|
1
|
Chen C, Bu X, Deng L, Xia J, Wang X, Chen L, Li W, Huang J, Chen Q, Wang C. Astragaloside IV as a promising therapeutic agent for liver diseases: current landscape and future perspectives. Front Pharmacol 2025; 16:1574154. [PMID: 40337517 PMCID: PMC12055773 DOI: 10.3389/fphar.2025.1574154] [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: 02/11/2025] [Accepted: 04/10/2025] [Indexed: 05/09/2025] Open
Abstract
Astragaloside IV (C41H68O14, AS-IV) is a naturally occurring saponin isolated from the root of Astragalus membranaceus, a widely used traditional Chinese botanical drug in medicine. In recent years, AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to its low toxicity as well as its anti-inflammatory, antioxidant and antitumour effects. Numerous preclinical studies have demonstrated its potential in the prevention and treatment of various liver diseases, including multifactorial liver injury, metabolic-associated fatty liver disease, liver fibrosis and liver cancer. Given the promising hepatoprotective potential of AS-IV and the growing interest in its research, this review provides a comprehensive summary of the current state of research on the hepatoprotective effects of AS-IV, based on literature available in databases such as CNKI, PubMed, ScienceDirect, Google Scholar and Web of Science. The hepatoprotective mechanisms of AS-IV are multifaceted, encompassing the inhibition of inflammatory responses, reduction of oxidative stress, improvement of insulin and leptin resistance, modulation of the gut microbiota, suppression of hepatocellular carcinoma cell proliferation and induction of tumour cell apoptosis. Notably, key molecular pathways involved in these effects include Nrf2/HO-1, NF-κB, NLRP3/Caspase-1, JNK/c-Jun/AP-1, PPARα/FSP1 and Akt/GSK-3β/β-catenin. Toxicity studies indicate that AS-IV has a high level of safety. In addition, this review discusses the sources, physicochemical properties, and current challenges in the development and clinical application of AS-IV, providing valuable insights into its potential as a hepatoprotective agent in the pharmaceutical and nutraceutical industries.
Collapse
Affiliation(s)
- Chunyan Chen
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaolan Bu
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Liping Deng
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jiayan Xia
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xinming Wang
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Li Chen
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Wen Li
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jie Huang
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Qixiang Chen
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Cheng Wang
- School of Clinical Medical, Chengdu Medical College, Chengdu, China
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| |
Collapse
|
|
2
|
Bouchab H, Ishaq A, Limami Y, Saretzki G, Nasser B, El Kebbaj R. Antioxidant Effects of Cactus Seed Oil against Iron-Induced Oxidative Stress in Mouse Liver, Brain and Kidney. Molecules 2024; 29:4463. [PMID: 39339457 PMCID: PMC11433720 DOI: 10.3390/molecules29184463] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
In recent times, exploring the protective potential of medicinal plants has attracted increasing attention. To fight reactive oxygen species (ROS), which are key players in hepatic, cerebral and renal diseases, scientists have directed their efforts towards identifying novel compounds with antioxidant effects. Due to its unique composition, significant attention has been given to Cactus Seed Oil (CSO). Iron, as a metal, can be a potent generator of reactive oxygen species, especially hydroxyl radicals, via the Fenton and Haber-Weiss reactions. Here, we employed ferrous sulfate (FeSO4) to induce oxidative stress and DNA damage in mice. Then, we used CSO and Colza oil (CO) and evaluated the levels of the antioxidants (superoxide dismutase [SOD], glutathione peroxidase [GPx] and glutathione [GSH]) as well as a metabolite marker for lipid peroxidation (malondialdehyde [MDA]) relating to the antioxidant balance in the liver, brain and kidney. In addition, we measured DNA damage levels in hepatic tissue and the effects of CSO on it. Our study found that iron-dependent GPx activity decreases in the liver and the kidney tissues. Additionally, while iron decreased SOD activity in the liver, it increased it in the kidney. Interestingly, iron treatment resulted in a significant increase in hepatic MDA levels. In contrast, in brain tissue, there was a significant decrease under iron treatment. In addition, we found varying protective effects of CSO in alleviating oxidative stress in the different tissues with ameliorating DNA damage after iron overload in a mouse liver model, adding compelling evidence to the protective potential of CSO.
Collapse
Affiliation(s)
- Habiba Bouchab
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University of Settat, Settat 26000, Morocco; (H.B.); (Y.L.)
- Higher Institute of Nursing Professions and Technical Health (ISPITS), Errachidia 52000, Morocco
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Science and Technology, Hassan First University of Settat, Settat 26000, Morocco;
- Biosciences Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE2 4HH, UK; (A.I.); (G.S.)
| | - Abbas Ishaq
- Biosciences Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE2 4HH, UK; (A.I.); (G.S.)
| | - Youness Limami
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University of Settat, Settat 26000, Morocco; (H.B.); (Y.L.)
| | - Gabriele Saretzki
- Biosciences Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE2 4HH, UK; (A.I.); (G.S.)
| | - Boubker Nasser
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Science and Technology, Hassan First University of Settat, Settat 26000, Morocco;
| | - Riad El Kebbaj
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University of Settat, Settat 26000, Morocco; (H.B.); (Y.L.)
