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Lu Z, Liao H, Zhang M, Huang M, Du M, Wang Y, Zhao Z, Shi S, Zhu Z. Tanshinone I inhibits the functions of T lymphocytes and exerts therapeutic effects on delayed-type hypersensitivity reaction via blocking STATs signaling pathways. Eur J Pharmacol 2024; 985:177128. [PMID: 39536856 DOI: 10.1016/j.ejphar.2024.177128] [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: 07/31/2024] [Revised: 10/21/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Delayed-type hypersensitivity (DTH) reactions are a kind of chronic inflammatory diseases initiated by antigens and antigen-specific T cells. Currently, the therapy of DTH reactions is limited by the poor curative effects and serious adverse reactions of existing agents. In this study, we investigated the regulatory effects of tanshinone Ⅰ, a natural compound isolated from Salvia miltiorrhiza, on the functions of multiple immune cells and its therapeutic effects on DNFB-induced DTH reaction, and then explored its immunosuppressive mechanisms. The results showed that tanshinone Ⅰ at 5-20 μM moderately inhibited the activation of macrophages and dendritic cells, but did not weaken the activation of neutrophils. Tanshinone Ⅰ at 1-4 μM intensively suppressed the activation, proliferation, and differentiation of CD4+ and CD8+ T cells, and slightly affected the functions of B cells. Tanshinone Ⅰ administration markedly alleviated the edema, inflammatory response, and the infiltrations of CD4+ T cells, CD8+ T cells, and CD11b+ cells in ear tissues of mice which were induced DTH reactions by DNFB. Transcriptome analysis revealed that tanshinone Ⅰ strongly inhibited CD4+ T cells to express genes involving in cell proliferation, metabolism, activation, and differentiation. Furthermore, immunoblotting analysis showed that tanshinone Ⅰ selectively inhibited the phosphorylation of STAT3 and STAT5 in CD4+ T cells stimulated by anti-CD3e and anti-CD28 antibodies or IL-2. Collectively, tanshinone Ⅰ can strongly inhibit the functions of T lymphocytes, exert therapeutic effects on DTH reaction by blocking STATs signaling pathways, and has potential to be developed into therapeutic drug for DTH reactions.
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Affiliation(s)
- Zihan Lu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Hanjing Liao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Mingliang Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Manjing Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Meng Du
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yaqin Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zongjie Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shepo Shi
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Zhixiang Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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Wang X, Wu L, Luo D, He L, Wang H, Peng B. Mechanism of action of Salvia miltiorrhiza on avascular necrosis of the femoral head determined by integrated network pharmacology and molecular dynamics simulation. Sci Rep 2024; 14:28479. [PMID: 39558045 PMCID: PMC11574184 DOI: 10.1038/s41598-024-79532-7] [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: 07/19/2024] [Accepted: 11/11/2024] [Indexed: 11/20/2024] Open
Abstract
Avascular necrosis of the femoral head (ANFH) is a progressive, multifactorial, and challenging clinical condition that often leads to hip dysfunction and deterioration. The pathogenesis of ANFH is complex, and there is no foolproof treatment strategy. Although some pharmacologic and surgical treatments have been shown to improve ANFH, the associated side effects and poor prognosis are of concern. Therefore, there is an urgent need to explore therapeutic interventions with superior efficacy and safety to improve the quality of life of patients with ANFH. Salvia miltiorrhiza (SM), a traditional Chinese medicine with a long history, is widely used for the treatment of cardiovascular and musculoskeletal diseases due to its multiple pharmacological activities. However, the molecular mechanism of SM for the treatment of ANFH is still unclear. Therefore, this study aimed to explore the potential targets and mechanisms of SM for the treatment of ANFH using network pharmacology and molecular modeling techniques. By searching multiple databases, we screened 52 compounds and 42 common targets involved in ANFH therapy and identified dan-shexinkum d, cryptotanshinone, tanshinone iia, and dihydrotanshinlactone as key compounds. Based on the protein-protein interaction (PPI) network, TP53, AKT1, EGFR, STAT3, BCL2, IL6, and TNF were identified as core targets. Subsequent enrichment analysis revealed that these targets were mainly enriched in the AGE-RAGE, IL-17, and TNF pathways, which were mainly associated with inflammatory responses, apoptosis, and oxidative stress. In addition, molecular docking and 100 nanoseconds molecular dynamics (MD) simulations showed that the bioactive compounds of SM had excellent affinity and binding strength to the core targets. Among them, dan-shexinkum d possessed the lowest binding free energy (-215.874 kcal/mol and - 140.277 kcal/mol, respectively) for AKT1 and EGFR. These results demonstrated the multi-component, multi-target, and multi-pathway intervention mechanism of SM in the treatment of ANFH, which provided theoretical basis and clues for further experimental validation and development of anti-ANFH drugs.
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Affiliation(s)
- Xiangjin Wang
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610000, China
| | - Lijiao Wu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China
| | - Dan Luo
- Basic Medical College of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China
| | - Langyu He
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610000, China
| | - Hao Wang
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610000, China
| | - Bo Peng
- Department of Respiratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China.
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Ding C, Wu Y, Zhan C, Naseem A, Chen L, Li H, Yang B, Liu Y. Research progress on the role and inhibitors of Keap1 signaling pathway in inflammation. Int Immunopharmacol 2024; 141:112853. [PMID: 39159555 DOI: 10.1016/j.intimp.2024.112853] [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: 06/18/2024] [Revised: 07/23/2024] [Accepted: 07/30/2024] [Indexed: 08/21/2024]
Abstract
Inflammation is a protective mechanism against endogenous and exogenous pathogens. It is a typical feature of numerous chronic diseases and their complications. Keap1 is an essential target in oxidative stress and inflammatory diseases. Among them, the Keap1-Nrf2-ARE pathway (including Keap1-Nrf2-HO-1) is the most significant pathway of Keap1 targets, which participates in the control of inflammation in multiple organs (including renal inflammation, lung inflammation, liver inflammation, neuroinflammation, etc.). Identifying new Keap1 inhibitors is crucial for new drug discovery. However, most drugs have specificity issues as they covalently bind to cysteine residues of Keap1, causing off-target effects. Therefore, direct inhibition of Keap1-Nrf2 PPIs is a new research idea. Through non-electrophilic and non-covalent binding, its inhibitors have better specificity and ability to activate Nrf2, and targeting therapy against Keap1-Nrf2 PPIs has become a new method for drug development in chronic diseases. This review summarizes the members and downstream genes of the Keap1-related pathway and their roles in inflammatory disease models. In addition, we summarize all the research progress of anti-inflammatory drugs targeting Keap1 from 2010 to 2024, mainly describing their biological functions, molecular mechanisms of action, and therapeutic roles in inflammatory diseases.
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Affiliation(s)
- Chao Ding
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China.
| | - Ying Wu
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Chaochao Zhan
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China.
| | - Anam Naseem
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
| | - Bingyou Yang
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China.
| | - Yan Liu
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China.
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Stoykova ID, Koycheva IK, Binev BK, Mihaylova LV, Benina MY, Alipieva KI, Georgiev MI. Myconoside and Calceolarioside E Restrain UV-Induced Skin Photoaging by Activating NRF2-Mediated Defense Mechanisms. Int J Mol Sci 2024; 25:2441. [PMID: 38397118 PMCID: PMC10888667 DOI: 10.3390/ijms25042441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced photodamage, mostly counteracting the acute skin effects and only mildly counteracting accelerated aging. Therefore, novel anti-photoaging and photopreventive compounds are a subject of increased scientific interest. Our previous investigations revealed that the endemic plant Haberlea rhodopensis Friv. (HRE) activates the antioxidant defense through an NRF2-mediated mechanism in neutrophiles. In the present study, we aimed to investigate the photoprotective potential of HRE and two of its specialized compounds-the phenylethanoid glycosides myconoside (MYC) and calceolarioside E (CAL)-in UVA/UVB-stimulated human keratinocytes in an in vitro model of photoaging. The obtained data demonstrated that the application of HRE, MYC, and CAL significantly reduced intracellular ROS formation in UVR-exposed HaCaT cells. The NRF2/PGC-1α and TGF-1β/Smad/Wnt signaling pathways were pointed out as having a critical role in the observed CAL- and MYC-induced photoprotective effect. Collectively, CAL is worth further evaluation as a potent natural NRF2 activator and a promising photoprotective agent that leads to the prevention of UVA/UVB-induced premature skin aging.
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Affiliation(s)
- Iva D. Stoykova
- Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria (L.V.M.)
- Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria
| | - Ivanka K. Koycheva
- Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria
| | - Biser K. Binev
- Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria
| | - Liliya V. Mihaylova
- Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria (L.V.M.)
- Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria
| | - Maria Y. Benina
- Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria (L.V.M.)
| | - Kalina I. Alipieva
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Milen I. Georgiev
- Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria (L.V.M.)
- Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000 Plovdiv, Bulgaria
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Ke L, Zhong C, Chen Z, Zheng Z, Li S, Chen B, Wu Q, Yao H. Tanshinone I: Pharmacological activities, molecular mechanisms against diseases and future perspectives. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 110:154632. [PMID: 36608501 DOI: 10.1016/j.phymed.2022.154632] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/20/2022] [Accepted: 12/26/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Tanshinone I (Tan I) is known as one of the important active components in Salvia miltiorrhiza. In recent years, Tan I has received a substantial amount of attention from the research community for various studies being updated and has been shown to possess favorable activities including anti-oxidative stress, regulation of cell autophagy or apoptosis, inhibition of inflammation, etc. PURPOSE: To summarize the investigation progress on the anti-disease efficacy and effect mechanism of Tan I in recent years, and provide perspectives for future study on the active ingredient. METHOD Web of Science and PubMed databases were used to search for articles related to "Tanshinone I" published from 2010 to 2022. Proteins or genes and signaling pathways referring to Tan I against diseases were summarized and classified along with its different therapeutic actions. Protein-protein interaction (PPI) analysis was then performed, followed by molecular docking between proteins with high node degree and Tan I, as well as bioinformactic analysis including GO, KEGG and DO enrichment analysis with the collected proteins or genes. RESULTS Tan I shows multiple therapeutic effects, including protection of the cardiovascular system, anti-cancer, anti-inflammatory, anti-neurodegenerative diseases, etc. The targets (proteins or genes) affected by Tan I against diseases involve Bcl-2, Bid, ITGA2, PPAT, AURKA, VEGF, PI3K, AKT, PRK, JNK, MMP9, ABCG2, CASP3, Cleaved-caspase-3, AMPKα, PARP, etc., and the regulatory pathways refer to Akt/Nrf2, SAPK/JNK, PI3K/Akt/mTOR, JAK/STAT3, ATF-2/ERK, etc. What's more, AKT1, CASP3, and STAT3 were predicted as the key action targets for Tan I by PPI analysis combined with molecular docking, and the potential therapeutic effects mechanisms against diseases were also further predicted by bioinformatics analyses based on the reported targets, providing new insights into the future investigation and helping to facilitate the drug development of Tan I.
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Affiliation(s)
- Liyuan Ke
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China
| | - Chenhui Zhong
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China
| | - Zhijie Chen
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China
| | - Ziyao Zheng
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China
| | - Shaoguang Li
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China
| | - Bing Chen
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China; Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Qiaoyi Wu
- Department of Trauma and Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Chazhong Road, Fuzhou, 350004, China.
| | - Hong Yao
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China; Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, 350122, China.
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6
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Lu M, Lan X, Wu X, Fang X, Zhang Y, Luo H, Gao W, Wu D. Salvia miltiorrhiza in cancer: Potential role in regulating MicroRNAs and epigenetic enzymes. Front Pharmacol 2022; 13:1008222. [PMID: 36172186 PMCID: PMC9512245 DOI: 10.3389/fphar.2022.1008222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 08/24/2022] [Indexed: 11/21/2022] Open
Abstract
MicroRNAs are small non-coding RNAs that play important roles in gene regulation by influencing the translation and longevity of various target mRNAs and the expression of various target genes as well as by modifying histones and DNA methylation of promoter sites. Consequently, when dysregulated, microRNAs are involved in the development and progression of a variety of diseases, including cancer, by affecting cell growth, proliferation, differentiation, migration, and apoptosis. Preparations from the dried root and rhizome of Salvia miltiorrhiza Bge (Lamiaceae), also known as red sage or danshen, are widely used for treating cardiovascular diseases. Accumulating data suggest that certain bioactive constituents of this plant, particularly tanshinones, have broad antitumor effects by interfering with microRNAs and epigenetic enzymes. This paper reviews the evidence for the antineoplastic activities of S. miltiorrhiza constituents by causing or promoting cell cycle arrest, apoptosis, autophagy, epithelial-mesenchymal transition, angiogenesis, and epigenetic changes to provide an outlook on their future roles in the treatment of cancer, both alone and in combination with other modalities.
