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Tiwari A, Shukla A, Kumar Samal P. Evaluation of Anti-Hyperlipidemic and Anti-Atherogenic Activity of Asiatic Acid and Its Effect on Lipid Peroxidation in Hyperlipidemic Rats. J Biochem Mol Toxicol 2025; 39:e70255. [PMID: 40262048 DOI: 10.1002/jbt.70255] [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: 10/16/2024] [Revised: 01/06/2025] [Accepted: 03/31/2025] [Indexed: 04/24/2025]
Abstract
Atherosclerosis is associated with several illnesses, such as coronary heart disease (CHD), peripheral vascular disease, and ischemic cerebrovascular disease. Atherosclerosis development and accompanying complications are predominantly influenced by Hyperlipidemia, which plays a crucial role. These illnesses are the primary cause of most sickness and death among those who are in their middle age or older. The incidence of dyslipidemia among Chinese adults aged 18 and older is 18.6%, indicating that there are around 160 million individuals affected by this condition. This represents the smallest number of patients globally. This analysis was derived from research undertaken in the field of epidemiology. Hence, developing a comprehensive approach for early prevention and treatment of Hyperlipidemia is imperative. The reason for this is that Hyperlipidemia has the potential to deteriorate progressively. Despite the notable progress made in treating Hyperlipidemia with synthetic drugs, there has been a renewed interest in medicinal plants and phytoconstituents known for their therapeutic capabilities. Asiatic acid, primarily present in Centella asiatica (L.), is classified as one of the phytocompounds that can decrease plasma lipids and lipid peroxidation. This plant may include asiaticoside, asiatic acid, and other components. Asiatic acid has the potential to prevent Hyperlipidemia. The aim of our research is to explore the anti-Hyperlipidemic and anti-atherosclerosis potential of Asiatic acid, which will help to explore its potential mechanism of action and a possibility of its usefulness in this regard.
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Affiliation(s)
- Aarti Tiwari
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
| | - Amit Shukla
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
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Zeng W, Li H, Liu S, Luo Z, Chen J, Zhou J. Biosynthesis and bioactivities of triterpenoids from Centella asiatica: Challenges and opportunities. Biotechnol Adv 2025; 80:108541. [PMID: 39978422 DOI: 10.1016/j.biotechadv.2025.108541] [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: 11/26/2024] [Revised: 02/17/2025] [Accepted: 02/17/2025] [Indexed: 02/22/2025]
Abstract
Centella asiatica (L.) Urban is an herbaceous perennial plant that has long been widely used in traditional medicine, due to its diverse wound-healing, neuroprotection, antioxidant and anti-inflammatory properties. The major functional bioactive secondary metabolites are the triterpenoids asiatic acid, madecassic acid, asiaticoside and madecassoside, collectively known as centellosides. Current extraction methods for C. asiatica are unable to meet market demand for extracts and pure functional components. Biotechnological approaches based on synthetic biology and microbial cell factories are a promising alternative. This review summarises the major secondary metabolites and their biological activities, and the biosynthetic pathway of functional triterpenoids in C. asiatica. Biotechnological production of centellosides is also described, including in vitro plant cultures and construction of microbial cell factories. Finally, current challenges and future perspectives for sustainable production of centellosides are discussed, and guidelines for future engineering are proposed.
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Affiliation(s)
- Weizhu Zeng
- Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; Jiangsu Province Engineering Research Center of Food Synthetic Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Hongbiao Li
- Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Shike Liu
- Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China
| | - Zhengshan Luo
- School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China
| | - Jian Chen
- Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; Jiangsu Province Engineering Research Center of Food Synthetic Biotechnology, Jiangnan University, Wuxi 214122, China.
| | - Jingwen Zhou
- Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; School of Biotechnology and Key Laboratory of Industrial Biotechnology of Ministry of Education, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; Jiangsu Province Engineering Research Center of Food Synthetic Biotechnology, Jiangnan University, Wuxi 214122, China.
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Chen M, Song L, Zeng A. Harnessing nature's arsenal: Targeting the TGF-β/Smad Cascade with novel natural anti-fibrotic agents. Fitoterapia 2025; 181:106372. [PMID: 39778722 DOI: 10.1016/j.fitote.2024.106372] [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: 07/15/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Hepatic fibrosis is a wound healing response that leads to excessive deposition of extracellular matrix (ECM) due to sustained liver injury. Hepatic stellate cells (HSCs) are key players in ECM synthesis, with the TGF-β/Smad signaling pathway being central to their activation. Despite advances in understanding the pathogenesis of hepatic fibrosis, effective anti-fibrotic therapies are still lacking. METHODS This treatise conducts a comprehensive review of the literature on the hepatoprotective effects of natural products, including natural medicine compounds, herbal extracts, and polysaccharides. The focus is on their ability to modulate the TGF-β pathway, which is critical in the activation of HSCs and ECM synthesis in hepatic fibrosis. RESULTS The review identifies a variety of natural products that have shown promise in inhibiting the TGF-β/Smad signaling cascade, thereby reducing the activation of HSCs and ECM accumulation. These findings highlight the potential of these natural products as therapeutic agents in the treatment of hepatic fibrosis. CONCLUSIONS The exploration of natural products as modulators of the TGF-β pathway presents a novel avenue for both clinical and preclinical research into hepatic fibrosis. Further investigation is warranted to fully understand the mechanisms of action and to develop these compounds into effective anti-fibrotic pharmaceuticals.
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Affiliation(s)
- Maohua Chen
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine,Chengdu, Sichuan 610041, PR China; Department of Plastic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China. Chengdu, Sichuan 610072, PR China
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
| | - Anqi Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine,Chengdu, Sichuan 610041, PR China.
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Luo K, Geng Y, Oosterhuis D, de Meijer VE, Olinga P. Evaluating the antifibrotic potential of naringenin, asiatic acid, and icariin using murine and human precision-cut liver slices. Physiol Rep 2024; 12:e16136. [PMID: 39501714 PMCID: PMC11538472 DOI: 10.14814/phy2.16136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 11/09/2024] Open
Abstract
Liver fibrosis is an exaggerated wound healing response defined by the excessive accumulation of extracellular matrix. This study investigated the antifibrotic potential of naringenin (NRG), asiatic acid (AA), and icariin (ICA) using murine and human precision-cut liver slices (PCLS). These natural products have shown promise in animal models, but human data are lacking. In this study, PCLS prepared from male mouse liver tissue (mPCLS), healthy human liver tissue (hhPCLS), and cirrhotic human liver tissue (chPCLS) were cultured for 48 h with varying concentrations of the three compounds. Our findings indicate that NRG reduced collagen type 1 (COL1A1) expression in a concentration-dependent manner in both mPCLS and chPCLS, decreased fibrosis-related gene expression, and significantly lowered pro-collagen type 1 (PCOL1A1) levels in the culture medium by 54 ± 21% (mPCLS) and 78 ± 35% (chPCLS). Furthermore, NRG effectively inhibited IL-1β and TNF-α in mPCLS and IL-1β in chPCLS on both gene and protein levels. AA specifically reduced COL1A1 and PCOL1A1 in chPCLS, while ICA selectively downregulated Col1a1 and Acta2 gene expression in mPCLS. This study suggests NRG's potential as an effective antifibrotic agent, warranting further investigation into its mechanisms and therapeutic applications in liver fibrosis.
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Affiliation(s)
- Ke Luo
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Yana Geng
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Dorenda Oosterhuis
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, University of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
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Jung H, Kyun ML, Kwon JI, Kim J, Kim JK, Park D, Lee YB, Moon KS. Amplified response of drug-induced liver fibrosis via immune cell co-culture in a 3D in vitro hepatic fibrosis model. Biomater Sci 2024. [PMID: 39483068 DOI: 10.1039/d4bm00874j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Liver fibrosis, a critical consequence of chronic liver diseases, is characterized by excessive extracellular matrix (ECM) deposition driven by inflammation. This process involves complex interactions among hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells, the liver's resident macrophages. Kupffer cells are essential in initiating fibrosis through the release of pro-inflammatory cytokines that activate HSCs. Although various in vitro liver fibrosis models have been developed, there is a lack of models that include the immune environment of the liver to clarify the influence of immune cells on the progression of liver fibrosis. We developed an in vitro liver fibrosis model by co-culturing hepatocytes (HepaRG), a hepatic stellate cell line (LX-2), and macrophages (differentiated THP-1). The effects of liver fibrosis inducers, transforming growth factor-beta1 (TGF-β1) and methotrexate (MTX), on the inflammatory response and stellate cell activation were evaluated in this triple co-culture model. A triple co-culture condition was developed as a 3D in vitro model using gelatin methacrylate (GelMA), offering a more biomimetic environment and achieving liver fibrosis via immune cell activation associated ECM deposition. In this study, the developed triple co-culture model has the potential to elucidate cell progression roles in liver fibrosis and can be applied in drug screening and toxicity assessments targeting liver fibrosis.
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Affiliation(s)
- Hyewon Jung
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
| | - Mi-Lang Kyun
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
| | - Ji-In Kwon
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Department of Food and Nutrition, University of Hannam, Daejeon, 34054, Republic of Korea
| | - Jeongha Kim
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Department of Food and Nutrition, University of Hannam, Daejeon, 34054, Republic of Korea
| | - Ju-Kang Kim
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
| | - Daeui Park
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
- Center for Biomimetic Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
| | - Yu Bin Lee
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
| | - Kyoung-Sik Moon
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
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Gayathri K, Abhinand P, Gayathri V, Prasanna Lakshmi V, Chamundeeswari D, Jiang L, Tian Z, Malathi N. Computational analysis of phytocompounds in Centella asiatica for its antifibrotic and drug-likeness properties - Herb to drug study. Heliyon 2024; 10:e33762. [PMID: 39027607 PMCID: PMC11255509 DOI: 10.1016/j.heliyon.2024.e33762] [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: 01/29/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/20/2024] Open
Abstract
Oral submucous fibrosis (OSMF) is a potentially malignant disorder with no permanent cure that affects the quality of life due to trismus. Computational pharmacology has accelerated the discovery of drug candidates for the treatment of incurable diseases. The present study aimed to screen the compounds of the miracle herb Centella asiatica with drug-likeness properties based on the absorption, distribution, metabolism, and excretion (ADME) properties. The pharmacological actions of these screened compounds against OSMF were identified by network pharmacology, gene ontology, pathway enrichment analysis, molecular docking, and simulation. Fifteen drug-like ligands were identified after virtual screening viz; asiatic acid, kaempferol, quercetin, luteolin, apigenin, bayogenin, gallic acid, isothankunic acid, madecassic acid, madasiatic acid, arjunolic acid, terminolic acid, catechin, epicatechin, and nobiletin. 850 potential targets were predicted for the ligands, which were analyzed against 354 proteins associated with OSMF. Compound pathway analysis and disease pathway analysis identified 53 common proteins. The GO enrichment analysis identified 472 biological process terms, 76 molecular function terms, and 44 cellular component terms. Pathway enrichment analysis predicted 142 KEGG pathways, 35 Biocarta pathways, and 236 Reactome pathways for the target proteins. The analysis revealed that the herb targets crucial events of fibrosis such as inflammation, oxidative stress, apoptosis, collagen deposition, and epithelial-mesenchymal transition. The common 53 proteins were used for protein-protein interaction (PPI) network analysis, which revealed 4 key proteins interacting with the phytocompounds viz; transforming growth factor-β1 (TGF-β1), mothers against decapentaplegic-3 (SMAD-3), mitogen-activated protein kinase-1 (MAPK-1) and proto-oncogene tyrosine-protein kinase (SRC). Molecular docking revealed that all ligands had a good binding affinity to the target proteins. Bayogenin had the highest binding affinity towards MAPK-1 (-9.7 kcal/mol), followed by isothankunic acid towards SRC protein (-9.3 kcal/mol). Madasiatic acid had the highest binding affinity to SMAD-3 (-7.6 kcal/mol) and TGF-β1 (-7.1 kcal/mol). Molecular dynamics simulation demonstrated stable ligand protein interactions of bayogenin and MAPK complex, isothankunic acid and SRC complex. This in silico study is the first to identify potential phytochemicals present in Centella asiatica and their target molecules, which might be responsible for reversing OSMF.
