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Mohammed MJ, Kadhim HM. The hepatoprotective effects of the polyphenol-enriched n-butanol fraction of Cnicus benedictus against carbon tetrachloride-induced liver fibrosis in rats: In vivo study. Toxicol Rep 2025; 14:101850. [PMID: 39758800 PMCID: PMC11697782 DOI: 10.1016/j.toxrep.2024.101850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/21/2024] [Accepted: 12/03/2024] [Indexed: 01/07/2025] Open
Abstract
Liver fibrosis is a continuous wound-healing response to chronic injury caused by various chemical, virus, and pathological disorders; the lack of approved drugs or methods to reverse or prevent liver fibrosis makes it an interesting area of research. This study investigates the potential hepatoprotective effects of the phenolic extract of Cnicus benedictus in rat's module of liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl4) for six consecutive weeks; the butanol fraction of Cnicus and silymarin was administered orally concurrently with CCl4. After six weeks, all animals were euthanized. Rat liver tissue levels of malondialdehyde (MDA) and glutathione (GSH) were measured, and serum liver enzymes and protein were measured using the ELISA technique. Histopathological study and immunohistochemistry of liver tissue for transforming growth factor (TGF-β1), alpha-smooth muscle actin (α-SMA), and hydroxyproline were assessed. In HPLC analysis, Cnicus extract showed several components, including quercetin, gallic acid, rutin, kaempferol, silibinin, and apigenin. Treatment with Cnicus butanol extract reduces serum ALT, AST, bilirubin, and albumin levels compared to induction. Additionally, Cnicus extract increases liver GSH levels and decreases liver MDA levels compared to induction. Liver tissue of TGF-β1, α-SMA, and hydroxyproline expression was downregulated in rats receiving Cnicus extract. Liver tissue histopathology showed improvement in its features compared to the induction group. In conclusion, oral administration of the polyphenol-enriched n-butanol fraction of Cnicus benedictus showed a protective effect on liver fibrosis caused by CCl4, possibly through antioxidant and anti-inflammatory mechanisms.
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Affiliation(s)
- Mohammed Jasim Mohammed
- Department of Pharmacology, College of Medicine, Al-Nahrain University, Baghdad, Iraq
- Ministry of Health and Environment, Kirkuk Health Directorate, Kirkuk, Iraq
| | - Haitham Mahmood Kadhim
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Nahrain University, Baghdad, Iraq
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Cuijpers I, Katsburg J, van Loon LJC, Troost FJ, Sthijns MMJPE. Nutritional strategies targeting age-related skeletal muscle fibrosis: underlying mechanisms. Crit Rev Food Sci Nutr 2025:1-21. [PMID: 40336331 DOI: 10.1080/10408398.2025.2498676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Aging is associated with a reduced number and function of muscle stem cells (MuSC). This results in a decreased muscle regenerative capacity and increased formation of fibrotic tissue, impairing skeletal muscle function. This review provides an overview of in vitro and in vivo animal studies investigating nutritional interventions with the potential to inhibit pathophysiological mechanisms involved in the development of skeletal muscle fibrosis. Mechanism targets include 1) MuSC function and myogenic differentiation, 2) M1 to M2 macrophage polarization, 3) myofibroblast activity or extracellular matrix (ECM) deposition, and 4) reactive oxygen species (ROS) mediated pathways, such as NOX2/4 activity. Most promising nutrients described in this review are phytonutrients, vitamins and amino acids. Quercetin targets multiple pathways (showing decreased inflammation, ECM expression and NOX2/4 activity) in various cell types and tissues (kidney, aorta, liver and (heart) muscle) of rodents and rabbits, which could contribute to fibrosis development. Additionally, sulforaphane is a promising candidate as it inhibits inflammation, ECM expression, and ROS production in mouse skeletal muscle. After validation of the effects in human skeletal muscle, supplementation with these nutrients could be implemented in a multifaceted intervention (including exercise and adequate protein intake) targeting age-related skeletal muscle fibrosis.
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Affiliation(s)
- Iris Cuijpers
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, The Netherlands
| | - Joey Katsburg
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, The Netherlands
| | - Luc J C van Loon
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Freddy J Troost
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, The Netherlands
| | - Mireille M J P E Sthijns
- Department of Human Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University Campus Venlo, Venlo, The Netherlands
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Niziński P, Krajewska A, Oniszczuk T, Polak B, Oniszczuk A. Hepatoprotective Effect of Kaempferol-A Review. Molecules 2025; 30:1913. [PMID: 40363718 DOI: 10.3390/molecules30091913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 04/18/2025] [Accepted: 04/20/2025] [Indexed: 05/15/2025] Open
Abstract
Liver diseases, including chronic inflammation and related metabolic dysfunction-associated steatotic liver disease (MASLD), fibrosis and cirrhosis remain a growing global health burden. Currently, available pharmacotherapy for liver dysfunction has limited efficacy. Kaempferol, a naturally occurring flavonoid, has demonstrated significant hepatoprotective effects in preclinical models. This substance activates the SIRT1/AMPK signalling pathway, improves mitochondrial function, inhibits proinflammatory cytokine production via TLR4/NF-κB suppression and attenuates hepatic stellate cell activation by modulating the TGF-β/Smad pathway. In addition, kaempferol regulates the composition of the gut microbiota, thus improving bile acid metabolism and alleviating steatosis and fibrosis. This review presents an integrated analysis of recent in vitro and in vivo studies on the mode of action and utility of kaempferol in liver disease and hepatoprotection.
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Affiliation(s)
- Przemysław Niziński
- Department of Pharmacology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Anna Krajewska
- Department of Comprehensive Paediatric and Adult Dentistry, Medical University of Lublin, Chodżki 6, 20-093 Lublin, Poland
| | - Tomasz Oniszczuk
- Department of Thermal Technology and Food Process Engineering, University of Life Sciences in Lublin, Głęboka 31, 20-612 Lublin, Poland
| | - Beata Polak
- Department of Physical Chemistry, Medical University of Lublin, Chodżki 4a, 20-093 Lublin, Poland
| | - Anna Oniszczuk
- Department of Inorganic Chemistry, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
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Chen J, Liu H, Fu Y, Chen X, Zhang S, Yang Y, Li S, Wang G, Lan T. Kaempferol attenuates macrophage M1 polarization and liver fibrosis by inhibiting mitogen-activated protein kinase/nuclear factor κB signaling pathway. J Pharmacol Exp Ther 2025; 392:103533. [PMID: 40139075 DOI: 10.1016/j.jpet.2025.103533] [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: 11/08/2024] [Revised: 02/19/2025] [Accepted: 02/24/2025] [Indexed: 03/29/2025] Open
Abstract
Chronic liver inflammation is a major cause of death in patients with liver fibrosis and cirrhosis, which pose a serious health threat worldwide, and there is no effective anti-hepatic fibrosis drug. Kaempferol (KA), a flavonoid polyphenol extracted from many edible plants and traditional Chinese medicine, has been reported to possess anti-inflammatory, antioxidant, and antitumor activities and has an ameliorating effect on liver fibrosis or other fibroproliferative diseases. However, the specific regulatory mechanism of KA-reversed macrophage M1 polarization is still obscure. This study aimed to investigate the protective effects of KA on carbon tetrachloride (CCl4)-induced liver fibrosis in mice through M1 polarization. C57BL/6 mice were intraperitoneally injected with CCl4 twice weekly to induce liver fibrosis. Male mice were randomly divided into 4 groups (n = 5): the oil group, the CCl4 group, the low-dose KA-treatment CCl4 group (50 mg/kg/day KA), and the high-dose KA-treatment CCl4 group (100 mg/kg/day KA). An equal amount of solvent was given to each group by intraperitoneal injection. The results indicated that KA decreased liver pathologic changes, hepatic macrophage recruitment, and serum alanine aminotransferase levels. Notably, it reduced the activation of M1-type macrophages in the liver. The expression of proinflammatory cytokines and genes associated with M1 macrophages, such as tumor necrosis factor-α, interleukin-6, interleukin-1β, and inducible nitric oxide synthase, was also decreased. The core targets, signaling pathways, and possible mechanisms related to the M1 polarization of KA were analyzed by network pharmacology and molecular docking. Further analysis revealed that KA regulated mitogen-activated protein kinase (MAPK)/nuclear factor κB (NF-κB) signaling pathways. Finally, the results indicated that KA regulates M1 macrophage activation by modulating the MAPK/NF-κB signaling pathways. This study revealed that KA ameliorated liver injury, inflammation, and fibrosis by inhibiting macrophage M1 polarization through the MAPK/NF-κB signaling pathway, highlighting KA as a potential novel agent for the prevention and treatment of liver fibrosis. SIGNIFICANCE STATEMENT: Chronic liver inflammation is a leading cause of mortality in patients with liver fibrosis and cirrhosis, presenting a significant global health threat. Kaempferol, as a traditional Chinese medicine, effectively suppresses M1 polarization of macrophages through the mitogen-activated protein kinase/nuclear factor κB signaling pathway, thereby ameliorating liver injury, inflammation, and fibrosis. These findings underscore the potential of kaempferol as an innovative therapeutic agent for the prevention and treatment of liver fibrosis.
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Affiliation(s)
- Jiajia Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Huanle Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanfang Fu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaolan Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shiqin Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yongqi Yang
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Shengwen Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Guixiang Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China; Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.
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Xiong S, Xie J, Xiang F, Yu J, Li Y, Xia B, Zhang Z, Li C, Lin L. Research progress on pharmacological effects against liver and eye diseases of flavonoids present in Chrysanthum indicum L., Chrysanthemum morifolium Ramat., Buddleja officinalis Maxim. and Sophora japonica L. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119094. [PMID: 39532220 DOI: 10.1016/j.jep.2024.119094] [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: 06/28/2024] [Revised: 10/07/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chrysanthemum indicum L., Chrysanthemum morifolium Ramat., Buddleja officinalis Maxim., and Sophora japonica L. have the effects of "Clearing the liver" and "Improving vision". Flavonoids are their main active ingredients, but there are few reports on their simultaneous liver and eye protective effects. AIM OF THE STUDY Overview of the role of flavonoids of the four medicinal flowers (FFMF) in the prevention and treatment of liver and eye diseases. MATERIALS AND METHODS The Web of Science, PubMed, CNKI, Google Scholar, and WanFang databases were searched for FFMF. Using "hepatitis", "liver fibrosis", "liver cancer", "dry eye syndrome", "cataracts", "glaucoma", "age-related macular degeneration", and "diabetic retinopathy" as the keywords, we summarized the main pathological mechanisms of these diseases and the role of FFMF in their prevention and treatment. RESULTS We found that the four medicinal flowers contained a total of 125 flavonoids. They can maintain liver and eye homeostasis by regulating pathological mechanisms such as oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial dysfunction, glucose and lipid metabolism disorders, and programmed cell death, exerting the effect of "clearing the liver and improving vision". CONCLUSION FFMF have a series of beneficial properties such as antioxidant, anti-inflammatory, antiviral, and antifibrotic activity, and the regulation of angiogenesis, glycolipid metabolism and programmed cell death, which may explain the efficacy of the four traditional Chinese medicines for "Clearing the liver" and "Improving vision".
