
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key laboratory of Anti-inflammatory and Immune medicines, Ministry of Education Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
| | - Jun Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key laboratory of Anti-inflammatory and Immune medicines, Ministry of Education Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
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Cheng L, Liu YY, Lu PH, Peng Y, Yuan Q, Gu XS, Jin Y, Chen MB, Bai XM. Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells. Oncotarget 2018; 8:28385-28394. [PMID: 28415690 PMCID: PMC5438657 DOI: 10.18632/oncotarget.16073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 02/27/2017] [Indexed: 01/07/2023] Open
Abstract
The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation. DNA-PKcs inhibition, knockdown or mutation facilitated TIC10-induced Foxo3a nuclear translocation, TRAIL/DR5 expression and cell apoptosis. Reversely, exogenous DNA-PKcs over-expression inhibited above actions by TIC10. In vivo, oral administration of TIC10 significantly inhibited HepG2 tumor growth in nude mice, which was further potentiated with Nu7026 co-administration. Thus, TIC10 shows promising anti-HCC activity, alone or together with DNA-PKcs inhibitors.
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Affiliation(s)
- Long Cheng
- Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Yuan-Yuan Liu
- Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China
| | - Pei-Hua Lu
- Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Yi Peng
- Department of Radiotherapy, Hubei Cancer Hospital, Wuhan, China
| | - Qiang Yuan
- Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Xin-Shi Gu
- Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Yong Jin
- Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Min-Bin Chen
- Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China
| | - Xu-Ming Bai
- Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
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Li S, Tan HY, Wang N, Cheung F, Hong M, Feng Y. The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8394818. [PMID: 29507653 PMCID: PMC5817364 DOI: 10.1155/2018/8394818] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 01/09/2018] [Indexed: 12/16/2022]
Abstract
Liver disease, involving a wide range of liver pathologies from fatty liver, hepatitis, and fibrosis to cirrhosis and hepatocellular carcinoma, is a serious health problem worldwide. In recent years, many natural foods and herbs with abundant phytochemicals have been proposed as health supplementation for patients with hepatic disorders. As an important category of phytochemicals, natural polyphenols have attracted increasing attention as potential agents for the prevention and treatment of liver diseases. The striking capacities in remitting oxidative stress, lipid metabolism, insulin resistance, and inflammation put polyphenols in the spotlight for the therapies of liver diseases. It has been reported that many polyphenols from a wide range of foods and herbs exert therapeutic effects on liver injuries via complicated mechanisms. Therefore, it is necessary to have a systematical review to sort out current researches to help better understand the potentials of polyphenols in liver diseases. In this review, we aim to summarize and update the existing evidence of natural polyphenols in the treatment of various liver diseases by in vitro, in vivo, and clinical studies, while special attention is paid to the action mechanisms.
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Affiliation(s)
- Sha Li
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hor Yue Tan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
- Shenzhen Institute of Research and Innovation, Pok Fu Lam, The University of Hong Kong, Hong Kong
| | - Fan Cheung
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Ming Hong
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
- Shenzhen Institute of Research and Innovation, Pok Fu Lam, The University of Hong Kong, Hong Kong
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Zhang B, Chen X, Zhang R, Zheng F, Du S, Zhang X. Metabolite Profiling, Pharmacokinetics, and In Vitro Glucuronidation of Icaritin in Rats by Ultra-Performance Liquid Chromatography Coupled with Mass Spectrometry. JOURNAL OF ANALYTICAL METHODS IN CHEMISTRY 2017; 2017:1073607. [PMID: 28785509 PMCID: PMC5529662 DOI: 10.1155/2017/1073607] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 05/23/2017] [Indexed: 06/07/2023]
Abstract
Icaritin is a naturally bioactive flavonoid with several significant effects. This study aimed to clarify the metabolite profiling, pharmacokinetics, and glucuronidation of icaritin in rats. An ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) assay was developed and validated for qualitative and quantitative analysis of icaritin. Glucuronidation rates were determined by incubating icaritin with uridine diphosphate glucuronic acid- (UDPGA-) supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. A total of 30 metabolites were identified or tentatively characterized in rat biosamples based on retention times and characteristic fragmentations, following proposed metabolic pathway which was summarized. Additionally, the pharmacokinetics parameters were investigated after oral administration of icaritin. Moreover, icaritin glucuronidation in rat liver microsomes was efficient with CLint (the intrinsic clearance) values of 1.12 and 1.56 mL/min/mg for icaritin-3-O-glucuronide and icaritin-7-O-glucuronide, respectively. Similarly, the CLint values of icaritin-3-O-glucuronide and icaritin-7-O-glucuronide in rat intestine microsomes (RIM) were 1.45 and 0.86 mL/min/mg, respectively. Taken altogether, dehydrogenation at isopentenyl group and glycosylation and glucuronidation at the aglycone were main biotransformation process in vivo. The general tendency was that icaritin was transformed to glucuronide conjugates to be excreted from rat organism. In conclusion, these results would improve our understanding of metabolic fate of icaritin in vivo.