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Affiliation(s)
- K. Gayathri
- Faculty of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
- Department of Oral Pathology and Microbiology, Sri Ramachandra Dental College, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
| | - P.A. Abhinand
- Department of Bioinformatics, Faculty of Engineering and Technology, Sri Ramachandra Institute of Higher Education & Research, Porur, Chennai, 600116, India
| | - V. Gayathri
- Centre for Toxicology and Developmental Research, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
| | - V. Prasanna Lakshmi
- Department of Bioinformatics, Faculty of Engineering and Technology, Sri Ramachandra Institute of Higher Education & Research, Porur, Chennai, 600116, India
| | - D. Chamundeeswari
- Faculty of Pharmacy, Meenakshi Academy of Higher Education and Research, Chennai, India
| | - Li Jiang
- Department of Oral Pathology, The Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Tian
- Department of Oral Pathology, The Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - N. Malathi
- Department of Oral Pathology and Microbiology, Sri Ramachandra Dental College, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India
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Zhang H, Li Y, Liu M, Guo M, Zhang R, Zhao K, Wu J, Zhao Z, Zhu H, Liu J. Asiatic acid alleviates vascular remodeling in BAPN-induced aortic dissection through inhibiting NF-κB p65/CX3CL1 signaling. FASEB J 2024; 38:e23645. [PMID: 38703043 DOI: 10.1096/fj.202302327r] [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: 11/10/2023] [Revised: 03/30/2024] [Accepted: 04/22/2024] [Indexed: 05/06/2024]
Abstract
Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti-inflammatory properties. Yet, its effects on β-aminopropionitrile (BAPN)-triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN-induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)-macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN-induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA-treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF-κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF-κB p65/CX3CL1 signaling pathway.
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Affiliation(s)
- Heng Zhang
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
| | - Yubin Li
- Department of Vascular Surgery, Linyi Peoples' Hospital, Linyi, Shandong, China
| | - Mingyuan Liu
- Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mingjin Guo
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
| | - Ruipeng Zhang
- Department of Interventional Vascular Surgery, Qingdao Huang Dao District Central Hospital, Binzhou Medical University, Shandong, China
| | - Kaiwen Zhao
- Department of Vascular Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jianlie Wu
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
| | - Zhenyuan Zhao
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
| | - Hongqiao Zhu
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
- Department of Vascular Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Junjun Liu
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
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Macedo C, Costa PC, Rodrigues F. Bioactive compounds from Actinidia arguta fruit as a new strategy to fight glioblastoma. Food Res Int 2024; 175:113770. [PMID: 38129059 DOI: 10.1016/j.foodres.2023.113770] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/10/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023]
Abstract
In recent years, there has been a significant demand for natural products as a mean of disease prevention or as an alternative to conventional medications. The driving force for this change is the growing recognition of the abundant presence of valuable bioactive compounds in natural products. On recent years Actinia arguta fruit, also known as kiwiberry, has attracted a lot of attention from scientific community due to its richness in bioactive compounds, including phenolic compounds, organic acids, vitamins, carotenoids and fiber. These bioactive compounds contribute to the fruit's diverse outstanding biological activities such as antioxidant, anti-inflammatory, neuroprotective, immunomodulatory, and anti-cancer properties. Due to these properties, the fruit may have the potential to be used in the treatment/prevention of various types of cancer, including glioblastoma. Glioblastoma is the most aggressive form of brain cancer, displaying 90 % of recurrence rate within a span of 2 years. Despite the employment of an aggressive approach, the prognosis remains unfavorable, emphasizing the urgent requirement for the development of new effective treatments. The preclinical evidence suggests that kiwiberry has potential impact on glioblastoma by reducing the cancer self-renewal, modulating the signaling pathways involved in the regulation of the cell phenotype and metabolism, and influencing the consolidation of the tumor microenvironment. Even though, challenges such as the imprecise composition and concentration of bioactive compounds, and its low bioavailability after oral administration may be drawbacks to the development of kiwiberry-based treatments, being urgent to ensure the safety and efficacy of kiwiberry for the prevention and treatment of glioblastoma. This review aims to highlight the potential impact of A. arguta bioactive compounds on glioblastoma, providing novel insights into their applicability as complementary or alternative therapies.
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Affiliation(s)
- Catarina Macedo
- REQUIMTE/LAQV, ISEP, Polytechnic of Porto, Rua Dr. António Bernardino de Almeida, 4249-015 Porto, Portugal; REQUIMTE/UCIBIO, MedTech-Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Paulo C Costa
- REQUIMTE/UCIBIO, MedTech-Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Francisca Rodrigues
- REQUIMTE/LAQV, ISEP, Polytechnic of Porto, Rua Dr. António Bernardino de Almeida, 4249-015 Porto, Portugal.
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Liu C, Li S, Zhang C, Jin CH. Recent Advances in Research on Active Compounds Against Hepatic Fibrosis. Curr Med Chem 2024; 31:2571-2628. [PMID: 37497688 DOI: 10.2174/0929867331666230727102016] [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: 12/16/2022] [Revised: 05/14/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Almost all chronic liver diseases cause fibrosis, which can lead to cirrhosis and eventually liver cancer. Liver fibrosis is now considered to be a reversible pathophysiological process and suppression of fibrosis is necessary to prevent liver cancer. At present, no specific drugs have been found that have hepatic anti-fibrotic activity. OBJECTIVE The research progress of anti-hepatic fibrosis compounds in recent ten years was reviewed to provide a reference for the design and development of anti-hepatic fibrosis drugs. METHODS According to the structure of the compounds, they are divided into monocyclic compounds, fused-heterocyclic compounds, and acyclic compounds. RESULTS In this article, the natural products and synthetic compounds with anti-fibrotic activity in recent ten years were reviewed, with emphasis on their pharmacological activity and structure-activity relationship (SAR). CONCLUSION Most of these compounds are natural active products and their derivatives, and there are few researches on synthetic compounds and SAR studies on natural product.
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Affiliation(s)
- Chuang Liu
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Siqi Li
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Changhao Zhang
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
| | - Cheng-Hua Jin
- Key Laboratory of Natural Resources of Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China
- Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin, 133002, China
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Shu G, Lei X, Li G, Zhang T, Wang C, Song A, Yu H, Wang X, Deng X. Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl 4-induced liver fibrosis in mice. Food Funct 2023; 14:10591-10604. [PMID: 37955610 DOI: 10.1039/d3fo03643j] [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: 11/14/2023]
Abstract
Ergothioneine (EGT) is a bioactive compound derived from certain edible mushrooms. The activation of hepatic stellate cells (HSCs) is critically involved in the etiology of liver fibrosis (LF). Here, we report that in LX-2 HSCs, EGT upregulates the expression of Hint1 and Smad7 and suppresses their activation provoked by TGFβ1. The EGT-triggered inhibition of HSC activation is abolished by knocking down the expression of Hint1. Overexpression of Hint1 increases Smad7 and represses TGFβ1-provoked activation of LX-2 HSCs. In silico predictions unveiled that in the promoter region of the human Hint1 gene, there are two conserved cis-acting elements that have the potential to interact with the transcription factor Foxa3 termed hFBS1 and hFBS2, respectively. The knockdown of Foxa3 obviously declined Hint1 expression at both mRNA and protein levels. Transfection of Foxa3 or EGT treatment increased the activity of the luciferase reporter driven by the Hint1 promoter in an hFBS2-dependent manner. The knockdown of Foxa3 eliminated EGT-mediated upregulation of Hint1 promoter activity. Additionally, EGT triggered the nuclear translocation of Foxa3 without obviously affecting its expression level. Molecular docking analysis showed that EGT has the potential to directly interact with the Foxa3 protein. Moreover, Foxa3 played a critical role in EGT-mediated hepatoprotection. EGT modulated the Foxa3/Hint1/Smad7 signaling in mouse primary HSCs and inhibited their activation. The gavage of EGT considerably relieved CCl4-induced LF in mice. Our data provide new insights into the anti-LF activity of EGT. Mechanistically, EGT triggers the nuclear translocation of Foxa3 in HSCs, which promotes Hint1 transcription and subsequently elevates Smad7.
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Affiliation(s)
- Guangwen Shu
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
| | - Xiao Lei
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
| | - Guangqiong Li
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
| | - Tiantian Zhang
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
| | - Chuo Wang
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
| | - Anning Song
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
| | - Huifan Yu
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xiaoming Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Xukun Deng
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei, China.
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11
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Paliwal VM, Kundu S, Kulhari U, Jala A, Ishteyaque S, Borkar RM, Mugale MN, Murty US, Sahu BD. Alternanthera brasiliana L. extract alleviates carbon tetrachloride-induced liver injury and fibrotic changes in mice: Role of matrix metalloproteinases and TGF-β/Smad axis. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:115992. [PMID: 36509261 DOI: 10.1016/j.jep.2022.115992] [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: 07/02/2022] [Revised: 11/20/2022] [Accepted: 11/25/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alternanthera brasiliana L. is a flowering plant belonging to the family Amaranthaceae and is popularly known as "penicillin". It is used in folk medicine to treat infections, coughs, wound healing, and inflammatory diseases. AIM OF THE STUDY We investigated the effect of Alternanthera brasiliana L. leaves hydroalcoholic extract (AB) against oxidative stress, inflammation, and fibrotic changes in an experimental model of carbon tetrachloride (CCl4)-induced liver injury and fibrosis in mice. MATERIALS AND METHODS Thirty-six male Balb/C mice were randomized into five groups: normal control, AB control, CCl4 control, CCl4 + AB-200 mg/kg, and CCl4 + AB-400 mg/kg. In mice, liver injury was induced by intraperitoneal injection of CCl4 (20% in corn oil, 5 ml/kg body weight) thrice a week for six consecutive weeks. AB extract at two doses (200 mg/kg and 400 mg/kg body weight) was administered orally for six consecutive weeks. Liver injury-related serum markers (ALT, AST, ALP), antioxidants (GSH, GST, SOD, and vitamin C), pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-18, ultrasonographic and histological alterations, proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), nuclear factor-κB (p65) (NF-κB), nod-like receptor protein 3 (NLRP3), and TGF-β/Smad signaling were accessed. LC-Q-TOF-MS/MS analysis of AB was performed. RESULTS AB treatment significantly decreased the CCl4-induced rise in serum ALT, AST, and ALP activities and improved the histological alterations. Compared with the CCl4-treated group, treatment with AB significantly restored the hepatic antioxidants and reduced the pro-inflammatory cytokines in the liver. The antioxidant activity of AB may be attributed to its terpenoid constituents, which was confirmed by LC-Q-TOF-MS/MS analysis. The CCl4-induced rise in expression of MMP-2 and MMP-9 and decrease in TIMP-1 were markedly restored in the AB-treated groups. Further findings revealed a significant reduction in the protein levels of phospho-NF-κB (p65), NLRP3, TGF-β, pSmad2/3, collagen I, and α-smooth muscle actin (α-SMA) in the AB treatment groups. CONCLUSIONS The hepatoprotective effect of AB may be attributed to the high content of terpenoid compounds and alleviates liver injury and associated fibrotic changes through modulating MMPs, NF-κB (p65), and the TGF-β/Smad axis.