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Affiliation(s)
- Suhui Xiong
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Jingchen Xie
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Feng Xiang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Jiahui Yu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Yamei Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Bohou Xia
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Zhimin Zhang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Chun Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Limei Lin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
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Huang L, Yang X, Feng Y, Huang HX, Hu JQ, Yan PY, Pan HD, Xie Y. ShaShen-MaiDong decoction attenuates bleomycin-induced pulmonary fibrosis by inhibiting TGF-β/smad3, AKT/MAPK, and YAP/TAZ pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118755. [PMID: 39209002 DOI: 10.1016/j.jep.2024.118755] [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: 06/26/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pulmonary fibrosis (PF) is progressive and terminal lung disease, which is also the most common sequelae of Corona Virus Disease (2019) (COVID-19) survivors. Unfortunately, there is currently no cure for PF. ShaShen-MaiDong decoction (SMT), a traditional Chinese medicine, has been employed in treating various lung diseases, which may offer potential therapeutic benefits for PF. AIM OF THE STUDY To investigate the antifibrotic efficacy of SMT and its major active ingredients as well as the underlying mechanisms for treating PF. MATERIALS AND METHODS Fist, we build the UPLC-MS based qualitative and quantitative profiling for the quality control of SMT. Then, the antifibrotic efficacy of SMT was investigated in bleomycin (BLM)-induced PF mice model. Network pharmacology was used to predict the mechanism and active components of SMT for the treatment of PF, which was further verified in vitro and in vivo. RESULTS SMT improved the weight loss and attenuated hydroxyproline, inflammatory cytokines, and collagen deposition in BLM-induced PF mice model in a dose-dependent manner. Mechanistically, as predicted by network pharmacology analysis, SMT and its active compounds (kaempferol, quercetin, and isorhamnetin) regulated the mitogen-activated protein kinase (MAPK) signaling pathways, TGF-β/Smad signaling pathway, and YAP/TAZ signaling pathway, which was further verified in the PF mice and TGF-β-induced A549 cell model. Moreover, SMT balanced the proportions of increased CD4+ and decreased CD8+ T cells in the peripheral blood of PF mice model. CONCLUSIONS Considering the high mortality and complex pathogenesis of fibrotic diseases, our results provide novel evidence that SMT would be beneficial for pulmonary fibrosis therapy by modulating MAPK, TGF-β/Smad, and YAP/TAZ signaling pathways at same time.
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Affiliation(s)
- Li Huang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, China
| | - Xi Yang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201 Kunming, China
| | - Yi Feng
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Hua-Xue Huang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, China
| | - Jia-Qin Hu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Pei-Yu Yan
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, China.
| | - Hu-Dan Pan
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Ying Xie
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Cen X, Wang W, Hong S, Wang Q, Wang N, Mo L, Li J, Li J. Integrated microbiome and metabolomic analyses revealed the antifibrotic effect of vanillic acid on thioacetamide-induced liver fibrosis in mice. Food Funct 2024; 15:11780-11794. [PMID: 39545308 DOI: 10.1039/d4fo02309a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Vanillic acid (VA) is a natural phenolic acid compound that is widely found in various foods and medicinal plants, with a remarkable antifibrotic effect observed in animal studies, but its exact antifibrotic mechanism remains unclear. Herein, hepatic function, fibrotic index, and histopathological, microbiome, and metabolomic methods were used to investigate the potential mechanisms behind the improvement effect of vanillic acid against thioacetamide (TAA)-induced liver fibrosis in mice. Our results showed that VA reversed TAA-induced liver fibrosis manifested a decrease in collagen fiber deposition, serum transaminase, serum hepatic fibrotic index, and liver inflammation indicator levels. When analyzed, TAA injection mainly increased the abundance of Akkermansia and Roseburia and significantly reduced the abundance of Anaerotruncus. VA reversed these changes back to normal levels to varying degrees. Metabolomic profiling demonstrated that VA treatment was efficacious in modulating several key liver metabolites involved in neuroactive ligand-receptor interaction, prolactin signaling pathway, estrogen signaling pathway, and glutathione metabolism. Conclusively, VA may ameliorate liver damage and suppress the fibrogenesis caused by thioacetamide by correcting intestinal microbiota disorders and promoting normal hepatic metabolism. This research provides a novel perspective on vanillic acid as a dietary supplement for hepatic fibrosis improvement.
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Affiliation(s)
- Xiaofeng Cen
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Wei Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Siyan Hong
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Qin Wang
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Na Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Ling Mo
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Jingjing Li
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, China
| | - Jingwen Li
- Department of Nutrition and Food Hygiene, School of Public Health, Guilin Medical University, Guilin, China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, 541199, Guilin, China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, School of Public Health, Guilin Medical University, 541199, Guilin, 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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Gostyńska A, Buzun K, Żółnowska I, Krajka-Kuźniak V, Mańkowska-Wierzbicka D, Jelińska A, Stawny M. Natural bioactive compounds-The promising candidates for the treatment of intestinal failure-associated liver disease. Clin Nutr 2024; 43:1952-1971. [PMID: 39032247 DOI: 10.1016/j.clnu.2024.07.004] [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: 02/26/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/23/2024]
Abstract
Parenteral nutrition (PN) is a life-saving procedure conducted to maintain a proper nutritional state in patients with severe intestinal failure who cannot be fed orally. A serious complication of PN therapy is liver failure, known as intestinal failure-associated liver disease (IFALD). The pathogenesis of IFALD is multifactorial and includes inhibition of the farnesoid X receptor (FXR) by PN components, bacteria translocation from impaired intestines, and intravenous line-associated bloodstream infection. Currently, the most frequently researched therapeutic option for IFALD is using lipid emulsions based on soy or fish oil and, therefore, free from phytosterols known as FXR antagonists. Nevertheless, the potential side effects of the lack of soybean oil delivery seem to outweigh the benefits, especially in the pediatric population. PN admixture provides all the necessary nutrients; however, it is deprived of exogenous natural bioactive compounds (NBCs) of plant origin, such as polyphenols, characterized by health-promoting properties. Among them, many substances have already been known to demonstrate the hepatoprotective effect in various liver diseases. Therefore, searching for new therapeutic options for IFALD among NBCs seems reasonable and potentially successful. This review summarizes the recent research on polyphenols and their use in treating various liver diseases, especially metabolic dysfunction-associated steatotic liver diseases (MASLD). Furthermore, based on scientific reports, we have described the molecular mechanism of action of selected NBCs that exert hepatoprotective properties. We also summarized the current knowledge on IFALD pathogenesis, described therapeutic options undergoing clinical trials, and presented the future perspective of the potential use of NBCs in PN therapy.
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Affiliation(s)
- Aleksandra Gostyńska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Kamila Buzun
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland.
| | - Izabela Żółnowska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
| | - Violetta Krajka-Kuźniak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Dorota Mańkowska-Wierzbicka
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland
| | - Anna Jelińska
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Maciej Stawny
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
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10
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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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11
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Liu L, Wang B, Ma Y, Sun K, Wang P, Li M, Dong J, Qin M, Li M, Wei C, Tan Y, He J, Guo K, Yu XA. A review of Phyllanthus urinaria L. in the treatment of liver disease: viral hepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma. Front Pharmacol 2024; 15:1443667. [PMID: 39185304 PMCID: PMC11341462 DOI: 10.3389/fphar.2024.1443667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
Due to the pathological production of liver disease in utility particularly complexity, the morbidity and mortality of liver disease including viral hepatitis, liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. Considering its insidious onset, rapid progression and drug resistance, finding an effective therapy is particularly worthwhile. Phyllanthus urinaria L. (P. urinaria), an ethnic medicine, can be applied at the stages of viral hepatitis, liver fibrosis/cirrhosis and HCC, which demonstrates great potential in the treatment of liver disease. Currently, there are numerous reports on the application of P. urinaria in treating liver diseases, but a detailed analysis of its metabolites and a complete summary of its pharmacological mechanism are still scarce. In this review, the phytochemical metabolites and ethnopharmacological applications of P. urinaria are summarized. Briefly, P. urinaria mainly contains flavonoids, lignans, tannins, phenolic acids, terpenoids and other metabolites. The mechanisms of P. urinaria are mainly reflected in reducing surface antigen secretion and interfering with DNA polymerase synthesis for anti-viral hepatitis activity, reducing hepatic stellate cells activity, inflammation and oxidative stress for anti-liver fibrosis/cirrhosis activity, as well as preventing tumor proliferation, invasion and angiogenesis for anti-HCC activity via relevant signaling pathways. Accordingly, this review provides insights into the future application of natural products in the trilogy of liver diseases and will provide a scientific basis for further research and rational utilization of P. urinaria.
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Affiliation(s)
- Linhua Liu
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
- State Key Laboratory of Chemical Oncogenomics, Institute of Biopharmaceutical and Health Engineering, Shenzhen lnternational Graduate School, Tsinghua University, Shenzhen, China
| | - Bing Wang
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Yibo Ma
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Kunhui Sun
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Ping Wang
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Meifang Li
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Junlin Dong
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Meirong Qin
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
| | - Mingshun Li
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Chunshan Wei
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Ying Tan
- State Key Laboratory of Chemical Oncogenomics, Institute of Biopharmaceutical and Health Engineering, Shenzhen lnternational Graduate School, Tsinghua University, Shenzhen, China
| | - Jinsong He
- Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Keying Guo
- Department of Biotechnology and Food Engineering, Guangdong-Technion Israel Institute of Technology, Shantou, China
| | - Xie-an Yu
- NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, China
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12
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Zhao B, Liu K, Liu X, Li Q, Li Z, Xi J, Xie F, Li X. Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis. Phytother Res 2024; 38:3122-3145. [PMID: 38613172 DOI: 10.1002/ptr.8193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 02/28/2024] [Accepted: 03/10/2024] [Indexed: 04/14/2024]
Abstract
Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.
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Affiliation(s)
- Bolin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kai Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhibei Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingjing Xi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fan Xie
- Hospital of Chengdu University of Traditional Chinese Medicine 610032, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Liu Q, Liu L, Xie L, Zheng L, Xu Q, Li W, Liu X. Screening and evaluation of quality markers of Radix Cudramiae for liver disease based on an integrated strategy of in vivo pharmacokinetics and in vitro HPLC fingerprint. J Pharm Biomed Anal 2024; 242:116055. [PMID: 38412792 DOI: 10.1016/j.jpba.2024.116055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/06/2024] [Accepted: 02/14/2024] [Indexed: 02/29/2024]
Abstract
Radix Cudramiae, the dried root of Cudrania cochinchinensis (Lour.) Kudo et Masam., is a valuable ethnomedicine with outstanding antihepatitis activity. However, the lack of reports on quality markers (Q-markers) hindered its quality evaluation and standardization, as a result restricted its clinical application. This paper aimed to discover the Q-markers of Radix Cudramiae with a comprehensive strategy based on in vivo pharmacokinetics and in vitro HPLC fingerprint. A rapid and sensitive ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analytical method was firstly developed and validated for simultaneous determination of six potential active ingredients (eriodictyol, dihydrokaempferol, dihydromorin, kaempferol, naringenin and morin) of Radix Cudramiae in rat plasma and tissues, which was successfully applied to the holistic comparison of pharmacokinetics and tissue distribution between normal and acute liver injury rats. On the other hand, a representative HPLC fingerprint of Radix Cudramiae was also established to elucidate the chemical profile for overall quality evaluation. Dihydrokaempferol-7-O-β-D-glucoside (the naturally existed chemical formation of dihydrokaempferol) and kaempferol screened out with high exposure levels in vivo and high resolution in HPLC fingerprint were finally selected as Q-markers of Radix Cudramiae. To the best of our knowledge, it was the first time for people to discover in vivo properties and pharmacokinetic parameters of components in Radix Cudramiae, as well as the first report on its representative HPLC fingerprint. Also, the integrated strategy could offer an effective way for TCMs Q-markers screening.
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Affiliation(s)
- Qing Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Anyang Hospital of Traditional Chinese Medicine, Anyang, Henan, PR China
| | - Luyao Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Lintong Xie
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Linyu Zheng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Qianwei Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Weidong Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China
| | - Xiao Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China; Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China.
