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Nazlić J, Gujinović D, Mudnić I, Boban Z, Dželalija AM, Tandara L, Gugo K, Radman M, Kovačić V, Boban M. Red wine consumption activates the erythropoietin-erythroferrone-hepcidin erythropoietic pathway in both apparently healthy individuals and patients with type 2 diabetes. Food Funct 2025; 16:1864-1871. [PMID: 39931951 DOI: 10.1039/d4fo04555f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
Alcohol consumption is associated with reduced expression of hepcidin, a key iron-regulatory hormone, which may lead to accumulation of iron in the body. Although polyphenols from wine may have effects on hepcidin expression and iron absorption contrary to that of alcohol, we recently showed that consumption of 300 ml of red wine for 3 weeks, after an alcohol-free lead-in period of 2 weeks, resulted in decreased serum hepcidin in apparently healthy individuals (n = 13) and subjects with type 2 diabetes (T2D) (n = 18). To determine the mechanism of decrease in hepcidin after wine intervention, additional biochemical analyses of spare serum samples from the same subjects were performed. The decrease in hepcidin was accompanied by increased erythropoietin levels in both groups, while the increase in erythroferrone reached statistical significance only in the T2D group. These results suggest activation of the erythropoietin-erythroferrone-hepcidin pathway by red wine consumption. As an indicator of the activation of the erythropoietin-erythroferrone-hepcidin pathway we observed an increase in the red cell distribution width in both groups and in the reticulocyte count in the T2D group, while serum ferritin decreased. Our study reveals a novel biological effect of wine that may be important in conditions influencing iron homeostasis and functions of hepcidin in general.
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Affiliation(s)
- Jurica Nazlić
- Department of Intensive Medicine and Clinical Pharmacology, University Hospital of Split, Šoltanska 1, Split 21000, Croatia
| | - Diana Gujinović
- Department of Pharmacology, University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia.
| | - Ivana Mudnić
- Department of Pharmacology, University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia.
| | - Zvonimir Boban
- Department of Medical Physics and Biophysics, University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia
| | - Ana Marija Dželalija
- Department of Pharmacology, University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia.
| | - Leida Tandara
- Department of Medical Laboratory Diagnostics, University Hospital of Split, Spinčićeva 1 and University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia
| | - Katarina Gugo
- Department of Medical Laboratory Diagnostics, University Hospital of Split, Spinčićeva 1 and University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia
| | - Maja Radman
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Split, Šoltanska 1, Split 21000, Croatia
| | - Vedran Kovačić
- Department of Intensive Medicine and Clinical Pharmacology, University Hospital of Split, Šoltanska 1, Split 21000, Croatia
| | - Mladen Boban
- Department of Pharmacology, University of Split School of Medicine, Šoltanska 2a, Split 21000, Croatia.
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Markowska J, Kasprzak-Drozd K, Niziński P, Dragan M, Kondracka A, Gondek E, Oniszczuk T, Oniszczuk A. Quercetin: A Promising Candidate for the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Molecules 2024; 29:5245. [PMID: 39598636 PMCID: PMC11596905 DOI: 10.3390/molecules29225245] [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: 09/30/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a chronic liver disease. The development of MASLD is influenced by a multitude of diseases associated with modern lifestyles, including but not limited to diabetes mellitus, hypertension, hyperlipidaemia and obesity. These conditions are often consequences of the adoption of unhealthy habits, namely a sedentary lifestyle, a lack of physical activity, poor dietary choices and excessive alcohol consumption. The treatment of MASLD is primarily based on modifying the patient's lifestyle and pharmacological intervention. Despite the absence of FDA-approved pharmacological agents for the treatment of MASLD, several potential therapeutic modalities have demonstrated efficacy in reversing the histopathological features of the disease. Among the botanical ingredients belonging to the flavonoid group is quercetin (QE). QE has been demonstrated to possess a number of beneficial physiological effects, including anti-inflammatory, anticancer and antifungal properties. Additionally, it functions as a natural antioxidant. Preclinical evidence indicates that QE may play a beneficial role in reducing liver damage and improving metabolic health. Early human studies also suggest that QE may be an effective treatment for MASLD due to its antioxidant, anti-inflammatory, and lipid-regulating properties. This review aims to summarize the available information on the therapeutic effects of QE in MASLD.