| |
Collapse
|
|
3
|
Jia CL, Li BL, Zhao ZH, Zhang Z, Qi-Chen, Song JX, Gou Y, Gao SY, Sun CS, He Y, Ji ES, Zhao Y. Rosmarinic Acid Liposomes Downregulate Hepcidin Expression via BMP6-SMAD1/5/8 Pathway in Mice with Iron Overload. Appl Biochem Biotechnol 2024; 196:6028-6044. [PMID: 38175414 DOI: 10.1007/s12010-023-04828-9] [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] [Accepted: 12/19/2023] [Indexed: 01/05/2024]
Abstract
The objective of this study is to examine the potential protective effect of rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on hepatic damage induced by iron overload. The characteristics, stability, and release of RosA-LIP in vitro were identified. The mice were randomly assigned to five groups: Control, Model, Model+DFO (DFO), Model+RosA (RosA), and Model+RosA-LIP (RosA-LIP). The iron overload model was induced by administering iron dextran (i.p.). The DFO, RosA, and RosA-LIP groups received iron dextran and were subsequently treated with DFO, RosA, and RosA-LIP for 14 days. We developed a novel formulation of RosA-LIP that exhibited stability and controlled release properties. Firstly, RosA-LIP improved liver function and ameliorated pathological changes in a mouse model of iron overload. Secondly, RosA-LIP demonstrated the ability to enhance the activities of T-SOD, GSH-Px, and CAT, while reducing the levels of MDA and 4-HNE, thereby effectively mitigating oxidative stress damage induced by iron overload. Thirdly, RosA-LIP reduced hepatic iron levels by downregulating FTL, FTH, and TfR1 levels. Additionally, RosA-LIP exerted a suppressive effect on hepcidin expression through the BMP6-SMAD1/5/8 signaling pathway. Furthermore, RosA-LIP upregulated FPN1 expression in both the liver and duodenum, thereby alleviating iron accumulation in these organs in mice with iron overload. Notably, RosA exhibited a comparable iron chelation effect, and RosA-LIP demonstrated superior efficacy in mitigating liver damage induced by excessive iron overload. RosA-LIP exhibited favorable sustained release properties, targeted delivery, and efficient protection against iron overload-induced liver damage.
Collapse
Affiliation(s)
- Cui-Ling Jia
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Bo-Liang Li
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Zi-Hao Zhao
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Pharmaceutical College, Hebei University of Chinese Medicine, Shijiazhuang City, 050200, Hebei Province, China
| | - Zhi Zhang
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Qi-Chen
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Ji-Xian Song
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Yujing Gou
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Si-Yu Gao
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Chen-Sha Sun
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Yingna He
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Pharmaceutical College, Hebei University of Chinese Medicine, Shijiazhuang City, 050200, Hebei Province, China.
- Hebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, 050200, Hebei, China.
| | - En-Sheng Ji
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China.
| | - Yashuo Zhao
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China.
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang, 050013, China.
| |
Collapse
|
|
4
|
Zhang Y, Chen Z, Chen L, Dong Q, Yang DH, Zhang Q, Zeng J, Wang Y, Liu X, Cui Y, Li M, Luo X, Zhou C, Ye M, Li L, He Y. Astragali radix (Huangqi): a time-honored nourishing herbal medicine. Chin Med 2024; 19:119. [PMID: 39215362 PMCID: PMC11363671 DOI: 10.1186/s13020-024-00977-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Astragali radix (AR, namded Huangqi in Chinese) is the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. As a widely used ethnomedicine, the biological activities of AR include immunomodulatory, anti-hyperglycemic, anti-oxidant, anti-aging, anti-inflammatory, anti-viral, anti-tumor, cardioprotective, and anti-diabetic effects, with minimum side effects. Currently, it is known that polysaccharides, saponins, and flavonoids are the indispensable components of AR. In this review, we will elaborate the research advancements of AR on ethnobotany, ethnopharmacological practices, phytochemicals, pharmacological activities, clinical uses, quality control, production developments, and toxicology. The information is expected to assist clinicians and scientists in developing useful therapeutic medicines with minimal systemic side effects.
Collapse
Affiliation(s)
- Yuyu Zhang
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Zhejie Chen
- Institute of Molecular Medicine (IMM), Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Liping Chen
- School of Comprehensive Health Management, Xihua University, Chengdu, 610039, China
| | - Qin Dong
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Dong-Hua Yang
- New York College of Traditional Chinese Medicine, Mineola, NY, 11501, USA
| | - Qi Zhang
- Pengzhou Hospital of Traditional Chinese Medicine, Pengzhou, 611930, China
| | - Jing Zeng
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Yang Wang
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Xiao Liu
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Yuan Cui
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Minglong Li
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Xiao Luo
- Chengdu Institute for Drug Control, NMPA Key Laboratory for Quality Monitoring and Evaluation of Traditional Chinese Medicine, Chengdu, 610045, China
| | - Chongjian Zhou
- HuBei Guizhenyuan Chinese Herbal Medicine Co.Ltd., Hong'an, 438400, China
| | - Mingzhu Ye
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China
| | - Ling Li
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China.
- Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
| | - Yuxin He
- School of Food and Bioengineering, Xihua University, Chengdu, 610039, China.
| |
Collapse
|
|
5
|
Lai Y, Gao FF, Ge RT, Liu R, Ma S, Liu X. Metal ions overloading and cell death. Cell Biol Toxicol 2024; 40:72. [PMID: 39162885 PMCID: PMC11335907 DOI: 10.1007/s10565-024-09910-4] [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: 04/10/2024] [Accepted: 08/06/2024] [Indexed: 08/21/2024]
Abstract
Cell death maintains cell morphology and homeostasis during development by removing damaged or obsolete cells. The concentration of metal ions whithin cells is regulated by various intracellular transporters and repositories to maintain dynamic balance. External or internal stimuli might increase the concentration of metal ions, which results in ions overloading. Abnormal accumulation of large amounts of metal ions can lead to disruption of various signaling in the cell, which in turn can produce toxic effects and lead to the occurrence of different types of cell deaths. In order to further study the occurrence and development of metal ions overloading induced cell death, this paper reviewed the regulation of Ca2+, Fe3+, Cu2+ and Zn2+ metal ions, and the internal mechanism of cell death induced by overloading. Furthermore, we found that different metal ions possess a synergistic and competitive relationship in the regulation of cell death. And the enhanced level of oxidative stress was present in all the processes of cell death due to metal ions overloading, which possibly due to the combination of factors. Therefore, this review offers a theoretical foundation for the investigation of the toxic effects of metal ions, and presents innovative insights for targeted regulation and therapeutic intervention. HIGHLIGHTS: • Metal ions overloading disrupts homeostasis, which in turn affects the regulation of cell death. • Metal ions overloading can cause cell death via reactive oxygen species (ROS). • Different metal ions have synergistic and competitive relationships for regulating cell death.