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Affiliation(s)
- Beibei Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaoli Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Rui Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Fangfang Zheng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shuzhang Du
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
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25
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The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415. Biochem Biophys Res Commun 2017; 487:494-499. [DOI: 10.1016/j.bbrc.2017.03.156] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/29/2017] [Indexed: 12/22/2022]
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Wang L, Hong X, Yao Z, Dai Y, Zhao G, Qin Z, Wu B, Gonzalez FJ, Yao X. Glucuronidation of icaritin by human liver microsomes, human intestine microsomes and expressed UDP-glucuronosyltransferase enzymes: identification of UGT1A3, 1A9 and 2B7 as the main contributing enzymes. Xenobiotica 2017; 48:357-367. [PMID: 28443723 DOI: 10.1080/00498254.2017.1323139] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
1. Icaritin is a natural flavonoid with anti-osteoporosis activity. This study aimed to characterize icaritin glucuronidation by pooled human liver microsomes (HLM) and pooled human intestine microsomes (HIM), and to determine the contribution of individual UDP-glucuronosyltrans-ferase (UGT) enzyme to icaritin glucuronidation. 2. Glucuronidation rates were determined by incubating icaritin with uridine diphosphate glucuronic acid (UDPGA)-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Relative activity factors and activity correlation analysis were performed to identify main UGT isoforms. 3. UGT1A3, 1A7, 1A8, 1A9 and 2B7 were mainly responsible for catalyzing the formation of two glucuronides (G1 and G2). Icaritin 3-O-glucuronidation (G1) was significantly correlated with Chenodeoxycholic acid (CDCA) glucuronidation (r = 0.787, p = 0.002), propofol glucuronidation (r = 0.661, p = 0.019) and Zidovudine (AZT) glucuronidation (r = 0.805, p = 0.002). Similarly, icaritin 7-O-glucuronidation (G2) was also correlated with CDCA glucuronidation (r = 0.640, p = 0.025), propofol glucuronidation (r = 0.592, p = 0.043) and AZT glucuronidation (r = 0.661, p = 0.019). In addition, UGT1A3, 1A9 and 2B7 contributed 37.5, 33.8 and 21.3% for G1 in pooled HLM, respectively. Also, UGT1A3, 1A9 and 2B7 contributed 34.3, 20.0 and 8.6% for G2 in pooled HLM, respectively. 4. Icaritin was subjected to significant glucuronidation, wherein UGT1A3, 1A7, 1A8, 1A9 and 2B7 were main contributing enzymes.