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Affiliation(s)
- Vinay M Paliwal
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Sourav Kundu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Uttam Kulhari
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Aishwarya Jala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Sharmeen Ishteyaque
- Toxicology & Experimental Medicine, CSIR- Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Roshan M Borkar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Madhav Nilakanth Mugale
- Toxicology & Experimental Medicine, CSIR- Central Drug Research Institute (CDRI), Lucknow, 226 031, India
| | - Upadhyayula Suryanarayana Murty
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India
| | - Bidya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, PIN-781101, Assam, India.
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12
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Zhang YW, Tu LL, Zhang Y, Pan JC, Zheng GL, Yin LN. Liver-targeted delivery of asiatic acid nanostructured lipid carrier for the treatment of liver fibrosis. Drug Deliv 2021; 28:2534-2547. [PMID: 34854788 PMCID: PMC8648005 DOI: 10.1080/10717544.2021.2008054] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Liver fibrosis is a major global health concern. Management of chronic liver disease is severely restricted in clinics due to ineffective treatment approaches. However, a lack of targeted therapy may aggravate this condition. Asiatic acid (AA), a pentacyclic triterpenoid acid, can effectively protect the liver from hepatic disorders. However, the pharmaceutical application of AA is limited by low oral bioavailability and poor targeting efficiency. This study synthesized a novel liver-targeting material from PEG-SA, chemically linked to ursodeoxycholic acid (UA), and utilized it to modify AA nanostructured lipid carriers (UP-AA-NLC) with enhanced targeting and improved efficacy. The formulation of UP-AA-NLC was optimized via the Box–Behnken Experimental Design (BBD) and characterized by size, zeta potential, TEM, DSC, and XRD. Furthermore, in vitro antifibrotic activity and proliferation of AA and NLCs were assessed in LX-2 cells. The addition of UP-AA-NLC significantly stimulated the TGF-beta1-induced expression of α-SMA, FN1, and Col I α1. In vivo near-infrared fluorescence imaging and distribution trials in rats demonstrated that UP-AA-NLC could significantly improve oral absorption and liver-targeting efficiency. Oral UP-AA-NLC greatly alleviated carbon tetrachloride-induced liver injury and fibrosis in rats in a dosage-dependent manner, as reflected by serum biochemical parameters (AST, ALT, and ALB), histopathological features (H&E and Masson staining), and antioxidant activity parameters (SOD and MDA). Also, treatment with UP-AA-NLC lowered liver hydroxyproline levels, demonstrating a reduction of collagen accumulation in the fibrotic liver. Collectively, optimized UP-AA-NLC has potential application prospects in liver-targeted therapy and holds great promise as a drug delivery system for treating liver diseases.
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Affiliation(s)
- Ya-Wen Zhang
- Institute of Materia Medica, Hangzhou Medical College, Hangzhou, China
| | - Ling-Lan Tu
- School of Biological Engineering, Hangzhou Medical College, Hangzhou, China
| | - Yi Zhang
- Institute of Materia Medica, Hangzhou Medical College, Hangzhou, China
| | - Jie-Chao Pan
- Hangzhou Xianju Technology Innovation Co. Ltd, Hangzhou, China
| | - Gao-Li Zheng
- Safety Evaluation Research Center, Hangzhou Medical College, Hangzhou, China
| | - Li-Na Yin
- Institute of Materia Medica, Hangzhou Medical College, Hangzhou, China
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13
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Shu G, Yusuf A, Dai C, Sun H, Deng X. Piperine inhibits AML-12 hepatocyte EMT and LX-2 HSC activation and alleviates mouse liver fibrosis provoked by CCl 4: roles in the activation of the Nrf2 cascade and subsequent suppression of the TGF-β1/Smad axis. Food Funct 2021; 12:11686-11703. [PMID: 34730139 DOI: 10.1039/d1fo02657g] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Piperine (PIP) is an alkaloid derived from peppercorns. Herein, we assessed its effects on hepatocyte EMT and HSC activation in vitro and CCl4-elicited liver fibrosis in mice. Further experiments were performed to unveil the molecular mechanisms underlying the hepatoprotective activity of PIP. We found that PIP inhibited TGF-β1-provoked AML-12 hepatocyte EMT and LX-2 HSC activation. Mechanistically, in AML-12 and LX-2 cells, PIP evoked Nrf2 nuclear translocation and increased transcriptions of Nrf2-responsive antioxidative genes. These events decreased TGF-β1-induced production of ROS. Moreover, PIP increased the expression of Smad7, suppressed phosphorylation and nuclear translocation of Smad2/3, and decreased the transcriptions of Smad2/3-downstream genes. Knockdown of Nrf2 abrogated the protective activity of PIP against TGF-β1. Modulatory effects of PIP on the TGF-β1/Smad cascade were also crippled, which suggested that activation of Nrf2 played critical roles in the regulatory effects of PIP on TGF-β1/Smad signaling. Experiments in vivo unveiled that PIP ameliorated mouse liver fibrosis provoked by CCl4. PIP modulated the intrahepatic contents of the markers of EMT and HSC activation. In mouse livers, PIP activated Nrf2 signaling and reduced Smad2/3-dependent gene transcriptions. Our findings collectively suggested PIP as a new chemical entity with the capacity of alleviating liver fibrosis. The activation of the Nrf2 cascade and subsequent suppression of the TGF-β1/Smad axis are implicated in the hepatoprotective activity of PIP.
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Affiliation(s)
- Guangwen Shu
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, Hubei, China.
| | - Arslan Yusuf
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, Hubei, China.
| | - Chenxi Dai
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, Hubei, China.
| | - Hui Sun
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, Hubei, China.
| | - Xukun Deng
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, Hubei, China.
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14
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Qian XP, Zhang XH, Sun LN, Xing WF, Wang Y, Sun SY, Ma MY, Cheng ZP, Wu ZD, Xing C, Chen BN, Wang YQ. Corosolic acid and its structural analogs: A systematic review of their biological activities and underlying mechanism of action. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 91:153696. [PMID: 34456116 DOI: 10.1016/j.phymed.2021.153696] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/29/2021] [Accepted: 07/31/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. PURPOSE This systematic review aims to summarize the medical applications of CA and its analogues. METHODS A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. 'corosolic acid', 'ursolic acid', 'oleanolic acid', 'maslinic acid', 'asiatic acid', 'betulinic acid', 'extraction', 'pharmacokinetic', 'pharmacological' were used to extract relevant literature. The PRISMA guidelines were followed. RESULTS At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. CONCLUSION CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.
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Affiliation(s)
- Xu-Ping Qian
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Xuzhou Medical University, Xuzhou, China
| | - Xue-Hui Zhang
- Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China
| | - Lu-Ning Sun
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Wei-Fan Xing
- Nanjing Chenxiang Pharmaceutical Research Co. Ltd
| | - Yu Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Shi-Yu Sun
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Meng-Yuan Ma
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Xuzhou Medical University, Xuzhou, China
| | - Zi-Ping Cheng
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China
| | - Zu-Dong Wu
- Nanjing Chenxiang Pharmaceutical Research Co. Ltd
| | - Chen Xing
- Nanjing Chenxiang Pharmaceutical Research Co. Ltd
| | - Bei-Ning Chen
- Department of Chemistry, University of Sheffield, Brookhill, Sheffield S3 7HF, United Kingdom.
| | - Yong-Qing Wang
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China; Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China.
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15
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Liu D, Qian T, Li P, Li W, Sun S, Jiang JJ. Asiatic Acid Improves Extracellular Matrix Remodeling in Vocal Fold Scarring Via SMAD7 Activation. Laryngoscope 2021; 132:1237-1244. [PMID: 34591990 DOI: 10.1002/lary.29884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/10/2021] [Accepted: 09/16/2021] [Indexed: 11/11/2022]
Abstract
OBJECTIVES/HYPOTHESIS Vocal fold (VF) fibroblasts are the central target for developing new strategies for the treatment of VF scarring and fibrosis. Asiatic acid (AA) is a triterpenoid derivate with antifibrotic properties. However, the effect of AA in VF scarring is poorly understood. The objective of this study was to investigate the potential application of AA as a therapeutic treatment in VF scarring. STUDY DESIGN Xxxxx. METHODS The functional expression of SMAD7 was knocked down with recombinant adenoviruses and adeno-associated viruses carrying shRNAs in the in vitro and in vivo models, which were constructed to investigate AA's antifibrotic function. The expression of collagens and SMADs in cultured human and rabbit cell lines and animal models was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry labeling, respectively. Cell migration capacity and contraction in VF fibroblast cell lines were also evaluated. RESULTS AA downregulated the downstream fibrotic activation in a dose-dependent manner. Meanwhile, AA attenuated VF scarring/fibrosis by reducing collagen deposition. Furthermore, the antifibrotic effects of AA were associated with the upregulation of SMAD7. In contrast, knockdown of SMAD7 inhibited the effect of AA on transforming growth factor-beta-1 (TGF-β1) stimulation, which suggests a central role for SMAD7 in AA-induced antifibrotic activities during VF fibrosis. CONCLUSION We concluded that AA, which is a novel therapeutic candidate for preventing VF scarring/fibrosis, might exert its antifibrotic effect via the TGF-β1/SMAD signaling pathway. LEVEL OF EVIDENCE N/A Laryngoscope, 2021.
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Affiliation(s)
- Danling Liu
- ENT Institute and Otorhinolaryngology, Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.,Fudan University School of Basic Medical Sciences, NHC Key Laboratory of Hearing Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, Shanghai, China
| | - Tingting Qian
- ENT Institute and Otorhinolaryngology, Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.,Fudan University School of Basic Medical Sciences, NHC Key Laboratory of Hearing Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, Shanghai, China
| | - Peifan Li
- ENT Institute and Otorhinolaryngology, Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.,Fudan University School of Basic Medical Sciences, NHC Key Laboratory of Hearing Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, Shanghai, China
| | - Wen Li
- ENT Institute and Otorhinolaryngology, Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.,Fudan University School of Basic Medical Sciences, NHC Key Laboratory of Hearing Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, Shanghai, China
| | - Shan Sun
- ENT Institute and Otorhinolaryngology, Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.,Fudan University School of Basic Medical Sciences, NHC Key Laboratory of Hearing Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, Shanghai, China.,Department of Surgery, Division of Otolaryngology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA
| | - Jack J Jiang
- ENT Institute and Otorhinolaryngology, Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.,Fudan University School of Basic Medical Sciences, NHC Key Laboratory of Hearing Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, Shanghai, China
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16
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Chung JYF, Chan MKK, Tang PCT, Chan ASW, Chung JSY, Meng XM, To KF, Lan HY, Leung KT, Tang PMK. AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF-β/Smad signalling in hepatocellular carcinoma. J Cell Mol Med 2021; 25:9805-9813. [PMID: 34514726 PMCID: PMC8505848 DOI: 10.1111/jcmm.16928] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/27/2021] [Accepted: 09/01/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance.
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Affiliation(s)
- Jeff Yat-Fai Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Max Kam-Kwan Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Philip Chiu-Tsun Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Alex Siu-Wing Chan
- Department of Applied Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Justin Shing-Yin Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Xiao-Ming Meng
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Kam-Tong Leung
- Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong
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Actions and Therapeutic Potential of Madecassoside and Other Major Constituents of Centella asiatica: A Review. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11188475] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Centella asiatica is a popular herb well-known for its wide range of therapeutic effects and its use as a folk medicine for many years. Its therapeutic properties have been well correlated with the presence of asiaticoside, madecassoside, asiatic and madecassic acids, the pentacyclic triterpenes. The herb has been extensively known to treat skin conditions; nevertheless, several pre-clinical and clinical studies have scientifically demonstrated its effectiveness in other disorders. Among the active constituents that have been identified in Centella asiatica, madecassoside has been the subject of only a relatively small number of scientific reports. Therefore, this review, while including other major constituents of this plant, focuses on the therapeutic potential, pharmacokinetics and toxicity of madecassoside.