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14
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Paravati MR, Procopio AC, Milanović M, Scarlata GGM, Milošević N, Ružić M, Milić N, Abenavoli L. Onion Polyphenols as Multi-Target-Directed Ligands in MASLD: A Preliminary Molecular Docking Study. Nutrients 2024; 16:1226. [PMID: 38674916 PMCID: PMC11054911 DOI: 10.3390/nu16081226] [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: 02/28/2024] [Revised: 03/28/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
A sedentary lifestyle associated with unregulated diets rich in high-calorie foods have contributed to the great prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) latterly, with up to 60% in the high-risk population and 25% in the general population. The absence of specific pharmacological strategies for this syndrome represents one of the major problems in the management of MASLD patients. Lifestyle interventions and adherence to a healthy diet are the main cornerstones of current therapies. The identification of nutraceuticals useful in the treatment of MASLD appears to be one of the most promising strategies for the development of new effective and safe treatments for this disease. The onion, one of the most widely studied foods in the field of nutraceuticals, serves as an inexhaustible reservoir of potent compounds with various beneficial effects. The following preliminary study analyzes, mediating in silico studies, the iteration of a library of typical onion compounds with 3-hydroxy-3-methylglutaryl-coenzyme A reductase, liver receptors X α and β, as well as peroxisome proliferator-activated receptors α and γ. In this study, for the first time promising smart molecules from the onion that could have a beneficial action in MASLD patients were identified.
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Affiliation(s)
- Maria Rosaria Paravati
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (A.C.P.); (G.G.M.S.)
| | - Anna Caterina Procopio
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (A.C.P.); (G.G.M.S.)
| | - Maja Milanović
- Department of Pharmacy, Faculty of Medicine Novi Sad, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia; (M.M.); (N.M.); (N.M.)
| | | | - Nataša Milošević
- Department of Pharmacy, Faculty of Medicine Novi Sad, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia; (M.M.); (N.M.); (N.M.)
| | - Maja Ružić
- Faculty of Medicine, University of Novi Sad, Clinic for Infectious Diseases, University Clinical Centre of Vojvodina, Hajduk Veljkova 1, 21000 Novi Sad, Serbia;
| | - Nataša Milić
- Department of Pharmacy, Faculty of Medicine Novi Sad, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia; (M.M.); (N.M.); (N.M.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (A.C.P.); (G.G.M.S.)
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15
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Kim TH, Heo SY, Chandika P, Kim YM, Kim HW, Kang HW, Je JY, Qian ZJ, Kim N, Jung WK. A literature review of bioactive substances for the treatment of periodontitis: In vitro, in vivo and clinical studies. Heliyon 2024; 10:e24216. [PMID: 38293511 PMCID: PMC10826675 DOI: 10.1016/j.heliyon.2024.e24216] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/16/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Periodontitis is a common chronic inflammatory disease of the supporting tissues of the tooth that involves a complex interaction of microorganisms and various cell lines around the infected site. To prevent and treat this disease, several options are available, such as scaling, root planning, antibiotic treatment, and dental surgeries, depending on the stage of the disease. However, these treatments can have various side effects, including additional inflammatory responses, chronic wounds, and the need for secondary surgery. Consequently, numerous studies have focused on developing new therapeutic agents for more effective periodontitis treatment. This review explores the latest trends in bioactive substances with therapeutic effects for periodontitis using various search engines. Therefore, this study aimed to suggest effective directions for therapeutic approaches. Additionally, we provide a summary of the current applications and underlying mechanisms of bioactive substances, which can serve as a reference for the development of periodontitis treatments.
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Affiliation(s)
- Tae-Hee Kim
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
| | - Seong-Yeong Heo
- Jeju Marine Research Center, Korea Institute of Ocean Science & Technology (KIOST), Jeju, 63349, Republic of Korea
| | - Pathum Chandika
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
| | - Young-Mog Kim
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
- Department of Food Science and Technology, Pukyong National University, Busan, 48513, Republic of Korea
| | - Hyun-Woo Kim
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
- Department of Marine Biology, Pukyong National University, Busan, 48513, Republic of Korea
| | - Hyun Wook Kang
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
- Major of Biomedical Engineering, Division of Smart Healthcare, College of Information Technology and Convergence and New-senior Healthcare Innovation Center (BK21 Plus), Pukyong National University, Busan, 48513, Republic of Korea
| | - Jae-Young Je
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Major of Human Bioconvergence, School of Smart Healthcare, Pukyong National University, Busan, 48513, Republic of Korea
| | - Zhong-Ji Qian
- College of Food Science and Technology, School of Chemistry and Environment, Guangdong Ocean University, Zhanjiang, 524088, China
- Shenzhen Institute of Guangdong Ocean University, Guangdong Ocean University, Shenzhen, 518108, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, 524025, China
| | - Namwon Kim
- Ingram School of Engineering, Texas State University, San Marcos, TX, 78666, USA
- Materials Science, Engineering, and Commercialization (MSEC), Texas State University, San Marcos, TX, 78666, USA
| | - Won-Kyo Jung
- Research Center for Marine Integrated Bionics Technology, Pukyong National University, Busan, 48513, Republic of Korea
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
- Major of Biomedical Engineering, Division of Smart Healthcare, College of Information Technology and Convergence and New-senior Healthcare Innovation Center (BK21 Plus), Pukyong National University, Busan, 48513, Republic of Korea
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Hu Q, Zhang W, Wei F, Huang M, Shu M, Song D, Wen J, Wang J, Nian Q, Ma X, Zeng J, Zhao Y. Human diet-derived polyphenolic compounds and hepatic diseases: From therapeutic mechanisms to clinical utilization. Phytother Res 2024; 38:280-304. [PMID: 37871899 DOI: 10.1002/ptr.8043] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/12/2023] [Accepted: 10/01/2023] [Indexed: 10/25/2023]
Abstract
This review focuses on the potential ameliorative effects of polyphenolic compounds derived from human diet on hepatic diseases. It discusses the molecular mechanisms and recent advancements in clinical applications. Edible polyphenols have been found to play a therapeutic role, particularly in liver injury, liver fibrosis, NAFLD/NASH, and HCC. In the regulation of liver injury, polyphenols exhibit anti-inflammatory and antioxidant effects, primarily targeting the TGF-β, NF-κB/TLR4, PI3K/AKT, and Nrf2/HO-1 signaling pathways. In the regulation of liver fibrosis, polyphenolic compounds effectively reverse the fibrotic process by inhibiting the activation of hepatic stellate cells (HSC). Furthermore, polyphenolic compounds show efficacy against NAFLD/NASH by inhibiting lipid oxidation and accumulation, mediated through the AMPK, SIRT, and PPARγ pathways. Moreover, several polyphenolic compounds exhibit anti-HCC activity by suppressing tumor cell proliferation and metastasis. This inhibition primarily involves blocking Akt and Wnt signaling, as well as inhibiting the epithelial-mesenchymal transition (EMT). Additionally, clinical trials and nutritional evidence support the notion that certain polyphenols can improve liver disease and associated metabolic disorders. However, further fundamental research and clinical trials are warranted to validate the efficacy of dietary polyphenols.
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Affiliation(s)
- Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Feng Wei
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Meilan Huang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mengyao Shu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dan Song
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jianxia Wen
- School of Food and Bioengineering, Xihua University, Chengdu, China
| | - Jundong Wang
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qing Nian
- Department of Blood Transfusion, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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17
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Wang T, Lu Z, Sun GF, He KY, Chen ZP, Qu XH, Han XJ. Natural Products in Liver Fibrosis Management: A Five-year Review. Curr Med Chem 2024; 31:5061-5082. [PMID: 38362686 DOI: 10.2174/0109298673288458240203064112] [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: 10/26/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.
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Affiliation(s)
- Tao Wang
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhuo Lu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
| | - Gui-Feng Sun
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Kai-Yi He
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhi-Ping Chen
- Department of Critical Care Medicine, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xin-Hui Qu
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xiao-Jian Han
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
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18
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Li JZ, Chen N, Ma N, Li MR. Mechanism and Progress of Natural Products in the Treatment of NAFLD-Related Fibrosis. Molecules 2023; 28:7936. [PMID: 38067665 PMCID: PMC10707854 DOI: 10.3390/molecules28237936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/22/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disorder worldwide, with liver fibrosis (LF) serving as a pivotal juncture in NAFLD progression. Natural products have demonstrated substantial antifibrotic properties, ushering in novel avenues for NAFLD treatment. This study provides a comprehensive review of the potential of natural products as antifibrotic agents, including flavonoids, polyphenol compounds, and terpenoids, with specific emphasis on the role of Baicalin in NAFLD-associated fibrosis. Mechanistically, these natural products have exhibited the capacity to target a multitude of signaling pathways, including Hedgehog, Wnt/β-catenin, TGF-β1, and NF-κB. Moreover, they can augment the activities of antioxidant enzymes, inhibit pro-fibrotic factors, and diminish fibrosis markers. In conclusion, this review underscores the considerable potential of natural products in addressing NAFLD-related liver fibrosis through multifaceted mechanisms. Nonetheless, it underscores the imperative need for further clinical investigation to authenticate their effectiveness, offering invaluable insights for future therapeutic advancements in this domain.
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Affiliation(s)
- Jin-Zhong Li
- Division of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Ning Chen
- General Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Nan Ma
- Center for Bioactive Natural Molecules and Innovative Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Min-Ran Li
- Division of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
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Rostami M, Aghaei M, Ghanadian M, Hashemnia M, Moezzi ND, Mohammadalipour A. Evaluation of the flavonol-rich fraction of Rosa damascena in an animal model of liver fibrosis by targeting the expression of fibrotic cytokines, antioxidant/oxidant ratio and collagen cross-linking. Life Sci 2023; 333:122143. [PMID: 37797686 DOI: 10.1016/j.lfs.2023.122143] [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: 08/03/2023] [Revised: 09/25/2023] [Accepted: 10/02/2023] [Indexed: 10/07/2023]
Abstract
INTRODUCTION The flavonoid-rich fraction of Rosa damascena (FRFRD) contains antioxidant and active compounds. Therefore, this study aimed to investigate the role of FRFRD, rich in quercetin and kaempferol, in liver fibrosis induced by CCl4. MATERIALS AND METHODS The FRFRD fraction was separated and standardized by High-Performance Liquid Chromatography (HPLC) based on the levels of quercetin and kaempferol. Liver fibrosis was induced over CCl4 over 12 weeks in 30 male Wistar rats, and three concentrations of FRFRD were administered to them during the last four weeks. Subsequently, after evaluation of liver serum markers and fibrotic parameters, the relative expression of transforming growth factor-beta-1 (TGF-β1), platelet-derived growth factor (PDGF), and lysyl oxidase homolog 2 (Loxl2) genes were assessed, along with the measurement of lysyl oxidase activity and oxidative markers. RESULTS Fibrotic markers demonstrated progressive recovery of liver damage in the treated group compared to the non-treatment group (p < 0.01). These results were accompanied by a significant decrease in the expression of TGF-β1, PDGF, and Loxl2 genes, as well as, a reduction in lysyl oxidase activity (p < 0.001). The antioxidant effects of the treatment were observed through a significant decrease in malondialdehyde (MDA) levels and an increase in catalase enzyme (CAT) and glutathione peroxidase (GPx) activity in the treatment group compared to the fibrotic group (p < 0.01). CONCLUSION The flavonoid-rich fraction of Rosa damascena ameliorates liver damage by affecting collagen cross-linking and lowering oxidative and inflammatory levels.