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Affiliation(s)
- Li Wang
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China
| | - Xiaodan Hong
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China
| | - Zhihong Yao
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China
| | - Yi Dai
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China
| | - Guoping Zhao
- c Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University , Guangzhou , P.R. China , and
| | - Zifei Qin
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China.,c Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University , Guangzhou , P.R. China , and
| | - Baojian Wu
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China.,c Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University , Guangzhou , P.R. China , and
| | - Frank J Gonzalez
- d Laboratory of Metabolism , Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Xinsheng Yao
- a College of Pharmacy, Jinan University , Guangzhou , P.R. China.,b Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University , Guangzhou , P.R. China.,c Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University , Guangzhou , P.R. China , and
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27
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Wang LL, Li WW, Wu CS, Zhang JL, Song YX, Song FJ, Fu H, Liu GX, Wang XM. Relationship between Tissue Distributions of Modified Wuzi Yanzong Prescription () in Rats and Meridian Tropism Theory. Chin J Integr Med 2016; 24:117-124. [PMID: 28000096 DOI: 10.1007/s11655-016-2270-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the relationship between tissue distributions of modified Wuzi Yanzong prescription (, MWP) in rats and meridian tropism theory. METHODS A high-performance liquid chromatography with Fourier transform-mass spectrometry (HPLC-FT) method was used to identify the metabolites of MWP in different tissues of rats after continued oral administration of MWP for 7 days. The relationship between MWP and meridian tropism theory was studied according to the tissue distributions of the metabolites of MWP in rats and the relevant literature. RESULTS Nineteen metabolites, mainly flavanoid compounds, were detected in the different rat tissues and classified to each herb in MWP. Further, it was able to establish that the tissue distributions of the metabolites of MWP were consistent with the descriptions of meridian tropism of MWP available in literature, this result might be useful in clarifying the mechanism of MWP on meridian tropism. In the long run, these data might provide scientific evidence of the meridian tropism theory to further promote the reasonable, effective utilization, and modernization of Chinese medicine. CONCLUSION The tissue distributions of MWP in vivo were consistent with the descriptions of meridian tropism of MWP.
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Affiliation(s)
- Lin-Lin Wang
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Wei-Wei Li
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Cai-Sheng Wu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Jin-Lan Zhang
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Yi-Xiang Song
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Fang-Jiao Song
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Hong Fu
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Geng-Xin Liu
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China
| | - Xue-Mei Wang
- Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, China.
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Peng X, Zhang D, Li Z, Fu M, Liu H. mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat. Biochem Biophys Res Commun 2016; 477:556-562. [PMID: 27311860 DOI: 10.1016/j.bbrc.2016.06.060] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 06/11/2016] [Indexed: 12/30/2022]
Abstract
Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients' poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat.
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Affiliation(s)
- Xingang Peng
- Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Donghui Zhang
- Department of Infectious Disease, Linyi People's Hospital, Linyi, China.
| | - Zhengling Li
- Department of Nursing, Tengzhou Central People's Hospital, Tengzhou, China.
| | - Meili Fu
- Department of Infectious Disease, Linyi People's Hospital, Linyi, China.
| | - Haiyan Liu
- Department of Nursing, Linyi People's Hospital, Linyi, China.
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Fu M, Shi W, Li Z, Liu H. Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells. Biochem Biophys Res Commun 2016; 477:527-533. [PMID: 27144317 DOI: 10.1016/j.bbrc.2016.04.147] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 04/30/2016] [Indexed: 11/30/2022]
Abstract
Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrin A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy.
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Affiliation(s)
- Meili Fu
- Department of Infectious Disease, Linyi People's Hospital, Linyi, China
| | - Wenhong Shi
- Department of Radiotherapy, Linyi Tumor Hospital, Linyi, China
| | - Zhengling Li
- Department of Nursing, Tengzhou Central People's Hospital, Tengzhou, China
| | - Haiyan Liu
- Department of Nursing, Linyi People's Hospital, No. 27 Jiefang Road, Linyi 276000, Shandong, China.
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Fu M, Wan F, Li Z, Zhang F. 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells. Biochem Biophys Res Commun 2016; 471:267-73. [PMID: 26773495 DOI: 10.1016/j.bbrc.2016.01.030] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 01/06/2016] [Indexed: 12/13/2022]
Abstract
The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation-inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells.
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Affiliation(s)
- Meili Fu
- Department of Infectious Disease, Linyi People's Hospital, Linyi 276000, China.