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Affiliation(s)
- Julia Markowska
- Science Circle of the Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland; (J.M.); (M.D.)
| | - Kamila Kasprzak-Drozd
- Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland;
| | - Przemysław Niziński
- Department of Pharmacology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland;
| | - Magdalena Dragan
- Science Circle of the Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland; (J.M.); (M.D.)
| | - Adrianna Kondracka
- Department of Obstetrics and Pathology of Pregnancy, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Ewa Gondek
- Department of Food Engineering and Process Management, Institute of Food Science, Warsaw University of Life Sciences, Nowoursynowska 159C, 02-776 Warsaw, Poland
| | - Tomasz Oniszczuk
- Department of Thermal Technology and Food Process Engineering, University of Life Sciences in Lublin, Głęboka 31, 20-612 Lublin, Poland;
| | - Anna Oniszczuk
- Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland;
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Liu J, Deng L, Qu L, Li X, Wang T, Chen Y, Jiang M, Zou W. Herbal medicines provide regulation against iron overload in cardiovascular diseases: Informing future applications. JOURNAL OF ETHNOPHARMACOLOGY 2024; 326:117941. [PMID: 38387684 DOI: 10.1016/j.jep.2024.117941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 02/04/2024] [Accepted: 02/18/2024] [Indexed: 02/24/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Iron is an essential micronutrient for maintaining physiological activities, especially for highly active cardiomyocytes. Inappropriate iron overload or deficiency has a significant impact on the incidence and severity of cardiovascular diseases (CVD). Iron overload exerts potentially deleterious effects on doxorubicin (DOX) cardiomyopathy, atherosclerosis, and myocardial ischemia-reperfusion injury (MI/RI) by participating in lipid peroxides production. Notably, iron overload-associated cell death has been defined as a possible mechanism for ferroptosis. At present, some traditional herbal medicines and extracts have been included in the study of regulating iron overload and the subsequent therapeutic effect on CVD. AIM OF THE STUDY To give an outline of iron metabolism and ferroptosis in cardiomyocytes and to focus on herbal medicines and extracts to prevent iron overload in CVD. MATERIALS AND METHODS Literature information was systematically collected from ScienceDirect, PubMed, Google Scholar, Web of Science, China National Knowledge Infrastructure, WanFang data, as well as classic books and clinical reports. RESULTS After understanding the mechanism of iron overload on CVD, this paper reviews the therapeutic function of various herbal medicines in eliminating iron overload in CVD. These include Chinese herbal compound prescriptions (Salvia miltiorrhiza injection, Gegen Qinlian decoction, Tongxinluo, Banxia-Houpu decoction), plant extracts, phenylpropanoids, flavonoids, terpenoids, and polyphenols. Among them, flavonoids are considered to be the most promising compounds because of their prominent iron chelation. Mechanically, these herbal medicines act on the Nrf2 signaling pathway, AMPK signaling pathway, and KAT5/GPX4 signaling pathway, thereby attenuating iron overload and lipid peroxidation in CVD. CONCLUSION Our review provides up-to-date information on herbal medicines that exert cardiovascular protective effects by modulating iron overload and ferroptosis. These herbal medicines hold promise as a template for preventing iron overload in CVD.
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Affiliation(s)
- Jia Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Liangyan Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Liping Qu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Xiaofen Li
- School of Basic Medicine Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China
| | - Tao Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Yuanyuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China
| | - Miao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
| | - Wenjun Zou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
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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.
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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.