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Patil S. Potential Application of an Aqueous Extract of Tinospora Cordifolia (Thunb.) Miers (Giloy) in Oral Submucous Fibrosis-An In Vitro Study. MATERIALS 2021; 14:ma14123374. [PMID: 34207082 PMCID: PMC8234184 DOI: 10.3390/ma14123374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/10/2021] [Accepted: 06/16/2021] [Indexed: 11/16/2022]
Abstract
The in vitro antifibrotic activity of Tinospora cordifolia (Thunb.) Miers (giloy) was assessed to explore its potential for the management of oral submucous fibrosis. Epithelial cells dissociated from the tissue obtained from histopathologically normal oral mucosa during surgical extraction of third molars were cultured and fibrosis was induced by TGF-β1 in the oral keratinocytes. Cell viability was assessed by MTT and comparative gene expression analysis was carried out in the fibrosis-induced oral keratinocytes treated with various concentrations of Tinospora cordifolia extract (TcE) for matricellular protein-related gene expression. Concentrations of 0.5 µg/mL and 1 µg/mL TcE demonstrated a significant reduction in the expression of CTGF, SERPINE1, COL1A1, FN1, MMP1, MMP2, MMP3, and TIMP2 and an increase in the expression of PLAU, COL3A1, TIMP1, and TIMP3. Although TcE was found to reduce the expression of several fibrotic genes and increase the expression of antifibrotic genes, a varied effect was found, causing increased expression of COL3A1 and decreased expression of TIMP2 on TGF-β1-induced human buccal epithelial cells. However, further studies are warranted to assess the exact mechanism of antifibrotic activity and its clinical applications.
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Affiliation(s)
- Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan 45142, Saudi Arabia
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19
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Fan Y, Yin X. Potential therapeutic targets and biological mechanisms of Centella asiatica on hepatic fibrosis: a study of network pharmacology. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:932. [PMID: 34350247 PMCID: PMC8263891 DOI: 10.21037/atm-21-2253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/26/2021] [Indexed: 11/26/2022]
Abstract
Background Liver fibrosis is a common result of the repair process of various chronic liver diseases. This study is a network pharmacology study on the potential therapeutic targets and biological mechanisms of Centella asiatica for liver fibrosis. Methods The chemical components and potential targets of Centella asiatica were screened through TCMSP, PubChem database, and Swiss Target Prediction database. The DisGeNET and GeneCards databases were used to obtain targets of HF. Venn diagrams were used to find key targets, and draw protein interaction maps. Cytoscape software was used to construct an interaction network map of drug-component-target-disease-pathway. The mechanisms of action were predicted through enrichment analysis and KEGG analysis. Results In total, 6 main components, 297 drug targets, 337 HF targets, and 48 drug-disease targets were obtained in Centella asiatica. The key targets involved IL6, TNF, VEGFA, TP53, IL1β, MMP9, CXCL8, EGFR, JUN, SRC, MMP2, and TGF-β, among others. A total of 1293 entries were obtained by Gene Ontology (GO) enrichment analysis, which mainly involved the regulation of reactive oxygen species metabolic process, the regulation of smooth muscle cells, and the regulation of DNA-binding transcription factor activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment mainly screened 191 pathways, including the MAPK signaling pathway, the relaxin signaling pathway, and the Toll-like receptor signaling pathway, among others. Conclusions Centella asiatica may have a therapeutic effect on HF through multiple targets and pathways. Its mechanism is mainly related to the MAPK signaling pathway and the relaxin signaling pathway.
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Affiliation(s)
- Yuli Fan
- Department of Clinical Infectious Disease, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Yin
- Department of Emergency, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Liu X, Liu W, Ding C, Zhao Y, Chen X, Ling D, Zheng Y, Cheng Z. Taxifolin, Extracted from Waste Larix olgensis Roots, Attenuates CCl 4-Induced Liver Fibrosis by Regulating the PI3K/AKT/mTOR and TGF-β1/Smads Signaling Pathways. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:871-887. [PMID: 33664566 PMCID: PMC7924258 DOI: 10.2147/dddt.s281369] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022]
Abstract
Purpose Taxifolin is a kind of dihydroflavone and is usually used as a food additive and health food for its antioxidant, anti-inflammatory, and anti-tumor activities. The purpose of this research is to probe into the hepatoprotective activity and the molecular mechanism of taxifolin. Materials and Methods The liver fibrosis model was established by intraperitoneal injection of 5 mL/kg body weight of CCl4 (20% CCl4 peanut oil solution), and taxifolin was dissolved with 0.9% physiological saline and administered intragastrically to mice. Results The results indicated that CCl4-induced significantly increased the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice. Histopathological examination showed severe hepatocyte necrosis and hepatic tissue lesion. Immunohistochemical staining and rt-PCR analysis demonstrated that the expressions of inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2), IL-1β, IL-6, and TNF-α were increased. These changes were significantly reversed when treated with taxifolin. In addition, TUNEL staining and Bcl-2/Bax pathway confirmed that taxifolin significantly inhibited hepatocyte apoptosis. Besides, the research confirmed that taxifolin also inhibited the activation of hepatic stellate cells and the production of extracellular matrix (ECM) by regulating PI3K/AKT/mTOR and TGF-β1/Smads pathways. Conclusion Taxifolin inhibited inflammation, and attenuated CCl4-induced oxidative stress and cell apoptosis by regulating PI3K/AKT/mTOR and TGF-β1/Smads pathways, which might in part contributed to taxifolin anti-hepatic fibrosis, further demonstrating that taxifolin may be an efficient hepatoprotective agent.
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Affiliation(s)
- Xinglong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Wencong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China.,State Local Joint Engineering Research Center of Ginseng Breeding and Application, Changchun 130118, People's Republic of China
| | - Chuanbo Ding
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Yingchun Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Xueyan Chen
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Dong Ling
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Yinan Zheng
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, People's Republic of China
| | - Zhiqiang Cheng
- College of Resources and Environment, Jilin Agricultural University, Changchun 130118, People's Republic of China
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Son YJ, Jung DS, Shin JM, Kim M, Yoo G, Nho CW. Yellow loosestrife (Lysimachia vulgaris var. davurica) ameliorates liver fibrosis in db/db mice with methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis. BMC Complement Med Ther 2021; 21:44. [PMID: 33494735 PMCID: PMC7836176 DOI: 10.1186/s12906-021-03212-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 01/10/2021] [Indexed: 12/20/2022] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH), a liver disease caused by a nonalcoholic fatty liver, is increasing in incidence worldwide. Owing to the complexity of its pathogenic mechanisms, there are no therapeutic agents for this disease yet. The ideal drug for NASH needs to concurrently decrease hepatic lipid accumulation and exert anti-inflammatory, antifibrotic, and antioxidative effects in the liver. Because of their multipurpose therapeutic effects, we considered that medicinal herbs are suitable for treating patients with NASH. Methods We determined the efficacy of the alcoholic extract of Lysimachia vulgaris var. davurica (LV), an edible medicinal herb, for NASH treatment. For inducing NASH, C57BLKS/J lar-Leprdb/Leprdb (db/db) male mice were fed with a methionine-choline deficient (MCD) diet ad libitum. After 3 weeks, the LV extract and a positive control (GFT505) were administered to mice by oral gavage for 3 weeks with a continued MCD diet as needed. Results In mice with diet-induced NASH, the LV extract could relieve the disease symptoms; that is, the extract ameliorated hepatic lipid accumulation and also showed antioxidative and anti-inflammatory effects. The LV extract also activated nuclear factor E2-related factor 2 (Nrf2) expression, leading to the upregulation of antioxidants and detoxification signaling. Moreover, the extract presented remarkable efficacy in alleviating liver fibrosis compared with GFT505. This difference was caused by significant LV extract-mediated reduction in the mRNA expression of fibrotic genes like the alpha-smooth muscle actin and collagen type 3 alpha 1. Reduction of fibrotic genes may thus relate with the downregulation of transforming growth factor beta (TGFβ)/Smad signaling by LV extract administration. Conclusions Lipid accumulation and inflammatory responses in the liver were alleviated by feeding LV extract to NASH-induced mice. Moreover, the LV extract strongly prevented liver fibrosis by blocking TGFβ/Smad signaling. Hence, LV showed sufficient potency for use as a therapeutic agent against NASH. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03212-6.
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Affiliation(s)
- Yang-Ju Son
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Da Seul Jung
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Ji Min Shin
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Myungsuk Kim
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Gyhye Yoo
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea
| | - Chu Won Nho
- Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-do, 25451, South Korea.
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Saeed NM, Mansour AM, Allam S. Lycopene induces insulin signaling and alleviates fibrosis in experimental model of non-alcoholic fatty liver disease in rats. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Wu L, Liu Y, Zhao Y, Li M, Guo L. Targeting DUSP7 signaling alleviates hepatic steatosis, inflammation and oxidative stress in high fat diet (HFD)-fed mice via suppression of TAK1. Free Radic Biol Med 2020; 153:140-158. [PMID: 32311490 DOI: 10.1016/j.freeradbiomed.2020.04.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/02/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023]
Abstract
The non-alcoholic fatty liver disease (NAFLD), as a critical liver disease, is still lack of effective treatments because the molecular mechanism revealing the NAFLD pathogenesis remains unclear. Dual specific phosphatase 6 (DUSP7) shows effects on inflammatory response and is a negative feedback mechanism of the mitogen-activated protein kinase (MAPK) superfamily, which are critical factors in regulating NAFLD progression. However, the effects of DUSP7 on hepatic steatosis are still not fully understood. Here, we found that DUSP7 functioned as a negative regulator of NAFLD and in various metabolic disorders. DUSP7 expression was markedly reduced in liver samples from patients with simple hepatic steatosis or non-alcoholic steatohepatitis (NASH), as well as in liver tissues from high fat diet (HFD)-challenged mice or genetically obese (ob/ob) mice. DUSP7 knockout markedly accelerated insulin resistance, glucose intolerance, liver dysfunction, fibrosis and hepatic steatosis in HFD-fed mice. In addition, inflammatory response was significantly exacerbated in HFD-challenged mice with DUSP7 deletion, which was associated with the elevated activation of nuclear factor-κB (NF-κB) and MAPKs signaling pathways. Moreover, oxidative stress was detected in liver of HFD-induced mice, and this phenomenon was aggravated in mice with DUSP7 knockout. Importantly, we demonstrated that DUSP7 physically interacted with transforming growth factor β (TGF-β)-activated kinase (TAK1). DUSP7 deletion considerably promoted the activation of TAK1 in mice after HFD feeding, contributing to the lipid deposition, inflammatory response and reactive oxygen species (ROS) production. Taken together, DUSP7 might function as a protective factor against NAFLD development and metabolic disorder through alleviating dyslipidemia, inflammation and oxidative stress by directly interacting with TAK1 in hepatocytes, which was involved in the suppression of fibrosis. Thus, we may provide an effective strategy for the treatment of hepatic steatosis via targeting DUSP7.