Collapse
Affiliation(s)
- Yun Lai
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Fen Fen Gao
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Ruo Ting Ge
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Rui Liu
- School of Public Health, Wenzhou Medical University, Wenzhou, China
| | - Shumei Ma
- School of Public Health, Wenzhou Medical University, Wenzhou, China.
| | - Xiaodong Liu
- School of Public Health, Wenzhou Medical University, Wenzhou, China.
- South Zhejiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Watershed Science and Health of Zhejiang Province, Wenzhou Medical University, Wenzhou, China.
| |
Collapse
|
|
6
|
Liu G, Wang YH, Zhang T, Li YQ, Chen XY, Dong W, Li W, Miao QX, Qiao WB, Tian HQ, Yin SL. Astragaloside-IV promotes autophagy via the Akt/mTOR pathway to improve cellular lipid deposition. Medicine (Baltimore) 2024; 103:e37846. [PMID: 38640324 PMCID: PMC11030007 DOI: 10.1097/md.0000000000037846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/22/2024] [Accepted: 03/19/2024] [Indexed: 04/21/2024] Open
Abstract
The current study aimed to investigate the potential role of astragaloside IV (AS-IV) in improving cellular lipid deposition and its underlying mechanism. A fatty liver cell model was established by treating hepatoma cells with palmitic acid. AS-IV and SC79 were used for treatment. Oil Red O staining was applied to detect intracellular lipid deposition, and transmission electron microscopy was utilized to assess autophagosome formation. Immunofluorescence double staining was applied to determine microtubule-associated proteins 1A/1B light chain 3 (LC3) expression. Western blot analysis was performed to detect the expression of LC3, prostacyclin, Beclin-1, V-akt murine thymoma viral oncogene homolog (Akt), phosphorylated Akt, mTOR, and phosphorylated mTOR. Oil Red O staining revealed that AS-IV reduced intracellular lipid accumulation. Further, it increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in the cells. It also reduced the phosphorylation levels of Akt and mTOR and the levels of prostacyclin. However, the effects of AS-IV decreased with SC79 treatment. In addition, LC3B + BODIPY493/503 fluorescence double staining showed that AS-IV reduced intracellular lipid deposition levels by enhancing autophagy. AS-IV can reduce lipid aggregation in fatty liver cells, which can be related to enhanced hepatocyte autophagy by inhibiting the Akt/mTOR signaling pathway.
Collapse
Affiliation(s)
- Guo Liu
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Ye-Hui Wang
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
- Sichuan Province Orthopedic Hospital, Chengdu, Sichuan, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Ting Zhang
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Ya-Qiong Li
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Xin-Yue Chen
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Wei Dong
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Wei Li
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Qi-Xiang Miao
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Wen-Bo Qiao
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Hui-Qiang Tian
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| | - Shi-Long Yin
- Qionglai Hospital of Traditional Chinese Medicine, Qionglai, Chengdu, Sichuan, China
| |
Collapse
|
|
7
|
Liu Y, Li G, Lu F, Guo Z, Cai S, Huo T. Excess iron intake induced liver injury: The role of gut-liver axis and therapeutic potential. Biomed Pharmacother 2023; 168:115728. [PMID: 37864900 DOI: 10.1016/j.biopha.2023.115728] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 10/23/2023] Open
Abstract
Excessive iron intake is detrimental to human health, especially to the liver, which is the main organ for iron storage. Excessive iron intake can lead to liver injury. The gut-liver axis (GLA) refers to the bidirectional relationship between the gut and its microbiota and the liver, which is a combination of signals generated by dietary, genetic and environmental factors. Excessive iron intake disrupts the GLA at multiple interconnected levels, including the gut microbiota, gut barrier function, and the liver's innate immune system. Excessive iron intake induces gut microbiota dysbiosis, destroys gut barriers, promotes liver exposure to gut microbiota and its derived metabolites, and increases the pro-inflammatory environment of the liver. There is increasing evidence that excess iron intake alters the levels of gut microbiota-derived metabolites such as secondary bile acids (BAs), short-chain fatty acids, indoles, and trimethylamine N-oxide, which play an important role in maintaining homeostasis of the GLA. In addition to iron chelators, antioxidants, and anti-inflammatory agents currently used in iron overload therapy, gut barrier intervention may be a potential target for iron overload therapy. In this paper, we review the relationship between excess iron intake and chronic liver diseases, the regulation of iron homeostasis by the GLA, and focus on the effects of excess iron intake on the GLA. It has been suggested that probiotics, fecal microbiota transfer, farnesoid X receptor agonists, and microRNA may be potential therapeutic targets for iron overload-induced liver injury by protecting gut barrier function.