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Affiliation(s)
- Mehdi Rostami
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahmoud Aghaei
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mustafa Ghanadian
- Department of Pharmacognosy, Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Hashemnia
- Department of Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Nasrin Deilami Moezzi
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Adel Mohammadalipour
- Department of Clinical Biochemistry, School of Pharmacy & Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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20
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Gupta M, Ahmad J, Ahamad J, Kundu S, Goel A, Mishra A. Flavonoids as promising anticancer therapeutics: Contemporary research, nanoantioxidant potential, and future scope. Phytother Res 2023; 37:5159-5192. [PMID: 37668281 DOI: 10.1002/ptr.7975] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 06/30/2023] [Accepted: 07/21/2023] [Indexed: 09/06/2023]
Abstract
Flavonoids are natural polyphenolic compounds considered safe, pleiotropic, and readily available molecules. It is widely distributed in various food products such as fruits and vegetables and beverages such as green tea, wine, and coca-based products. Many studies have reported the anticancer potential of flavonoids against different types of cancers, including solid tumors. The chemopreventive effect of flavonoids is attributed to various mechanisms, including modulation of autophagy, induction of cell cycle arrest, apoptosis, and antioxidant defense. Despite of significant anticancer activity of flavonoids, their clinical translation is limited due to their poor biopharmaceutical attributes (such as low aqueous solubility, limited permeability across the biological membranes (intestinal and blood-brain barrier), and stability issue in biological systems). A nanoparticulate system is an approach that is widely utilized to improve the biopharmaceutical performance and therapeutic efficacy of phytopharmaceuticals. The present review discusses the significant anticancer potential of promising flavonoids in different cancers and the utilization of nanoparticulate systems to improve their nanoantioxidant activity further to enhance the anticancer activity of loaded promising flavonoids. Although, various plant-derived secondary metabolites including flavonoids have been recommended for treating cancer, further vigilant research is warranted to prove their translational values.
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Affiliation(s)
- Mukta Gupta
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Javed Ahamad
- Department of Pharmacognosy, Faculty of Pharmacy, Tishk International University, Erbil, Iraq
| | - Snehashis Kundu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
| | - Archit Goel
- All India Institute of Medical Sciences (AIIMS), Bathinda, Punjab, India
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India
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21
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Ouyang JY, Lin WJ, Dong JM, Yang Y, Yang HK, Zhou ZL, Wang RQ. Exploring the pharmacological mechanism of Wuzhuyu decoction on hepatocellular carcinoma using network pharmacology. World J Clin Cases 2023; 11:6327-6343. [PMID: 37900230 PMCID: PMC10601014 DOI: 10.12998/wjcc.v11.i27.6327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/24/2023] [Accepted: 07/28/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Wuzhuyu decoction, a traditional Chinese medicinal formula, is effective in treating hepatocellular carcinoma (HCC). AIM To explore the potential mechanism of action of Wuzhuyu decoction against HCC. METHODS The active components of each Chinese herbal medicinal ingredient in Wuzhuyu decoction and their targets were obtained from the Traditional Chinese Medicine Database and Analysis Platform. HCC was used as a search query in GeneCards, Online Mendelian Inheritance in Man, Malacards, DisGeNET, Therapeutic Target Database, and Comparative Toxicogenomics Database. The overlapping targets of the Wuzhuyu decoction and HCC were defined, and then protein-protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. CytoHubba was used to select hub genes, and their binding activities and key active components were verified using molecular docking. RESULTS A total of 764 compounds, 77 active compounds, and 204 potential target genes were identified in Wuzhuyu decoction. For HCC, 9468 potential therapeutic target genes were identified by combining the results from the six databases and removing duplicates. A total of 179 overlapping targets of Wuzhuyu decoction and HCC were defined, including 10 hub genes (tumor necrosis factor, interleukin-6, AKT1, TP53, caspase-3, mitogen-activated protein kinase 1, epidermal growth factor receptor, MYC, mitogen-activated protein kinase 8, and JUN). There were six main active components (quercetin, kaempferol, ginsenoside Rh2, rutaecarpine, β-carotene, and β-sitosterol) that may act on hub genes to treat HCC in Wuzhuyu decoction. Kyoto Encyclopedia of Genes and Genomes enrichment analysis mainly involved the mitogen-activated protein kinase, p53, phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt, Janus kinase-signal transducer of activators of transcription, and Hippo signaling pathways. Further verification based on molecular docking results showed that the small molecule compounds (quercetin, kaempferol, ginsenoside Rh2, rutaecarpine, β-carotene, and β-sitosterol) contained in Wuzhuyu decoction generally have excellent binding affinity to the macromolecular target proteins encoded by the top 10 genes. CONCLUSION This study revealed that Wuzhuyu decoction may be a latent multicomponent, multitarget, and multipathway treatment for HCC. It provided novel insights for verifying the mechanism of Wuzhuyu decoction in the treatment of HCC.
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Affiliation(s)
- Jia-Ying Ouyang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
| | - Wei-Jie Lin
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
| | - Jia-Mei Dong
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
| | - Yang Yang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
| | - Hai-Kui Yang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
| | - Zhi-Ling Zhou
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
| | - Rui-Qi Wang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, Guangdong Province, China
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22
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Pei Q, Yi Q, Tang L. Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities. Int J Mol Sci 2023; 24:ijms24119671. [PMID: 37298621 DOI: 10.3390/ijms24119671] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach's efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis.
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Affiliation(s)
- Qiying Pei
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Qian Yi
- Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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23
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Li H, Guan T, Qin S, Xu Q, Yin L, Hu Q. Natural products in pursuing novel therapies of nonalcoholic fatty liver disease and steatohepatitis. Drug Discov Today 2023; 28:103471. [PMID: 36610488 DOI: 10.1016/j.drudis.2022.103471] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/04/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are hepatic manifestations of systemic metabolic dysfunction, which affect one-quarter of the adult population worldwide as estimated, and exhibit high risk in progressing to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Current drug discovery focuses on modifying homeostasis of lipids, carbohydrates, and cholesterol, as well as inhibiting inflammation and fibrogenesis. Many natural products show promising activities on various molecular targets involving these mechanisms; however, they have not been fully exploited. Since some compounds are components of healthy food, they may be employed in chemoprevention as adjuvants to lifestyle modification, while natural products such as alkaloids and sesquiterpenoids could serve as promising starting points for structural modifications and deserve further development.
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Affiliation(s)
- Haiyan Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, Guangzhou, China
| | - Ting Guan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, Guangzhou, China
| | - Shi Qin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, Guangzhou, China
| | - Qihao Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, Guangzhou, China.
| | - Lina Yin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, Guangzhou, China.
| | - Qingzhong Hu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 232 East Waihuan Road, Panyu, Guangzhou, China.
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24
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Li H, Weng Q, Gong S, Zhang W, Wang J, Huang Y, Li Y, Guo J, Lan T. Kaempferol prevents acetaminophen-induced liver injury by suppressing hepatocyte ferroptosis via Nrf2 pathway activation. Food Funct 2023; 14:1884-1896. [PMID: 36723004 DOI: 10.1039/d2fo02716j] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Acetaminophen (APAP)-induced liver injury (AILI) has become a growing public health problem. Ferroptosis, an iron-dependent form of cell death associated with lipid peroxide accumulation, has been recently implicated in AILI. The activation of the Nrf2 signaling pathway is a potential therapy for AILI. Kaempferol (KA), a flavonoid widely existing in edible plants, has been reported to exert profound anti-inflammatory and antioxidant activities. This study aimed to investigate whether KA exerts anti-AILI effects via the Nrf2 signaling pathway. Mice were fasted for 22 h and injected intraperitoneally with APAP (250 mg kg-1) to induce AILI. Mice were pre-injected intragastrically with KA for 2 h followed by APAP injection. The hepatic injury was observed by H&E staining. Biochemical parameters of the serum and liver were measured using kits. KA alleviated hepatic injury and inflammatory response in AILI mice and ameliorated APAP-induced hepatic iron overload and oxidative stress in mice. In addition, the protective effects of KA against APAP-induced hepatotoxicity were examined in L02 cells in vitro. Cell viability was assayed by the CCK8 assay. Mitochondrial reactive oxygen species (ROS) in L02 cells were detected by MitoSox fluorescence. KA reversed the APAP-induced decrease in cell viability and GSH levels and inhibited the accumulation of intracellular ROS. Furthermore, KA activated the Nrf2 pathway and upregulated Gpx4 in mouse livers and L02 cells to inhibit ferroptosis induced by APAP. Finally, molecular docking indicated the potential interaction of KA with Keap1. Taken together, KA ameliorated oxidative stress and ferroptosis-mediated AILI by activating Nrf2 signaling.
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Affiliation(s)
- Huiyi Li
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Qiqing Weng
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Shuai Gong
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Weixian Zhang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Jiaqi Wang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Yuqiao Huang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Yuanjun Li
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Jiao Guo
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
| | - Tian Lan
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou 510006, China. .,Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China.,Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China.,Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
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Hepatoprotective Effect of Kaempferol: A Review of the Dietary Sources, Bioavailability, Mechanisms of Action, and Safety. Adv Pharmacol Pharm Sci 2023; 2023:1387665. [PMID: 36891541 PMCID: PMC9988374 DOI: 10.1155/2023/1387665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/27/2022] [Accepted: 02/03/2023] [Indexed: 03/02/2023] Open
Abstract
The liver is the body's most critical organ that performs vital functions. Hepatic disorders can affect the physiological and biochemical functions of the body. Hepatic disorder is a condition that describes the damage to cells, tissues, structures, and functions of the liver, which can cause fibrosis and ultimately result in cirrhosis. These diseases include hepatitis, ALD, NAFLD, liver fibrosis, liver cirrhosis, hepatic failure, and HCC. Hepatic diseases are caused by cell membrane rupture, immune response, altered drug metabolism, accumulation of reactive oxygen species, lipid peroxidation, and cell death. Despite the breakthrough in modern medicine, there is no drug that is effective in stimulating the liver function, offering complete protection, and aiding liver cell regeneration. Furthermore, some drugs can create adverse side effects, and natural medicines are carefully selected as new therapeutic strategies for managing liver disease. Kaempferol is a polyphenol contained in many vegetables, fruits, and herbal remedies. We use it to manage various diseases such as diabetes, cardiovascular disorders, and cancers. Kaempferol is a potent antioxidant and has anti-inflammatory effects, which therefore possesses hepatoprotective properties. The previous research has studied the hepatoprotective effect of kaempferol in various hepatotoxicity protocols, including acetaminophen (APAP)-induced hepatotoxicity, ALD, NAFLD, CCl4, HCC, and lipopolysaccharide (LPS)-induced acute liver injury. Therefore, this report aims to provide a recent brief overview of the literature concerning the hepatoprotective effect of kaempferol and its possible molecular mechanism of action. It also provides the most recent literature on kaempferol's chemical structure, natural source, bioavailability, and safety.
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Hosseini A, Alipour A, Baradaran Rahimi V, Askari VR. A comprehensive and mechanistic review on protective effects of kaempferol against natural and chemical toxins: Role of NF-κB inhibition and Nrf2 activation. Biofactors 2022; 49:322-350. [PMID: 36471898 DOI: 10.1002/biof.1923] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022]
Abstract
Different toxins, including chemicals and natural, can be entered from various routes and influence human health. Herbal medicines and their active components can attenuate the toxicity of agents via multiple mechanisms. For example, kaempferol, as a flavonoid, can be found in fruits and vegetables, and has an essential role in improving disorders such as cardiovascular disorders, neurological diseases, cancer, pain, and inflammation situations. The beneficial effects of kaempferol may be related to the inhibition of oxidative stress, attenuation of inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and nuclear factor ĸB (NF-ĸB) as well as the modulation of apoptosis and mitogen-activated protein kinase (MAPK) signaling pathways. This flavonoid boasts a wide spectrum of toxin targeting effects in tissue fibrosis, inflammation, and oxidative stress thus shows promising protective effects against natural and chemical toxin induced hepatotoxicity, nephrotoxicity, cardiotoxicity, neurotoxicity, lung, and intestinal in the in vitro and in vivo setting. The most remarkable aspect of kaempferol is that it does not focus its efforts on just one organ or one molecular pathway. Although its significance as a treatment option remains questionable and requires more clinical studies, it seems to be a low-risk therapeutic option. It is crucial to emphasize that kaempferol's poor bioavailability is a significant barrier to its use as a therapeutic option. Nanotechnology can be a promising way to overcome this challenge, reviving optimism in using kaempferol as a viable treatment agent against toxin-induced disorders.