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Affiliation(s)
- Liping Wu
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Yongcun Liu
- Department of Oncology, The First People's Hospital of Xianyang, Xianyang, 712000, China
| | - Yuan Zhao
- Department of Gerontology, Shaanxi Provincial People's Hospita, Xi'an, 710068, China
| | - Meng Li
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ling Guo
- Department of Oncology, The First People's Hospital of Xianyang, Xianyang, 712000, China
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Chen X, Zhang Y, Zhao P, Chen Y, Zhou Y, Wang S, Yin L. Preparation and evaluation of PEGylated asiatic acid nanostructured lipid carriers on anti-fibrosis effects. Drug Dev Ind Pharm 2020; 46:57-69. [DOI: 10.1080/03639045.2019.1701002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- Xiaoxiao Chen
- College of Pharmacy, Zhejiang Chinese Medicine University, Hangzhou, China
- Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou, China
| | - Yawen Zhang
- Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou, China
| | - Pengfei Zhao
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yan Chen
- College of Pharmacy, Zhejiang Chinese Medicine University, Hangzhou, China
- Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou, China
| | - Yunli Zhou
- College of Pharmacy, Zhejiang Chinese Medicine University, Hangzhou, China
- Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou, China
| | - Shenghao Wang
- College of Pharmacy, Zhejiang Chinese Medicine University, Hangzhou, China
- Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou, China
| | - Lina Yin
- Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou, China
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Huang J, Wang H, Huang M, Zong Z, Wu X, Xu J, Lan H, Zheng J, Zhang X, Lee YW, Wei B, Cui L, Li G, Lin S. Asiatic Acid Attenuates Bone Loss by Regulating Osteoclastic Differentiation. Calcif Tissue Int 2019; 105:531-545. [PMID: 31435709 DOI: 10.1007/s00223-019-00596-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 08/07/2019] [Indexed: 01/26/2023]
Abstract
Anti-resorptive agents like bisphosphonates have been widely used for the treatment of postmenopausal osteoporosis. However, their long-term safety and efficacy are still controversial. This study is to examine the effect of Asiatic acid (AA) in osteoclastic differentiation, and further to investigate its effect on bone quality in animals. Effect of AA on osteoclastic differentiation was measured by Tartrate-resistant acid phosphatase stain, bone resorption pit assays, and quantitative real-time polymerase chain reaction. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor-β (TGF-β) signaling were measured by western blot before and after AA treatment. Ovariectomized (OVX) wild-type or Smad7 partially knock out mice were used to evaluate the effects of AA on bone quality by micro-computed tomography, mechanical test, and histomorphometry. Results revealed a dose-dependent inhibitory effect of AA on osteoclastic differentiation. After AA treatment, Smad7 was upregulated, while NF-κB and TGF-β signaling were inhibited during osteoclastic differentiation. Results from animal study revealed that AA prevented bone from further loss caused by OVX and increased the mechanical properties of femur in wild-type animals. AA also prevented bone loss in the Smad7-deficient animals. When combining with OVX in the Smad7-deficient mice, AA could only partially preserve their bone mass. Taken together, we found that AA effectively inhibited osteoclastic differentiation and attenuated osteoporosis, which effects may be through TGF-β and NF-κB pathways. This study reveals that AA may be a potential anti-resorptive agent for postmenopausal osteoporosis.
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Affiliation(s)
- Jianping Huang
- Department of Pharmacology, The Public Service Platform of South China Sea for R&D Marine Biomedicine Resources, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, People's Republic of China
- Department of Stomatology, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Haixing Wang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China
| | - Meiling Huang
- Department of Rehabilitation, The Second People's Hospital of Shenzhen, Shenzhen, People's Republic of China
| | - Zhixian Zong
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Xinyou Wu
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Jianbin Xu
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Huiyao Lan
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, People's Republic of China
| | - Jinchang Zheng
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Xiaoting Zhang
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China
| | - Yuk Wai Lee
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China
| | - Bo Wei
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Liao Cui
- Department of Pharmacology, The Public Service Platform of South China Sea for R&D Marine Biomedicine Resources, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
- The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China.
- The Chinese University of Hong Kong, Prince of Wales Hospital, Room 74038, 5/F, Lui Chee Woo Clinical Science Building, Shatin, NT, Hong Kong, SAR, People's Republic of China.
| | - Sien Lin
- Department of Pharmacology, The Public Service Platform of South China Sea for R&D Marine Biomedicine Resources, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, People's Republic of China.
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, People's Republic of China.
- Minimally Invasive Orthopaedic Lab, 2/F, Clinical Skill Training Building, Affiliated Hospital of Guangdong Medical University, Xiashan, Zhanjiang, 524002, People's Republic of China.
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Zhangdi HJ, Su SB, Wang F, Liang ZY, Yan YD, Qin SY, Jiang HX. Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J Gastroenterol 2019; 25:4835-4849. [PMID: 31543677 PMCID: PMC6737310 DOI: 10.3748/wjg.v25.i33.4835] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/24/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.
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Affiliation(s)
- Han-Jing Zhangdi
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Si-Biao Su
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fei Wang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zi-Yu Liang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Dong Yan
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shan-Yu Qin
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hai-Xing Jiang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Asiatic acid inhibits cardiac fibrosis throughNrf2/HO-1 and TGF-β1/Smads signaling pathways in spontaneous hypertension rats. Int Immunopharmacol 2019; 74:105712. [DOI: 10.1016/j.intimp.2019.105712] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 05/26/2019] [Accepted: 06/18/2019] [Indexed: 01/13/2023]
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Hsu WH, Liao SC, Chyan YJ, Huang KW, Hsu SL, Chen YC, Siu ML, Chang CC, Chung YS, Huang CYF. Graptopetalum paraguayense Inhibits Liver Fibrosis by Blocking TGF-β Signaling In Vivo and In Vitro. Int J Mol Sci 2019; 20:2592. [PMID: 31137784 PMCID: PMC6566198 DOI: 10.3390/ijms20102592] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/16/2019] [Accepted: 05/24/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND AIMS Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, which occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. Activated hepatic perivascular stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines, such as TGF-β1. The inhibition of TGF-β1 function or synthesis is a major target for the development of antifibrotic therapies. Our previous study showed that the water and ethanol extracts of Graptopetalum paraguayense (GP), a Chinese herbal medicine, can prevent dimethylnitrosamine (DMN)-induced hepatic inflammation and fibrosis in rats. METHODS We used rat hepatic stellate HSC-T6 cells and a diethylnitrosamine (DEN)-induced rat liver injury model to test the potential mechanism of GP extracts and its fraction, HH-F3. RESULTS We demonstrated that GP extracts and HH-F3 downregulated the expression levels of extracellular matrix (ECM) proteins and inhibited the proliferation and migration via suppression of the TGF-β1 pathway in rat hepatic stellate HSC-T6 cells. Moreover, the HH-F3 fraction decreased hepatic collagen content and reduced plasma AST, ALT, and γ-GT activities in a DEN-induced rat liver injury model, suggesting that GP/HH-F3 has hepatoprotective effects against DEN-induced liver fibrosis. CONCLUSION These findings indicate that GP/HH-F3 may be a potential therapeutic agent for the treatment of liver fibrosis. The inhibition of TGF-β-mediated fibrogenesis may be a central mechanism by which GP/HH-F3 protects the liver from injury.
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Affiliation(s)
- Wei-Hsiang Hsu
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Se-Chun Liao
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Yau-Jan Chyan
- Development of Natural Resource, Institute of Pharmaceutics, Development Center for Biotechnology (DCB), Taipei 11571, Taiwan.
| | - Kai-Wen Huang
- Department of Surgery & Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei 10051, Taiwan.
| | - Shih-Lan Hsu
- Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
| | - Yi-Chen Chen
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Ma-Li Siu
- Development of Natural Resource, Institute of Pharmaceutics, Development Center for Biotechnology (DCB), Taipei 11571, Taiwan.
| | - Chia-Chuan Chang
- Department of Pharmacy, School of Pharmacy, National Taiwan University, Taipei 10050, Taiwan.
| | - Yuh-Shan Chung
- Development of Natural Resource, Institute of Pharmaceutics, Development Center for Biotechnology (DCB), Taipei 11571, Taiwan.
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
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Ko J, Yeh WJ, Huang WC, Yang HY. Camellia Oleifera Seed Extract Mildly Ameliorates Carbon Tetrachloride-Induced Hepatotoxicity in Rats by Suppressing Inflammation. J Food Sci 2019; 84:1586-1591. [PMID: 31116885 DOI: 10.1111/1750-3841.14645] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 04/05/2019] [Accepted: 04/11/2019] [Indexed: 11/25/2022]
Abstract
The objective of this study was to evaluate the effects of a hot-water extract of defatted Camellia oleifera seeds (CSE) in carbon tetrachloride (CCl4 )-induced liver damage in rats. Wistar rats were separated into four groups including the normal (N) and CCl4 control (C) groups, which are fed a control diet, and the CCL (low-dose CSE) and CCH (high-dose CSE) groups, which are fed with a control diet plus different amount of CSE for an 8-week experimental period. Liver injury in the C, CCL, and CCH groups was induced by injecting CCl4 (i.p.) twice a week from the 5th week to the end of the study. In CCl4 -treated rats, the alanine transaminase (ALT) and aspartate transaminase (AST) activities and malondialdehyde (MDA) concentration significantly increased compared to the normal group. Lower antioxidative enzyme activities and higher proinflammatory cytokines, transforming growth factor-β (TGF-β) and hydroxyproline concentrations in the liver were also found in the CCl4 -treated group compared to the normal group. In contrast, the administration of CSE alleviated the biochemical and histopathological changes including inflammation, liver cell damage, and fibrosis caused by CCl4 in rats. Our results indicated that CSE exhibited hepatoprotective effects in CCl4 -induced liver hepatotoxicity through alleviating hepatic inflammation and fibrosis in rats. PRACTICAL APPLICATION: Camellia oleifera are widely used for edible oil production while the defatted seeds pomace is often discarded. We found that extract of C. oleifera pomace containing phenolic compounds, saponins, and polysaccharides showed protective effects chemical-driven liver damage and, therefore, may be used in further studies and developing functional foods.
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Affiliation(s)
- Jung Ko
- School of Nutrition and Health Sciences, Taipei Medical Univ., 250 Wuxing St, Taipei, 11031, Taiwan
| | - Wan-Ju Yeh
- Dept. of Food Science, College of Agriculture, Tunghai Univ., Taichung, Taiwan
| | - Wen-Chih Huang
- Dept. of Anatomic Pathology, Far Eastern Memorial Hospital, No.21, Sec. 2, Nanya S. Rd., Banciao District, New Taipei City, Taiwan.,College of Nursing, National Taipei Univ. of Nursing and Health Sciences, No.365, Mingte Road, Peitou District, Taipei City, Taiwan
| | - Hsin-Yi Yang
- Dept. of Nutritional Science, Fu Jen Catholic Univ., No.510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City, 24205, Taiwan
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Li X, Liu Y, Yue W, Tan Y, Wang H, Zhang L, Chen J. A Compound of Chinese Herbs Protects against Alcoholic Liver Fibrosis in Rats via the TGF- β1/Smad Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2019; 2019:9121347. [PMID: 31118972 PMCID: PMC6500606 DOI: 10.1155/2019/9121347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/11/2019] [Accepted: 03/31/2019] [Indexed: 02/06/2023]
Abstract
Alcoholic liver fibrosis (ALF) has become a major public health concern owing to its health impacts and the lack of effective treatment strategies for the disease. In this study, we investigated the effect of a compound composed of Chinese herbs Pueraria lobata (Willd.), Salvia miltiorrhiza, Schisandra chinensis, and Silybum marianum on ALF. An ALF model was established. Rats were fed with modified Lieber-Decarli alcohol liquid diet and injected with trace CCl4 at late stage. The rats were then treated with several doses of the compound. Biochemical and fibrosis-relevant parameters were measured from the sera obtained from the rats. Liver tissues were obtained for hematoxylin and eosin and Masson's trichrome staining. Matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 were determined by immunohistochemistry assays. The mRNA and protein expression levels of transforming growth factor-β1 (TGF-β1), Smad2, Smad3, and Smad7 on the livers were also measured by quantitative polymerase chain reaction and Western blot. Results showed that the compound treatment alleviated pathological lesions in the liver, decreased the serum levels of hyaluronan, laminin, and hydroxyproline, and diminished the expression of hepatic tissue inhibitor of metalloproteinase-1. Compound treatment also increased hepatic matrix metalloproteinase-13 expression and inhibited the TGF-β1/Smad signaling pathway. In conclusion, the compound has a protective effect against ALF in rats, and an underlying mechanism is involved in the TGF-β1/Smad signaling pathway.