Collapse
Affiliation(s)
- Yu Liu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Guangyan Li
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Fayu Lu
- School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Ziwei Guo
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China
| | - Shuang Cai
- The First Affiliated Hospital of China Medical University, Shenyang 110001, China.
| | - Taoguang Huo
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China; Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China.
| |
Collapse
|
|
8
|
Bouchab H, Essadek S, El Kamouni S, Moustaid K, Essamadi A, Andreoletti P, Cherkaoui-Malki M, El Kebbaj R, Nasser B. Antioxidant Effects of Argan Oil and Olive Oil against Iron-Induced Oxidative Stress: In Vivo and In Vitro Approaches. Molecules 2023; 28:5924. [PMID: 37570894 PMCID: PMC10420636 DOI: 10.3390/molecules28155924] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 08/13/2023] Open
Abstract
Recently, the study of the protective powers of medicinal plants has become the focus of several studies. Attention has been focused on the identification of new molecules with antioxidant and chelating properties to counter reactive oxygen species (ROS) involved as key elements in several pathologies. Considerable attention is given to argan oil (AO) and olive oil (OO) due to their particular composition and preventive properties. Our study aimed to determine the content of AO and OO on phenolic compounds, chlorophylls, and carotenoid pigments and their antioxidant potential by FRAP and DPPH tests. Thus, several metallic elements can induce oxidative stress, as a consequence of the formation of ROS. Iron is one of these metal ions, which participates in the generation of free radicals, especially OH from H2O2 via the Fenton reaction, initiating oxidative stress. To study the antioxidant potential of AO and OO, we evaluated their preventives effects against oxidative stress induced by ferrous sulfate (FeSO4) in the protozoan Tetrahymena pyriformis and mice. Then, we evaluated the activities of the enzymatic (superoxide dismutase (SOD), glutathione peroxidase (GPx)) and metabolite markers (lipid peroxidation (MDA) and glutathione (GSH)) of the antioxidant balance. The results of the antioxidant compounds show that both oils contain phenolic compounds and pigments. Moreover, AO and OO exhibit antioxidant potential across FRAP and DPPH assays. On the other hand, the results in Tetrahymena pyriformis and mice show a variation in the level of iron-changed SOD and GPx activities and MDA and GSH levels. By contrast, treating Tetrahymena pyriformis and mice with argan and olive oils shows significant prevention in the SOD and GPx activities. These results reveal that the iron-changed ROS imbalance can be counteracted by AO and OO, which is probably related to their composition, especially their high content of polyphenols, sterols, and tocopherols, which is underlined by their antioxidant activities.
Collapse
Affiliation(s)
- Habiba Bouchab
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences and Technologies, Hassan First University, Settat 26000, Morocco; (H.B.); (S.E.); (S.E.K.); (A.E.)
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University, Settat 26000, Morocco
| | - Soukaina Essadek
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences and Technologies, Hassan First University, Settat 26000, Morocco; (H.B.); (S.E.); (S.E.K.); (A.E.)
- Bio-PeroxIL Laboratory, EA7270, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France; (P.A.); (M.C.-M.)
| | - Soufiane El Kamouni
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences and Technologies, Hassan First University, Settat 26000, Morocco; (H.B.); (S.E.); (S.E.K.); (A.E.)
| | - Khadija Moustaid
- Laboratory of Applied Chemistry and Environment, Faculty of Sciences and Technologies, Hassan First University, Settat 26000, Morocco;
| | - Abdelkhalid Essamadi
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences and Technologies, Hassan First University, Settat 26000, Morocco; (H.B.); (S.E.); (S.E.K.); (A.E.)
| | - Pierre Andreoletti
- Bio-PeroxIL Laboratory, EA7270, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France; (P.A.); (M.C.-M.)
| | - Mustapha Cherkaoui-Malki
- Bio-PeroxIL Laboratory, EA7270, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France; (P.A.); (M.C.-M.)
| | - Riad El Kebbaj
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University, Settat 26000, Morocco
| | - Boubker Nasser
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences and Technologies, Hassan First University, Settat 26000, Morocco; (H.B.); (S.E.); (S.E.K.); (A.E.)
| |
Collapse
|
|
9
|
Ezzat GM, Nassar AY, Bakr MH, Mohamed S, Nassar GA, Kamel AA. Acetylated Oligopeptide and N-acetyl cysteine Protected Against Oxidative Stress, Inflammation, Testicular-Blood Barrier Damage, and Testicular Cell Death in Iron-Overload Rat Model. Appl Biochem Biotechnol 2023; 195:5053-5071. [PMID: 36947366 DOI: 10.1007/s12010-023-04457-2] [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] [Accepted: 03/15/2023] [Indexed: 03/23/2023]
Abstract
Multiple organs, including the testes, are damaged by iron overload. It has been shown that N-acetyl cysteine (NAC) influences oxidative stress in iron overload. The present study aimed to evaluate the roles of acetylated peptide (AOP) and NAC in the inhibition of iron-overload induced-testicular damage. At the beginning of the experiment, NAC (150 mg /kg) was given for a week to all 40 rats. Then, four groups were formed by dividing the animals (10 rats/group). Group I included healthy control rats. Group II (iron overload) was given intraperitoneal iron dextran (60 mg/kg/day) 5 days a week for 4 weeks. Group III (NAC) was given NAC orally at a dose of 150 mg/kg/day for 4 weeks in addition to iron dextran. Group IV (AOP) was given AOP orally at a dose of 150 mg/kg/day for 4 weeks besides iron dextran. When the experiment time was over, testosterone serum level, testicular B cell lymphoma-2 (BCL-2) and protein kinase B (PKB) protein levels, nuclear factor kappa-B (NF-κB), and Beclin1 mRNA expression levels, and malondialdehyde (MDA), and reduced glutathione (GSH) were determined by ELISA, quantitative reverse transcription-PCR, and chemical methods. Finally, histopathological examinations and immunohistochemical detection of claudin-1 and CD68 were performed. The iron overload group exhibited decreased testosterone, BCL-2, PKB, claudin-1, and GSH and increased MDA, NF-κB, Beclin1, and CD68, while both NAC and AOP treatments protected against the biochemical and histopathological disturbances occurring in the iron overload model. We concluded that NAC and AOP can protect against testes damage by iron overload via their antioxidant, anti-inflammatory, antiapoptotic, and ant-autophagic properties. The NAC and AOP may be used as preventative measures against iron overload-induced testicular damage.