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Affiliation(s)
- Azar Hosseini
- Pharmacological Research Centre of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alieh Alipour
- Pharmacological Research Centre of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Reza Askari
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Wu CC, Lee TY, Cheng YJ, Cho DY, Chen JY. The Dietary Flavonol Kaempferol Inhibits Epstein-Barr Virus Reactivation in Nasopharyngeal Carcinoma Cells. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238158. [PMID: 36500249 PMCID: PMC9736733 DOI: 10.3390/molecules27238158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/13/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022]
Abstract
Kaempferol (KP, 3,4',5,7-tetrahydroxyflavone), a dietary flavonol, has anti-cancer, antioxidant, anti-inflammatory, antimicrobial, and antimutagenic functions. However, it is unknown whether kaempferol possesses anti-Epstein-Barr virus (EBV) activity. Previously, we demonstrated that inhibition of EBV reactivation represses nasopharyngeal carcinoma (NPC) tumourigenesis, suggesting the importance of identifying EBV inhibitors. In this study, Western blotting, immunofluorescence staining, and virion detection showed that kaempferol repressed EBV lytic gene protein expression and subsequent virion production. Specifically, kaempferol was found to inhibit the promoter activities of Zta and Rta (Zp and Rp) under various conditions. A survey of the mutated Zp constructs revealed that Sp1 binding regions are critical for kaempferol inhibition. Kaempferol treatment repressed Sp1 expression and decreased the activity of the Sp1 promoter, suggesting that Sp1 expression was inhibited. In conclusion, kaempferol efficiently inhibits EBV reactivation and provides a novel choice for anti-EBV therapy and cancer prevention.
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Affiliation(s)
- Chung-Chun Wu
- Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung City 40447, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan
- Correspondence: (C.-C.W.); (J.-Y.C.)
| | - Ting-Ying Lee
- Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung City 40447, Taiwan
| | - Yu-Jhen Cheng
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan 35053, Taiwan
| | - Der-Yang Cho
- Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung City 40447, Taiwan
| | - Jen-Yang Chen
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan
- Correspondence: (C.-C.W.); (J.-Y.C.)
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Mechanisms of Xiaochaihu Decoction on Treating Hepatic Fibrosis Explored by Network Pharmacology. DISEASE MARKERS 2022; 2022:8925637. [PMID: 36246566 PMCID: PMC9553551 DOI: 10.1155/2022/8925637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022]
Abstract
Purpose. To explore the material basis and pharmacological mechanism of Xiaochaihu Decoction (XCHD), the classic Traditional Chinese Medicine (TCM) formula in inhibiting hepatic fibrosis (HF). Methods. The main components in XCHD were screened from the TCMSP database, ETCM database, and literature, and their potential targets were detected and predicted using the Swiss Target Prediction platform. The HF-related targets were retrieved and screened through GeneCard database and OMIM database, combined with GEO gene chips. The XCHD targets and HF targets were mapped to search common targets. The protein-protein interaction (PPI) network was acquired via the STRING11.0 database and analyzed visually using Cytoscape 3.8.0 software. The potential mechanisms of the common targets identified through GO and KEGG pathway enrichment analysis were analyzed by using Metascape database. The results were visualized through OmicShare Tools. The “XCHD compound-HF target” network was visually constructed by Cytoscape 3.8.0 software. AutoDockVina1.1.2 and PyMoL software were used to verify the molecular docking of XCHD main active compounds and HF key targets. Results. A total of 164 potential active compounds from XCHD were screened to act on 95 HF-related targets. Bioinformatics analysis revealed that quercetin, β-sitosterol, and kaempferol may be candidate agents, which acted on multiple targets like PTGS2, HSP90AA1, and PTGS1 and regulate multiple key biological pathways like IL-17 signaling pathway, TNF signaling pathway and PI3K-Akt signaling pathway to relieve HF. Moreover, molecular docking suggested that quercetin and PTGS2 could statically bind and interact with each other through amino acid residues val-349, LEU-352, PHE-381, etc. Conclusion. This work provides a systems perspective to study the relationship between Chinese medicines and diseases. The therapeutic efficacy of XCHD on HF was the sum of multitarget and multi-approach effects from the bioactive ingredients. This study could be one of the cornerstones for further research.
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Zhang JB, Jin HL, Feng XY, Feng SL, Zhu WT, Nan HM, Yuan ZW. The combination of Lonicerae Japonicae Flos and Forsythiae Fructus herb-pair alleviated inflammation in liver fibrosis. Front Pharmacol 2022; 13:984611. [PMID: 36059967 PMCID: PMC9437263 DOI: 10.3389/fphar.2022.984611] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: To explore the active components and epigenetic regulation mechanism underlying the anti-inflammatory effects of Lonicerae Japonicae Flos and Forsythiae Fructus herb-pair (LFP) in carbon tetrachloride (CCl4)-induced rat liver fibrosis. Methods: The main active ingredients and disease-related gene targets of LFP were determined using TCMSP and UniProt, and liver fibrosis disease targets were screened in the GeneCards database. A network was constructed with Cytoscape 3.8.0 and the STRING database, and potential protein functions were analyzed using bioinformatics analysis. Based on these analyses, we determined the main active ingredients of LFP and evaluated their effects in a CCl4-induced rat liver fibrosis model. Serum biochemical indices were measured using commercial kits, hepatocyte tissue damage and collagen deposition were evaluated by histopathological studies, and myofibroblast activation and inflammation were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. High-performance liquid chromatography-mass spectrometry was performed to determine the levels of homocysteine, reduced glutathione, and oxidized glutathione, which are involved in inflammation and oxidative stress. Results: The main active components of LFP were quercetin, kaempferol, and luteolin, and its main targets were α-smooth muscle actin, cyclooxygenase-2, formyl-peptide receptor-2, prostaglandin-endoperoxide synthase 1, nuclear receptor coactivator-2, interleukinβ, tumor necrosis factor α, CXC motif chemokine ligand 14, and transforming growth factor β1. A combination of quercetin, kaempferol, and luteolin alleviated the symptoms of liver fibrosis. Conclusion: The results of this study support the role of LFP in the treatment of liver fibrosis, and reveal that LFP reduces collagen formation, inflammation, and oxidative stress. This study suggests a potential mechanism of action of LFP in the treatment of liver fibrosis.
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Affiliation(s)
- Jing-Bei Zhang
- Collage of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China
| | - Hong-Liu Jin
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Xiao-Ying Feng
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Sen-ling Feng
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Wen-Ting Zhu
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Hong-Mei Nan
- Collage of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, China
- Department of Encephalopathy, Affiliated Hospital of Changchun University of Chinese Medicine, Jilin, China
- *Correspondence: Hong-Mei Nan, ; Zhong-Wen Yuan,
| | - Zhong-Wen Yuan
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
- *Correspondence: Hong-Mei Nan, ; Zhong-Wen Yuan,
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Exploring mechanisms of Chaihu-Shugan-San against liver fibrosis by integrated multi-omics and network pharmacology approach. Biosci Rep 2022; 42:231546. [PMID: 35791909 PMCID: PMC9301292 DOI: 10.1042/bsr20221030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/19/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022] Open
Abstract
Chaihu-Shugan-San (CHSGS), a noted traditional Chinese medicine formula, has been used as a complementary and alternative therapy for liver fibrosis. However, the antifibrotic mechanisms of CHSGS still remain unclear. Thus, we used network pharmacology approach in combination with single cell and bulk transcriptomics to elucidate the antifibrotic mechanisms of CHSGS. We first screened out 134 bioactive ingredients of CHSGS through the defined criteria. Then, 1,150 genes were predicted to be targets for CHSGS, while 625 liver fibrosis-associated genes were identified by single cell transcriptomics analysis. Next, 71 intersecting genes of CHSGS and liver fibrosis were defined as the therapeutic targets in CHSGS against liver fibrosis. Further, 21 core targets and 12 core ingredients of CHSGS against liver fibrosis were also identified. Meanwhile, enrichment analyses of core targets highlighted that the key mechanisms of CHSGS against liver fibrosis include modulation of inflammation responses, inhibition of angiogenesis, and regulation of ECM remodeling, of which the most important mechanism was the regulation of ECM remodeling. The molecular docking simulation validated strong binding affinity between the core targets and core ingredients. Furthermore, 62-gene signature may be used for determining the prognosis in cirrhotic patients based on the results of ssGSEA-Cox analysis. In conclusion, this study revealed the multiple pharmacological targets and therapeutic mechanisms of CHSGS against liver fibrosis, which may thus serve as an effective antifibrotic therapy. Meanwhile, CHSGS may improve survival of patients with liver cirrhosis by the interaction of 62-gene signature.
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Zhou G, Li C, Zhang R, Zhan Y, Lin L, Lang Z, Tao Q, Zheng J. Kaempferol Inhibits Hepatic Stellate Cell Activation by Regulating miR-26b-5p/Jag1 Axis and Notch Pathway. Front Pharmacol 2022; 13:881855. [PMID: 35721153 PMCID: PMC9198265 DOI: 10.3389/fphar.2022.881855] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/26/2022] [Indexed: 01/10/2023] Open
Abstract
Kaempferol, a natural flavonoid molecule, has demonstrated anti-inflammatory, antimicrobial and antioxidant activities. Recent studies have shown the beneficial effects of kaempferol on liver fibrosis. Notch pathway has been reported to be involved in the aberrant activation of hepatic stellate cells (HSCs). However, whether Notch pathway plays a key role in the anti-fibrotic effects of kaempferol is largely unknown. In this study, kaempferol significantly suppressed liver fibrosis in CCl4 mice, with reduced collagen deposition as well as restored liver function. In vitro, kaempferol enhanced the suppression of HSC activation, with a decrease in α-SMA as well as collagen level. It was found that Notch pathway played an important role in kaempferol-reduced the activation of HSCs. Jag1, a ligand of Notch pathway, was obviously inhibited by kaempferol. Overexpression of Jag1 effectively abolished kaempferol-induced HSC inactivation. Furthermore, Jag1 was demonstrated as a target of microRNA-26b-5p (miR-26b-5p). Interestingly, miR-26b-5p inhibitor prevented HSC activation inhibition caused by kaempferol. Further studies indicated that kaempferol inhibited Notch pathway via miR-26b-5p and Jag1, leading to HSC inactivation. Collectively, we demonstrate that kaempferol could inhibit HSC activation, at least in part, via miR-26b-5p-mediated Jag1 axis and Notch pathway. Kaempferol may serve as a promising drug in the application of treating liver fibrosis.