| | - Fuqiang Wan
- Department of Head and Neck Surgery, Linyi Tumor Hospital, Linyi 276000, China
| | - Zhengling Li
- Department of Nursing, Tengzhou Central People's Hospital, Tengzhou 277500, China
| | - Fenghua Zhang
- Department of Operating Room, Linyi People's Hospital, Linyi 276000, China
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Jiang J, Zhao BJ, Song J, Jia XB. Pharmacology and Clinical Application of Plants in Epimedium L. CHINESE HERBAL MEDICINES 2016. [DOI: 10.1016/s1674-6384(16)60003-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK. Tumour Biol 2015; 37:8047-55. [DOI: 10.1007/s13277-015-4707-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 12/20/2015] [Indexed: 12/31/2022] Open
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Chen XJ, Tang ZH, Li XW, Xie CX, Lu JJ, Wang YT. Chemical Constituents, Quality Control, and Bioactivity of Epimedii Folium (Yinyanghuo). THE AMERICAN JOURNAL OF CHINESE MEDICINE 2015; 43:783-834. [DOI: 10.1142/s0192415x15500494] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Epimedii Folium (Yinyanghuo in Chinese) is one of the most commonly used traditional Chinese medicines. Its main active components are flavonoids, which exhibit multiple biological activities, such as promotion of bone formation and sexual function, protection of the nervous system, and prevention of cardiovascular diseases. Flavonoids also show anti-inflammatory and anticancer effects. Various effective methods, including genetic and chemical approaches, have been developed for the quality control of Yinyanghuo. In this review, the studies conducted in the last decade about the chemical constituents, quality control, and bioactivity of Yinyanghuo are summarized and discussed.
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Affiliation(s)
- Xiao-Jia Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Zheng-Hai Tang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Xi-Wen Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Cai-Xiang Xie
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Yi-Tao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
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Xiao YZ, Dong Y, Liu CY, Zhang LH, Yu C, Wan L, Han J, Yuan HL. Study on Integral Dissolution Model Based on Biological Potency for Compound Chinese Materia Medica. CHINESE HERBAL MEDICINES 2015. [DOI: 10.1016/s1674-6384(15)60030-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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35
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Zheng J, Ma LT, Ren QY, Li L, Zhang Y, Shi HJ, Liu Y, Li CH, Dou YQ, Li SD, Zhang H, Yang MH. The influence of astragalus polysaccharide and β-elemene on LX-2 cell growth, apoptosis and activation. BMC Gastroenterol 2014; 14:224. [PMID: 25551689 PMCID: PMC4297370 DOI: 10.1186/s12876-014-0224-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 12/17/2014] [Indexed: 01/24/2023] Open
Abstract
Background Activated hepatic stellate cells are the main source of excessive collagen deposition in liver fibrosis. Here we report the inhibitory effects of the combinational treatment of two natural products, astragalus polysaccharide (APS) and β-elemene (ELE) on the activation of human liver hepatic stellate cell line LX-2 cells. Methods Cultured LX-2 cells were treated with different concentrations of APS or ELE for 24 or 48 hours. Cell viability/apoptosis was measured by MTT assay and Annexin V/PI staining , activation related genes including α-SMA and CD44 expressions were measured by real-time PCR and western blot respectively. Results The majority of LX-2 cells showed morphological change in the presence of APS or ELE for 24 hours. Treatment with APS + ELE for 24 or 48 hours significantly inhabited the cell proliferation compared with APS or ELE treatment alone on LX-2 cells. APS + ELE may block the up-regulation of α-SMA and CD44 both in mRNA and protein levels through TGF-β pathway in LX-2 cells. Conclusion APS or ELE treatment alone on LX-2 cells could inhibit cell proliferation and induce apoptosis. The combinational treatment using APS + ELE significantly increased the killing efficiency on LX-2 cells. α-SMA and CD44 expressions was inhibited upon APS + ELE treatment through TGF-β pathway in LX-2 cells. The results indicated a novel treatment using natural products for liver diseases with anti-fibrotic effect.