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Affiliation(s)
- Meng Lu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xintian Lan
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xi Wu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xiaoxue Fang
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yegang Zhang
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Haoming Luo
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Wenyi Gao
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Wenyi Gao, ; Donglu Wu,
| | - Donglu Wu
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
- School of Clinical Medical, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Wenyi Gao, ; Donglu Wu,
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Huang X, Jin L, Deng H, Wu D, Shen QK, Quan ZS, Zhang CH, Guo HY. Research and Development of Natural Product Tanshinone I: Pharmacology, Total Synthesis, and Structure Modifications. Front Pharmacol 2022; 13:920411. [PMID: 35903340 PMCID: PMC9315943 DOI: 10.3389/fphar.2022.920411] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Salvia miltiorrhiza (S. miltiorrhiza), which has been used for thousands of years to treat cardiovascular diseases, is a well-known Chinese medicinal plant. The fat-soluble tanshinones in S. miltiorrhiza are important biologically active ingredients including tanshinone I, tanshinone IIA, dihydrotanshinone, and cryptotanshinone. Tanshinone I, a natural diterpenoid quinone compound widely used in traditional Chinese medicine, has a wide range of biological effects including anti-cancer, antioxidant, neuroprotective, and anti-inflammatory activities. To further improve its potency, water solubility, and bioavailability, tanshinone I can be used as a platform for drug discovery to generate high-quality drug candidates with unique targets and enhanced drug properties. Numerous derivatives of tanshinone I have been developed and have contributed to major advances in the identification of new drugs to treat human cancers and other diseases and in the study of related molecular mechanisms. This review focuses on the structural modification, total synthesis, and pharmacology of tanshinone I. We hope that this review will help understanding the research progress in this field and provide constructive suggestions for further research on tanshinone I.
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Affiliation(s)
| | | | | | | | | | | | | | - Hong-Yan Guo
- *Correspondence: Chang-hao Zhang, ; Hong-Yan Guo,
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Zhang A, Zou Y, Xu Q, Tian S, Wang J, Li Y, Dong R, Zhang L, Jiang J, Wang L, Tao K, Meng Z, Liu Y. Investigation of the Pharmacological Effect and Mechanism of Jinbei Oral Liquid in the Treatment of Idiopathic Pulmonary Fibrosis Using Network Pharmacology and Experimental Validation. Front Pharmacol 2022; 13:919388. [PMID: 35784749 PMCID: PMC9240387 DOI: 10.3389/fphar.2022.919388] [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: 04/13/2022] [Accepted: 05/06/2022] [Indexed: 12/02/2022] Open
Abstract
Overview: Idiopathic pulmonary fibrosis (IPF) is a disease caused by many factors, eventually resulting in lung function failure. Jinbei oral liquid (JBOL) is a traditional Chinese clinical medicine used to treat pulmonary diseases. However, the pharmacological effects and mechanism of the action of JBOL on IPF remain unclear. This study investigated the protective effects and mechanism of the action of JBOL on IPF using network pharmacology analysis, followed by in vivo and in vitro experimental validation. Methods: The components of JBOL and their targets were screened using the TCMSP database. IPF-associated genes were obtained using DisGeNET and Drugbank. The common targets of JBOL and IPF were identified with the STRING database, and a protein-protein interaction (PPI) network was constructed. GO and KEGG analyses were performed. Sprague-Dawley rats were injected with bleomycin (BLM) to establish an IPF model and treated orally with JBOL at doses of 5.4, 10.8, and 21.6 ml/kg. A dose of 54 mg/kg of pirfenidone was used as a control. All rats were treated for 28 successive days. Dynamic pulmonary compliance (Cdyn), minute ventilation volume (MVV), vital capacity (VC), and lung resistance (LR) were used to evaluate the efficacy of JBOL. TGF-β-treated A549 cells were exposed to JBOL, and epithelial-to-mesenchymal transition (EMT) changes were assessed. Western blots were performed. Results: Two hundred seventy-eight compounds and 374 targets were screened, and 103 targets related to IPF were identified. Core targets, including MAPK1 (ERK2), MAPK14 (p38), JUN, IL-6, AKT, and others, were identified by constructing a PPI network. Several pathways were involved, including the MAPK pathway. Experimentally, JBOL increased the levels of the pulmonary function indices (Cdyn, MVV, and VC) in a dose-dependent manner and reduced the RL level in the BLM-treated rats. JBOL increased the epithelial marker E-cadherin and suppressed the mesenchymal marker vimentin expression in the TGF-β-treated A549 cells. The suppression of ERK1/2, JNK, and p38 phosphorylation by JBOL was validated. Conclusion: JBOL had therapeutic effects against IPF by regulating pulmonary function and EMT through a systemic network mechanism, thus supporting the need for future clinical trials of JBOL.
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Affiliation(s)
- Aijun Zhang
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Yixuan Zou
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qingcui Xu
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Shuo Tian
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yilin Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Renchao Dong
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Liangzong Zhang
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Juanjuan Jiang
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Lili Wang
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Kai Tao
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Zhaoqing Meng
- Institute of Chinese Materia Medica, Shandong Hongji-tang Pharmaceutical Group Co., Ltd., Jinan, China
| | - Yanqiu Liu
- Shandong University of Traditional Chinese Medicine, Jinan, China
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Zhao H, Han B, Li X, Sun C, Zhai Y, Li M, Jiang M, Zhang W, Liang Y, Kai G. Salvia miltiorrhiza in Breast Cancer Treatment: A Review of Its Phytochemistry, Derivatives, Nanoparticles, and Potential Mechanisms. Front Pharmacol 2022; 13:872085. [PMID: 35600860 PMCID: PMC9117704 DOI: 10.3389/fphar.2022.872085] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/08/2022] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is one of the most deadly malignancies in women worldwide. Salvia miltiorrhiza, a perennial plant that belongs to the genus Salvia, has long been used in the management of cardiovascular and cerebrovascular diseases. The main anti-breast cancer constituents in S. miltiorrhiza are liposoluble tanshinones including dihydrotanshinone I, tanshinone I, tanshinone IIA, and cryptotanshinone, and water-soluble phenolic acids represented by salvianolic acid A, salvianolic acid B, salvianolic acid C, and rosmarinic acid. These active components have potent efficacy on breast cancer in vitro and in vivo. The mechanisms mainly include induction of apoptosis, autophagy and cell cycle arrest, anti-metastasis, formation of cancer stem cells, and potentiation of antitumor immunity. This review summarized the main bioactive constituents of S. miltiorrhiza and their derivatives or nanoparticles that possess anti-breast cancer activity. Besides, the synergistic combination with other drugs and the underlying molecular mechanisms were also summarized to provide a reference for future research on S. miltiorrhiza for breast cancer treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yi Liang
- *Correspondence: Yi Liang, ; Guoyin Kai,
| | - Guoyin Kai
- *Correspondence: Yi Liang, ; Guoyin Kai,
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10
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Wu M, Yang F, Huang D, Ye C. Tanshinone I attenuates fibrosis in fibrotic kidneys through down-regulation of inhibin beta-A. BMC Complement Med Ther 2022; 22:110. [PMID: 35439976 PMCID: PMC9020026 DOI: 10.1186/s12906-022-03592-3] [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: 11/17/2021] [Accepted: 04/11/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Tanshinone I (Tan-I), an ingredient of Salvia miltiorrhiza, displays protective effects in several disease models. We aim to study the effect of Tan-I on renal fibrosis and explore its underlining mechanism. METHODS Rat renal fibroblasts (NRK-49F) were used as an in vitro model to study the effect of Tan-I. Mouse renal fibrosis model was induced by unilateral ureteral obstruction (UUO) or peritoneally injection of aristolochic acid I (AAI). RESULTS We found that Tan-I dose-dependently inhibited the expression of pro-fibrotic markers in rat renal fibroblasts. Masson staining and Western blotting analysis showed that Tan-I treatment attenuated renal fibrosis in UUO or AAI induced fibrotic kidneys. RNA sequencing analysis identified inhibin beta-A (INHBA), a ligand of TGF-β superfamily, as a downstream target of Tan-I in fibrotic kidneys, which were further verified by qPCR. Western blotting analysis showed that INHBA is up-regulated in UUO or AAI induced fibrotic kidneys and Tan-I reduced the expression of INHBA in fibrotic kidneys. Inhibition of INHBA by Tan-I was further confirmed in rat fibroblasts. Moreover, knockdown of INHBA reduced the expression of pro-fibrotic markers and abolished the ani-fibrotic effect of Tan-I in rat renal fibroblasts. CONCLUSIONS We conclude that Tan-I attenuates fibrosis in fibrotic kidneys through inhibition of INHBA.
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Affiliation(s)
- Ming Wu
- grid.412585.f0000 0004 0604 8558Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, 201203 PR China ,grid.412540.60000 0001 2372 7462TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, Shanghai, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Feng Yang
- grid.412585.f0000 0004 0604 8558Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, 201203 PR China ,grid.412540.60000 0001 2372 7462TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, Shanghai, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Di Huang
- grid.412585.f0000 0004 0604 8558Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, 201203 PR China ,grid.412540.60000 0001 2372 7462TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, Shanghai, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Chaoyang Ye
- grid.412585.f0000 0004 0604 8558Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, 201203 PR China ,grid.412540.60000 0001 2372 7462TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, Shanghai, China ,grid.419897.a0000 0004 0369 313XKey Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
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11
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Wang Y, Zhang YH, Tang YR, Lan J, Huang ZY, Tian W, Huang Q, Peng Y, Gao Y, Hu YQ, Zhang XN. Protective effects of tanshinone Ⅰ against cisplatin-induced nephrotoxicity in mice. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:414-418. [PMID: 35656184 PMCID: PMC9148410 DOI: 10.22038/ijbms.2022.58959.13102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 02/12/2022] [Indexed: 11/23/2022]
Abstract
Objective(s): Cisplatin (CDDP) is a highly effective chemotherapeutic agent, but its clinical application has been limited by nephrotoxicity. Tanshinone Ⅰ (T-I), a phenanthrenequinone compound extracted from the Chinese herb Danshen, has been used to improve circulation and treat cardiovascular diseases. The aim of this study was to investigate the protective effect of T-I on CDDP-induced nephrotoxicity in mice. Materials and Methods: The BALB/c mouse models of nephrotoxicity were established by a single intraperitoneal injection of 20 mg/kg CDDP on the first day of the experiment. Three hours prior to CDDP administration, the mice were dosed with 10 mg/kg and 30 mg/kg T-I for 3 consecutive days intraperitoneally to explore nephroprotection of T-I. Results: Treatment with T-I significantly reduced blood urea nitrogen and creatinine levels in serum observed in CDDP-administered mice, especially at a dose of 30 mg/kg. T-I at 30 mg/kg significantly decreased malondialdehyde levels and increased glutathione levels and the enzymatic activity of catalase in kidney tissue compared to CDDP. Additionally, T-I (30 mg/kg) significantly reversed the CDDP-decreased expression level of superoxide dismutase 2 protein in renal tissue. Histopathological evaluation of the kidneys further confirmed the protective effect of T-I. Conclusion: The findings of this study demonstrate that T-I can protect against CDDP-induced nephrotoxicity through suppression of oxidative stress.
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Affiliation(s)
- Yan Wang
- Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, P.R. China
| | - Yun-Hui Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Yin-Ru Tang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Jie Lan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Zhi-Ying Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China
| | - Wei Tian
- Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, P.R. China
| | - Qian Huang
- Department of Nephrology, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital,Yichang 443003, P.R. China
| | - Yan Peng
- Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, P.R. China
| | - Yuan Gao
- Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, P.R. China
| | - Yue-Qin Hu
- Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, P.R. China
| | - Xue-Nong Zhang
- Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, P.R. China
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12
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Wu XY, Wang T, Hu HX, Zhang K, Zhao Y, Zhao BB, Lou HX, Wang XN, Shen T. The alleviative effect of flavonol-type Nrf2 activator rhamnazin from Physalis alkekengi L. var. franchetii (Mast.) Makino on pulmonary disorders. Phytother Res 2022; 36:1692-1707. [PMID: 35129872 DOI: 10.1002/ptr.7403] [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: 03/20/2021] [Revised: 01/06/2022] [Accepted: 01/08/2022] [Indexed: 11/10/2022]
Abstract
Rhamnazin (RN) is a flavonol isolated from the calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino, which has been used for treating pulmonary diseases in traditional Chinese medicine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a therapeutic target for pulmonary diseases. In the present study, the underlying mechanism and pharmacological effect of RN against pulmonary disorders are investigated. Human lung epithelial Beas-2B cell and RAW 264.7 murine macrophage-based cell models, and a cigarette smoke (CS)-induced pulmonary impairment mice model are adopted for investigation in vitro and in vivo. RN is identified to be an Nrf2 activator, which promotes Nrf2 dissociation from Keap1 via reacting with the Cys151 cysteine residue of Keap1, and suppresses Nrf2 ubiquitination. In addition, RN is able to attenuate toxicant-stimulated oxidative stress and inflammatory response in vitro. Importantly, RN significantly relieves CS-induced oxidative insult and inflammation, and RN-induced inhibition of inflammation is related to inhibition of nuclear transcription factor-κB (NF-κB) and induction of cell autophagy. In conclusion, our data indicate that RN is an activator of the Nrf2 pathway and evidently alleviates pulmonary disorders via restricting NF-κB activation and promoting autophagy. RN is a promising candidate for the therapy of pulmonary disorders.