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Affiliation(s)
- Guangyao Zhou
- Department of Infectious Diseases, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chunxue Li
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rongrong Zhang
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yating Zhan
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lifan Lin
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhichao Lang
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qiqi Tao
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jianjian Zheng
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Bangar SP, Chaudhary V, Sharma N, Bansal V, Ozogul F, Lorenzo JM. Kaempferol: A flavonoid with wider biological activities and its applications. Crit Rev Food Sci Nutr 2022; 63:9580-9604. [PMID: 35468008 DOI: 10.1080/10408398.2022.2067121] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Kaempferol and its derivatives are naturally occurring phytochemicals with promising bioactivities. This flavonol can reduce the lipid oxidation in the human body, prevent the organs and cell structure from deterioration and protect their functional integrity. This review has extensively highlighted the antioxidant, antimicrobial, anticancer, neuroprotective, and hepatoprotective activity of kaempferol. However, poor water solubility and low bioavailability of kaempferol greatly limit its applications. The utilization of advanced delivery systems can improve its stability, efficacy, and bioavailability. This is the first review that aimed to comprehensively collate some of the vital information published on biosynthesis, mechanism of action, bioactivities, bioavailability, and toxicological potential of kaempferol. Besides, it provides insights into the future direction on the improvement of bioavailability of kaempferol for wide applications.
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Affiliation(s)
- Sneh Punia Bangar
- Department of Food, Nutrition and Packaging Sciences, Clemson University, Clemson, SC, USA
| | - Vandana Chaudhary
- College of Dairy Science and Technology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana, India
| | - Nitya Sharma
- Food Customization Research Lab, Centre for Rural Development and Technology, Indian Institute of Technology, Delhi, New Delhi, India
| | - Vasudha Bansal
- Department of Foods and Nutrition, Government of Home Science College, Chandigarh, India
| | - Fatih Ozogul
- Department of Seafood Processing Technology, Faculty of Fisheries, University of Cukurova, Adana, Turkey
| | - Jose M Lorenzo
- Centro Tecnológico de la Carne de Galicia, Ourense, Spain
- Área de Tecnología de los Alimentos, Facultad de Ciencias de Ourense, Universidade de Vigo, Ourense, Spain
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Explore the Mechanism of Astragalus mongholicus Bunge against Nonalcoholic Fatty Liver Disease Based on Network Pharmacology and Experimental Verification. Gastroenterol Res Pract 2022; 2022:4745042. [PMID: 35422858 PMCID: PMC9005278 DOI: 10.1155/2022/4745042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
Objective Astragalus mongholicus Bunge [Fabaceae] (AMB), a traditional Chinese medicine (TCM), has been widely used to treat liver diseases in the clinic. However, the efficacy and mechanism of AMB in the treatment of nonalcoholic fatty liver disease (NAFLD) remain unclear. The purpose of this study was to systematically investigate the active components and mechanisms of AMB against NAFLD based on network pharmacology, molecular docking, and experimental verification. Methods First, the bioactive components and relevant targets of AMB were screened from the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database, and NAFLD-related targets were obtained from the GeneCards database. Then, the AMB-NAFLD protein target interaction network was built by the STRING database. GO and KEGG pathway enrichment analyses were performed using the DAVID database. The component targets were visualized using Cytoscape software. Finally, molecular docking and experiments were used to verify the results of network pharmacological prediction. Results Network pharmacology predicted that quercetin may be the main active component in AMB, and the TNF and MAPK signaling pathways may be the key targets of AMB against NAFLD. Molecular docking validation results demonstrated that quercetin, as the main active component of AMB, had the highest binding affinity with TNF. Furthermore, quercetin played a distinct role in alleviating NAFLD through in vitro experiments. Quercetin upregulated the phosphorylation levels of AMPK and inhibited the expression of p-MAPK and TNF-α. In addition, we further discovered that quercetin could increase ACC phosphorylation and CPT1α expression in PA-induced HepG2 cells. Conclusions Our results indicated that quercetin, as the main active component in AMB, exerts an anti-NAFLD effect by regulating the AMPK/MAPK/TNF-α and AMPK/ACC/CPT1α signaling pathways to inhibit inflammation and alleviate lipid accumulation.
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Chen Y, Li T, Tan P, Shi H, Cheng Y, Cai T, Bai J, Du Y, Fu W. Kaempferol From Penthorum chinense Pursh Attenuates Hepatic Ischemia/Reperfusion Injury by Suppressing Oxidative Stress and Inflammation Through Activation of the Nrf2/HO-1 Signaling Pathway. Front Pharmacol 2022; 13:857015. [PMID: 35431932 PMCID: PMC9011142 DOI: 10.3389/fphar.2022.857015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/07/2022] [Indexed: 12/30/2022] Open
Abstract
The purpose of this study is to investigate the protective effect of kaempferol (KAE), the main active monomer from Penthorum chinense Pursh, on hepatic ischemia/reperfusion injury (HI/RI) and its specific mechanism. HI/RI is a common complication closely related to the prognosis of liver surgery, and effective prevention and treatment methods are still unavailable. Ischemia/reperfusion (I/R) injury is caused by tissue damage during ischemia and sustained oxidative stress and inflammation during reperfusion. Penthorum chinense Pursh is a traditional Chinese medicine widely used to treat liver disease since ancient times. Kaempferol (KAE), a highly purified flavonoid active monomer isolated and extracted from Penthorum chinense Pursh, was investigated for its protective effect on HI/RI. Our study indicates that KAE pretreatment alleviated I/R-induced transaminase elevation and pathological changes. Further analysis revealed that KAE pretreatment attenuates I/R-induced oxidative stress (as measured by the content of MDA, SOD and GSH) in vivo and reduces hypoxia/reoxygenation (H/R) -induced reactive oxygen species (ROS) generation in vitro. Meanwhile, KAE inhibits activation of NF-κB/p65 and reduces the release of pro-inflammatory factors (TNF-α and IL-6) to protect the liver from I/R-induced inflammation. Nuclear erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotection regulator because it induces anti-inflammatory, antioxidant, and cytoprotective genes. Therefore, we analyzed the protein levels of Nrf2 and its downstream heme oxygenase-1 (HO-1) in the liver of mice and hepatocytes of humankind, respectively, and discovered that KAE pretreatment activates the Nrf2/HO-1 signaling pathway. In summary, this study confirmed the hepatoprotective effect of KAE on HI/RI, which inhibits oxidative stress and inflammation by activating the Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Yifan Chen
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tongxi Li
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Peng Tan
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hao Shi
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yonglang Cheng
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Tianying Cai
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Junjie Bai
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yichao Du
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: Yichao Du, ; Wenguang Fu,
| | - Wenguang Fu
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: Yichao Du, ; Wenguang Fu,
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Alshehri AS, El-Kott AF, El-Gerbed MSA, El-Kenawy AE, Albadrani GM, Khalifa HS. Kaempferol prevents cadmium chloride-induced liver damage by upregulating Nrf2 and suppressing NF-κB and keap1. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:13917-13929. [PMID: 34599712 DOI: 10.1007/s11356-021-16711-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 09/21/2021] [Indexed: 06/13/2023]
Abstract
This study evaluated the protective effect of kaempferol, a natural flavonoid, against cadmium chloride (CdCl2)-induced liver damage and examined the possible anti-inflammatory and antioxidant mechanisms of protection. Adult male rats were divided into 4 groups (each of 8 rats) as control, kaempferol (50 mg/kg/day orally), CdCl2 (15 ppm/day), and CdCl2 (15 ppm/day) + kaempferol (50 mg/kg/day). All treatments were given for 30 days. With no effect on attenuating the reduced food intake, kaempferol significantly increased body weight and lowered serum levels of liver injury markers including bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase 1 (γ-GTT1) in the CdCl2-treated rats. It also restored normal liver architectures, prevented hepatocyte, loss, and swelling and reduced inflammatory cell infiltration. These effects were associated with a reduction in mitochondrial permeability transition pore, as well as in the expression of cytochrome-c and cleaved caspase-3, markers of mitochondrial damage, and intrinsic cell death. In both the control positive and CdCl2-treated rats, kaempferol significantly lowered the hepatic levels of reactive oxygen species, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), Interleukine-6 (IL-6), and the nuclear activity and localization of NF-κB p65. Besides, kaempferol significantly increased the hepatic total and nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1, as well as levels of superoxide dismutase (SOD) and reduced glutathione (GSH) but reduced the cytoplasmic protein levels of keap1. In conclusion, the protective effect of kaempferol against CdCl2-induced hepatic damage is mediated by antioxidant and anti-inflammatory effects driven by upregulating Nrf2/HO-1 axis and suppressing the NF-κB p65 and keap1.
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Affiliation(s)
- Ali S Alshehri
- Biology Department, College of Science, King Khalid University, Abha, 61421, Saudi Arabia
| | - Attalla F El-Kott
- Biology Department, College of Science, King Khalid University, Abha, 61421, Saudi Arabia.
- Zoology Department, College of Science, Damanhour University, Damanhour, 22511, Egypt.
| | - Mohamed S A El-Gerbed
- Zoology Department, College of Science, Damanhour University, Damanhour, 22511, Egypt
| | - Ayman E El-Kenawy
- Pathology Department, College of Medicine, Taif University, Taif, 21944, Saudi Arabia
| | - Ghadeer M Albadrani
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, 11474, Saudi Arabia
| | - Heba S Khalifa
- Zoology Department, College of Science, Damanhour University, Damanhour, 22511, Egypt
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Kulkarni C, Sharma S, Bora PS, Verma S, Rajput S, Porwal K, Rath SK, Gayen JR, Sharma U, Chattopadhyay N. A novel extraction method enhanced the osteogenic and anti-osteoporosis effect of tea extract without any hepatotoxicity in ovariectomized rats. Front Endocrinol (Lausanne) 2022; 13:951800. [PMID: 36060935 PMCID: PMC9434695 DOI: 10.3389/fendo.2022.951800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/04/2022] [Indexed: 11/16/2022] Open
Abstract
Tea (Camellia sinensis) has several reported health benefits, including that on bone health attributed to catechins of which the most abundant is epigallocatechin-3-gallate (EGCG). However, several preclinical and clinical studies raise safety concerns about EGCG in tea extract causing acute liver failure. Tea also contains kaempferol, albeit scanty, and it has hepatoprotective and osteogenic effects. Here, we utilized a novel extraction procedure of acid hydrolysis to enhance the osteogenic effect of tea extract while reducing its hepatotoxicity. The resultant extract (USKECSE) has a ~40-fold increase in kaempferol and a 2.5-fold reduction in EGCG content compared with the hydroethanolic extract (USCSE). In a female Sprague Dawley (SD) rat femur osteotomy model, USKECSE (100 mg/kg) but not USCSE promoted bone regeneration. In a rat postmenopausal osteoporosis model induced by bilateral ovariectomy (OVX), USKECSE through an osteogenic mechanism maintained bone mass, strength, and microarchitecture to the levels of ovary-intact rats with no hepatotoxic effect. After a single oral dose (100 mg/kg) of USKECSE to adult rats, kaempferol was detectable for 48 hours, suggesting its significant absorption and distribution in plasma. Peak kaempferol concentration in plasma (Cmax) was 483 ng/ml (2 μM), and at this concentration, kaempferol induces osteoblast differentiation. USKECSE had no genotoxicity, and its safety index assessed by preclinical toxicity studies, including safety pharmacology, was >20-fold. Taken together, we report a novel extraction process that enhanced the osteogenicity and concomitantly reduced hepatotoxicity of tea extract with significant kaempferol bioavailability and a favorable systemic safety profile. Based on these data, we propose assessing the USKECSE effect for postmenopausal osteoporosis treatment.