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Affiliation(s)
- Xiaomeng Li
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Yunjie Liu
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Wuyang Yue
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Yuefeng Tan
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - He Wang
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Lishi Zhang
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
| | - Jinyao Chen
- West China School of Public Health and West China fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, China
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Chen D, Zhang XY, Sun J, Cong QJ, Chen WX, Ahsan HM, Gao J, Qian JJ. Asiatic Acid Protects Dopaminergic Neurons from Neuroinflammation by Suppressing Mitochondrial Ros Production. Biomol Ther (Seoul) 2019; 27:442-449. [PMID: 30971058 PMCID: PMC6720531 DOI: 10.4062/biomolther.2018.188] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/20/2018] [Accepted: 02/20/2019] [Indexed: 11/05/2022] Open
Abstract
This study sought to evaluate the effects of Asiatic acid in LPS-induced BV2 microglia cells and 1-methyl-4-phenyl-pyridine (MPP+)-induced SH-SY5Y cells, to investigate the potential anti-inflammatory mechanisms of Asiatic acid in Parkinsons disease (PD). SH-SY5Y cells were induced using MPP+ to establish as an in vitro model of PD, so that the effects of Asiatic acid on dopaminergic neurons could be examined. The NLRP3 inflammasome was activated in BV2 microglia cells to explore potential mechanisms for the neuroprotective effects of Asiatic acid. We showed that Asiatic acid reduced intracellular production of mitochondrial reactive oxygen species and altered the mitochondrial membrane potential to regulate mitochondrial dysfunction, and suppressed the NLRP3 inflammasome in microglia cells. We additionally found that treatment with Asiatic acid directly improved SH-SY5Y cell viability and mitochondrial dysfunction induced by MPP+. These data demonstrate that Asiatic acid both inhibits the activation of the NLRP3 inflammasome by downregulating mitochondrial reactive oxygen species directly to protect dopaminergic neurons from, and improves mitochondrial dysfunction in SH-SY5Y cells, which were established as a model of Parkinsons disease. Our finding reveals that Asiatic acid protects dopaminergic neurons from neuroinflammation by suppressing NLRP3 inflammasome activation in microglia cells as well as protecting dopaminergic neurons directly. This suggests a promising clinical use of Asiatic acid for PD therapy.
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Affiliation(s)
- Dong Chen
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Xiao-Ya Zhang
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Jing Sun
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qi-Jie Cong
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Wei-Xiong Chen
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Hafiz Muhammad Ahsan
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China.,Department of Pharmacology, Faculty of Pharmacy, University of Central Punjab, Lahore 53000, Pakistan
| | - Jing Gao
- Neurobiology & Mitochondrial Key Laboratory, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Jin-Jun Qian
- Department of Neurology, The Fourth People's Hospital of Zhenjiang, Zhenjiang 212013, China
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Asiatic acid enhances intratumor delivery and the antitumor effect of pegylated liposomal doxorubicin by reducing tumor-stroma collagen. Acta Pharmacol Sin 2019; 40:539-545. [PMID: 29921887 DOI: 10.1038/s41401-018-0038-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 05/03/2018] [Indexed: 02/06/2023]
Abstract
Tumor-targeted drug delivery systems (Tt-DDSs) are proposed as a promising strategy for cancer care. However, the dense collagen network in tumors stroma significantly reduces the penetration and efficacy of Tt-DDS. In order to investigate the effect of asiatic acid (AA) on antitumor effect of pegylated liposomal doxorubicin (PLD) by attenuating stroma-collagen, colon cancer xenograft mice (SW620 cell line) were treated by PLD, AA, or combined regimes, respectively; the collagen levels were estimated by Sirius red/fast green dual staining and immunohistochemistry (IHC) staining; the intratumor exposure of doxorubicin was visualized by ex vivo fluorescence imaging and quantified by HPLC/MS analysis. In addition, the impact of AA on collagen synthesis of fibroblast cell (HFL-1) and cytotoxic effect of PLD and doxorubicin to cancer cell (SW620) were studied in vitro. In the presence of AA (4 mg/kg), the intratumor collagen level was restricted in vivo (reduced by 22%, from 4.14% ± 0.30% to 3.24% ± 0.25%, P = 0.051) and in vitro. Subsequently, doxorubicin level was increased by ~30%. The antitumor activity of PLD was significantly improved (57.3% inhibition of tumor growth and 44% reduction in tumor weight) by AA combination. Additionally, no significant improvement in cytotoxic effect of PLD or doxorubicin induced by AA was observed. In conclusion, AA is a promising sensitizer for tumor treatment by enhancing intratumor drug exposure via stromal remodeling.
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Fan J, Chen Q, Wei L, Zhou X, Wang R, Zhang H. Asiatic acid ameliorates CCl 4-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:3595-3605. [PMID: 30464391 PMCID: PMC6208532 DOI: 10.2147/dddt.s179876] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Purpose Currently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-κB)/IκBα, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways. Methods Rats were induced liver fibrosis by carbon tetrachloride (CCl4) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson’s trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-κB, IκBα, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting. Results Our results showed that AA treatment dramatically ameliorated CCl4-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-κB to inhibit NF-κB/IκBα signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3. Conclusion These results demonstrate that AA ameliorates CCl4-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis.
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Affiliation(s)
- Jie Fan
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China,
| | - Qingshan Chen
- Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Liwen Wei
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China,
| | - Xiaoming Zhou
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Rong Wang
- Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China,
| | - Hai Zhang
- Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China,
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Xu Z, Li T, Li M, Yang L, Xiao R, Liu L, Chi X, Liu D. eRF3b-37 inhibits the TGF-β1-induced activation of hepatic stellate cells by regulating cell proliferation, G0/G1 arrest, apoptosis and migration. Int J Mol Med 2018; 42:3602-3612. [PMID: 30272252 DOI: 10.3892/ijmm.2018.3900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 09/20/2018] [Indexed: 11/05/2022] Open
Abstract
The therapeutic management of liver fibrosis remains an unresolved clinical problem. The activation of hepatic stellate cells (HSCs) serves a pivotal role in the formation of liver fibrosis. In our previous study, matrix‑assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF MS) was employed to identify potential serum markers for liver cirrhosis, such as eukaryotic peptide chain releasing factor 3b polypeptide (eRF3b‑37), which was initially confirmed by our group to serve a protective role in liver tissues in a C‑C motif chemokine ligand 4‑induced liver cirrhosis mouse model. Therefore, eRF3b‑37 was hypothesized to affect the activation state of HSCs, which was determined by the expression of pro‑fibrogenic associated factors in HSCs. In the present study, peptide synthesis technology was employed to elucidate the role of eRF3b‑37 in the expression of pro‑fibrogenic factors induced by transforming growth factor‑β1 (TGF‑β1) in LX‑2 cells that were treated with either control, TGF‑β1 and TGF‑β1+eRF3b‑37. 3‑(4,5‑Dimethyl‑2‑thiazolyl)‑2,5‑diphenyltetrazolium bromide and flow cytometric assays, and fluorescent microscope examinations were performed to evaluate the effects of eRF3b‑37 on proliferation viability, G0/G1 arrest, apoptosis and cell migration. The results of the present study indicated that eRF3b‑37 inhibited the activation of HSCs. The increased mRNA and protein expression of the pro‑fibrogenic factors collagen I, connective tissue growth factor and α‑smooth muscle actin (SMA) stimulated by TGF‑β1 were reduced by eRF3b‑37 via the following mechanisms: i) Inhibiting LX‑2 cell proliferation, leading to G0/G1 cell cycle arrest and inhibition of DNA synthesis by downregulating the mRNA expressions of Cyclin D1 and cyclin dependent kinase‑4, and upregulating the levels of P21; ii) increasing cell apoptosis by upregulating the mRNA level of B‑cell lymphoma-2 (Bcl‑2)‑associated X protein (Bax) and Fas, and downregulating the expression of Bcl‑2; and iii) reducing cell migration by downregulating the mRNA and protein expression of α‑SMA. In addition, eRF3b‑37 is thought to serve a role in HSCs by inhibiting TGF‑β signaling. Therefore, eRF3b‑37 may be a novel therapeutic agent for targeting HSCs for hepatic fibrosis.
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Affiliation(s)
- Zhengrong Xu
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Tao Li
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Man Li
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Lei Yang
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Rudan Xiao
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Li Liu
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Xin Chi
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Dianwu Liu
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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Nagoor Meeran MF, Goyal SN, Suchal K, Sharma C, Patil CR, Ojha SK. Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise. Front Pharmacol 2018; 9:892. [PMID: 30233358 PMCID: PMC6131672 DOI: 10.3389/fphar.2018.00892] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 07/23/2018] [Indexed: 12/16/2022] Open
Abstract
Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.
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Affiliation(s)
- Mohamed Fizur Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | | | - Kapil Suchal
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
| | - Charu Sharma
- Department of Internal Meicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Chandragouda R. Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
| | - Shreesh K. Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Wei G, Xu Q, Liu L, Zhang H, Tan X, Zhang C, Han C, Guo Y, Han G, Zhang C. LY2109761 reduces TGF-β1-induced collagen production and contraction in hypertrophic scar fibroblasts. Arch Dermatol Res 2018; 310:615-623. [PMID: 30046895 DOI: 10.1007/s00403-018-1849-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/13/2018] [Accepted: 07/17/2018] [Indexed: 10/28/2022]
Abstract
Hypertrophic scars (HS) are fibro-hyperproliferative dermal lesions with effusive continuous accumulation of extracellular matrix components, particularly collagen. They usually occur after dermal injury in genetically susceptible individuals and cause both physical and psychological distress for the affected individuals. Transforming growth factor-β1 (TGF-β1) is known to mediate wound healing process by regulating cell differentiation, collagen production and extracellular matrix degradation. The sustained high expression of TGF-β1 is believed to result in the formation of hypertrophic scars. Inhibition of TGF-β1 signaling pathway may represent one of effective strategies for limiting excessive scarring. LY2109761, an orally active TβRI/II kinase dual inhibitor, has been previously reported that it had inhibitory effects on carcinomas and attenuates Radiation-induced pulmonary murine fibrosis. Our results revealed that LY2109761 reduced TGF-β1-induced collagen production and α-smooth muscle actin (α-SMA) expression, and attenuated TGF-β1-induced cell contraction in hypertrophic scar fibroblasts. The data from this study provide evidence supporting the potential use of LY2109761 as a novel treatment for hypertrophic scars.
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Affiliation(s)
- Guo Wei
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Qingqing Xu
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Lin Liu
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Huanhuan Zhang
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Xi Tan
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Chunhong Zhang
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Changyu Han
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China
| | - Yanxia Guo
- Institute of Medical Sciences, the Second Hospital of Shandong University, Jinan, 250033, Shandong, China
| | - Ganwen Han
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China.,Department of Dermatology, Peking University International Hospital, Beijing, 102206, China
| | - Chunmin Zhang
- Department of Dermato-venereology, the Second Hospital of Shandong University, 247 Beiyuan Dajie Street, Jinan, 250033, Shandong, China.