Collapse
Affiliation(s)
- Ghada M Ezzat
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Ahmed Y Nassar
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Marwa H Bakr
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shimma Mohamed
- Department of Medical Biochemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Gamal A Nassar
- Metabolic and Genetic disorders unit, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Amira A Kamel
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| |
Collapse
|
|
10
|
Ghasemi F, Ghaffari F, Omidifar N, Taheri Azandaryani M, Nili-Ahmadabadi A. Hepatic Response to the Interaction Between Thymoquinone and Iron-Dextran: an In Vitro and In Vivo Study. Biol Trace Elem Res 2023; 201:1358-1367. [PMID: 35484332 DOI: 10.1007/s12011-022-03249-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/15/2022] [Indexed: 02/07/2023]
Abstract
Iron is one of the most important essential elements for cell function. However, iron overload can exert destructive effects on various tissues, especially the liver. The present study was designed to evaluate the effect of thymoquinone (TQ) on hepatotoxicity induced by iron-overload in in vitro and mouse model. After in vitro studies, thirty mice were divided into five groups, six each. Group 1 received normal saline. Group 2 received five doses of iron dextran (i.p; 100 mg/kg, one dose every 2 days). Group 3 received TQ (orally, 2 mg/kg/day). Groups 4 and 5 were administrated iron dextran saline (i.p; 100 mg/kg, one dose every 2 days) following treatment with 0.5 and 2 mg/kg/day of TQ, respectively. Based on the findings of the DPPH experiment, although TQ has significant anti-radical potential, at a safe dose of 15 × 10+3 nM, it reduced the IC50 of iron dextran on HepG2 cells by about 25%, in in vitro. Following administration of low-dose TQ (0.5 mg/kg), a significant improvement was observed in serum hepatic enzymes activity and hepatic lipid peroxidation compared to iron dextran. However, administration of TQ-high dose (2 mg/kg) led to decrease antioxidant defense alongside increased serum hepatic enzymes and pathological damages in iron dextran-treated animals. Due to the different efficacy of TQ in treatment groups, it seems that the TQ therapeutic index is low and does not have significant safety in the iron overload status.
Collapse
Affiliation(s)
- Farzad Ghasemi
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Faculty of Pharmacy, Eastern Mediterranean University, 99628, Via Mersin 10, Famagusta, North Cyprus, Turkey
| | - Fatemeh Ghaffari
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Navid Omidifar
- Medical Education Research Center, Department of Pathology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Amir Nili-Ahmadabadi
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
| |
Collapse
|
|
11
|
Fan G, Li F, Wang P, Jin X, Liu R. Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases. Int J Mol Sci 2022; 23:ijms232315109. [PMID: 36499429 PMCID: PMC9739742 DOI: 10.3390/ijms232315109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/11/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022] Open
Abstract
Autophagy is essential for the maintenance of hepatic homeostasis, and autophagic malfunction has been linked to the pathogenesis of substantial liver diseases. As a popular source of drug discovery, natural products have been used for centuries to effectively prevent the progression of various liver diseases. Emerging evidence has suggested that autophagy regulation is a critical mechanism underlying the therapeutic effects of these natural products. In this review, relevant studies are retrieved from scientific databases published between 2011 and 2022, and a novel scoring system was established to critically evaluate the completeness and scientific significance of the reviewed literature. We observed that numerous natural products were suggested to regulate autophagic flux. Depending on the therapeutic or pathogenic role autophagy plays in different liver diseases, autophagy-regulative natural products exhibit different therapeutic effects. According to our novel scoring system, in a considerable amount of the involved studies, convincing and reasonable evidence to elucidate the regulatory effects and underlying mechanisms of natural-product-mediated autophagy regulation was missing and needed further illustration. We highlight that autophagy-regulative natural products are valuable drug candidates with promising prospects for the treatment of liver diseases and deserve more attention in the future.
Collapse
Affiliation(s)
- Guifang Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Fanghong Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Ping Wang
- Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xuejing Jin
- Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
- Correspondence: (X.J.); (R.L.); Tel.: +86-15632374331 (X.J.); +86-10-53912122 (R.L.)
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
- Correspondence: (X.J.); (R.L.); Tel.: +86-15632374331 (X.J.); +86-10-53912122 (R.L.)
| |
Collapse
|
|
12
|
Yang Y, Hong M, Lian WW, Chen Z. Review of the pharmacological effects of astragaloside IV and its autophagic mechanism in association with inflammation. World J Clin Cases 2022; 10:10004-10016. [PMID: 36246793 PMCID: PMC9561601 DOI: 10.12998/wjcc.v10.i28.10004] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 05/23/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
Astragalus membranaceus Bunge, known as Huangqi, has been used to treat various diseases for a long time. Astragaloside IV (AS-IV) is one of the primary active ingredients of the aqueous Huangqi extract. Many experimental models have shown that AS-IV exerts broad beneficial effects on cardiovascular disease, nervous system diseases, lung disease, diabetes, organ injury, kidney disease, and gynaecological diseases. This review demonstrates and summarizes the structure, solubility, pharmacokinetics, toxicity, pharmacological effects, and autophagic mechanism of AS-IV. The autophagic effects are associated with multiple signalling pathways in experimental models, including the PI3KI/Akt/mTOR, PI3K III/Beclin-1/Bcl-2, PI3K/Akt, AMPK/mTOR, PI3K/Akt/mTOR, SIRT1–NF-κB, PI3K/AKT/AS160, and TGF-β/Smad signalling pathways. Based on this evidence, AS-IV could be used as a replacement therapy for treating the multiple diseases referenced above.