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Affiliation(s)
- Chirag Kulkarni
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shivani Sharma
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Prateek Singh Bora
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Division of Chemical Technology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, India
| | - Saurabh Verma
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Division of Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, India
| | - Swati Rajput
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Konica Porwal
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
| | - Srikanta Kumar Rath
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, India
| | - Jiaur Rahaman Gayen
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Division of Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, India
| | - Upendra Sharma
- Division of Chemical Technology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- *Correspondence: Naibedya Chattopadhyay,
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Ben-Abdallah S, Sefi M, Soudani N, Hamdi A, Bejaoui S, Issaoui H, El Cafsi M, Karray-Bouraoui N. Potential antioxidant effects of Narcissus tazetta phenolic compounds against cadmium chloride-induced hepatotoxicity in Swiss albino mice. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:66193-66205. [PMID: 34331222 DOI: 10.1007/s11356-021-15497-8] [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: 01/06/2021] [Accepted: 07/14/2021] [Indexed: 06/13/2023]
Abstract
Narcissus tazetta (Amaryllidaceae) is a medicinal plant widely used for cut flowers and potted ornamental plant in Tunisia flora. The current study evaluated the phenolic composition and antioxidant properties of its flower extracts and investigated its potential protective activity against cadmium chloride (CdCl2)-induced hepatotoxicity in mice. Mice were divided into six groups of six each: group 1, serving as negative controls, received by intraperitoneal way only distilled water; group 2 received by intraperitoneal way CdCl2 (0.16 mg/kg bw); groups 3 and 4 received CdCl2 at the same dose of group 2 and 100 or 200 mg/kg bw of Narcissus tazetta flower extracts via oral route; groups 5 and 6, serving as positive controls, received only Narcissus tazetta flower extracts. Polyphenolic compounds of the extract were analyzed by colorimetric and high-performance liquid chromatography-mass spectrometry (HPLC-MS) methods. Total antioxidant activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging potential of the extract were estimated using colorimetric method. Results indicated that ethanolic flower extract contained high levels of total phenolic and flavonoid along with a strong total antioxidant and DPPH free radical scavenging activities. HPLC-MS analysis identified eight phenolic compounds, including rutin, kaempferol glycosides, and chlorogenic acids. The extract also exhibited marked hepatoprotective effects against CdCl2 toxicity by reducing hepatic levels of malondialdehyde, advanced oxidation protein products, hydrogen peroxide, metallothioneins, and DNA degradation. Additionally, co-administration of Narcissus tazetta flower extracts lowered the plasma activities of transaminases, gamma glutamyl transpeptidase, and lactate dehydrogenase and increased hepatic levels of reduced glutathione, nonprotein thiols, vitamin C, and catalase activity. The hepatoprotective effects of the extract were demonstrated by histopathological improvement of liver disorders. The current study provided ethnopharmacological application of Narcissus tazetta flower extracts against CdCl2-induced oxidative stress, suggesting its chemoprevention role of its phenolic compounds as a natural antioxidant.
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Affiliation(s)
- Saoussen Ben-Abdallah
- Laboratory of Plant Productivity and Environmental Constraints, LR18ES04, Department of Biology, Faculty of Sciences of Tunisia, University Tunis El Manar, 2092, Tunis, Tunisia.
| | - Mediha Sefi
- Laboratory of Ecology, Biology and Physiology of Aquatic Organisms, LR18ES41, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, 2092, Tunis, Tunisia
- Animal Physiology Laboratory, Department of Life Sciences, University of Sfax, Sfax, Tunisia
| | - Nejla Soudani
- Laboratory of Ecology, Biology and Physiology of Aquatic Organisms, LR18ES41, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, 2092, Tunis, Tunisia
| | - Amel Hamdi
- Laboratory of Plant Productivity and Environmental Constraints, LR18ES04, Department of Biology, Faculty of Sciences of Tunisia, University Tunis El Manar, 2092, Tunis, Tunisia
- Phytochemicals and Food Quality Group, Instituto de la Grasa (CSIC), 41013, Seville, Spain
| | - Safa Bejaoui
- Laboratory of Ecology, Biology and Physiology of Aquatic Organisms, LR18ES41, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, 2092, Tunis, Tunisia
| | - Hela Issaoui
- Laboratory of Plant Productivity and Environmental Constraints, LR18ES04, Department of Biology, Faculty of Sciences of Tunisia, University Tunis El Manar, 2092, Tunis, Tunisia
| | - Mhamed El Cafsi
- Laboratory of Ecology, Biology and Physiology of Aquatic Organisms, LR18ES41, Department of Biology, Faculty of Sciences of Tunis, University Tunis El Manar, 2092, Tunis, Tunisia
| | - Najoua Karray-Bouraoui
- Laboratory of Plant Productivity and Environmental Constraints, LR18ES04, Department of Biology, Faculty of Sciences of Tunisia, University Tunis El Manar, 2092, Tunis, Tunisia
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Xiao X, Hu Q, Deng X, Shi K, Zhang W, Jiang Y, Ma X, Zeng J, Wang X. Old wine in new bottles: Kaempferol is a promising agent for treating the trilogy of liver diseases. Pharmacol Res 2021; 175:106005. [PMID: 34843960 DOI: 10.1016/j.phrs.2021.106005] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023]
Abstract
As a source of various compounds, natural products have long been important and valuable for drug development. Kaempferol (KP) is the most common flavonol with bioactive activity and has been extracted from many edible plants and traditional Chinese medicines. It has a wide range of pharmacological effects on inflammation, oxidation, and tumour and virus regulation. The liver is an important organ and is involved in metabolism and activity. Because the pathological process of liver diseases is extremely complicated, liver diseases involving ALD, NASH, liver fibrosis, and HCC are often complicated and difficult to treat. Fortunately, there have been many reports that KP has a good pharmacological effect on a series of complex liver diseases. To fully understand the mechanism of KP and provide new ideas for its clinical application in the treatment of liver diseases, this article reviews the pharmacological mechanism and potential value of KP in different studies involving various liver diseases. In the trilogy of liver disease, high concentrations of ROS stimulate peroxidation and activate the inflammatory signal cascade, which involves signalling pathways such as MAPK/JAK-STAT/PERK/Wnt/Hipp, leading to varying degrees of cell degradation and liver damage. The development of liver disease is promoted in an inflammatory environment, which is conducive to the activation of TGF-β1, leading to increased expression of pro-fibrosis and pro-inflammatory genes. Inflammation and oxidative stress promote the formation of tumour microenvironments, and uncontrolled autophagy of cancer cells further leads to the development of liver cancer. The main pathway in this process is AMPK/PTEN/PI3K-Akt/TOR. KP can not only protect liver parenchymal cells through a variety of antioxidant and anti-apoptotic mechanisms but also reduces the immune inflammatory response in the liver microenvironment, thereby preventing cell apoptosis; it can also inhibit the ER stress response, prevent inflammation and inhibit tumour growth. KP exerts multiple therapeutic effects on liver disease by regulating precise signalling targets and is expected to become an emerging therapeutic opportunity to treat liver disease in the future.
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Affiliation(s)
- Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Kaiyun Shi
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yinxiao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Jinhao Zeng
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Xiaoyin Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Zhang Z, Qiao Y, Yang L, Chen Z, Li T, Gu M, Li C, Liu M, Li R. Kaempferol 3-O-gentiobioside, an ALK5 inhibitor, affects the proliferation, migration, and invasion of tumor cells via blockade of the TGF-β/ALK5/Smad signaling pathway. Phytother Res 2021; 35:6310-6323. [PMID: 34514657 DOI: 10.1002/ptr.7278] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 08/08/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022]
Abstract
Overactivation of TGF-β/ALK5/Smad signaling pathway has been observed in the advanced stage of various human malignancies. As a key component of TGF-β/ALK5/Smad signaling pathway transduction, TGF-β type I receptor (also known as ALK5) has emerged as a promising therapeutic target for cancer treatment. In this study, to discover a novel ALK5 inhibitor, a commercial natural products library was screened using docking-based virtual screening, followed by luciferase reporter assay. A flavonoid glycoside kaempferol 3-O-gentiobioside (KPF 3-O-G) was identified as a potent ALK5 inhibitor through directly bound to the ATP-site of ALK5, resulting in the inhibitory effects on phosphorylation and translocation of Smad2 and expression of Smad4. Additionally, we found that KPF 3-O-G reduced cell proliferation and inhibited TGF-β-induced cell migration and invasion. Moreover, western blotting and immunofluorescent analysis showed that KPF 3-O-G significantly reversed the TGF-β-induced EMT biomarkers, including upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and snail. In vivo study showed that KPF 3-O-G administration reduced tumor growth in human ovarian cancer xenograft mouse model, without obvious toxic effect. This study provided novel insight into the anticancer effects of KPF-3-O-G and indicated that KPF-3-O-G might be developed as potential therapeutics for cancer treatment after further validation.
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Affiliation(s)
- Zihao Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yu Qiao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Li Yang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zuwang Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Tao Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - MingZhen Gu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Chong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Mingming Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Rong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
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Sharma N, Biswas S, Al-Dayan N, Alhegaili AS, Sarwat M. Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma. Antioxidants (Basel) 2021; 10:1419. [PMID: 34573051 PMCID: PMC8470426 DOI: 10.3390/antiox10091419] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 01/04/2023] Open
Abstract
Reactive oxygen species (ROS) are noxious to cells because their increased level interacts with the body's defense mechanism. These species also cause mutations and uncontrolled cell division, resulting in oxidative stress (OS). Prolonged oxidative stress is responsible for incorrect protein folding in the endoplasmic reticulum (ER), causing a stressful condition, ER stress. These cellular stresses (oxidative stress and ER stress) are well-recognized biological factors that play a prominent role in the progression of hepatocellular carcinoma (HCC). HCC is a critical global health problem and the third leading cause of cancer-related mortality. The application of anti-oxidants from herbal sources significantly reduces oxidative stress. Kaempferol (KP) is a naturally occurring, aglycone dietary flavonoid that is present in various plants (Crocus sativus, Coccinia grandis, Euphorbia pekinensis, varieties of Aloe vera, etc.) It is capable of interacting with pleiotropic proteins of the human body. Efforts are in progress to develop KP as a potential candidate to prevent HCC with no adverse effects. This review emphasizes the molecular mechanism of KP for treating HCC, targeting oxidative stress.
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Affiliation(s)
- Nidhi Sharma
- Amity Institute of Pharmacy, Amity University, Noida 201313, Uttar Pradesh, India;
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India;
| | - Noura Al-Dayan
- Medical Laboratory Department, Applied Medical Science, Prince Sattam bin Abdul Aziz University, Al-Kharj 16278, Saudi Arabia; (N.A.-D.); (A.S.A.)
| | - Alaa Saud Alhegaili
- Medical Laboratory Department, Applied Medical Science, Prince Sattam bin Abdul Aziz University, Al-Kharj 16278, Saudi Arabia; (N.A.-D.); (A.S.A.)
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Noida 201313, Uttar Pradesh, India;
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Rouf R, Ghosh P, Uzzaman MR, Sarker DK, Zahura FT, Uddin SJ, Muhammad I. Hepatoprotective Plants from Bangladesh: A Biophytochemical Review and Future Prospect. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:1633231. [PMID: 34504532 PMCID: PMC8423546 DOI: 10.1155/2021/1633231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/17/2021] [Indexed: 12/14/2022]
Abstract
Liver diseases are quite prevalant in many densely populated countries, including Bangladesh. The liver and its hepatocytes are targeted by virus and microbes, as well as by chemical environmental toxicants, causing wide-spread disruption of metabolic fuctions of the human body, leading to death from end-stage liver diseases. The aim of this review is to systematically explore and record the potential of Bangladeshi ethnopharmacological plants to treat liver diseases with focus on their sources, constituents, and therapeutic uses, including mechanisms of actions (MoA). A literature survey was carried out using Pubmed, Google Scholar, ScienceDirect, and Scopus databases with articles reported until July, 2020. A total of 88 Bangladeshi hepatoprotective plants (BHPs) belonging to 47 families were listed in this review, including Euphorbiaceae, Cucurbitaceae, and Compositae families contained 20% of plants, while herbs were the most cited (51%) and leaves were the most consumed parts (23%) as surveyed. The effect of BHPs against different hepatotoxins was observed via upregulation of antioxidant systems and inhibition of lipid peroxidation which subsequently reduced the elevated liver biomarkers. Different active constituents, including phenolics, curcuminoids, cucurbitanes, terpenoids, fatty acids, carotenoids, and polysaccharides, have been reported from these plants. The hepatoameliorative effect of these constituents was mainly involved in the reduction of hepatic oxidative stress and inflammation through activation of Nrf2/HO-1 and inhibition of NF-κB signaling pathways. In summary, BHPs represent a valuable resource for hepatoprotective lead therapeutics which may offer new alternatives to treat liver diseases.