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Liao J, Wei M, Wang J, Zeng J, Liu D, Du Q, Ge J, Mei Z. Naotaifang formula attenuates OGD/R-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through BMP6/SMADs signaling pathway. Biomed Pharmacother 2023; 167:115465. [PMID: 37713988 DOI: 10.1016/j.biopha.2023.115465] [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: 06/03/2023] [Revised: 08/16/2023] [Accepted: 09/07/2023] [Indexed: 09/17/2023] Open
Abstract
BACKGROUND Cerebral ischemia-reperfusion injury (CIRI), a subsequent injury caused by thrombolytic reperfusion post ischemic stroke (IS). Naotaifang (NTF) formula, a novel traditional Chinese medicine (TCM) remedy against IS, was shown to exert beneficial effects in inhibiting inflammation and inhibiting lipid peroxide synthesis in our previous research. PURPOSE This study aimed to further explore the role of NTF in attenuating oxygen-glucose deprivation//reoxygenation (OGD/R)-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through the bone morphogenetic protein 6（BMP6）/SMADs signaling pathway. METHODS BV2 microglia were used to establish an OGD/R model. The effects of NTF on inflammation and ferroptosis in OGD/R-injured BV2 cells were separately detected by immunofluorescence assay, fluorescent probe, DCFH-DA flow cytometry, enzyme-linked immunosorbent assay, and western-blot. RESULTS The present results revealed that the M1 phenotype of microglia promoted the secretion of pro-inflammatory cytokines and aggravated ferroptosis and brain damage following OGD/R. However, an inhibitor of BMP6, LND-193189, reversed the aforementioned effects. Similarly, NTF promoted the shift of microglia from M1 to M2. Besides, NTF treatment effectively inhibited the expression of hepcidin, BMP6, SMADs and promoted the expression of ferroportin (FPN, SLC40A1) and γ-L-glutamyl-L-cysteinylglycine (glutathione or GSH) peroxidase 4 (GPX4). CONCLUSION Microglial M1/M2 polarization plays a pivotal role in inflammation and ferroptosis during OGD/R. The BMP6/SMADs signaling pathway is a potential therapeutical target of inflammation and ferroptosis induced by the transformation of microglia. Moreover, NTF could alleviate inflammation and ferroptosis through the BMP6/SMADs signaling pathway in OGD/R-injured microglia.
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Affiliation(s)
- Jun Liao
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
| | - Mengzhen Wei
- Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jianjun Wang
- Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jinsong Zeng
- Neurosurgery Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Danhong Liu
- Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Qiusi Du
- Vascular Biology Laboratory, Medical College, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jinwen Ge
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Academy of Traditional Chinese Medicine, Changsha, Hunan 410031, China.
| | - Zhigang Mei
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
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Liu J, Chen H, Lin H, Peng S, Chen L, Cheng X, Yao P, Tang Y. Iron-frataxin involved in the protective effect of quercetin against alcohol-induced liver mitochondrial dysfunction. J Nutr Biochem 2023; 114:109258. [PMID: 36587874 DOI: 10.1016/j.jnutbio.2022.109258] [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: 01/04/2022] [Revised: 12/17/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022]
Abstract
Emerging evidence supports the beneficial effect of quercetin on liver mitochondrial disorders. However, the molecular mechanism by which quercetin protects mitochondria is limited, especially in alcoholic liver disease. In this study, C57BL/6N mice were fed with Lieber De Carli liquid diet (28% ethanol-derived calories) for 12 weeks plus a single binge ethanol and intervened with quercetin (100 mg/kg.bw). Moreover, HepG2CYP2E1+/+ were stimulated with ethanol (100 mM) and quercetin (50 µM) to investigate the effects of mitochondrial protein frataxin. The results indicated that quercetin alleviated alcohol-induced histopathological changes and mitochondrial functional disorders in mice livers. Consistent with increased PINK1, Parkin, Bnip3 and LC3II as well as decreased p62, TOM20 and VDAC1 expression, the inhibition of mitophagy by ethanol was blocked by quercetin. Additionally, quercetin improved the imbalance of iron metabolism-related proteins expression in alcohol-fed mice livers. Compared with ethanol-treated Lv-empty HepG2CYP2E1+/+ cells, frataxin deficiency further exacerbated the inhibition of mitochondrial function. Conversely, restoration of frataxin expression ameliorated the effect of ethanol. Furthermore, frataxin deficiency reduced the protective effects of quercetin on mitochondria disordered by ethanol. Attentively, ferric ammonium citrate (FAC) and deferiprone decreased or increased frataxin expression in HepG2CYP2E1+/+, respectively. Notably, we further found FAC reversed the increasing effect of quercetin on frataxin expression. Ultimately, silencing NCOA4 attenuated the inhibition of quercetin on LDH release and mitochondrial membrane potential increase, and similar results were observed by adding FAC. Collectively, these findings demonstrated quercetin increased frataxin expression through regulating iron level, thereby mitigating ethanol-induced mitochondrial dysfunction.