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Affiliation(s)
- Xue-Yi Wu
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Tian Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Hui-Xin Hu
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Kan Zhang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Yu Zhao
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Bao-Bing Zhao
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Hong-Xiang Lou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Xiao-Ning Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
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13
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Tanshinone I Mitigates Steroid-Induced Osteonecrosis of the Femoral Head and Activates the Nrf2 Signaling Pathway in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2021:8002161. [PMID: 35111227 PMCID: PMC8803433 DOI: 10.1155/2021/8002161] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 11/11/2021] [Indexed: 11/17/2022]
Abstract
Steroid-induced osteonecrosis of the femoral head (SIONFH) is a frequent orthopedic disease caused by long-term or high-dose administration of corticosteroids. Tanshinone I (TsI), a flavonoid compound isolated from Salvia miltiorrhiza Bunge, has been reported to inhibit osteoclastic differentiation in vitro. This study aimed to investigate whether TsI can ameliorate SIONFH. Herein, SIONFH was induced by intraperitoneal injection of 20 μg/kg lipopolysaccharide every 24 h for 2 days, followed by an intramuscular injection of 40 mg/kg methylprednisolone every 24 h for 3 days. Four weeks after the final injection of methylprednisolone, the rats were intraperitoneally administrated with low-dose (5 mg/kg) and high-dose (10 mg/kg) TsI once daily for 4 weeks. Results showed that TsI significantly alleviated osteonecrotic lesions of the femoral heads as determined by micro-CT analysis. Furthermore, TsI increased alkaline phosphatase activity and expressions of osteoblastic markers including osteocalcin, type I collagen, osteopontin, and Runt-related transcription factor 2 and decreased tartrate-resistant acid phosphatase activity and expressions of osteoclastic markers including cathepsin K and acid phosphatase 5. TsI also reduced inflammatory response and oxidative stress and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in the femoral heads. Taken together, our findings show that TsI can relieve SIONFH, indicating that it may be a candidate for preventing SIONFH.
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14
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Yang Y, Wei S, Chu K, Li Q, Zhou Y, Ma Y, Xue L, Tian H, Tao S. Upregulation of autophagy in M2 macrophage by vitamin D alleviates crystalline silica-induced pulmonary inflammatory damage. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 225:112730. [PMID: 34478973 DOI: 10.1016/j.ecoenv.2021.112730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/19/2021] [Accepted: 08/27/2021] [Indexed: 06/13/2023]
Abstract
Crystalline silica (CS) is a universal environmental pollutant, which causes a typical inflammatory lung injury. Vitamin D shows huge potential against particles-induced lung injury, while little known about the molecular mechanism involved in macrophage autophagy. In this study, we aim to identify the protective effects of vitamin D on CS caused lung inflammatory injury and clarify the detail mechanism. After exposure to CS (3 mg/mice in 50 μl PBS), wildtype and Atg7flox/flox Lyz2-cre mice were treated with or without vitamin D3 (40,000 IU/kg). The results indicated that exposure to CS caused an obvious lung injury, manifesting as pathological structural changes, macrophage-dominated inflammatory cell infiltration and increased pro-inflammatory cytokines. Remarkably, these damages were more serious in Atg7flox/flox Lyz2-cre mice. Vitamin D was found to inverse CS-induced inflammatory cell infiltration and restored anti-inflammatory M2 macrophages by inducing autophagy, which attenuated lung injury, as determined by decreased levels of apoptosis and inflammatory response. While, this effects of vitamin D were slashed in Atg7flox/flox Lyz2-cre mice. This study reveals the adverse effect of CS on lung tissue and the protective mechanism of vitamin D involved in M2 macrophages autophagy, which attenuates CS-caused lung injury.
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Affiliation(s)
- Youjing Yang
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Shuhui Wei
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Kaimiao Chu
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Qianmin Li
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Yujia Zhou
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Yu Ma
- Chongqing University Central Hospital & Chongqing Emergency Medical Center, No. 1 Jiankang Road, Yuzhong District, Chongqing 400014, China
| | - Lian Xue
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Hailin Tian
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Shasha Tao
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China; Chongqing University Central Hospital & Chongqing Emergency Medical Center, No. 1 Jiankang Road, Yuzhong District, Chongqing 400014, China.
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15
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Chau B, Witten ML, Cromey D, Chen Y, Lantz RC. Lung developmental is altered after inhalation exposure to various concentrations of calcium arsenate. Toxicol Appl Pharmacol 2021; 432:115754. [PMID: 34634286 PMCID: PMC8572171 DOI: 10.1016/j.taap.2021.115754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/30/2021] [Accepted: 10/05/2021] [Indexed: 11/16/2022]
Abstract
Exposure to dust from active and abandoned mining operations may be a very significant health hazard, especially to sensitive populations. We have previously reported that inhalation of real-world mine tailing dusts during lung development can alter lung function and structure in adult male mice. These real-world dusts contain a mixture of metal(loid)s, including arsenic. To determine whether arsenic in inhaled dust plays a role in altering lung development, we exposed C57Bl/6 mice to a background dust (0 arsenic) or to the background dust containing either 3% or 10% by mass, calcium arsenate. Total level of exposure was kept at 100 μg/m3. Calcium arsenate was selected since arsenate is the predominant species found in mine tailings. We found that inhalation exposure during in utero and postnatal lung development led to significant increases in pulmonary baseline resistance, airway hyper-reactivity, and airway collagen and smooth muscle expression in male C57Bl/6 mice. Responses were dependent on the level of calcium arsenate in the simulated dust. These changes were not associated with increased expression of TGF-β1, a marker of epithelial to mesenchymal transition. However, responses were correlated with decreases in the expression of club cell protein 16 (CC16). Dose-dependent decreases in CC16 expression and increases in collagen around airways was seen for animals exposed in utero only (GD), animals exposed postnatally only (PN) and animals continuously exposed throughout development (GDPN). These data suggest that arsenic inhalation during lung development can decrease CC16 expression leading to functional and structural alterations in the adult lung.
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Affiliation(s)
- Binh Chau
- Department of Cellular & Molecular Medicine, University of Arizona College of Medicine, Tucson, AZ 85719, United States of America.
| | - Mark L Witten
- Phoenix Biometrics, Inc., Tucson, AZ 85710, United States of America
| | - Doug Cromey
- Department of Cellular & Molecular Medicine, University of Arizona College of Medicine, Tucson, AZ 85719, United States of America.
| | - Yin Chen
- Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy, United States of America.
| | - R Clark Lantz
- Department of Cellular & Molecular Medicine, University of Arizona College of Medicine, Tucson, AZ 85719, United States of America.
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16
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Dang YY, Luo H, Li YM, Zhou Y, Luo X, Lin SM, Liu SP, Lee SMY, Li CW, Dai XY. Curcumin prevents As 3+-induced carcinogenesis through regulation of GSK3β/Nrf2. Chin Med 2021; 16:116. [PMID: 34758851 PMCID: PMC8582166 DOI: 10.1186/s13020-021-00527-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/31/2021] [Indexed: 12/19/2022] Open
Abstract
Background Arsenic (As3+) is a carcinogen with considerable environmental and occupational relevancy. Its mechanism of action and methods of prevention remain to be investigated. Previous studies have demonstrated that ROS is responsible for As3+-induced cell transformation, which is considered as the first stage of As3+ carcinogenesis. The NF-E2 p45-related factor-2 (Nrf2) signaling pathway regulates the cellular antioxidant response, and activation of Nrf2 has recently been shown to limit oxidative damage following exposure to As3+ Methods and results In this study, molecular docking was used to virtually screen natural antioxidant chemical databases and identify molecules that interact with the ligand-binding site of Keap1 (PDB code 4L7B). The cell-based assays and molecular docking findings revealed that curcumin has the best inhibitory activity against Keap1-4L7B. Co-immunoprecipitation (Co-IP) results indicated that curcumin is a potent Keap1 Kelch domain-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. The increased activation of Nrf2 and its target antioxidant genes by curcumin could significantly decrease As3+-generated ROS. Moreover, curcumin induced autophagy in As3+-treated BEAS-2B via inducing autophagy by the formation of a p62/LC-3 complex and increasing autophagic flux by promoting transcription factor EB (TFEB) and lysosome-associated membrane protein 1 (LAMP1) expression. Knockdown of Nrf2 abolished curcumin-induced autophagy and downregulated ROS. Further studies showed that inhibition of autophagosome and lysosome fusion with bafilomycin a1 (BafA1) could block curcumin and prevented As3+-induced cell transformation. These results demonstrated that curcumin prevents As3+-induced cell transformation by inducing autophagy via the activation of the Nrf2 signaling pathway in BEAS-2B cells. However, overexpression of Keap-1 showed a constitutively high level of Nrf2 in As3+-transformed BEAS-2B cells (AsT) is Keap1-independent regulation. Overexpression of Nrf2 in AsT demonstrated that curcumin increased ROS levels and induced cell apoptosis via the downregulation of Nrf2. Further studies showed that curcumin decreased the Nrf2 level in AsT by activating GSK-3β to inhibit the activation of PI3K/AKT. Co-IP assay results showed that curcumin promoted the interaction of Nrf2 with the GSK-3β/β-TrCP axis and ubiquitin. Moreover, the inhibition of GSK-3β reversed Nrf2 expression in curcumin-treated AsT, indicating that the decrease in Nrf2 is due to activation of the GSK-3β/β-TrCP ubiquitination pathway. Furthermore, in vitro and in vivo results showed that curcumin induced cell apoptosis, and had anti-angiogenesis and anti-tumorigenesis effects as a result of activating the GSK-3β/β-TrCP ubiquitination pathway and subsequent decrease in Nrf2. Conclusions Taken together, in the first stage, curcumin activated Nrf2, decreased ROS, and induced autophagy in normal cells to prevent As3+-induced cell transformation. In the second stage, curcumin promoted ROS and apoptosis and inhibited angiogenesis via inhibition of constitutive expression of Nrf2 in AsT to prevent tumorigenesis. Our results suggest that antioxidant natural compounds such as curcumin can be evaluated as potential candidates for complementary therapies in the treatment of As3+-induced carcinogenesis.
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Affiliation(s)
- Yuan-Ye Dang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Hua Luo
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Yong-Mei Li
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Yang Zhou
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Xiu Luo
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Shui-Mu Lin
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Shou-Ping Liu
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Simon Ming-Yuen Lee
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Chu-Wen Li
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China.
| | - Xiao-Yan Dai
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, PR China.
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Zhang Z, Costa M. p62 functions as a signal hub in metal carcinogenesis. Semin Cancer Biol 2021; 76:267-278. [PMID: 33894381 PMCID: PMC9161642 DOI: 10.1016/j.semcancer.2021.04.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 04/06/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022]
Abstract
A number of metals are toxic and carcinogenic to humans. Reactive oxygen species (ROS) play an important role in metal carcinogenesis. Oxidative stress acts as the converging point among various stressors with ROS being the main intracellular signal transducer. In metal-transformed cells, persistent expression of p62 and erythroid 2-related factor 2 (Nrf2) result in apoptosis resistance, angiogenesis, inflammatory microenvironment, and metabolic reprogramming, contributing to overall mechanism of metal carcinogenesis. Autophagy, a conserved intracellular process, maintains cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles. In addition to being a substrate of autophagy, p62 is also a crucial molecule in a myriad of cellular functions and in molecular events, which include oxidative stress, inflammation, apoptosis, cell proliferation, metabolic reprogramming, that modulate cell survival and tumor growth. The multiple functions of p62 are appreciated by its ability to interact with several key components involved in various oncogenic pathways. This review summarizes the current knowledge and progress in studies of p62 and metal carcinogenesis with emphasis on oncogenic pathways related to oxidative stress, inflammation, apoptosis, and metabolic reprogramming.
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Affiliation(s)
- Zhuo Zhang
- Department of Environmental Medicine, NYU School of Medicine, 341 East 25th Street, New York, NY 10010, USA
| | - Max Costa
- Department of Environmental Medicine, NYU School of Medicine, 341 East 25th Street, New York, NY 10010, USA.