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Sun L, Peng Q, Qu L, Gong L, Si J. Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells. Mol Med Rep 2014; 11:3094-100. [PMID: 25434584 DOI: 10.3892/mmr.2014.3007] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 10/31/2014] [Indexed: 11/06/2022] Open
Abstract
Icaritin is an active ingredient derived from the plant Herba epimedium, which exhibits various pharmacological and biological activities. However, the function, and the underlying mechanisms of icaritin on the growth of SMMC‑7721 human hepatoma cells have yet to be elucidated. The present study aimed to investigate the function and underlying mechanisms of icaritin in the growth of SMMC‑7721 cells. The cells were treated with varying concentrations of icaritin for 12, 24 and 48 h, respectively, prior to cytotoxic analysis. Apoptosis of SMMC‑7721 cells following treatment with icaritin was measured using flow cytometry. The gene expression of mitochondria‑ and Fas‑mediated caspase‑dependent pathways was detected by reverse transcription‑quantitative polymerase chain reaction and western blotting. Statistical analysis was performed by Student's t‑test and one‑way analysis or variance. The present study demonstrated that treatment with icaritin significantly inhibited growth, and induced apoptosis of SMMC‑7721 cells, in a time‑ and dose‑dependent manner. In addition, icaritin triggered the mitochondrial/caspase apoptotic pathway, by decreasing the Bcl‑2/Bax protein ratio and increasing activation of caspase‑3. Icaritin also activated the Fas‑mediated apoptosis pathway, as was evident by the increased expression levels of Fas and activation of caspase‑8. These data suggest that icaritin may be a potent growth inhibitor and induce apoptosis of SMMC‑7721 cells through the mitochondria‑ and Fas‑mediated caspase‑dependent pathways. The present study may provide experimental evidence for preclinical and clinical evaluations of icaritin for HCC therapy.
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Affiliation(s)
- Li Sun
- Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Qisong Peng
- Department of Laboratory Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China
| | - Lili Qu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Lailing Gong
- Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Jin Si
- Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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Sun B, Zhang X, Cheng X, Zhang Y, Chen L, Shi L, Liu Z, Qian H, Wu M, Yin Z. Intratumoral hepatic stellate cells as a poor prognostic marker and a new treatment target for hepatocellular carcinoma. PLoS One 2013; 8:e80212. [PMID: 24278260 PMCID: PMC3835887 DOI: 10.1371/journal.pone.0080212] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 09/30/2013] [Indexed: 12/29/2022] Open
Abstract
Hepatic stellate cells (HSCs), a specialized stromal cytotype in the liver, have been demonstrated to actively contribute to hepatocellular carcinoma (HCC) development. However, the previous studies were performed using HSC cell lines, and the prognostic value of intratumoral HSCs (tHSCs) was unclear. Here we isolated tHSCs from fresh human HCC tissues, and analyzed the abilities of tHSCs to promote HCC progression by using in vitro assays for cell viability, migration and invasion as well as epithelial-mesenchymal transition (EMT) phenotype. 252 HCC patients who underwent hepatectomy were enrolled for analysis of tHSCs and E-cadherin expression in tumor tissues, and 55 HCC patients for analysis of tHSCs in tumor tissues and circulating tumor cells (CTCs) in blood. Prognostic factors were then identified. The results showed that coculture of tHSCs with HCC cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition (EMT) phenotype. In vivo cotransplantation of HCC cells with tHSCs into nude mice more efficiently promoted tumor formation and growth. Icaritin, a known apoptosis inducer of HSCs, was demonstrated to effectively inhibit tHSC proliferation in vitro and tHSC-induced HCC-promoting effects in vivo. Clinical evidence indicated that tHSCs were rich in 45% of the HCC specimens, tHSC-rich subtypes were negatively correlated either with E-cadherin expression in tumor tissues (r = -0.256, p < 0.001) or with preoperative CTCs in blood (r = -0.287, p = 0.033), and were significantly correlated with tumor size (p = 0.027), TNM staging (p = 0.018), and vascular invasion (p = 0.008). Overall and recurrence-free survival rates of tHSC-rich patients were significantly worse than those for tHSC-poor patients. Multivariate analysis revealed tHSC-rich as an independent factor for overall and recurrence-free survival. In conclusion, tHSCs provide a promising prognostic biomarker and a new treatment target for HCC.