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Asiatic acid attenuates CCl 4 -induced liver fibrosis in rats by regulating the PI3K/AKT/mTOR and Bcl-2/Bax signaling pathways. Int Immunopharmacol 2018; 60:1-8. [DOI: 10.1016/j.intimp.2018.04.016] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 03/21/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
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Lian GY, Wang QM, Tang PMK, Zhou S, Huang XR, Lan HY. Combination of Asiatic Acid and Naringenin Modulates NK Cell Anti-cancer Immunity by Rebalancing Smad3/Smad7 Signaling. Mol Ther 2018; 26:2255-2266. [PMID: 30017880 DOI: 10.1016/j.ymthe.2018.06.016] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 06/13/2018] [Accepted: 06/16/2018] [Indexed: 01/01/2023] Open
Abstract
Transforming growth factor β1 (TGF-β1) plays a promoting role in tumor growth via a mechanism associated with hyperactive Smad3 and suppressed Smad7 signaling in the tumor microenvironment. We report that retrieving the balance between Smad3 and Smad7 signaling with asiatic acid (AA, a Smad7 inducer) and naringenin (NG, a Smad3 inhibitor) effectively inhibited tumor progression in mouse models of invasive melanoma (B16F10) and lung carcinoma (LLC) by promoting natural killer (NK) cell development and cytotoxicity against cancer. Mechanistically, we found that Smad3 physically bound Id2 and IRF2 to suppress NK cell production and NK cell-mediated cytotoxicity against cancer. Treatment with AA and NG greatly inhibited Smad3 translation and phosphorylation while it restored Smad7 expression, and, therefore, it largely promoted NK cell differentiation, maturation, and cytotoxicity against cancer via Id2/IRF2-associated mechanisms. In contrast, silencing Id2 or IRF2 blunted the protective effects of AA and NG on NK cell-dependent anti-cancer activities. Thus, treatment with AA and NG produced an additive effect on inactivating TGF-β1/Smad3 signaling, and, therefore, it suppressed melanoma and lung carcinoma growth by promoting NK cell immunity against cancer via a mechanism associated with Id2 and IRF2.
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Affiliation(s)
- Guang-Yu Lian
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Qing-Ming Wang
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shuang Zhou
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao-Ru Huang
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hui-Yao Lan
- Department of Medicine & Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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The correlation between pulmonary fibrosis and methylation of peripheral Smad3 in cases of pigeon breeder's lung in a Chinese Uygur population. Oncotarget 2018; 8:43104-43113. [PMID: 28562330 PMCID: PMC5522131 DOI: 10.18632/oncotarget.17763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 04/06/2017] [Indexed: 11/25/2022] Open
Abstract
Smad3 is a key protein in the transforming growth factor-beta (TGF-β)/Smad signaling pathway, which is involved in fibrosis in many organs. We investigated the relationship between Smad3 gene methylation and pulmonary fibrosis in pigeon breeder's lung (PBL). Twenty Uygur PBL patients with pulmonary fibrosis in Kashi between October 2015 and March 2016 were enrolled. Twenty PBL-free pigeon breeders and 20 healthy non-pigeon breeders enrolled during the same period constituted the negative and normal control groups, respectively. Participants’ data and peripheral blood samples were collected, and three Smad3 CpG loci were examined. Distributions of CpG_2 and CpG_4 methylation rates did not differ across groups, whereas distributions of CpG_3 methylation rates were significantly different among the three groups. The CpG_3 methylation rate was significantly lower in the patient group than in the negative control group. Smad3 mRNA expression was significantly higher in the patient group than in the negative control group but did not differ between the two control groups. TGF-βlevels were significantly higher in the patient group than in either control group (both P<0.01). Smad3 gene methylation and Smad3 mRNA expression were negatively correlated, with a correlation coefficient of -0.84. The number of pigeons bred during the preceding three months was positively correlated with Smad3 mRNA expression, with a correlation coefficient of 0.77. Smad3 gene hypomethylation might promote pulmonary fibrosis in Uygur PBL patients via increased Smad3 mRNA expression. Smad3 methylation, Smad3 mRNA expression and TGF-β level were correlated with the number of pigeons bred by patients.
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Wang W, Zhang J, Wang X, Wang H, Ren Q, Li Y. Effects of melatonin on diabetic nephropathy rats via Wnt/β-catenin signaling pathway and TGF-β-Smad signaling pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2488-2496. [PMID: 31938361 PMCID: PMC6958295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 03/26/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE This research aimed to explore the protective effect of melatonin on diabetic nephropathy (DN) rats induced by streptozotocin (STZ) and its related signaling pathways. METHODS 100 SPF male Sprague-Dawley rats were divided into four groups: low dose melatonin group, medium dose melatonin group and high dose melatonin group. Rats were 35 mg/kg STZ once to establish a DN model, and control rats were given the corresponding dose of normal saline. A renal function test was used to measure urine protein (UP), blood urea nitrogen (BUN) and serum creatinine (Scr). Pathological changes of renal tissues were obtained by HE staining and Masson staining. Oxidative stress-related indicators were measured in a STZ-induced DN rat. Western blot was used to measure target proteins in renal tissues. RESULTS The levels of UP, BUN and Scr in the model group were significantly higher than control group (P<0.05). After administration of melatonin, each administration group was significantly decreased compared to the model group. Pathological changes of renal tissues in the high dose group were the closest to the control group. After administration of melatonin, activities of SOD, CAT and GSH-Px were significantly increased in the medium dose group and the high dose group (P<0.05), while the activity of MDA was significantly decreased (P<0.05). The expression of Wnt4 and β-catenin in the model group were higher than the control group (P<0.01). When melatonin was given, the expression of Wnt4 and β-catenin in the medium dose group and the high dose group were significantly lower than the model group. Levels of TGF-β1, p-Samd2 and p-Samd3 in the control group were lower than the model group (P<0.05), and were decreased in the medium dose group and the high dose group. CONCLUSIONS Melatonin improves renal function, relieves oxidative stress, and protects the renal tissue via the Wnt/β-catenin signaling pathway and the TGF-β1-Smad2/3 signaling pathway in STZ-induced DN rats.
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Affiliation(s)
- Weichao Wang
- Department of Endocrinology, The Third Hospital of Hebei Medical UniversityChina
| | - Jie Zhang
- Department of Ophthalmology, Shijiazhuang Third HospitalChina
| | | | - Hong Wang
- Department of Geriatrics, Shijiazhuang First HospitalChina
| | - Qiaohua Ren
- Department of Endocrinology, Shijiazhuang First HospitalChina
| | - Yukun Li
- Department of Endocrinology, The Third Hospital of Hebei Medical UniversityChina
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Jing Y, Wang G, Xiao Q, Zhou Y, Wei Y, Gong Z. Antiangiogenic effects of AA-PMe on HUVECs in vitro and zebrafish in vivo. Onco Targets Ther 2018; 11:1871-1884. [PMID: 29670362 PMCID: PMC5894717 DOI: 10.2147/ott.s157747] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA) has demonstrated anticancer properties and we suspect this might be attributable to an effect on angio-genesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-L-proline methyl ester (AA-PMe), has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear. Methods In this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF) present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP) transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline phosphatase assay. VEGFR2 expression in whole embryos following AA-PMe treatment was also determined. Results We found AA-PMe decreased cell viability and inhibited migration and tube formation in a dose-dependent manner in HUVECs. Similarly, AA-PMe disrupted the formation of intersegmental vessels, the dorsal aorta, and the posterior cardinal vein in zebrafish embryos. Both in vitro and in vivo AA-PMe surpassed AA in its ability to block angiogenesis by suppressing VEGF-induced phosphorylation of VEGFR2 and disrupting downstream extracellular regulated protein kinase and AKT signaling. Conclusion For the first time, this study reveals that AA-PMe acts as a potent VEGFR2 kinase inhibitor and exerts powerful antiangiogenic activity, suggesting it to be a promising therapeutic candidate for further research.
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Affiliation(s)
- Yue Jing
- Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China.,Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Gang Wang
- Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Qi Xiao
- Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Yachun Zhou
- Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Yingjie Wei
- Key Laboratory of Oral Drug Delivery System of Chinese Materia Medica of State Administration of Traditional Chinese Medicine, Jiangsu Branch of China Academy of Chinese Medical Science, Nanjing, China
| | - Zhunan Gong
- Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China
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Xia X, Dai C, Yu H, Huang X, Chen A, Tan Y, Wang L. Asiatic acid prevents the development of interstitial lung disease in a hypochlorous acid-induced mouse model of scleroderma. Oncol Lett 2018; 15:8711-8716. [PMID: 29805609 DOI: 10.3892/ol.2018.8412] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 02/15/2018] [Indexed: 12/15/2022] Open
Abstract
Interstitial lung disease is the most common complication of systemic sclerosis (SSc) and is associated with a high rate of mortality. Due to the complex pathogenesis of SSc, the therapies currently available remain limited. In the present study, the effect of asiatic acid (AA) on SSc-associated pulmonary fibrosis (PF) and its association with the transforming growth factor-β1 (TGF-β1)/Smad2/3 signaling pathway were evaluated. A hypochlorous acid (HOCl)-induced model of SSc was used to evaluate the therapeutic effect of AA on PF in SSc, where AA was administered to SSc mice by gavage. PF was alleviated in the AA-treated SSc mice groups when examined under light microscopy. In addition, there was a decrease in histopathological progression and collagen in the lungs. AA significantly reduced expression of type I collagen in the lungs of mice with SSc. It also significantly suppressed α-smooth muscle actin expression, which attenuated the conversion of fibroblasts into muscle fibroblasts. These AA-associated antifibrosis and anti-immune effects were mediated through the significant downregulation of advanced oxidation protein product, E-selectin, and anti-DNA topoisomerase-1 autoantibody levels in the serum. Furthermore, the expression levels of TGF-β1 and the phosphorylated-Smad2/3/Smad2/3 ratios in AA-treated SSc mice were similar to the control. The presence of pulmonary inflammation and fibrosis was confirmed in the HOCl-induced SSc mice and the results demonstrated that selective inhibition of reactive oxygen species prevented PF. By focusing on the classical TGF-β1/Smad2/3 signaling pathway, a mechanism of action of AA was identified to be associated with the inhibition of Smad2/3 activation through negative regulation of Smad2/3 phosphorylation.
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Affiliation(s)
- Xiaoru Xia
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Caijun Dai
- Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Zhejiang University Jinhua Hospital, Jinhua, Zhejiang 321000, P.R. China
| | - Hua Yu
- Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoying Huang
- Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Ali Chen
- Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yingxia Tan
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Liangxing Wang
- Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Asiatic acid ameliorates hepatic ischemia/reperfusion injury in rats via mitochondria-targeted protective mechanism. Toxicol Appl Pharmacol 2018; 338:214-223. [DOI: 10.1016/j.taap.2017.11.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 11/23/2017] [Accepted: 11/27/2017] [Indexed: 01/14/2023]
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Feng J, Chen K, Xia Y, Wu L, Li J, Li S, Wang W, Lu X, Liu T, Guo C. Salidroside ameliorates autophagy and activation of hepatic stellate cells in mice via NF-κB and TGF-β1/Smad3 pathways. Drug Des Devel Ther 2018; 12:1837-1853. [PMID: 29970958 PMCID: PMC6021006 DOI: 10.2147/dddt.s162950] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
PURPOSE Liver fibrosis is commonly seen and a necessary stage in chronic liver disease. The aim of this study was to explore the effect of salidroside on liver fibrosis in mice and its potential mechanisms. MATERIALS AND METHODS Two mouse liver fibrosis models were established by intraperitoneal injection of carbon tetrachloride (CCl4) for 8 weeks and bile duct ligation for 14 days. Salidroside was injected intraperitoneally at doses of 10 and 20 mg/kg once a day. Gene and protein expression levels were determined by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, Western blot, immunohistochemistry, and immunofluorescence. RESULTS Salidroside inhibited the production of extracellular matrix (ECM) and regulated the balance between MMP2 and TIMP1 and, therefore, alleviated liver fibrosis in the two fibrosis models. Salidroside reduced the production of transforming growth factor (TGF)-β1 in Kupffer cells and hepatic stellate cells (HSCs) via the nuclear factor-κB signaling pathway and, therefore, inhibited the activation of HSCs and autophagy by downregulation of the TGF-β1/Smad3 signaling pathway. CONCLUSION Salidroside can effectively attenuate liver fibrosis by inhibiting the activation of HSCs in mice.