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Brasil FB, de Almeida FJS, Luckachaki MD, Dall'Oglio EL, de Oliveira MR. Suppression of Mitochondria-Related Bioenergetics Collapse and Redox Impairment by Tanshinone I, a Diterpenoid Found in Salvia miltiorrhiza Bunge (Danshen), in the Human Dopaminergic SH-SY5Y Cell Line Exposed to Chlorpyrifos. Neurotox Res 2021; 39:1495-1510. [PMID: 34351569 DOI: 10.1007/s12640-021-00400-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/24/2021] [Accepted: 07/27/2021] [Indexed: 01/01/2023]
Abstract
Tanshinone I (T-I, C18H12O3) is a diterpene found in Salvia miltiorrhiza Bunge (Danshen) and promotes cytoprotection in several experimental models. Chlorpyrifos (CPF) is an agrochemical that causes bioenergetics failure, redox impairment, inflammation, and cell death in animal tissues. Here, we investigated whether T-I would be able to prevent the consequences resulting from the exposure of the human dopaminergic SH-SY5Y cells to CPF. We found that a pretreatment with T-I at 2.5 µM for 2 h suppressed lipid peroxidation and protein carbonylation and nitration on the membranes of mitochondria extracted from the CPF-treated cells. Also, T-I reduced the production of radical superoxide (O2-•) by the mitochondria of the CPF-challenged cells. The production of nitric oxide (NO•) and hydrogen peroxide (H2O2) was also decreased by T-I in the cells exposed to CPF. The CPF-induced decrease in the activity of the complexes I-III, II-III, and V was abolished by a pretreatment with T-I. Loss of mitochondrial membrane potential (ΔΨm) and reduction in the production of adenosine triphosphate (ATP) were also prevented by T-I in the CPF-treated cells. T-I also induced anti-inflammatory effects in the CPF-treated cells by decreasing the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and the activity of the nuclear factor-κB (NF-κB). Inhibition of heme oxygenase-1 (HO-1) or silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) blocked the T-I-promoted mitochondrial protection and anti-inflammatory action. Overall, T-I depended on the Nrf2/HO-1 axis to prevent the deleterious effects caused by CPF in this experimental model.
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Affiliation(s)
- Flávia Bittencourt Brasil
- Department of Natural Sciences, Rio das Ostras Universitary Campus - Fluminense Federal University (UFF), Rio de Janeiro, Brazil
| | - Fhelipe Jolner Souza de Almeida
- Graduate Program in Health Sciences (PPGCS), Federal University of Mato Grosso (UFMT), Cuiaba, MT, Brazil
- Research Group in Neurochemistry and Neurobiology of Bioactive Molecules, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, Cuiaba, MT, 2367, 78060-900, Brazil
| | - Matheus Dargesso Luckachaki
- Research Group in Neurochemistry and Neurobiology of Bioactive Molecules, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, Cuiaba, MT, 2367, 78060-900, Brazil
| | - Evandro Luiz Dall'Oglio
- Research Group in Neurochemistry and Neurobiology of Bioactive Molecules, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, Cuiaba, MT, 2367, 78060-900, Brazil
| | - Marcos Roberto de Oliveira
- Research Group in Neurochemistry and Neurobiology of Bioactive Molecules, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, Cuiaba, MT, 2367, 78060-900, Brazil.
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Jiang M, Chen H, Liu J, Du Q, Lu S, Liu C. Genome-wide identification and functional characterization of natural antisense transcripts in Salvia miltiorrhiza. Sci Rep 2021; 11:4769. [PMID: 33637790 PMCID: PMC7910453 DOI: 10.1038/s41598-021-83520-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 01/29/2021] [Indexed: 01/01/2023] Open
Abstract
Salvia miltiorrhiza is one of the most widely used traditional medicines. Natural antisense transcripts (NATs) are a class of long noncoding RNAs that can regulate gene expression. Here, we identified 812 NATs, including 168 cis-NATs and 644 trans-NATs from twelve root, flower, and leaf samples of S. miltiorrhiza using RNA-seq. The expression profiles for 41 of 50 NATs and their sense transcripts (STs) obtained from RNA-Seq were validated using qRT-PCR. The expression profiles of 17 NATs positively correlated with their STs. GO and KEGG pathway analyses mapped the STs for cis-NATs to pathways for biosynthesis of secondary metabolites. We characterized four NATs in detail, including NAT0001, NAT0002, NAT0004, and NAT00023. Their STs are kaurene synthase-like 1 and the homologs of UDP-glucose flavonoid 3-O-glucosyltransferase 6, UDP-glycosyltransferase 90A1, and beta-glucosidase 40, respectively. The first gene is involved in the biosynthesis of bioactive tanshinones, the next two are involved in anthocyanin biosynthesis, whereas the last is involved in phenylpropanoid biosynthesis. Besides, we found seven STs that are potential targets of miRNAs. And we found two miRNAs including miR156a and miR7208, might originate from NATs, NAT0112 and NAT0086. The results suggest that S. miltiorrhiza NATs might interact with STs, produce miRNAs, and be regulated by miRNAs. They potentially play significant regulatory roles in the biosynthesis of bioactive compounds.
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Affiliation(s)
- Mei Jiang
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine From Ministry of Education, Engineering Research Center of Chinese Medicine Resources From Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, People's Republic of China
| | - Haimei Chen
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine From Ministry of Education, Engineering Research Center of Chinese Medicine Resources From Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, People's Republic of China
| | - Jingting Liu
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine From Ministry of Education, Engineering Research Center of Chinese Medicine Resources From Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, People's Republic of China
| | - Qing Du
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine From Ministry of Education, Engineering Research Center of Chinese Medicine Resources From Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, People's Republic of China.,College of Pharmacy, Key Laboratory of Plant Resources of Qinghai-Tibet Plateau in Chemical Research, Qinghai Nationalities University, Xining, 810007, Qinghai, People's Republic of China
| | - Shanfa Lu
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine From Ministry of Education, Engineering Research Center of Chinese Medicine Resources From Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, People's Republic of China.
| | - Chang Liu
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine From Ministry of Education, Engineering Research Center of Chinese Medicine Resources From Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, People's Republic of China.
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20
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Tao S, Yang Y, Li J, Wang H, Ma Y. Bixin Attenuates High-Fat Diet-Caused Liver Steatosis and Inflammatory Injury through Nrf2/PPAR α Signals. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6610124. [PMID: 33603948 PMCID: PMC7872754 DOI: 10.1155/2021/6610124] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/29/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is the most common liver disease worldwide. Hepatic steatosis and oxidative stress are the main characteristics of NAFLD (nonalcoholic fatty liver disease), which also affect its prognosis. Bixin acts as novel Nrf2 (NF-E2 p45-related factor 2) activator with the cytoprotection against oxidative stress and inflammation; this study mainly focused on the mechanism of Nrf2 activation by bixin and explored its potential feasibilities in long-term high-fat diet- (HFD-) caused hepatic steatosis and inflammatory response in vitro and in vivo. Bixin was found to activate Nrf2 signals by the modification of critical Keap1 (Kelch-like ECH-associated protein 1) cystine and competitive interaction with Keap1 with upregulating P62 mRNA and protein expression. In human liver cells exposed to FFA (free fatty acid), bixin displayed a pronounced cytoprotective activity with upregulation of Nrf2-mediated gene expression, such as PPARα and its targets related with fatty acid oxidation. In HFD-fed mice, systemic administration of bixin attenuated lipid accumulation, decreased oxidant inflammatory damage in the liver, and reduced circulating lipid levels through Nrf2. Different from most of other established inducers, bixin activated Nrf2 signals through two different mechanisms with safe administration for protection of oxidant inflammatory damage and attenuation of lipid accumulation in the in vivo long-term HFD-fed mice. Bixin represents a prototype Nrf2 activator that displays cytoprotective activity upon system administration targeting hepatic steatosis and oxidant inflammation originating from long-term HFD-fed mice. And bixin-based Nrf2-directed systemic intervention may also provide therapeutic benefit in protecting other organs in the process of metabolic syndrome.
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Affiliation(s)
- Shasha Tao
- Chongqing University Central Hospital & Chongqing Emergency Medical Center, No. 1 Jiankang Road, Yuzhong District, Chongqing 400014, China
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Youjing Yang
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, China
| | - Jianzhong Li
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Hongyan Wang
- Chongqing University Central Hospital & Chongqing Emergency Medical Center, No. 1 Jiankang Road, Yuzhong District, Chongqing 400014, China
| | - Yu Ma
- Chongqing University Central Hospital & Chongqing Emergency Medical Center, No. 1 Jiankang Road, Yuzhong District, Chongqing 400014, China
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21
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Zeng H, Wang L, Zhang J, Pan T, Yu Y, Lu J, Zhou P, Yang H, Li P. Activated PKB/GSK-3 β synergizes with PKC- δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I. Acta Pharm Sin B 2021; 11:71-88. [PMID: 33532181 PMCID: PMC7838031 DOI: 10.1016/j.apsb.2020.09.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/30/2020] [Accepted: 08/31/2020] [Indexed: 12/16/2022] Open
Abstract
Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3β signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3β/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale.
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Affiliation(s)
| | | | | | | | | | | | | | - Hua Yang
- Corresponding authors. Tel./fax: +86 25 83271379.
| | - Ping Li
- Corresponding authors. Tel./fax: +86 25 83271379.
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22
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Li J, Yang Y, Wei S, Chen L, Xue L, Tian H, Tao S. Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation. Front Cell Dev Biol 2020; 8:576988. [PMID: 33313043 PMCID: PMC7704619 DOI: 10.3389/fcell.2020.576988] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 10/19/2020] [Indexed: 01/02/2023] Open
Abstract
Bixin, a natural carotenoid extracted from the seeds of Bixa orellana, has antioxidant and anti-inflammation effects. However, the pharmacological effects and underlying mechanisms of bixin in kidney interstitial fibrosis remain unknown. Partial epithelial-to-mesenchymal transition (EMT) of tubular cells has been linked to renal interstitial fibrosis. Here, we found that in the unilateral ureteral obstruction model, bixin administration could ameliorate kidney interstitial fibrosis. The expression of signal transducer and activator of transcription 6 (STAT6) was dramatically increased in renal tubular cells. Bixin treatment inhibited STAT6 induction. The activation of STAT6 signaling was essential for transforming growth factor β1, fibrotic markers, and EMT-related protein expression in HK2 cells, which was confirmed by using the Stat6-/- mice. Ubiquitination, but not the acetylation level of STAT6, was induced by bixin treatment and promoted the suppression of phosphorylation and stability of STAT6. P62-dependent autophagy might be involved in this process. The study demonstrated that bixin can be exploited therapeutically to alleviate renal interstitial fibrosis by targeting STAT6 signaling deactivation.
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Affiliation(s)
- Jianzhong Li
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Youjing Yang
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Shuhui Wei
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Ling Chen
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Lian Xue
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Hailin Tian
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Shasha Tao
- School of Public Health, Medical College of Soochow University, Suzhou, China
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Muralidharan P, Jones B, Allaway G, Biswal SS, Mansour HM. Design and development of innovative microparticulate/nanoparticulate inhalable dry powders of a novel synthetic trifluorinated chalcone derivative and Nrf2 agonist. Sci Rep 2020; 10:19771. [PMID: 33188247 PMCID: PMC7666129 DOI: 10.1038/s41598-020-76585-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/30/2020] [Indexed: 01/21/2023] Open
Abstract
Chalcone derivatives are shown to possess excellent anti-inflammatory and anti-oxidant properties which are of great interest in treating respiratory diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF). This study successfully designed and developed dry powder inhaler (DPI) formulations of TMC (2-trifluoromethyl-2'-methoxychalone), a new synthetic trifluorinated chalcone and Nrf2 agonist, for targeted pulmonary inhalation aerosol drug delivery. An advanced co-spray drying particle engineering technique was used to design and produce microparticulate/nanoparticulate formulations of TMC with a suitable excipient (mannitol) as inhalable particles with tailored particle properties for inhalation. Raw TMC and co-spray dried TMC formulations were comprehensively characterized for the first time using scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) spectroscopy, thermal analysis, X-ray powder diffraction (XRPD), and molecular fingerprinting as dry powders by ATR-FTIR spectroscopy and Raman spectroscopy. Further, biocompatibility and suitability of formulations were tested with in vitro cellular transepithelial electrical resistance (TEER) in air-interface culture (AIC) using a human pulmonary airway cell line. The ability of these TMC formulations to perform as aerosolized dry powders was systematically evaluated by design of experiments (DOEs) using three different FDA-approved human inhaler devices followed by interaction parameter analyses. Multiple spray drying pump rates (25%, 75%, and 100%) successfully produced co-spray dried TMC:mannitol powders. Raw TMC exhibited a first-order phase transition temperature at 58.15 ± 0.38 °C. Furthermore, the results demonstrate that these innovative TMC dry powder particles are suitable for targeted delivery to the airways by inhalation.