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Affiliation(s)
- Bin Sun
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiaofeng Zhang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xianshuo Cheng
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yu Zhang
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lei Chen
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lehua Shi
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhenyu Liu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Haihua Qian
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Mengchao Wu
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhengfeng Yin
- Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- * E-mail:
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Hong J, Zhang Z, Lv W, Zhang M, Chen C, Yang S, Li S, Zhang L, Han D, Zhang W. Icaritin synergistically enhances the radiosensitivity of 4T1 breast cancer cells. PLoS One 2013; 8:e71347. [PMID: 23977023 PMCID: PMC3744569 DOI: 10.1371/journal.pone.0071347] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 07/01/2013] [Indexed: 01/15/2023] Open
Abstract
Icaritin (ICT) is a hydrolytic form of icariin isolated from plants of the genus Epimedium. This study was to investigate the radiosensitization effect of icaritin and its possible underlying mechanism using murine 4T1 breast cancer cells. The combination of Icaritin at 3 µM or 6 µM with 6 or 8 Gy of ionizing radiation (IR) in the clonogenic assay yielded an ER (enhancement ratio) of 1.18 or 1.28, CI (combination index) of 0.38 or 0.19 and DRI (dose reducing index) of 2.51 or 5.07, respectively. These strongly suggest that Icaritin exerted a synergistic killing (?) effect with radiation on the tumor cells. This effect might relate with bioactivities of ICT: 1) exert an anti-proliferative effect in a dose- and time-dependent manner, which is different from IR killing effect but likely work together with the IR effect; 2) suppress the IR-induced activation of two survival paths, ERK1/2 and AKT; 3) induce the G2/M blockage, enhancing IR killing effect; and 4) synergize with IR to enhance cell apoptosis. In addition, ICT suppressed angiogenesis in chick embryo chorioallantoic membrane (CAM) assay. Taken together, ICT is a new radiosensitizer and can enhance anti-cancer effect of IR or other therapies.
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Affiliation(s)
- Jinsheng Hong
- Department of Radiation Oncology, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Division of Radiation Biology, Central Research Lab, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zhenhuan Zhang
- Department of Radiation Oncology, UF Shands Cancer Center, Gainesville, Florida, United States of America
| | - Wenlong Lv
- Department of Radiation Oncology, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Mei Zhang
- Department of Radiation Oncology, UF Shands Cancer Center, Gainesville, Florida, United States of America
| | - Chun Chen
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Shanmin Yang
- Department of Radiation Oncology, UF Shands Cancer Center, Gainesville, Florida, United States of America
| | - Shan Li
- Department of Radiation Oncology, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Lurong Zhang
- Department of Radiation Oncology, UF Shands Cancer Center, Gainesville, Florida, United States of America
| | - Deping Han
- Division of Radiation Biology, Central Research Lab, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- * E-mail: (WZ); (DH)
| | - Weijian Zhang
- Department of Radiation Oncology, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Division of Radiation Biology, Central Research Lab, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- * E-mail: (WZ); (DH)
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Protective effect of genistein isolated from Hydrocotyle sibthorpioides on hepatic injury and fibrosis induced by chronic alcohol in rats. Toxicol Lett 2012; 217:102-10. [PMID: 23274713 DOI: 10.1016/j.toxlet.2012.12.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 12/16/2012] [Accepted: 12/17/2012] [Indexed: 12/27/2022]
Abstract
This study examined the effect of genistein isolated from Hydrocotyle sibthorpioides on chronic alcohol-induced hepatic injury and fibrosis. Rats underwent intragastric administration of alcohol (5.0-9.5g/kg) once a day for 24 weeks. A subset of rats were also intragastrically treated with genistein (0.5, 1 or 2mg/kg) once a day. Genistein significantly decreased the plasma alcohol concentration, inhibited the activities of alanine and aspartate aminotransferases and decreased levels of inflammatory mediators, including interleukin 6, tumor necrosis factor-α and myeloperoxidase, via down-regulation of nuclear factor-κB. Moreover, genistein effectively inhibited collagen deposition and reduced pathological tissue damage as determined by hepatic fibrosis biomarkers, such as total hyaluronic acid, laminin, and type III collagen. Mechanistically, studies showed that genistein markedly reduced lipid peroxidation, recruited the anti-oxidative defense system, inhibited CYP2El activity, promoted extracellular matrix degradation by modulating the levels of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-2, induced HSC apoptosis by down-regulating B-cell lymphoma 2 mRNA, and inhibited the expression of α-smooth muscle actin and transforming growth factor β(1) proteins. In conclusion, genistein exerts a preventative effect to ameliorate developing liver injury and even liver fibrosis induced by chronic alcohol administration in rats.