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Affiliation(s)
- Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wenwen Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiya Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Correspondence: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang Road, Jing’an, Shanghai 200072, China, Tel +86 21 6630 2535, Fax +86 21 6630 3983, Email
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Hu Z, You P, Xiong S, Gao J, Tang Y, Ye X, Xia Y, Zhang D, Liu Y. Carapax Trionycis extracts inhibit fibrogenesis of activated hepatic stellate cells via TGF-β1/Smad and NFκB signaling. Biomed Pharmacother 2017; 95:11-17. [DOI: 10.1016/j.biopha.2017.08.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 07/17/2017] [Accepted: 08/02/2017] [Indexed: 12/12/2022] Open
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Xuanfei L, Hao C, Zhujun Y, Yanming L, Jianping G. Imidazoline I2 receptor inhibitor idazoxan regulates the progression of hepatic fibrosis via Akt-Nrf2-Smad2/3 signaling pathway. Oncotarget 2017; 8:21015-21030. [PMID: 28423499 PMCID: PMC5400562 DOI: 10.18632/oncotarget.15472] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/07/2017] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is a global health problem and its relationship with imidazoline I2 receptor has not been reported. This study aimed to investigate the effects and underlying mechanisms of imidazoline I2 receptor (I2R) inhibitor idazoxan (IDA) on carbon tetrachloride (CCl4)-induced liver fibrosis. In vivo liver fibrosis in mice was induced by intraperitoneally injections of CCl4 for eight weeks, and in vitro studies were performed on activated LX2 cells treated with transforming growth factor-β (TGF-β). Our results showed that IDA significantly improved liver inflammation, ameliorated hepatic stellate cells activation and reduced collagen accumulation by suppressing the pro-fibrogenic signaling of TGF-β/Smad. Further investigation showed that IDA significantly balanced oxidative stress through improving the expressions and activities of anti-oxidant and detoxifying enzymes and activating Nrf2-the key defender against oxidative stress with anti-fibrotic potentials. Even more impressively, knock out of Nrf2 or suppression of Akt by perifosine (PE) eliminated the anti-oxidant and anti-fibrotic effects of IDA in vivo and in vitro, suggesting that Akt/Nrf2 constitutes a critical component of IDA's protective functions. Taken together, IDA exhibits potent effects against liver fibrosis via Akt-Nrf2-Smad2/3 signaling pathway, which suggests that specifically targeting I2R may be a potentially useful therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Li Xuanfei
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China
| | - Chen Hao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China
| | - Yi Zhujun
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China
| | - Liu Yanming
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430041, Hubei, P. R. China
| | - Gong Jianping
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China
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Xu Y, Yao J, Zou C, Zhang H, Zhang S, Liu J, Ma G, Jiang P, Zhang W. Asiatic acid protects against hepatic ischemia/reperfusion injury by inactivation of Kupffer cells via PPARγ/NLRP3 inflammasome signaling pathway. Oncotarget 2017; 8:86339-86355. [PMID: 29156799 PMCID: PMC5689689 DOI: 10.18632/oncotarget.21151] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 08/21/2017] [Indexed: 01/17/2023] Open
Abstract
Hepatic ischemia/reperfusion (I/R) contributes to major complications in clinical practice affecting perioperative morbidity and mortality. Recent evidence suggests the key role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammaosme activation on the pathogenesis of I/R injury. Asiatic acid (AA) is a pentacyclic triterpene derivative presented with versatile activities, including antioxidant, anti-inflammation and hepatoprotective effects. This study was designed to determine whether AA had potential hepatoprotective benefits against hepatic I/R injury, as well as to unveil the underlying mechanisms involved in the putative effects. Mice subjected to warm hepatic I/R, and Kupffer cells (KCs) or RAW264.7 cells challenged with lipopolysaccharide (LPS)/H2O2, were pretreated with AA. Administration of AA significantly attenuated hepatic histopathological damage, global inflammatory level, apoptotic signaling level, as well as NLRP3 inflammasome activation. These effects were correlated with increased expression of peroxisome proliferator-activated receptor gamma (PPARγ). Conversely, pharmacological inhibition of PPARγ by GW9662 abolished the protective effects of AA on hepatic I/R injury and in turn aggravated NLRP3 inflammasome activation. Activation of NLRP3 inflammasome was most significant in nonparenchymal cells (NPCs). Depletion of KCs by gadolinium chloride (GdCl3) further attenuated the detrimental effects of GW9662 on hepatic I/R as well as NLRP3 activation. In vitro, AA concentration-dependently inhibited LPS/H2O2-induced NLRP3 inflammaosome activation in KCs and RAW264.7 cells. Either GW9662 or genetic knockdown of PPARγ abolished the AA-mediated inactivation of NLRP3 inflammasome. Mechanistically, AA attenuated I/R or LPS/H2O2-induced ROS production and phosphorylation level of JNK, p38 MAPK and IκBα but not ERK, a mechanism dependent on PPARγ. Finally, AA blocked the deleterious effects of LPS/H2O2-induced macrophage activation on hepatocyte viability in vitro, and improved survival in a lethal hepatic I/R injury model in vivo. Collectively, these data suggest that AA is effective in mitigating hepatic I/R injury through attenuation of KCs activation via PPARγ/NLRP3 inflammasome signaling pathway.
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Affiliation(s)
- Ying Xu
- Department of Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jun Yao
- Department of Gastroenterology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Zou
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Heng Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shouliang Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Jun Liu
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Gui Ma
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Wenbo Zhang
- Department of General Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
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Zhang C, Tian X, Zhang K, Li GY, Wang HY, Wang JH. Protective effects of Foeniculum vulgare root bark extract against carbon tetrachloride-induced hepatic fibrosis in mice. World J Gastroenterol 2017; 23:5722-5731. [PMID: 28883697 PMCID: PMC5569286 DOI: 10.3748/wjg.v23.i31.5722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/14/2017] [Accepted: 06/12/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the protective effects of Foeniculum vulgare root bark (FVRB), a traditional Uyghur medicine, against carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice.
METHODS Mice were randomly divided into eight groups (n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected (i.p.) with 0.1% CCl4-olive oil mixture at 10 mL/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB (88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), hexadecenoic acid (HA), laminin (LN), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured. Hematoxylin-eosin (H and E) staining and Masson trichrome (MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β1 (TGF-β1), matrix metalloprotein 9 (MMP-9) and metallopeptidase inhibitor 1 (TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β1 and alpha-smooth muscle actin (α-SMA) protein expression was measured by Western blot.
RESULTS A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β1 and α-SMA detected by Western blot was decreased by FVRB treatment.
CONCLUSION Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.
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Affiliation(s)
- Cai Zhang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Xing Tian
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Ke Zhang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Guo-Yu Li
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Hang-Yu Wang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
| | - Jin-Hui Wang
- School of Pharmacy, Shihezi University, Shihezi 832002, Xinjiang Uygur Autonomous Region, China
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Xiao W, Jiang W, Li K, Hu Y, Li S, Zhou L, Wan R. Protective effect of asiatic acid in an experimental cerulein-induced model of acute pancreatitis in mice. Am J Transl Res 2017; 9:3842-3852. [PMID: 28861174 PMCID: PMC5575197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 07/20/2017] [Indexed: 06/07/2023]
Abstract
Asiatic acid (AA), a triterpenoid derived from the medicinal plant Centella asiatica, is considered to have anti-inflammatory, anti-fibrotic and anti-tumor effects, but its effects in acute pancreatitis (AP) are unknown. Our purpose of this study was to investigate the effects of AA in a mouse model of cerulein-induced pancreatitis. We evaluated AA in an experimental model of AP induced in mice by six hourly intraperitoneal injections of cerulein 50 µg/kg. Mice were pretreated with vehicle or AA 50 mg/kg 2 h before the first cerulein injection. The severity of AP was evaluated histologically and by biochemistry, myeloperoxidase activity, proinflammatory cytokine production, and nuclear factor (NF)-κB activity. Administration of AA significantly reduced the severity of AP, and was associated with reduction of serum amylase and lipase levels, decreased pancreatic histological damage, and decreased myeloperoxidase activity. The serum levels and mRNA expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and NF-κB activity were reduced. AA also significantly improved the in vitro viability of pancreatic acinar cells induced by cholecystokinin (CCK) and suppressed NF-κB activity. AA protected against experimental AP, possibly by reducing production of proinflammatory cytokines via suppression NF-κB activation.
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Affiliation(s)
- Wenqin Xiao
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University301 Yanchang Road, Jingan District, Shanghai 200072, People’s Republic of China
| | - Weiliang Jiang
- Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University100 Haining Road, Hongkou District, Shanghai 200080, People’s Republic of China
| | - Kai Li
- Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University100 Haining Road, Hongkou District, Shanghai 200080, People’s Republic of China
| | - Yangyang Hu
- Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University100 Haining Road, Hongkou District, Shanghai 200080, People’s Republic of China
| | - Sisi Li
- Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University100 Haining Road, Hongkou District, Shanghai 200080, People’s Republic of China
| | - Li Zhou
- Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University100 Haining Road, Hongkou District, Shanghai 200080, People’s Republic of China
| | - Rong Wan
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University301 Yanchang Road, Jingan District, Shanghai 200072, People’s Republic of China
- Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University100 Haining Road, Hongkou District, Shanghai 200080, People’s Republic of China
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Lv H, Qi Z, Wang S, Feng H, Deng X, Ci X. Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure. Front Immunol 2017; 8:785. [PMID: 28736552 PMCID: PMC5500632 DOI: 10.3389/fimmu.2017.00785] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 06/21/2017] [Indexed: 01/17/2023] Open
Abstract
Inflammation and oxidative stress are essential for the pathogenesis of fulminant hepatic failure (FHF). Asiatic acid (AA), which is a pentacyclic triterpene that widely occurs in various vegetables and fruits, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of AA against lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced FHF and the underlying molecular mechanisms. Our findings suggested that AA treatment effectively protected against LPS/d-GalN-induced FHF by lessening the lethality; decreasing the alanine transaminase and aspartate aminotransferase levels, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α production, malondialdehyde formation, myeloperoxidase level and reactive oxygen species generation (i.e., H2O2, NO, and O2−), and increasing the glutathione and superoxide dismutase contents. Moreover, AA treatment significantly inhibited mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway activation via the partial induction of programmed cell death 4 (PDCD4) protein expressions, which are involved in inflammatory responses. Furthermore, AA treatment dramatically induced the expression of the glutamate-cysteine ligase modifier subunit, the glutamate-cysteine ligase catalytic subunit, heme oxygenase-1, and NAD (P) H: quinoneoxidoreductase 1 (NQO1), which are largely dependent on activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) through the induction of AMP-activated protein kinase (AMPK) and glycogen synthase kinase-3β (GSK3β) phosphorylation. Accordingly, AA exhibited protective roles against LPS/d-GalN-induced FHF by inhibiting oxidative stress and inflammation. The underlying mechanism may be associated with the inhibition of MAPK and NF-κB activation via the partial induction of PDCD4 and upregulation of Nrf2 in an AMPK/GSK3β pathway activation-dependent manner.
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Affiliation(s)
- Hongming Lv
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhimin Qi
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Sisi Wang
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Haihua Feng
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xuming Deng
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xinxin Ci
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, China
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