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Affiliation(s)
- Jingjing Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Henan Center for Disease Control and Prevention, Zhengzhou 450016, China
| | - Huimin Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongkun Lin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shufen Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xueer Cheng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuhan Tang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Brandão-Bezerra L, Aparecida da Rosa A, Figueiredo de Oliveira RM, Neves RH, Corrêa CL, Machado-Silva JR. Impact of acute schistosomiasis mansoni and long-term ethanol intake on mouse liver pathology. Exp Parasitol 2022; 242:108388. [PMID: 36174706 DOI: 10.1016/j.exppara.2022.108388] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 09/08/2022] [Accepted: 09/21/2022] [Indexed: 11/26/2022]
Abstract
While the effect of ethanol and schistosomiasis mansoni on liver injury has been well-documented, the influence of comorbidity on liver pathology remains unclear. To address this gap, schistosomiasis-infected mice were given one daily dose of 18% ethanol for 28 consecutive days, from day 35 post-infection. Mice were assigned to four groups: A. control; B. uninfected/ethanol gavage; C. infected; and D. infected/ethanol gavage. At day 64 post-infection, mice were euthanized by CO2 asphyxiation, livers were excised, fixed in 10% buffered formalin, paraffin embedded and cut into 5 μm sections. These were stained with hematoxylin and eosin (HE), Lennert's Giemsa and picrosirius red (for polarization microscopy) to assess histopathological and stereological changes. Group B showed alcoholic liver disease (ALD), including microsteatosis, hepatocyte karyopyknosis, karyorrhexis, karyolysis, increased frequency of Kupffer cells, hydropic degeneration of hepatocyte, thickened plasma membrane and binucleated hepatocytes. Infected mice showed typical exudative and exudative-productive hepatic granulomas, and destruction of the adjacent hepatic parenchyma, resulting in necrotic tissue and periovular leukocyte infiltrate. Group D showed hyperemia (parenchymal panlobular lesions), and liquefactive necrosis in hepatic abscess area. There was also reduced liver collagen deposition (-76%; p = 0.0001) and reduced microsteatosis (-80%, p = 0.0079) compared to group C and group B, respectively. In conclusion, comorbidity exacerbated liver damage.
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Affiliation(s)
- Luciana Brandão-Bezerra
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Aline Aparecida da Rosa
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Regina Maria Figueiredo de Oliveira
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Renata Heisler Neves
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil
| | - Christiane Leal Corrêa
- Department of Pathology and Laboratories, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Brazil. Medical College, Estácio de Sá University, Rio de Janeiro, Brazil
| | - José Roberto Machado-Silva
- Romero Lascasas Porto Laboratory of Helminthology, Department of Microbiology, Immunology and Parasitology, Medical Sciences College (FCM), Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil.
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Ma C, Han L, Zhu Z, Heng Pang C, Pan G. Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases. Biochem Pharmacol 2022; 205:115242. [PMID: 36084708 DOI: 10.1016/j.bcp.2022.115242] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/02/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide. Minerals including iron, copper, zinc, and selenium, fulfil an essential role in various biochemical processes. Moreover, the identification of ferroptosis and cuproptosis further underscores the importance of intracellular mineral homeostasis. However, perturbation of minerals has been frequently reported in patients with NAFLD and related diseases. Interestingly, studies have attempted to establish an association between mineral disorders and NAFLD pathological features, including oxidative stress, mitochondrial dysfunction, inflammatory response, and fibrogenesis. In this review, we aim to provide an overview of the current understanding of mineral metabolism (i.e., absorption, utilization, and transport) and mineral interactions in the pathogenesis of NAFLD. More importantly, this review highlights potential therapeutic strategies, challenges, future directions for targeting mineral metabolism in the treatment of NAFLD.