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Affiliation(s)
- Priya Muralidharan
- Colleges of Pharmacy and Medicine, University of Arizona, 1703 E. Mabel St, Tucson, AZ, 85721, USA
| | | | | | - Shyam S Biswal
- Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
- Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Heidi M Mansour
- Colleges of Pharmacy and Medicine, University of Arizona, 1703 E. Mabel St, Tucson, AZ, 85721, USA.
- Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona College of Medicine, Tucson, AZ, USA.
- The BIO5 Research Institute, The University of Arizona, Tucson, AZ, USA.
- Institute of the Environment, The University of Arizona, Tucson, AZ, USA.
- National Cancer Institute Comprehensive Cancer Center, The University of Arizona, Tucson, AZ, USA.
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Li J, Yang Y, Wei S, Chen L, Xue L, Tian H, Tao S. Bixin Confers Prevention against Ureteral Obstruction-Caused Renal Interstitial Fibrosis through Activation of the Nuclear Factor Erythroid-2-Related Factor2 Pathway in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8321-8329. [PMID: 32706966 DOI: 10.1021/acs.jafc.0c03674] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Bixin is a natural carotenoid isolated from the seeds of Bixa orellana, with numerous important pharmacological activities, including antioxidant and antifibrotic effects. The nuclear factor erythroid-2-related factor2 (Nrf2) signaling pathway induced by bixin is involved in the process. Excessive reactive oxygen species generation in tubular cells contributes to kidney interstitial fibrosis. The potential therapeutic strategy for bixin in alleviating kidney fibrosis remains largely unclear. In this study, we used unilateral ureteral obstruction (UUO) to establish a renal fibrotic model. Dramatic oxidative DNA damage occurs in kidneys, especially in tubular cells after UUO. In cultured tubular cells, bixin could induce Nrf2 signaling activation by suppressing Nrf2 ubiquitination and increasing its protein stability. Transforming growth factor beta 1-induced epithelial-to-mesenchymal transition (EMT) and extracellular matrix production were suppressed by bixin, and blockade of Nrf2 activation by small interfering RNA could largely reverse the protective effect of bixin. In vivo studies showed that administration of bixin induces Nrf2 signaling activation in tubular cells and markedly attenuates partial EMT of tubular cells and kidney interstitial fibrosis after subjecting to UUO. Together, this study implies that bixin may protect against kidney interstitial fibrosis through stimulating Nrf2 activation in renal tubular cells.
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Affiliation(s)
- Jianzhong Li
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Youjing Yang
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Shuhui Wei
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Ling Chen
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Lian Xue
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Hailin Tian
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Shasha Tao
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
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Wang T, Dai F, Li GH, Chen XM, Li YR, Wang SQ, Ren DM, Wang XN, Lou HX, Zhou B, Shen T. Trans-4,4'-dihydroxystilbene ameliorates cigarette smoke-induced progression of chronic obstructive pulmonary disease via inhibiting oxidative stress and inflammatory response. Free Radic Biol Med 2020; 152:525-539. [PMID: 31760092 DOI: 10.1016/j.freeradbiomed.2019.11.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 12/11/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease resulted from airflow obstructions, and there is a driving requirement for novel and effective preventive and therapeutic agents of COPD. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been regarded to be a promising therapeutic target for COPD. Resveratrol is a natural Nrf2 activator with antioxidant and anti-inflammatory properties, however, its application is limited by its relative low efficiency and poor bioavailability. Herein, based on the skeleton of resveratrol, trans-4,4'-dihydroxystilbene (DHS) has been firstly identified to be an Nrf2 activator, which is more potent than the well-known sulforaphane (SF) and resveratrol. Our results indicate that DHS blocks Nrf2 ubiquitylation through specifically reacting with Cys151 cysteine in Keap1 protein to activate Nrf2-regulated defensive response, and thus enhances intracellular antioxidant capability. Furthermore, DHS relieves lipopolysaccharide (LPS)-stimulated inflammatory response via inhibition of NF-κB. Importantly, DHS significantly ameliorates pathological alterations (e.g. infiltration of leukocytes and fibrosis), downregulates the levels of oxidant biomarkers malondialdehyde (MDA) and 8-oxo-7,8-dihydro-2'-deoxyguanosin (8-oxo-dG), and inhibits the overproductions of inflammatory mediators [e.g. tumor necrosis factor α (TNF-α), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9)] in a cigarette smoke (CS)-induced pulmonary impairment mice model. Taken together, this study demonstrates that DHS attenuates the CS-induced pulmonary impairments through inhibitions of oxidative stress and inflammatory response targeting Nrf2 and NF-κB in vitro and in vivo, and could be developed into a preventive agent against pulmonary impairments induced by CS.
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Affiliation(s)
- Tian Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Fang Dai
- State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou, People's Republic of China
| | - Guo-Hui Li
- Department of Pharmacy, Jinan Maternity and Child Care Hospital, Jinan, People's Republic of China
| | - Xue-Mei Chen
- Department of Health Management, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yan-Ru Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Shu-Qi Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Dong-Mei Ren
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Xiao-Ning Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Hong-Xiang Lou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China
| | - Bo Zhou
- State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou, People's Republic of China
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China.
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Yang WJ, Chen XM, Wang SQ, Hu HX, Cheng XP, Xu LT, Ren DM, Wang XN, Zhao BB, Lou HX, Shen T. 4β-Hydroxywithanolide E from Goldenberry (Whole Fruits of Physalis peruviana L.) as a Promising Agent against Chronic Obstructive Pulmonary Disease. JOURNAL OF NATURAL PRODUCTS 2020; 83:1217-1228. [PMID: 32159343 DOI: 10.1021/acs.jnatprod.9b01265] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Environmental toxicant- and oxidant-induced [e.g., cigarette smoke (CS)] respiratory oxidative stress and inflammatory response play a vital role in the onset and progression of COPD. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents an important mechanism for regulating intracellular oxidative stress and inflammatory response and is a promising target for developing agents against COPD. Herein, a bioactivity-guided purification of goldenberry (whole fruits of Physalis peruviana L.) led to the isolation of a novel and potent Nrf2 activator 4β-hydroxywithanolide E (4β-HWE). Our study indicated that (i) 4β-HWE activated the Nrf2-mediated defensive response through interrupting Nrf2-Keap1 protein-protein interaction (PPI) via modification of Cys151 and Cys288 cysteine residues in Keap1 and accordingly suppressing the ubiquitination of Nrf2. (ii) 4β-HWE enhanced intracellular antioxidant capacity and inhibited oxidative stress in normal human lung epithelial Beas-2B cells and wild-type AB zebrafish. (iii) 4β-HWE blocked LPS-stimulated inflammatory response and inhibited LPS-stimulated NF-κB activation in RAW 264.7 murine macrophages. (iv) 4β-HWE effectively suppressed oxidative stress and inflammatory response in a CS-induced mice model of pulmonary injury. Collectively, these results display the feasibility of using 4β-HWE to prevent or alleviate the pathological progression of COPD and suggest that 4β-HWE is a candidate or a leading molecule against COPD.
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Affiliation(s)
- Wen-Jing Yang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Xue-Mei Chen
- Department of Maternity, Binzhou Central Hospital, Binzhou Shandong 256603, People's Republic of China
| | - Shu-Qi Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Hui-Xin Hu
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Xin-Ping Cheng
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Lin-Tao Xu
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Dong-Mei Ren
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Xiao-Ning Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Bao-Bing Zhao
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Hong-Xiang Lou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China
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Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM 2.5-Induced Xenotoxic Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2908108. [PMID: 32377294 PMCID: PMC7181013 DOI: 10.1155/2020/2908108] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 02/07/2020] [Indexed: 12/14/2022]
Abstract
Humans in modern industrial and postindustrial societies face sustained challenges from environmental pollutants, which can trigger tissue damage from xenotoxic stress through different mechanisms. Thus, the identification and characterization of compounds capable of conferring antioxidant effects and protection against these xenotoxins are warranted. Here, we report that the natural extract of Polypodium leucotomos named Fernblock®, known to reduce aging and oxidative stress induced by solar radiations, upregulates the NRF2 transcription factor and its downstream antioxidant targets, and this correlates with its ability to reduce inflammation, melanogenesis, and general cell damage in cultured keratinocytes upon exposure to an experimental model of fine pollutant particles (PM2.5). Our results provide evidence for a specific molecular mechanism underpinning the protective activity of Fernblock® against environmental pollutants and potentially other sources of oxidative stress and damage-induced aging.
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A high-throughput method for dereplication and assessment of metabolite distribution in Salvia species using LC-MS/MS. J Adv Res 2020; 24:79-90. [PMID: 32211205 PMCID: PMC7082496 DOI: 10.1016/j.jare.2020.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 01/07/2023] Open
Abstract
Dereplication of crude plant extracts through liquid chromatography-mass spectrometry is a powerful technique for the discovery of novel natural products. Unfortunately, this technique is often plagued by a low level of confidence in natural product identification. This is mainly due to the lack of extensive chromatographic and mass spectrometric optimizations that result in improper and incomplete MS/MS fragmentation data. This study proposes a solution to this problem by the optimization of chromatographic separation and mass spectrometry parameters. We report herein a direct and high-throughput strategy for natural product dereplication in five Salvia species using high-resolution ESI-QTOF-MS/MS data. In the present study, we were able to identify a total of forty-seven natural products in crude extracts of five Salvia species using MS/MS fragmentation data. In addition to dereplication of Salvia species, quantitative profiling of twenty-one bioactive constituents of the genus was also performed on an ion trap mass spectrometer. For the quantitation study, method development focused on chromatographic optimizations to achieve maximum sensitivity. The developed dereplication and quantitation strategy can be extended to develop comprehensive metabolic profiles of other plant genera and species and thus can prove useful in the field of drug discovery from plants.
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Paunkov A, Chartoumpekis DV, Ziros PG, Chondrogianni N, Kensler TW, Sykiotis GP. Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway. Curr Pharm Des 2020; 25:1828-1846. [PMID: 31267862 DOI: 10.2174/1381612825666190701165821] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 06/20/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Natural compounds with potential antioxidant properties have been used in the form of food supplements or extracts with the intent to prevent or treat various diseases. Many of these compounds can activate the cytoprotective Nrf2 pathway. Besides, some of them are known to impact the thyroid gland, often with potential side-effects, but in other instances, with potential utility in the treatment of thyroid disorders. OBJECTIVE In view of recent data regarding the multiple roles of Nrf2 in the thyroid, this review summarizes the current bibliography on natural compounds that can have an effect on thyroid gland physiology and pathophysiology, and it discusses the potential implication of the Nrf2 system in the respective mechanisms. METHODS & RESULTS Literature searches for articles from 1950 to 2018 were performed in PubMed and Google Scholar using relevant keywords about phytochemicals, Nrf2 and thyroid. Natural substances were categorized into phenolic compounds, sulfur-containing compounds, quinones, terpenoids, or under the general category of plant extracts. For individual compounds in each category, respective data were summarized, as derived from in vitro (cell lines), preclinical (animal models) and clinical studies. The main emerging themes were as follows: phenolic compounds often showed potential to affect the production of thyroid hormones; sulfur-containing compounds impacted the pathogenesis of goiter and the proliferation of thyroid cancer cells; while quinones and terpenoids modified Nrf2 signaling in thyroid cell lines. CONCLUSION Natural compounds that modify the activity of the Nrf2 pathway should be evaluated carefully, not only for their potential to be used as therapeutic agents for thyroid disorders, but also for their thyroidal safety when used for the prevention and treatment of non-thyroidal diseases.
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Affiliation(s)
- Ana Paunkov
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
| | - Dionysios V Chartoumpekis
- Department of Internal Medicine, Endocrinology Unit, Patras University Medical School, Patras, Greece
| | - Panos G Ziros
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
| | - Niki Chondrogianni
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Thomas W Kensler
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Gerasimos P Sykiotis
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
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Liu P, Tian W, Tao S, Tillotson J, Wijeratne EMK, Gunatilaka AAL, Zhang DD, Chapman E. Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation. Cell Chem Biol 2019; 26:1427-1435.e5. [PMID: 31402317 PMCID: PMC6800637 DOI: 10.1016/j.chembiol.2019.07.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/23/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023]
Abstract
The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this is the first detailed structure-activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.
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Affiliation(s)
- Pengfei Liu
- College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207, USA
| | - Wang Tian
- College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207, USA
| | - Shasha Tao
- College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207, USA
| | - Joseph Tillotson
- College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207, USA
| | - E M Kithsiri Wijeratne
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85706-6800, USA
| | - A A Leslie Gunatilaka
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85706-6800, USA
| | - Donna D Zhang
- College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207, USA.
| | - Eli Chapman
- College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721-0207, USA.