Collapse
Affiliation(s)
- Ying Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Meng Hong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Wen-Wen Lian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| |
Collapse
|
|
13
|
Roots of Astragalus propinquus Schischkin Regulate Transmembrane Iron Transport and Ferroptosis to Improve Cerebral Ischemia-Reperfusion Injury. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:7410865. [PMID: 35958925 PMCID: PMC9363172 DOI: 10.1155/2022/7410865] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022]
Abstract
Background The dried roots of the Astragalus propinquus Schischkin (RAP) plant, as a traditional Chinese medicine, has been widely used to treat stroke, cerebral ischemia, qi deficiency, and hypertension. Buyang Huanwu decoction is traditionally used to treat stroke in China for more than 200 years and has a significant effect on cerebral ischemia, and RAP is monarch medicine of Buyang Huanwu decoction. Therefore, this study was designed to observe the regulatory effect of RAP on transmembrane iron transporters and ferroptosis-related factors in cerebral ischemia-reperfusion injury (CIRI) in rats. Methods Middle cerebral artery occlusion (MCAO) was used to block blood flow in the blood supply area of the middle cerebral artery in seventy male SD rats to induce focal CIRI to establish a rat model of CIRI. RAP was administered to explore the regulatory effect of RAP on iron transmembrane transport under the condition of CIRI. The infarct size was measured using 2,3,5-triphenyl-tetrazolium chloride (TTC) staining, the pathological structure of brain tissue was observed by HE staining, and neuronal injury was evaluated by Nissl staining after treatment. Then, changes in the iron transporters ferritin (Fn), ferritin heavy chain (FHC), ferritin light chain (FLC), transferrin (Tf), transferrin receptor (TfR), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), transient receptor potential canonical 6 (TRPC6), and ferroportin 1 (FPN1) were observed by immunohistochemistry staining (IHC) and Western blotting. The expression of key factors of ferroptosis, including the membrane sodium-dependent cystine/glutamate antiporter System Xc− (System Xc−) light chain subunit (XCT) and heavy chain subunit (SLC3A2), glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2), heme oxygenase-1 (HO-1), and iron-responsive element-binding protein 2 (IREB2) in the brain tissues of rats was assessed by Western blotting. RAP decreased the infarct size and neuronal injury after CIRI in rats. Similarly, RAP treatment regulated the expression of iron transporters. As such, RAP was able to reduce the expression of Fn, FHC, FLC, Tf, TfR, DMT1, and TRPC6 and increase the expression of FPN1 through a Tf/TfR-independent pathway after CIRI in rats. Conclusion RAP stimulation inhibited ferroptosis by regulating the expression of the key ferroptosis factors XCT, SLC3A2, GPX4, NRF2, HO-1, and IREB2. In conclusion, RAP regulates transmembrane iron transport and ferroptosis to improve CIRI.
Collapse
|
|
14
|
Qin LY, Guan P, Wang JX, Chen Y, Zhao YS, Yang SC, Guo YJ, Wang N, Ji ES. Therapeutic Potential of Astragaloside IV Against Adriamycin-Induced Renal Damage in Rats via Ferroptosis. Front Pharmacol 2022; 13:812594. [PMID: 35370757 PMCID: PMC8971812 DOI: 10.3389/fphar.2022.812594] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/21/2022] [Indexed: 11/29/2022] Open
Abstract
Adriamycin (ADR) has been utilized to treat cancer for several decades. However, ADR-induced renal injury is one of the most common side effects accompanying ADR therapy. In the present study, we revealed that astragaloside IV (ASIV) was beneficial for renal injury caused by Adriamycin. We demonstrated that ASIV significantly ameliorated kidney injury, improved renal dysfunction, reduced oxidative stress, alleviated iron accumulation, and inhibited the induction of ferroptosis by ADR. ASIV also rescued the intracellular levels of nuclear factor-erythroid-2-related factor 2 (Nrf2) and promoted nuclear translocation of Nrf2. These protective effects of ASIV on renal injury might be attained through the ASIV-induced activation of the Pi3K/Akt signaling pathway. In vitro, the treatment of the HK-2 cells with fer-1 or deferoxamine mesylate obviously improved cell viability during Adriamycin administration. On the other hand, the protective role of ASIV can be abrogated by RSL3 to some extent. Moreover, ASIV lowered the expression of transferrin receptor 1 and divalent metal transporter 1 while enhancing the expression of ferropotin 1 and glutathione peroxidase 4 in ADR administrated cells, the effects of which were akin to those of deferoxamine mesylate. Furthermore, ASIV increased the phosphorylation of Pi3K, Akt, and the expression of Nrf2 and glutathione peroxidase 4 compared to HK-2 cells stimulated by ADR. However, Pi3K inhibitor LY294002 abrogated these activations. In conclusion, ferroptosis may involve in ADR-induced nephrotoxicity, and ASIV might protect nephrocytes against ADR-induced ferroptosis, perhaps via activations of the Pi3K/Akt and Nrf2 signaling pathways.