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Affiliation(s)
- Chenhui Ma
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo 315100, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Han
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zheying Zhu
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
| | - Cheng Heng Pang
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo 315100, China.
| | - Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting Ferroptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9947191. [PMID: 35075382 PMCID: PMC8783728 DOI: 10.1155/2022/9947191] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/10/2021] [Accepted: 12/11/2021] [Indexed: 12/14/2022]
Abstract
Cisplatin is widely used in the treatment of solid tumors, but its application is greatly limited due to its nephrotoxicity; thus, there is still no effective medicine for the treatment of cisplatin-induced acute kidney injury (Cis-AKI). We previously identified that polydatin (PD) exerts nephroprotective effects by antioxidative stress in AKI models. Recent evidence suggests that oxidative stress-induced molecular events overlap with the process of ferroptosis and that there are common molecular targets, such as glutathione (GSH) depletion and lipid peroxidation. Nevertheless, whether the nephroprotective effect of PD is related to anti-ferroptosis remains unclear. In this study, the inhibitory effect of PD on ferroptosis was observed in both cisplatin-treated HK-2 cells (20 μM) in vitro and a Cis-AKI mouse model (20 mg/kg, intraperitoneally) in vivo, characterized by the reversion of excessive intracellular free iron accumulation and reactive oxygen species (ROS) generation, a decrease in malondialdehyde (MDA) content and GSH depletion, and an increase in glutathione peroxidase-4 (GPx4) activity. Remarkably, PD dose-dependently alleviated cell death induced by the system Xc− inhibitor erastin (10 μM), and the effect of the 40 μM dose of PD was more obvious than that of ferrostatin-1 (1 μM) and deferoxamine (DFO, 100 μM), classical ferroptosis inhibitors. Our results provide insight into nephroprotection with PD in Cis-AKI by inhibiting ferroptosis via maintenance of the system Xc−-GSH-GPx4 axis and iron metabolism.
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11
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Li S, Zhang H, Chang J, Li D, Cao P. Iron overload and mitochondrial dysfunction orchestrate pulmonary fibrosis. Eur J Pharmacol 2021; 912:174613. [PMID: 34740581 DOI: 10.1016/j.ejphar.2021.174613] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 09/06/2021] [Accepted: 09/11/2021] [Indexed: 12/26/2022]
Abstract
Pulmonary fibrosis (PF) is a chronic, progressive heterogeneous disease of lung tissues with poor lung function caused by scar tissue. Due to our limited understanding of its mechanism, there is currently no treatment strategy that can prevent the development of PF. In recent years, iron accumulation and mitochondrial damage have been reported to participate in PF, and drugs that reduce iron content and improve mitochondrial function have shown significant efficacy in animal experimental models. Excessive iron leads to mitochondrial impairment, which may be the key cause that results in the dysfunction of various kinds of pulmonary cells and further promotes PF. As an emerging research hotspot, there are few targeted effective therapeutic strategies at present due to limited mechanistic understanding. In this review, the roles of iron homeostasis imbalance and mitochondrial damage in PF are summarized and discussed, highlighting a promising direction for finding truly effective therapeutics for PF.
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Affiliation(s)
- Shuxin Li
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China
| | - Hongmin Zhang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China
| | - Jing Chang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China
| | - Dongming Li
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China.
| | - Pengxiu Cao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People's Republic of China.