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Chai NL, Fu Q, Shi H, Cai CH, Wan J, Xu SP, Wu BY. Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells. World J Gastroenterol 2012; 18:4199-206. [PMID: 22919254 PMCID: PMC3422802 DOI: 10.3748/wjg.v18.i31.4199] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 06/26/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the potential mechanism of Arg-Gly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl4-induced hepatic fibrosis in rats.
METHODS: We constructed a rat model of CCl4-induced hepatic fibrosis and treated the rats with different formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phosphatase, hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-1 as well as type I procollagen via quantitative real-time polymerase chain reaction. To detect cell viability and apoptosis of hepatic stellate cells (HSCs), we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy.
RESULTS: OM attenuated CCl4-induced hepatic fibrosis, as defined by reducing serum alkaline phosphatase (344.47 ± 27.52 U/L vs 550.69 ± 43.78 U/L, P < 0.05), attenuating liver injury and improving collagen deposits (2.36% ± 0.09% vs 7.70% ± 0.60%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L, P < 0.05), liver injury, collagen deposits (0.26% ± 0.09% vs 2.36% ± 0.09%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). Moreover, in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis.
CONCLUSION: OM attenuated hepatic fibrosis by inhibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting efficiency for HSCs and the therapeutic effect.
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Lin X, Zhang S, Huang Q, Wei L, Zheng L, Chen Z, Jiao Y, Huang J, Fu S, Huang R. Protective effect of Fufang-Liu-Yue-Qing, a traditional Chinese herbal formula, on CCl4 induced liver fibrosis in rats. JOURNAL OF ETHNOPHARMACOLOGY 2012; 142:548-556. [PMID: 22658988 DOI: 10.1016/j.jep.2012.05.040] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 05/23/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chinese prescription Fufang-Liu-Yue-Qing (FLYQ) has long been employed clinically to treat chronic hepatitis B, and we have reported its beneficial effects on liver fibrosis in vitro. The present study was investigated to verify protective effects of FLYQ on liver fibrosis in a rat model and to investigate the underlying mechanisms which have not been explored yet. MATERIALS AND METHODS Liver fibrosis was established by intragastric administration of 2 ml/kg CCl(4) twice a week for 12 weeks. During the experiment, the model group received CCl(4) only, and the normal control group received an equal volume of saline. Treatment groups received not only CCl(4) for 12 weeks, but also the corresponding drugs, colchicine (1.00 mg/kg/day) or FLYQ (300, 150, 75 mg/kg/day) from 5 to 12 weeks. RESULTS Analysis experiments showed that FLYQ could significantly alleviate liver injury, as indicated by decreasing levels of ALT, AST, ALP, GGT, IL-6 and TNF-α. Moreover, FLYQ could effectively inhibit collagen deposition and reduce the pathological tissue damage. Research on mechanism showed that FLYQ was able to markedly reduce lipid peroxidation, recruit the anti-oxidative defense system, promote ECM degradation by modulating the levels of TIMP-1 and MMP-2, and induce HSC apoptosis by down-regulating bcl-2 mRNA, as well as inhibit the expressions of α-SMA and TGF-β(1) proteins. CONCLUSIONS Our results show that FLYQ is effective in attenuating hepatic injury and fibrosis in the CCl(4)-induced rat model, which should be developed as a new drug for treatment of liver fibrosis and even cirrhosis.
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Affiliation(s)
- Xing Lin
- Guangxi Medical University, Nanning 530021, China
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Huang QF, Zhang SJ, Zheng L, Liao M, He M, Huang R, Zhuo L, Lin X. Protective effect of isoorientin-2″-O-α-l-arabinopyranosyl isolated from Gypsophila elegans on alcohol induced hepatic fibrosis in rats. Food Chem Toxicol 2012; 50:1992-2001. [DOI: 10.1016/j.fct.2012.03.044] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 03/02/2012] [Accepted: 03/08/2012] [Indexed: 01/08/2023]
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Zhuo L, Liao M, Zheng L, He M, Huang Q, Wei L, Huang R, Zhang S, Lin X. Combination Therapy with Taurine, Epigallocatechin Gallate and Genistein for Protection against Hepatic Fibrosis Induced by Alcohol in Rats. Biol Pharm Bull 2012; 35:1802-10. [DOI: 10.1248/bpb.b12-00548] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
| | | | | | - Min He
- Guangxi Medical University
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