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Wang C, Niu Q, Ma R, Song G, Hu Y, Xu S, Li Y, Wang H, Li S, Ding Y. The Variable Regulatory Effect of Arsenic on Nrf2 Signaling Pathway in Mouse: a Systematic Review and Meta-analysis. Biol Trace Elem Res 2019; 190:362-383. [PMID: 30357758 DOI: 10.1007/s12011-018-1549-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 10/11/2018] [Indexed: 02/07/2023]
Abstract
Arsenic is known to cause oxidative damage. Nuclear factor E2-relate factor-2 (Nrf2) can resist this toxicity. Scholars demonstrated that Nrf2 pathway was activated by arsenic. In contrast, other articles established arsenic-induced inhibition of Nrf2 pathway. To resolve the contradiction and elucidate the mechanism of Nrf2 induced by arsenic, 39 publications involving mouse models were identified through exhaustive database retrieval and were analyzed. The pooled results suggested that arsenic obviously elevated transcription and translation levels of Nrf2 and its downstream genes, NAD(P)H dehydrogenase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and GST-glutathione-S-transferase1/2 (GSTO1/2). Arsenic increased the level of reactive oxygen species (ROS), but reduced the level of glutathione (GSH). Subgroup analysis between arsenic and control groups showed that the levels of Nrf2 and its downstream genes are greater in high dose than that in the low dose, higher in short-term exposure than long term, female subjects tolerated better than males, higher in mice than the rats, and greater in other organs than the liver. However, the contents of genes of Nrf2 pathway between the arsenic and control groups were lower in rats than in mice and were less for long-term exposure than the short term (P < 0.05). Conclusively, a variable regulation of arsenic on Nrf2 pathway is noted. Higher dose and short-term exposure of female mice organs except for liver promoted Nrf2 pathway. On the other hand, arsenic inhibited Nrf2 pathway for long-term exposure on rats.
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Affiliation(s)
- Cheng Wang
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Qiang Niu
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Rulin Ma
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Guanling Song
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Yunhua Hu
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Shangzhi Xu
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Yu Li
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Haixia Wang
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China
| | - Shugang Li
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China.
| | - Yusong Ding
- Department of Public Health and Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China.
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Chong CM, Su H, Lu JJ, Wang Y. The effects of bioactive components from the rhizome of Salvia miltiorrhiza (Danshen) on the characteristics of Alzheimer's disease. Chin Med 2019; 14:19. [PMID: 31139246 PMCID: PMC6528372 DOI: 10.1186/s13020-019-0242-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/15/2019] [Indexed: 12/31/2022] Open
Abstract
Alzheimer's disease (AD) is a common human neurodegenerative disease, which is characterized by the progressive loss of memory and the cognitive impairment. Since the etiology of AD is still unknown, it is extremely difficult to develop the effective drugs for preventing or slowing the AD process. The major characteristics of AD such as amyloid β plaques, neurofibrillary tangles, mitochondrial dysfunction, and autophagy dysfunction are commonly used as the important indicators for evaluating the effects of potential candidate drugs. The rhizome of Salvia miltiorrhiza (known as 'Danshen' in Chinese), a famous traditional Chinese medicine, which is widely used for the treatment of hyperlipidemia, stroke, cardiovascular and cerebrovascular diseases. Increasing evidences suggest that the bioactive components of Danshen can improve cognitive deficits in mice, protect neuronal cells, reduce tau hyperphosylation, prevent amyloid-β fiber formation and disaggregation. Here we briefly summarize the studies regarding the effects of bioactive component from Danshen on those major characteristics of AD in preclinical studies, as well as explore the potential of these Danshen component in the treatment of AD.
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Affiliation(s)
- Cheong-Meng Chong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
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33
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Tao S, Zhang H, Xue L, Jiang X, Wang H, Li B, Tian H, Zhang Z. Vitamin D protects against particles-caused lung injury through induction of autophagy in an Nrf2-dependent manner. ENVIRONMENTAL TOXICOLOGY 2019; 34:594-609. [PMID: 30698894 DOI: 10.1002/tox.22726] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/05/2019] [Accepted: 01/13/2019] [Indexed: 06/09/2023]
Abstract
Fine particulate matter is a well-known air pollutant threatening public health. Studies have confirmed long-term exposure to the particles could decrease the pulmonary function, induce asthma exacerbation, and chronic obstructive pulmonary disease, as well as increase the incidence and mortality of lung cancer. A clinical study has explored that the prevalence and risks of vitamin D (VD) deficiency in various chronic disease and toxins induced tissue damage. Our current study aimed to explore the mechanism and further therapeutic potential of VD administration to ameliorate fine particles exposure induced pulmonary damage in vivo and in vitro. To elucidate the effects and mechanisms of VD in particles-induced pulmonary damage, a murine model was established with fine particles intratracheal instillation along with VD intramuscular injection. Our study demonstrated that treatment with VD attenuated particles-induced pulmonary damage and promoted tissue repair by repressing of TGFβ1 signaling pathway and upregulation of MMP9 expression. VD treatment could also regulate the autophagy-related signals along with activation of Nrf2 transcription factor. Furthermore, the results from the in vitro study demonstrated that VD protected against particles-induced cells' damage through the induction of autophagy in an Nrf2-dependent manner. VD treatment caused the degradation of P62 and its bound Keap1, which decreased the Nrf2 ubiquitination and increasing its protein stability. Our work explored a novel potential mechanism in the protection of VD in particles-induced pulmonary injury and tissue repair, and could further bring insights into exploring antifine particles exposure caused inflammation among other natural products and contributes to inflammation disease medical therapies.
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Affiliation(s)
- Shasha Tao
- Department of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China
| | - Hong Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China
| | - Lian Xue
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China
| | - Xiaoyan Jiang
- Department of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
| | - Hongyan Wang
- Department of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
| | - Bingyan Li
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China
| | - Hailin Tian
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China
| | - Zengli Zhang
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China
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Zhang Y, Ji A, Xu Z, Luo H, Song J. The AP2/ERF transcription factor SmERF128 positively regulates diterpenoid biosynthesis in Salvia miltiorrhiza. PLANT MOLECULAR BIOLOGY 2019; 100:83-93. [PMID: 30847712 DOI: 10.1007/s11103-019-00845-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 02/18/2019] [Indexed: 05/02/2023]
Abstract
The novel AP2/ERF transcription factor SmERF128 positively regulates diterpenoid tanshinone biosynthesis by activating the expression of SmCPS1, SmKSL1, and SmCYP76AH1 in Salvia miltiorrhiza. Certain members of the APETALA2/ethylene-responsive factor (AP2/ERF) family regulate plant secondary metabolism. Although it is clearly documented that AP2/ERF transcription factors (TFs) are involved in sesquiterpenoid biosynthesis, the regulation of diterpenoid biosynthesis by AP2/ERF TFs remains elusive. Here, we report that the novel AP2/ERF TF SmERF128 positively regulates diterpenoid tanshinone biosynthesis in Salvia miltiorrhiza. Overexpression of SmERF128 increased the expression levels of copalyl diphosphate synthase 1 (SmCPS1), kaurene synthase-like 1 (SmKSL1) and cytochrome P450 monooxygenase 76AH1 (SmCYP76AH1), whereas their expression levels were decreased when SmERF128 was silenced. Accordingly, the content of tanshinone was reduced in SmERF128 RNA interference (RNAi) hairy roots and dramatically increased in SmERF128 overexpression hairy roots, as demonstrated through Ultra Performance Liquid Chromatography (UPLC) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) analysis. Furthermore, SmERF128 activated the expression of SmCPS1, SmKSL1, and SmCYP76AH1 by binding to the GCC box, and to the CRTDREHVCBF2 (CBF2) and RAV1AAT (RAA) motifs within their promoters during in vivo and in vitro assays. Our findings not only reveal the molecular basis of how the AP2/ERF transcription factor SmERF128 regulates diterpenoid biosynthesis, but also provide useful information for improving tanshinone production through genetic engineering.
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Affiliation(s)
- Yu Zhang
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
- College of Chinese Materia Medica, Shanxi University of Chinese Medicine, Jinzhong, 030619, China
| | - Aijia Ji
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zhichao Xu
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
| | - Hongmei Luo
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China
- Engineering Research Center of Chinese Medicine Resource, Ministry of Education, Beijing, 100193, China
| | - Jingyuan Song
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100193, China.
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Jinghong, 666100, China.
- Engineering Research Center of Chinese Medicine Resource, Ministry of Education, Beijing, 100193, China.
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Yang WJ, He JX, Zhou MX, Huang M, Wang SQ, Wang XN, Lou HX, Ren DM, Shen T. An isopentenyl-substituted flavonoid norartocarpin activates Nrf2 signalling pathway and prevents oxidative insults in human lung epithelial cells. Free Radic Res 2019; 53:348-358. [DOI: 10.1080/10715762.2019.1582769] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Wen-Jing Yang
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
| | - Ji-Xiang He
- School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China
| | - Ming-Xing Zhou
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
| | - Min Huang
- School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China
| | - Shu-Qi Wang
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
| | - Xiao-Ning Wang
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
| | - Hong-Xiang Lou
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
| | - Dong-Mei Ren
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
| | - Tao Shen
- Key Laboratory of Chemical Biology (MOE) School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China
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Zhang H, Xue L, Li B, Zhang Z, Tao S. Vitamin D Protects Against Alcohol‐Induced Liver Cell Injury Within an NRF2–ALDH2 Feedback Loop. Mol Nutr Food Res 2019; 63:e1801014. [DOI: 10.1002/mnfr.201801014] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/06/2018] [Indexed: 12/23/2022]
Affiliation(s)
- Hong Zhang
- School of Public HealthMedical College of Soochow University 199 Ren'ai Road Suzhou 215123 Jiangsu China
| | - Lian Xue
- School of Public HealthMedical College of Soochow University 199 Ren'ai Road Suzhou 215123 Jiangsu China
| | - Bingyan Li
- Experimental Center of Medical CollegeSoochow University 199 Ren'ai Road Suzhou 215123 Jiangsu China
| | - Zengli Zhang
- School of Public HealthMedical College of Soochow University 199 Ren'ai Road Suzhou 215123 Jiangsu China
| | - Shasha Tao
- School of Public HealthMedical College of Soochow University 199 Ren'ai Road Suzhou 215123 Jiangsu China
- J. Key Laboratory of Preventive and Translational Medicine for Geriatric DiseaseSchool of Public HealthSoochow University Suzhou 215123 PR China
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Zhang H, Xue L, Li B, Tian H, Zhang Z, Tao S. Therapeutic potential of bixin in PM2.5 particles-induced lung injury in an Nrf2-dependent manner. Free Radic Biol Med 2018; 126:166-176. [PMID: 30120979 DOI: 10.1016/j.freeradbiomed.2018.08.015] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 08/12/2018] [Accepted: 08/13/2018] [Indexed: 12/15/2022]
Abstract
Fine particulate matter (PM 2.5) is a well-known air pollutant threatening public health. Studies has confirmed that long-term exposure to the particles could reduce the pulmonary function, cause exacerbation of asthma and chronic obstructive pulmonary disease, and increase incidence and mortality of lung cancer. Bixin is a natural compound that is widely used as a food additive. Our previous studies demonstrated that bixin i.p. administration could protect against particles intratracheal exposure (56 days)-induced lung injury in an Nrf2-dependent manner. But the detail mechanisms are still unclarified. Our current study aimed to explore the further therapeutic potential and mechanism of bixin to slow the progression of lung injury and inflammation in vivo and in vitro. The results from the in vivo study showed that bixin treatment attenuated the accumulation of inflammatory cells, decreased the levels of tissue apoptosis, and increase the ability of cell proliferation. Besides that, bixin also could regulate the expression of MMP9, TGFβ1, and its downstream Fibronectin (FN), along with activation of Nrf2 signals. In vitro experiments in human bronchial epithelial cells demonstrated that Nrf2 activated by bixin contributes to tissue repair by alleviating oxidative stress, increasing proliferation and migration, decreasing apoptosis, which may be partially through modulating the expression of MMP9, TGFβ1, and FN. This study provides convincing experimental evidences that bixin could be used therapeutically to promote tissue repair and improve pulmonary injury induced by particles exposure.
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Affiliation(s)
- Hong Zhang
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, Jiangsu, China
| | - Lian Xue
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, Jiangsu, China
| | - Bingyan Li
- Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, Jiangsu, China
| | - Hailin Tian
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, Jiangsu, China
| | - Zengli Zhang
- School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, Jiangsu, China
| | - Shasha Tao
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou 215123, China; School of Public Health, Medical College of Soochow University, 199 Ren'ai Road, Suzhou 215123, Jiangsu, China.