Collapse
Affiliation(s)
- Lu-Yun Qin
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Peng Guan
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
- College of Life Science, Hebei Normal University, Shijiazhuang, China
| | - Jian-Xin Wang
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yu Chen
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Ya-Shuo Zhao
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Sheng-Chang Yang
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Ya-Jing Guo
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Na Wang
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Technology Innovation Center of TCM Formula Preparations, Shijiazhuang, China
- *Correspondence: Na Wang, ; En-Sheng Ji,
| | - En-Sheng Ji
- Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Technology Innovation Center of TCM Formula Preparations, Shijiazhuang, China
- *Correspondence: Na Wang, ; En-Sheng Ji,
| |
Collapse
|
|
15
|
Xu G, Li X, Zhu Z, Wang H, Bai X. Iron Overload Induces Apoptosis and Cytoprotective Autophagy Regulated by ROS Generation in Mc3t3-E1 Cells. Biol Trace Elem Res 2021; 199:3781-3792. [PMID: 33405076 DOI: 10.1007/s12011-020-02508-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/19/2020] [Indexed: 12/18/2022]
Abstract
Iron overload has been found very common in diseases such as hereditary hemochromatosis, thalassemia, and sickle cell disease and in healthy postmenopausal women. Recent studies have shown that iron overload is considered an independent risk factor for osteoporosis. Studies have demonstrated that iron overload could induce apoptosis and inhibit viability in osteoblasts. However, the underlying mechanism still remains poorly understood. The purpose of the present study is to investigate possible mechanism of iron overload-induced apoptosis, and the roles autophagy and reactive oxygen species (ROS) played under iron overload conditions. Ferric ammonium citrate (FAC) (100-1600 μM) was utilized as iron donor to induce iron overload conditions. Intracellular iron concentration was measured using Iron Assay Kit. The viability was assessed by CCK-8 assay. Cell apoptosis was examined using Annexin V-FITC/PI staining with a flow cytometry, and levels of Bax, Bcl-2, cleaved caspase-3, and cleaved PARP were evaluated with Western blot. Cell autophagy was detected by evaluating LC3 with immunofluorescence and Western blot. The expressions of Beclin-1 and P62 were also assessed with Western blot. The intracellular ROS level was evaluated using a DCFH-DA probe with a flow cytometry, and NADPH oxidase 4 (Nox4) expressions were assessed with Western blot. Our results showed that FAC increased intracellular iron concentration and significantly inhibited cell viability. Furthermore, iron overload induced apoptosis and autophagy in osteoblast cells. What's more, pretreatment with autophagy inhibitor chloroquine (CQ) enhanced iron overload-induced osteoblast apoptosis via the activation of caspases. Moreover, iron overload increased ROS production and Nox4 expression. Inhibition of autophagy increased ROS production, and scavenging of ROS by antioxidant N-Acetyl-L-cysteine (NAC) inhibited caspases activity and rescued iron overload-induced apoptosis. These results suggested that autophagy exerted cytoprotective effect, and scavenging excessive intracellular ROS could be a novel approach for the treatment of iron overload-induced osteoporosis.
Collapse
Affiliation(s)
- Guanpeng Xu
- Department of Sports Medicine and Joint Surgery, The People's Hospital of China Medical University, 33 Wenyi Road, Shenhe District, Shenyang, 110016, People's Republic of China
| | - Xi Li
- Department of Sports Medicine and Joint Surgery, The People's Hospital of China Medical University, 33 Wenyi Road, Shenhe District, Shenyang, 110016, People's Republic of China
| | - Zhiyong Zhu
- Department of Sports Medicine and Joint Surgery, The People's Hospital of China Medical University, 33 Wenyi Road, Shenhe District, Shenyang, 110016, People's Republic of China
| | - Huisheng Wang
- Department of Sports Medicine and Joint Surgery, The People's Hospital of China Medical University, 33 Wenyi Road, Shenhe District, Shenyang, 110016, People's Republic of China
| | - Xizhuang Bai
- Department of Sports Medicine and Joint Surgery, The People's Hospital of China Medical University, 33 Wenyi Road, Shenhe District, Shenyang, 110016, People's Republic of China.
| |
Collapse
|
|
16
|
Lee GS, Jeong HY, Yang HG, Seo YR, Jung EG, Lee YS, Nam KW, Kim WJ. Astragaloside IV Suppresses Hepatic Proliferation in Regenerating Rat Liver after 70% Partial Hepatectomy via Down-Regulation of Cell Cycle Pathway and DNA Replication. Molecules 2021; 26:2895. [PMID: 34068164 PMCID: PMC8152973 DOI: 10.3390/molecules26102895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022] Open
Abstract
Astragaloside IV (AS-IV) is one of the major bio-active ingredients of huang qi which is the dried root of Astragalus membranaceus (a traditional Chinese medicinal plant). The pharmacological effects of AS-IV, including anti-oxidative, anti-cancer, and anti-diabetic effects have been actively studied, however, the effects of AS-IV on liver regeneration have not yet been fully described. Thus, the aim of this study was to explore the effects of AS-IV on regenerating liver after 70% partial hepatectomy (PHx) in rats. Differentially expressed mRNAs, proliferative marker and growth factors were analyzed. AS-IV (10 mg/kg) was administrated orally 2 h before surgery. We found 20 core genes showed effects of AS-IV, many of which were involved with functions related to DNA replication during cell division. AS-IV down-regulates MAPK signaling, PI3/Akt signaling, and cell cycle pathway. Hepatocyte growth factor (HGF) and cyclin D1 expression were also decreased by AS-IV administration. Transforming growth factor β1 (TGFβ1, growth regulation signal) was slightly increased. In short, AS-IV down-regulated proliferative signals and genes related to DNA replication. In conclusion, AS-IV showed anti-proliferative activity in regenerating liver tissue after 70% PHx.