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Affiliation(s)
- Razina Rouf
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Puja Ghosh
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh
| | - Md. Raihan Uzzaman
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh
| | - Dipto Kumer Sarker
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh
| | - Fatima Tuz Zahura
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh
| | - Shaikh Jamal Uddin
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh
| | - Ilias Muhammad
- National Center for Natural Products Research, School of Pharmacy, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA
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Lysimachiae Herba Inhibits Inflammatory Reactions and Improves Lipopolysaccharide/D-Galactosamine-Induced Hepatic Injury. Antioxidants (Basel) 2021; 10:antiox10091387. [PMID: 34573019 PMCID: PMC8471683 DOI: 10.3390/antiox10091387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 11/16/2022] Open
Abstract
This study aimed to determine the anti-inflammatory and hepatoprotective effects of Lysimachiae Herba ethanolic extract (LHE) in lipopolysaccharide (LPS)-stimulated macrophages and in a LPS/D-galactosamine (GalN)-induced acute hepatitis mouse model. Then, the production of inflammatory mediators and the activation of related pathways in macrophages were explored. Finally, we assessed the serum aminotransferase levels and the expression of inflammatory/antioxidant molecules in liver tissues in mice. Results revealed that LHE treatment significantly inhibited the production of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Molecular data showed that LHE remarkably increased the activities of the antioxidant pathway and inhibited the phosphorylation of mitogen-activated protein kinase as well as the transcriptional activity of nuclear factor-κB induced by LPS. Furthermore, it prevented acute liver damage caused by LPS/D-GalN-induced hepatitis by inhibiting aminotransferase levels and histopathological changes in mice. Moreover, treatment with LHE significantly inhibited the activation of inflammatory pathways and increased the expression of antioxidant molecules including heme oxygenase-1/Nuclear factor erythroid 2-related factor 2. In conclusion, LHE has potent anti-inflammatory and hepatoprotective effects in LPS-stimulated macrophages and the LPS/D-GalN-induced acute hepatitis mouse model. Thus, it can be a treatment option for inflammation, hepatitis, and liver injury.
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Ji D, Zhao Q, Qin Y, Tong H, Wang Q, Yu M, Mao C, Lu T, Qiu J, Jiang C. Germacrone improves liver fibrosis by regulating the PI3K/AKT/mTOR signalling pathway. Cell Biol Int 2021; 45:1866-1875. [PMID: 33835632 DOI: 10.1002/cbin.11607] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 03/22/2021] [Accepted: 04/01/2021] [Indexed: 01/26/2023]
Abstract
Liver fibrosis is a primary threat to public health, owing to limited therapeutic options. Germacrone (GM) has been shown to exert various curative effects against human diseases, including liver injury. The aim of this study was to investigate the pharmacological effects of GM in the pathophysiology of hepatic fibrosis and determine its potential mechanisms of action. A liver fibrosis rat model was established via carbon tetrachloride (CCl4 ) treatment, and LX-2 cells were stimulated with TGF-β1. The effects of GM on liver fibrosis and its relationship with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway were investigated. In the CCl4 fibrosis-induced rat model, GM improved histological damage, inhibited the activity of hepatic α-smooth muscle actin and improved serum alanine aminotransferase and aspartate aminotransferase levels in a dose-dependent manner. GM potently inhibited hepatic stellate cells (HSCs) growth and epithelial-mesenchymal transition (EMT) progression, as reflected by the altered expression of proliferative (Ki-67, PCNA and cleaved caspase-3) and EMT-related (E-cadherin and vimentin) proteins. In TGF-β1-stimulated LX-2 cells, GM significantly inhibited the survival and activation of HSCs and induced cell apoptosis. GM also suppressed the migration ability and reversed the EMT process in HSCs. Following GM treatment, the phosphorylation of the PI3K, AKT and mTOR proteins was reduced in the liver of CCl4 -treated rats and TGF-β1-stimulated LX-2 cells, indicating that GM may attenuate hepatic fibrosis via the PI3K/AKT/mTOR signalling pathway. These outcomes highlight the anti-fibrotic effects of GM and suggest that it is a potential therapeutic agent for the treatment of liver fibrosis.
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Affiliation(s)
- De Ji
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qi Zhao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Chinese Medicinal Resources, Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, China
| | - Yuwen Qin
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Chinese Medicinal Resources, Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, China
| | - Huangjin Tong
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacy, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qiaohan Wang
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengting Yu
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chunqin Mao
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Tulin Lu
- Department of Chinese Medicinal Processing, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinchun Qiu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chengxi Jiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Chinese Medicinal Resources, Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, China
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Wang S, Tang C, Zhao H, Shen P, Lin C, Zhu Y, Han D. Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis. Front Pharmacol 2021; 12:656115. [PMID: 34276360 PMCID: PMC8281251 DOI: 10.3389/fphar.2021.656115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/02/2021] [Indexed: 01/08/2023] Open
Abstract
Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear. Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays. Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation. Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.
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Affiliation(s)
- Siliang Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Cheng Tang
- Department of Respiratory Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Heng Zhao
- Department of Endocrinology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Peiliang Shen
- School of Pharmacy, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chao Lin
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Dan Han
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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From the hive to the table: Nutrition value, digestibility and bioavailability of the dietary phytochemicals present in the bee pollen and bee bread. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.01.042] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Nutraceutical Properties of Polyphenols against Liver Diseases. Nutrients 2020; 12:nu12113517. [PMID: 33203174 PMCID: PMC7697723 DOI: 10.3390/nu12113517] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/08/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
Current food tendencies, suboptimal dietary habits and a sedentary lifestyle are spreading metabolic disorders worldwide. Consequently, the prevalence of liver pathologies is increasing, as it is the main metabolic organ in the body. Chronic liver diseases, with non-alcoholic fatty liver disease (NAFLD) as the main cause, have an alarming prevalence of around 25% worldwide. Otherwise, the consumption of certain drugs leads to an acute liver failure (ALF), with drug-induced liver injury (DILI) as its main cause, or alcoholic liver disease (ALD). Although programs carried out by authorities are focused on improving dietary habits and lifestyle, the long-term compliance of the patient makes them difficult to follow. Thus, the supplementation with certain substances may represent a more easy-to-follow approach for patients. In this context, the consumption of polyphenol-rich food represents an attractive alternative as these compounds have been characterized to be effective in ameliorating liver pathologies. Despite of their structural diversity, certain similar characteristics allow to classify polyphenols in 5 groups: stilbenes, flavonoids, phenolic acids, lignans and curcuminoids. Herein, we have identified the most relevant compounds in each group and characterized their main sources. By this, authorities should encourage the consumption of polyphenol-rich products, as most of them are available in quotidian life, which might reduce the socioeconomical burden of liver diseases.
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Hu Q, Wei S, Wen J, Zhang W, Jiang Y, Qu C, Xiang J, Zhao Y, Peng X, Ma X. Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease. BioData Min 2020; 13:11. [PMID: 32863886 PMCID: PMC7450930 DOI: 10.1186/s13040-020-00224-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver (NAFLD) is a chronic disease worldwide, which poses a huge threat to human health. Xiaochaihu decoction is a well-known traditional Chinese medicine prescription. It has been proven effective in treating NAFLD but its mechanism is still unclear. OBJECTIVE Multiple mechanisms of Xiaochaihu decoction are explored by identifying and connecting potential targets and active ingredients in the treatment of NAFLD. METHODS Active ingredients and related targets of seven herbs were collected from TCMSP database. The related targets of NAFLD were obtained from Genes cards database, TDD and OMIM database. The intersected targets of disease targets and drug targets were input into STRING database to construct protein-protein interaction network. DAVID database was used for GO enrichment analysis and KEGG enrichment analysis. RESULTS After screening and removal of duplicates, a total of 145 active ingredients and 105 potential targets were obtained. PPI network manifested that AKT1, IL6, JUN MAPK8 and STAT3 were the key target proteins. The results of GO enrichment analysis mainly involved cytokine receptor binding, cytokine activity, and heme binding. The results of KEGG analysis suggested that the mechanism mainly involved in AGE-RAGE signaling pathway in diabetic complications, Hepatitis C, fluid shear stress and atherosclerosis. The signaling pathways were further integrated as network manner, including AGE-RAGE signaling pathway in diabetic complications, Fluid shear stress and atherosclerosis, Insulin resistance, HIF-1 signaling pathway, Th17 cell differentiation and IL-17 signaling pathway. The network contained immunity regulation, metabolism regulation and oxidative stress regulation. CONCLUSION Xiaochaihu decoction plays a key role in the treatment of NAFLD with multiple targets and pathways. Immunity regulation, metabolism regulation and oxidative stress regulation consist of the crucial regulation cores in mechanism. GRAPHICAL ABSTRACT Design and workflow of this study.
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Affiliation(s)
- Qichao Hu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Shizhang Wei
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Jianxia Wen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Wenwen Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Yinxiao Jiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Caiyan Qu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Junbao Xiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Yanling Zhao
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, 100039 China
| | - Xi Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Xiao Ma
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
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Xu T, Huang S, Huang Q, Ming Z, Wang M, Li R, Zhao Y. Kaempferol attenuates liver fibrosis by inhibiting activin receptor-like kinase 5. J Cell Mol Med 2019; 23:6403-6410. [PMID: 31273920 PMCID: PMC6714241 DOI: 10.1111/jcmm.14528] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 06/03/2019] [Accepted: 06/14/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a common public health problem. Patients with liver fibrosis are more likely to develop cirrhosis, or hepatocellular carcinoma (HCC) as a more serious consequence. Numerous therapeutic approaches have emerged, but the final clinical outcome remains unsatisfactory. Here, we discovered a flavonoid natural product kaempferol that could dramatically ameliorate liver fibrosis formation. Our data showed that intraperitoneal injection of kaempferol could significantly decrease the necroinflammatory scores and collagen deposition in the liver tissue. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), laminin (LN) and hyaluronic acid (HA) levels were significantly down-regulated in kaempferol treatment group compared with those in the control group. Our study also demonstrated that kaempferol markedly inhibited the synthesis of collagen and activation of hepatic stellate cells (HSCs) both in vivo and in vitro. Furthermore, the results of Western blotting revealed that kaempferol could down-regulate Smad2/3 phosphorylation dose-dependently. These bioactivities of kaempferol may result from its targeted binding to the ATP-binding pocket of activin receptor-like kinase 5 (ALK5), as suggested by the molecular docking study and LanthaScreen Eu kinase binding assay. Above all, our data indicate that kaempferol may prove to be a novel agent for the treatment of liver fibrosis or other fibroproliferative diseases.
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Affiliation(s)
- Taifu Xu
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China.,Department of General Surgery, The Fourth Affiliated Hospital, Guangxi Medical University, Guangxi, China
| | - Shan Huang
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Qianrong Huang
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Zhiyong Ming
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Min Wang
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Rongrui Li
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
| | - Yinnong Zhao
- Department of Hepatobiliary Surgery, Affiliated Guangxi Tumor Hospital, Guangxi Medical University, Guangxi, China
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