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Li YR, Li GH, Zhou MX, Xiang L, Ren DM, Lou HX, Wang XN, Shen T. Discovery of natural flavonoids as activators of Nrf2-mediated defense system: Structure-activity relationship and inhibition of intracellular oxidative insults. Bioorg Med Chem 2018; 26:5140-5150. [PMID: 30227999 DOI: 10.1016/j.bmc.2018.09.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/01/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022]
Abstract
Continuous overproduction of reactive oxygen species (ROS), termed as oxidative stress, plays a crucial role in the onset and progression of many human diseases. Activation of nuclear transcription factor erythroid 2-related factor (Nrf2) by small molecules could eliminate ROS, and thus block the pathogenesis of oxidative stress-induced diseases. In this study, a natural flavonoid library was established and tested for their potential Nrf2 inducing effects. Based on QR inducing effect of flavonoids, their structure-activity relationship (SAR) on Nrf2 induction was summarized, and twenty flavonoids were firstly identified to be potential activators of Nrf2-mediated defensive response. Then, 7-O-methylbiochanin A (7-MBA) was further investigated for its capability on the Nrf2 activation and prevention against oxidative insults in human lung epithelial cells. Further studies indicated that 7-MBA activated Nrf2 signaling pathway and protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Activation of Nrf2 by 7-MBA upregulated intracellular antioxidant capacity, which was produced by enhancement of Nrf2 stabilization, blockage of Nrf2 ubiquitination, as well as Nrf2 phosphorylation by mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase R-like endoplasmic reticulum kinase (PERK), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Taken together, 7-MBA is a novel isoflavone-type Nrf2 activator displaying potential preventive effect against oxidative damages in human lung epithelial cells.
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Affiliation(s)
- Yan-Ru Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Guo-Hui Li
- Department of Pharmacy, Jinan Maternity and Child Care Hospital, Jinan, PR China
| | - Ming-Xing Zhou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Lan Xiang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Dong-Mei Ren
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Hong-Xiang Lou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xiao-Ning Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.
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Therapeutic Potential of Salviae Miltiorrhizae Radix et Rhizoma against Human Diseases Based on Activation of Nrf2-Mediated Antioxidant Defense System: Bioactive Constituents and Mechanism of Action. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:7309073. [PMID: 30050659 PMCID: PMC6040253 DOI: 10.1155/2018/7309073] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/17/2018] [Accepted: 04/29/2018] [Indexed: 12/11/2022]
Abstract
Oxidative stress plays a central role in the pathogenesis of many human diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating the intracellular antioxidant response and is an emerging target for the prevention and therapy of oxidative stress-related diseases. Salviae Miltiorrhizae Radix et Rhizoma (SMRR) is a traditional Chinese medicine (TCM) and is commonly used for the therapy of cardiac cerebral diseases. Cumulative evidences indicated that the extract of SMRR and its constituents, represented by lipophilic diterpenoid quinones and hydrophilic phenolic acids, were capable of activating Nrf2 and inhibiting oxidative stress. These bioactive constituents demonstrated a therapeutic potential against human diseases, exemplified by cardiovascular diseases, neurodegenerative diseases, diabetes, nephropathy, and inflammation, based on the induction of Nrf2-mediated antioxidant response and the inhibition of oxidative stress. In the present review, we introduced the SMRR and Nrf2 signaling pathway, summarized the constituents with an Nrf2-inducing effect isolated from SMRR, and discussed the molecular mechanism and pharmacological functions of the SMRR extract and its constituents.
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Xue L, Zhang H, Zhang J, Li B, Zhang Z, Tao S. Bixin protects against particle-induced long-term lung injury in an NRF2-dependent manner. Toxicol Res (Camb) 2018; 7:258-270. [PMID: 30090580 PMCID: PMC6060687 DOI: 10.1039/c7tx00304h] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 01/10/2018] [Indexed: 01/07/2023] Open
Abstract
Scope: Particle-induced lung injury is a kind of comprehensive pulmonary disease with not only inflammation but also fibrosis. Bixin is a natural compound that is widely used as a food additive. Our previous studies demonstrated that bixin could alleviate inflammation in ventilation-induced acute lung injury as well as UV-exposure caused skin damage. But whether it could depress silica-induced long-term comprehensive lung injury and the mechanism of bixin in this protection have not yet been studied. Methods: A murine SiO2-induced long-term comprehensive lung injury model was established through silica intratracheal instillation. To elucidate the effects and mechanisms of bixin in silica-induced pulmonary inflammation and fibrosis, we treated mice with bixin following silica instillation. Results: Bixin treatment attenuated the accumulation of inflammatory cells which significantly ameliorated pathological inflammation and fibrotic development in the lungs. In addition, intraperitoneal (i.p.) injection of bixin in mice led to the upregulation of the NRF2 response in the lungs. Since alveolar macrophage activation plays a vital role in the initiation and progression of this injury, the mechanism was further studied in the THP-1 macrophage cells. Bixin activated NRF2 signals via blocking KEAP1 mediated ubiquitylation and degradation of NRF2. Conclusions: Our work has brought insights into exploring anti-particle-induced lung injury activities in the daily consumption of natural products. In addition, our study also inspires the discovery of new beneficial effects of bixin and its application in the treatment of other inflammatory diseases.
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Affiliation(s)
- Lian Xue
- School of Public Health , Medical College of Soochow University , 199 Ren'ai Road , Suzhou 215123 , Jiangsu , China . ; ; Tel: +86-0512-656883323
| | - Hong Zhang
- School of Public Health , Medical College of Soochow University , 199 Ren'ai Road , Suzhou 215123 , Jiangsu , China . ; ; Tel: +86-0512-656883323
| | - Jie Zhang
- School of Public Health , Medical College of Soochow University , 199 Ren'ai Road , Suzhou 215123 , Jiangsu , China . ; ; Tel: +86-0512-656883323
| | - Bingyan Li
- Experimental Center of Medical College , Soochow University , 199 Ren'ai Road , Suzhou 215123 , Jiangsu , China
| | - Zengli Zhang
- School of Public Health , Medical College of Soochow University , 199 Ren'ai Road , Suzhou 215123 , Jiangsu , China . ; ; Tel: +86-0512-656883323
| | - Shasha Tao
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease , School of Public Health , Soochow University , Suzhou , 215123 , PR China . ; ; Tel: +86-0512-65698540
- School of Public Health , Medical College of Soochow University , 199 Ren'ai Road , Suzhou 215123 , Jiangsu , China . ; ; Tel: +86-0512-656883323
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Zhang Y, Xu Z, Ji A, Luo H, Song J. Genomic survey of bZIP transcription factor genes related to tanshinone biosynthesis in Salvia miltiorrhiza. Acta Pharm Sin B 2018; 8:295-305. [PMID: 29719790 PMCID: PMC5925414 DOI: 10.1016/j.apsb.2017.09.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 07/24/2017] [Accepted: 08/06/2017] [Indexed: 01/06/2023] Open
Abstract
Tanshinones are a class of bioactive components in the traditional Chinese medicine Salvia miltiorrhiza, and their biosynthesis and regulation have been widely studied. Current studies show that basic leucine zipper (bZIP) proteins regulate plant secondary metabolism, growth and developmental processes. However, the bZIP transcription factors involved in tanshinone biosynthesis are unknown. Here, we conducted the first genome-wide survey of the bZIP gene family and analyzed the phylogeny, gene structure, additional conserved motifs and alternative splicing events in S. miltiorrhiza. A total of 70 SmbZIP transcription factors were identified and categorized into 11 subgroups based on their phylogenetic relationships with those in Arabidopsis. Moreover, seventeen SmbZIP genes underwent alternative splicing events. According to the transcriptomic data, the SmbZIP genes that were highly expressed in the Danshen root and periderm were selected. Based on the prediction of bZIP binding sites in the promoters and the co-expression analysis and co-induction patterns in response to Ag+ treatment via quantitative real-time polymerase chain reaction (qRT-PCR), we concluded that SmbZIP7 and SmbZIP20 potentially participate in the regulation of tanshinone biosynthesis. These results provide a foundation for further functional characterization of the candidate SmbZIP genes, which have the potential to increase tanshinone production.
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Magnetic molecularly imprinted polymers based on silica modified by deep eutectic solvents for the rapid simultaneous magnetic-based solid-phase extraction of Salvia miltiorrhiza bunge
, Glycine max (Linn.) Merr
and green tea. Electrophoresis 2018; 39:1111-1118. [DOI: 10.1002/elps.201700474] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/20/2017] [Accepted: 01/09/2018] [Indexed: 12/12/2022]
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Abstract
The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.
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Affiliation(s)
- Qin M Chen
- Department of Pharmacology, College of Medicine, University of Arizona , Tucson, Arizona
| | - Anthony J Maltagliati
- Department of Pharmacology, College of Medicine, University of Arizona , Tucson, Arizona
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Liu C, Sun HN, Luo YH, Piao XJ, Wu DD, Meng LQ, Wang Y, Zhang Y, Wang JR, Wang H, Xu WT, Li JQ, Liu Y, Wu YQ, Han YH, Shen GN, Jin MH, Zang YQ, Li JC, Fang NZ, Cui YD, Jin CH. Cryptotanshinone induces ROS-mediated apoptosis in human gastric cancer cells. Oncotarget 2017; 8:115398-115412. [PMID: 29383168 PMCID: PMC5777780 DOI: 10.18632/oncotarget.23267] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/03/2017] [Indexed: 02/07/2023] Open
Abstract
Cryptotanshinone (CT), isolated from the plant Salvia miltiorrhiza Bunge, has been reported to have potential anticancer effects on human prostate and breast cancer cells. However, the mechanisms of action of CT on gastric cancer (GC) cells are not well understood. Here we investigated the antitumor effects of CT on GC cells and its possible molecular mechanism. We found CT suppressed viability of twelve GC cell lines in a dose-dependent manner. CT induced cell cycle arrest at the G2/M phase and mitochondrial apoptosis accompanying the accumulation of reactive oxygen species (ROS). Pretreatment with ROS inhibitor N-acetyl-L-cysteine (NAC) blocked CT-induced apoptosis. CT increased p-JNK and p-p38, and decreased p-ERK and p-STAT3 protein expression, these effects were prevented by NAC. Furthermore, a xenograft assay showed that CT significantly inhibited MKN-45 cell-induced tumor growth in vivo by increasing expression of pro-apoptotic proteins (p-JNK, p-38 and cleaved-caspase-3) and reducing expression of anti-apoptotic proteins (p-ERK and p-STAT3) without adverse effects on nude mice weight. In conclusion, CT induced apoptosis and cell cycle arrest in GC cells via ROS-mediated MAPK and AKT signaling pathways, and this CT may be a useful compound for the developing anticancer agents for GC.
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Affiliation(s)
- Chang Liu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Hu-Nan Sun
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Ying-Hua Luo
- College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Xian-Ji Piao
- Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Harbin Medical University, Daqing 163316, China
| | - Dan-Dan Wu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Ling-Qi Meng
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yue Wang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yi Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Jia-Ru Wang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Hao Wang
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Wan-Ting Xu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Jin-Qian Li
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yang Liu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yi-Qin Wu
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Ying-Hao Han
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Gui-Nan Shen
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Mei-Hua Jin
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yan-Qing Zang
- College of Food Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Jing-Chun Li
- College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Nan-Zhu Fang
- Department of Animal Science, College of Agriculture, Yanbian University, Gongyuan-jie, Yanji 133002, China
| | - Yu-Dong Cui
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Cheng-Hao Jin
- Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
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Li J, Zhao L, Zhang Y, Li W, Duan X, Chen J, Guo Y, Yang S, Sun G, Li B. Imbalanced immune responses involving inflammatory molecules and immune-related pathways in the lung of acute and subchronic arsenic-exposed mice. ENVIRONMENTAL RESEARCH 2017; 159:381-393. [PMID: 28843991 DOI: 10.1016/j.envres.2017.08.036] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 06/07/2023]
Abstract
Inorganic arsenic has been claimed to increase the risk of pulmonary diseases through ingestion, as opposed to inhalation, which makes it a unique and intriguing environmental toxicant. However, the immunotoxic effects of lung, one of the targets of arsenic exposure, have not been extensively investigated in vivo. In the present study, we first confirmed that 2.5, 5 and 10mg/kg NaAsO2 orally for 24h dose-dependently triggered the infiltration of neutrophils, lymphocytes and macrophages in BALF. Not only the transcription activity, but also the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α were consistently raised in the lung and BALF of acute arsenic-exposed mice. Acute oral administration of NaAsO2 also raised pulmonary MPO activity and mRNA levels of chemokine Mip-2 and Mcp-1. Meanwhile, obvious histopathological damages with inflammatory cells infiltration and erythrocyte aggregation around the capillaries were verified in the lung of mice drank arsenic-rich water freely for 3 months. Furthermore, we affirmed notable disturbance of CD4+ T-cell differentiation in the lung of acute arsenic-exposed mice, as demonstrated by up-regulated mRNA levels of regulator Gata3 and cytokine Il-4 of Th2, enhanced Foxp3 and Il-10 of Treg, down-regulated T-bet and Ifn-γ of Th1, as well as lessened Ror-γt and Il-23 of Th17. However, impressive elevation of cytokine Ifn-γ and Il-23, as well as moderate enhancement of Il-4 and Il-10 were found in the lung by subchronic arsenic administration. Finally, our present study demonstrated that both a single and sustained arsenic exposure prominently increased the expression of immune-related p38, JNK, ERK1/2 and NF-κB proteins in the lung tissue. While disrupting the pulmonary redox homeostasis by increasing MDA levels, exhausting GSH and impaired enzyme activities of CAT and GSH-Px, antioxidant regulator NRF2 and its downstream targets HO-1 and GSTO1/2 were also up-regulated by both acute and subchronic arsenic treatment. Conclusively, our present study demonstrated both acute and subchronic oral administration of arsenic triggers multiple pulmonary immune responses involving inflammatory molecules and T-cell differentiation, which might be closely associated with the imbalanced redox status and activation of immune-related MAPKs, NF-κB and anti-inflammatory NRF2 pathways.