Collapse
Affiliation(s)
- Gyeong-Seok Lee
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Hee-Yeon Jeong
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Hyeon-Gung Yang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Chungcheongnam-do, Korea;
| | - Young-Ran Seo
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Eui-Gil Jung
- Seoul Center, Korea Basic Science Institute, Seoul 02855, Korea;
| | - Yong-Seok Lee
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Kung-Woo Nam
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Wan-Jong Kim
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| |
Collapse
|
|
17
|
Bouchab H, Ishaq A, El Kebbaj R, Nasser B, Saretzki G. Protective effect of argan oil on DNA damage in vivo and in vitro. Biomarkers 2021; 26:425-433. [PMID: 33843382 DOI: 10.1080/1354750x.2021.1905068] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: Iron-overload is a well-known cause for the development of chronic liver diseases and known to induce DNA damage.Material and methods: The protective effect of argan oil (AO) from the Argania spinosa fruit and olive oil (OO) (6% AO or OO for 28 days) was evaluated on a mouse model of iron overload (3.5mg Fe2+/liter) and in human fibroblasts where DNA damage was induced via culture under hyperoxia (40% oxygen).Results: Iron treatment induced DNA damage in liver tissue while both oils were able to decrease it. We confirmed this effect in vitro in MRC-5 fibroblasts under hyperoxia. A cell-free ABTS assay suggested that improvement of liver toxicity by both oils might depend on a high content in tocopherol, phytosterol and polyphenol compounds known for their antioxidant potential. The antioxidant effect of AO was confirmed in fibroblasts by reduced intracellular peroxide levels after hyperoxia. However, we could not find a significant decrease of genes encoding pro-inflammatory cytokines (TNFα, IL-6, IL-1β, COX-2) or senescence markers (p16 and p21) for the oils in mouse liver.Conclusion: We found a striking effect of AO by ameliorating DNA damage after iron overload in a mouse liver model and in human fibroblasts by hyperoxia adding compelling evidence to the protective mechanisms of AO and OO.
Collapse
Affiliation(s)
- Habiba Bouchab
- Laboratoire Biochimie, Neurosciences, Ressources naturelles et Environnement, Faculté des Sciences et Techniques, Hassan First University of Settat, Settat, Morocco.,Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Abbas Ishaq
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Riad El Kebbaj
- Laboratoire Biochimie, Neurosciences, Ressources naturelles et Environnement, Faculté des Sciences et Techniques, Hassan First University of Settat, Settat, Morocco.,Laboratory of Health Sciences and Technologies, Hassan First University of Settat, Higher Institute of Health Sciences, Settat, Morocco
| | - Boubker Nasser
- Laboratoire Biochimie, Neurosciences, Ressources naturelles et Environnement, Faculté des Sciences et Techniques, Hassan First University of Settat, Settat, Morocco
| | - Gabriele Saretzki
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| |
Collapse
|
|
18
|
Astragaloside IV protects against retinal iron overload toxicity through iron regulation and the inhibition of MAPKs and NF-κB activation. Toxicol Appl Pharmacol 2020; 410:115361. [PMID: 33285147 DOI: 10.1016/j.taap.2020.115361] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/27/2020] [Accepted: 12/01/2020] [Indexed: 12/27/2022]
Abstract
Iron overload toxicity has been implicated in retinal pigment epithelial cell injury in age-related macular degeneration. This study investigates the effects of astragaloside IV (AS-IV), a potential retinal protective agent, on the toxicity process of retinal iron overload in vivo and in vitro. AS-IV partially restored the retinal expression of rhodopsin and retinal pigment epithelium-specific 65 kDa protein, suppressed oxidative stress and inflammatory markers, and alleviated iron deposition and retinal pathological changes in vivo. Also, AS-IV inhibited the phosphorylation of p38 and ERK mitogen-activated protein kinases (MAPKs), as well as the nuclear translocation of nuclear factor-kappa B (NF-κB). Furthermore, AS-IV prevented cell death by decreasing the ratio of Bax/Bcl-2, caspase-3, and cleaved caspase-3 expression in vitro. Although there are no chelation effects between AS-IV and iron, AS-IV can reduce intracellular iron by regulating iron-handling proteins in ARPE-19 cells (Cav1.2, divalent metal transporter-1, transferrin receptor 1, and heavy-chain ferritin). In conclusion, the results show that AS-IV has significant protective effects against retinal iron overload toxicity and suggest that iron regulation and the inhibition of MAPKs and NF-κB activation might be mechanisms underlying the effects of AS-IV.
Collapse
|
|
19
|
Chemical Discrimination of Astragalus mongholicus and Astragalus membranaceus Based on Metabolomics Using UHPLC-ESI-Q-TOF-MS/MS Approach. Molecules 2019; 24:molecules24224064. [PMID: 31717584 PMCID: PMC6891664 DOI: 10.3390/molecules24224064] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 10/30/2019] [Accepted: 11/06/2019] [Indexed: 12/17/2022] Open
Abstract
Astragalus mongholicus (MG) and Astragalus membranaceus (MJ), both generally known as Huangqi in China, are two perennial herbals widely used in variety diseases. However, there were still some differences in the chemical ingredients between MG and MJ. In this paper, metabolomics combined with the ultra-high performance liquid chromatography coupled with electrospray ionization/quadrupole time-of-flight mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) was employed to contrastively analyze the chemical constituents between MG and MJ. As a result, principal component analysis showed that MG and MJ were separated clearly. A total of 53 chemical markers were successfully identified for the discrimination of MG and MJ. Of them, the contents of 36 components including Astragaloside I~III, Astragaloside IV, Agroastragaloside I, etc. in MJ were significantly higher than those in MG. On the contrary, the contents of 17 other components including coumaric acid, formononetin, sophoricoside, etc. in MG were obviously higher than those in MJ. The results showed that the distinctive constituents in MG and MJ were remarkable, and MJ may own stronger pharmacological activities than MG. In a word, MG and MJ may be treated as two different herbs. This paper demonstrated that metabolomics was a vitally credible technology to rapidly screen the characteristic chemical composition of traditional Chinese medicine.
Collapse
|