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Affiliation(s)
- Jinlong Li
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China; Department of Occupational and Environmental Health, Key Laboratory of Occupational Health and Safety for Coal Industry in Hebei Province, School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China
| | - Lu Zhao
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China
| | - Yang Zhang
- Chengde City Center for Disease Prevention and Control, Chengde City, Hebei Province 069000, China
| | - Wei Li
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China
| | - Xiaoxu Duan
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, Liaoning, China
| | - Jinli Chen
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China
| | - Yuanyuan Guo
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China
| | - Shan Yang
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China
| | - Guifan Sun
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China
| | - Bing Li
- Environment and Non-Communicable Disease Research Center, Key Laboratory of Arsenic-related Biological Effects and Prevention and Treatment in Liaoning Province, School of Public Health, China Medical University, Shenyang 110122, China.
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Li XY, Tang HJ, Zhang L, Yang L, Li P, Chen J. A selective knockout method for discovery of minor active components from plant extracts: Feasibility and challenges as illustrated by an application to Salvia miltiorrhiza. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1068-1069:253-260. [PMID: 29132906 DOI: 10.1016/j.jchromb.2017.10.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 08/18/2017] [Accepted: 10/06/2017] [Indexed: 12/21/2022]
Abstract
Natural products have been recognized to play an invaluable role in drug discovery. However, efficient discovery of minor active constituents from natural sources is challenging due to the low abundance and complex matrices. In this study, we developed a selective knockout method to discover minor bioactive components from complex phytochemical mixtures, using a Chinese medicine as an example. Based on the chromatographic fingerprint, six major components in the ethyl acetate extract of the root of Salvia miltiorrhiza (EASM) were selectively knocked out via high-resolution peak fraction (HRPF) approach. The remaining extract was automatically enriched and fractionated to generate a chemical library consisting of 62 minor components with contents less than 3‰. Simultaneously, a parallel mass-spectrometry (MS) analysis was performed to ensure purity and to characterize the structure of the compound in each fraction. Via an antioxidant response element (ARE)-driven luciferase reporter system, 33 minor components were screened out as nuclear factor erythroid 2-related factor 2 (Nrf2) activators and 30 components were identified. Here, the Nrf2 activation activities of 21 components have been reported for the first time. Different from the existing methods for discovery of active compounds from natural products, in the developed method of this manuscript, the major components are selectively removed, and the fractions of the minor components are prepared after several times of preparative HPLC enrichment by high-resolution peak fraction approach. It improves the prospective discovery of minor active components from complex medicinal herbs.
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Affiliation(s)
- Xue-Yan Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Hong-Jin Tang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Liu Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Lin Yang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jun Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
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Zhou MX, Li GH, Sun B, Xu YW, Li AL, Li YR, Ren DM, Wang XN, Wen XS, Lou HX, Shen T. Identification of novel Nrf2 activators from Cinnamomum chartophyllum H.W. Li and their potential application of preventing oxidative insults in human lung epithelial cells. Redox Biol 2017; 14:154-163. [PMID: 28942193 PMCID: PMC5608562 DOI: 10.1016/j.redox.2017.09.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 08/25/2017] [Accepted: 09/11/2017] [Indexed: 12/16/2022] Open
Abstract
Human lung tissue, directly exposed to the environmental oxidants and toxicants, is apt to be harmed to bring about acute or chronic oxidative insults. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents a central cellular defense mechanism, and is a target for developing agents against oxidative insult-induced human lung diseases. Our previous study found that the EtOH extract of Cinnamomum chartophyllum protected human bronchial epithelial cells against oxidative insults via Nrf2 activation. In this study, a systemic phytochemical investigation of the aerial parts of C. chartophyllum led to the isolation of thirty chemical constituents, which were further evaluated for their Nrf2 inducing potential using NAD(P)H: quinone reductase (QR) assay. Among these purified constituents, a sesquiterpenoid bearing α, β-unsaturated ketone group, 3S-(+)-9-oxonerolidol (NLD), and a diphenyl sharing phenolic groups, 3, 3′, 4, 4′-tetrahydroxydiphenyl (THD) significantly activated Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO-1), and γ-glutamyl cysteine synthetase (γ-GCS), and enhanced the nuclear translocation and stabilization of Nrf2 in human lung epithelial cells. Importantly, NLD and THD had no toxicities under the Nrf2 inducing doses. THD also demonstrated a potential of interrupting Nrf2-Keap1 protein–protein interaction (PPI). Furthermore, NLD and THD protected human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. Taken together, we conclude that NLD and THD are two novel Nrf2 activators with potential application of preventing acute and chronic oxidative insults in human lung tissue.
The chemical compositions of Cinnamomum chartophyllum are firstly identified. The active ingredients supporting the biological functions of C. chartophyllum are verified. NLD and THD are identified to be Nrf2 activators for the first time. NLD and THD protect human lung epithelial cells against As(III)-induced cytotoxicity.
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Affiliation(s)
- Ming-Xing Zhou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Guo-Hui Li
- Department of Pharmacy, Jinan Maternity and Child Care Hospital, Jinan, PR China
| | - Bin Sun
- National Glycoengineering Research Center, Shandong University, Jinan 250012, PR China
| | - You-Wei Xu
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Ai-Ling Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Yan-Ru Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Dong-Mei Ren
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xiao-Ning Wang
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xue-Sen Wen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Hong-Xiang Lou
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.
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Xing L, Tan ZR, Cheng JL, Huang WH, Zhang W, Deng W, Yuan CS, Zhou HH. Bioavailability and pharmacokinetic comparison of tanshinones between two formulations of Salvia miltiorrhiza in healthy volunteers. Sci Rep 2017; 7:4709. [PMID: 28680091 PMCID: PMC5498502 DOI: 10.1038/s41598-017-02747-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 04/19/2017] [Indexed: 02/04/2023] Open
Abstract
Salvia miltiorrhiza (SM) is widely used to treat microcirculatory disturbance-related diseases; its lipophilic components play important roles in this application. Cryptotanshinone (CTS), tanshinone I (TSI) and tanshinone IIA (TSA) are the most widely-studied lipophilic ingredients, but low oral bioavailability limits their clinical application. It has been proven that micronization could improve the bioavailability of some drugs, so we’ve conducted this randomized study to investigate whether micronized granular powder (GP) of SM could improve the bioavailability of tanshinones compared with traditional decoction (TD). An oral dose of TD or GP of SM was administrated to subjects and blood samples were collected at predetermined time points. The plasma concentrations of tanshinones were detected by a validated method and pharmacokinetic parameters were calculated using a non-compartmental model. GP of SM resulted in a significant increase in mean maximum plasma concentration (Cmax), elimination half-life and area under concentration-time curve (AUC) of tanshinones, with the plasma AUC of CTS, TSI and TSA in GP 5–184, 4–619 and 5–130 times higher than TD. In addition, the individual variances of Cmax and AUC were much lower after GP administration. Summarily, tanshinones in micronized GP of SM had higher oral bioavailability and lower individual variances, thus we speculate that it may indicate a better clinical efficacy and be a better choice than current treatments.
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Affiliation(s)
- Lu Xing
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, P.R. China
| | - Zhi-Rong Tan
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. .,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, P.R. China.
| | - Jin-Le Cheng
- Key Laboratory of Cell-broken Decoction Pieces Technology and Application of State Administration of Traditional Chinese Medicine, Zhongshan, 528437, P.R. China
| | - Wei-Hua Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, P.R. China.,Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, P.R. China
| | - Wen Deng
- Key Laboratory of Cell-broken Decoction Pieces Technology and Application of State Administration of Traditional Chinese Medicine, Zhongshan, 528437, P.R. China
| | - Chun-Su Yuan
- Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, P.R. China. .,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, P.R. China.
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Ghosh S, Forney LA, Wanders D, Stone KP, Gettys TW. An integrative analysis of tissue-specific transcriptomic and metabolomic responses to short-term dietary methionine restriction in mice. PLoS One 2017; 12:e0177513. [PMID: 28520765 PMCID: PMC5433721 DOI: 10.1371/journal.pone.0177513] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 04/29/2017] [Indexed: 12/12/2022] Open
Abstract
Dietary methionine restriction (MR) produces a coordinated series of transcriptional responses in peripheral tissues that limit fat accretion, remodel lipid metabolism in liver and adipose tissue, and improve overall insulin sensitivity. Hepatic sensing of reduced methionine leads to induction and release of fibroblast growth factor 21 (FGF21), which acts centrally to increase sympathetic tone and activate thermogenesis in adipose tissue. FGF21 also has direct effects in adipose to enhance glucose uptake and oxidation. However, an understanding of how the liver senses and translates reduced dietary methionine into these transcriptional programs remains elusive. A comprehensive systems biology approach integrating transcriptomic and metabolomic readouts in MR-treated mice confirmed that three interconnected mechanisms (fatty acid transport and oxidation, tricarboxylic acid cycle, and oxidative phosphorylation) were activated in MR-treated inguinal adipose tissue. In contrast, the effects of MR in liver involved up-regulation of anti-oxidant responses driven by the nuclear factor, erythroid 2 like 2 transcription factor, NFE2L2. Metabolomic analysis provided evidence for redox imbalance, stemming from large reductions in the master anti-oxidant molecule glutathione coupled with disproportionate increases in ophthalmate and its precursors, glutamate and 2-aminobutyrate. Thus, cysteine and its downstream product, glutathione, emerge as key early hepatic signaling molecules linking dietary MR to its metabolic phenotype.
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Affiliation(s)
- Sujoy Ghosh
- Laboratory of Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America
- Program in Cardiovascular & Metabolic Disorders and Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore
| | - Laura A. Forney
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America
| | - Desiree Wanders
- Department of Nutrition, Georgia State University, Atlanta, GA, United States of America
| | - Kirsten P. Stone
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America
| | - Thomas W. Gettys
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America
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Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia. Antioxidants (Basel) 2017; 6:antiox6020027. [PMID: 28383481 PMCID: PMC5488007 DOI: 10.3390/antiox6020027] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 03/31/2017] [Accepted: 04/03/2017] [Indexed: 12/14/2022] Open
Abstract
The importance of the tumor microenvironment for cancer progression and therapeutic resistance is an emerging focus of cancer biology. Hypoxia, or low oxygen, is a hallmark of solid tumors that promotes metastasis and represents a significant obstacle to successful cancer therapy. In response to hypoxia, cancer cells activate a transcriptional program that allows them to survive and thrive in this harsh microenvironment. Hypoxia-inducible factor 1 (HIF-1) is considered the main effector of the cellular response to hypoxia, stimulating the transcription of genes involved in promoting angiogenesis and altering cellular metabolism. However, growing evidence suggests that the cellular response to hypoxia is much more complex, involving coordinated signaling through stress response pathways. One key signaling molecule that is activated in response to hypoxia is nuclear factor, erythroid 2 like-2 (Nrf2). Nrf2 is a transcription factor that controls the expression of antioxidant-response genes, allowing the cell to regulate reactive oxygen species. Nrf2 is also activated in various cancer types due to genetic and epigenetic alterations, and is associated with poor survival and resistance to therapy. Emerging evidence suggests that coordinated signaling through Nrf2 and HIF-1 is critical for tumor survival and progression. In this review, we discuss the distinct and overlapping roles of HIF-1 and Nrf2 in the cellular response to hypoxia, with a focus on how targeting Nrf2 could provide novel chemotherapeutic modalities for treating solid tumors.
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