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12
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Associations of Food and Nutrient Intake with Serum Hepcidin and the Risk of Gestational Iron-Deficiency Anemia among Pregnant Women: A Population-Based Study. Nutrients 2021; 13:nu13103501. [PMID: 34684502 PMCID: PMC8537751 DOI: 10.3390/nu13103501] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022] Open
Abstract
Hepcidin is a regulator of iron metabolism. Diet affects the body's iron status, but how it influences hepcidin concentrations and the risk of gestational iron-deficiency anemia (IDA) remains unclear. We investigated relationships of food and nutrient intake with serum hepcidin levels in relation to the iron status at a population scale. A retrospective cross-sectional study was conducted based on data obtained from the Nationwide Nutrition and Health Survey in pregnant women, Taiwan (2017~2020). In total, 1430 pregnant women aged 20~45 years with a singleton pregnancy were included. Data from blood biochemistry, 24-h dietary recall, and a food frequency questionnaire were collected during a prenatal checkup. Adjusted multivariate linear and logistic regression analyses were employed to measure the beta coefficient (ß) and 95% confidence interval (CI) of serum hepcidin and the odds ratio (OR) of IDA. In IDA women, serum hepcidin levels were positively correlated with the intake frequency of Chinese dim sum and related foods (β = 0.037 (95% CI = 0.015~0.058), p = 0.001) and dark leafy vegetables (β = 0.013 (0.001~0.025), p = 0.040), but they were negatively correlated with noodles and related products (β = -0.022 (-0.043~-0.001), p = 0.038). An adjusted multivariate logistic regression analysis showed that dietary protein [OR: 0.990 (0.981~1.000), p = 0.041], total fiber [OR: 0.975 (0.953~0.998), p = 0.031], and rice/rice porridge [OR: 1.007 (1.00~1.014), p = 0.041] predicted gestational IDA. Total carbohydrates [OR: 1.003 (1.000~1.006), p = 0.036], proteins [OR: 0.992 (0.985~0.999), p = 0.028], gourds/shoots/root vegetables [OR: 1.007 (0.092~1.010), p = 0.005], and to a lesser extent, savory and sweet glutinous rice products [OR: 0.069 (0.937~1.002), p = 0.067] and dark leafy vegetables [OR: 1.005 (0.999~1.011), p = 0.088] predicted IDA. The risk of IDA due to vegetable consumption decreased with an increasing vitamin C intake (p for trend = 0.024). Carbohydrates and vegetables may affect the gestational iron status through influencing hepcidin levels. Vitamin C may lower the risk of gestational IDA due to high vegetable consumption.
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13
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Xu T, Zhang X, Liu Y, Wang H, Luo J, Luo Y, An P. Effects of dietary polyphenol supplementation on iron status and erythropoiesis: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2021; 114:780-793. [PMID: 33871598 DOI: 10.1093/ajcn/nqab068] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/23/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The iron-chelating activities of polyphenols raise concern whether there is a risk of iron deficiency or anemia induced by polyphenol supplementation. Results from clinical trials regarding the effects of polyphenol supplementation on iron status and erythropoiesis are inconclusive. OBJECTIVE We performed a systematic review and meta-analysis of randomized controlled trials to determine the effects of polyphenol supplementation on iron status and erythropoiesis. METHODS Published articles were searched between May 1988 and 7 December, 2020. Finally, we identified 34 randomized controlled trials. Random-effects meta-analyses were performed to obtain the weighted mean difference of serum iron (SI), transferrin saturation (TS), ferritin, and hemoglobin concentration. Funnel plots and Egger's test were used to determine the risk of bias. The robustness of the effect sizes was examined by sensitivity analysis. RESULTS Polyphenol supplementation had an inhibitory effect on the SI concentration (-13.72 μg/dL; 95% CI: -20.74, -6.71) and TS (-3.10%; 95% CI: -4.93, -1.27), with no effect on ferritin (-9.34 ng/mL; 95% CI: -28.55, 9.87). Polyphenols increased the hemoglobin concentration (8.53 g/L; 95% CI: 3.33, 13.73). In healthy participants, polyphenol reduced the TS (-3.83%; 95% CI: -7.47, -0.19) and increased the hemoglobin concentration (12.87 g/L; 95% CI: 1.61, 24.14). Similarly, polyphenol reduced the SI concentration (-8.60 μg/dL; 95% CI: -16.10, -1.10) and increased the hemoglobin concentration (8.50 g/L; 95% CI: 0.86, 16.15) in patients with metabolic diseases. In patients with β-thalassemia, polyphenol decreased the SI concentration (-23.19 μg/dL; 95% CI: -35.84, -10.55), TS (-3.23%; 95% CI: -5.54, -0.91), and ferritin concentration (-223.62 ng/mL; 95% CI: -359.32, -87.91), but had no effect on the hemoglobin concentration. CONCLUSION Healthy individuals and patients with metabolic diseases may benefit from the positive impact of polyphenols on erythropoiesis. Patients with β-thalassemia may benefit from the effect of polyphenols on reducing SI. This trial was registered at PROSPERO (International prospective register of systematic reviews) as CRD42020161983.
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Affiliation(s)
- Teng Xu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xu Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Yuning Liu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Hao Wang
- Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou, China
| | - Junjie Luo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Yongting Luo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Peng An
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
- College of Science, China Agricultural University, Beijing, China
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14
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Zhao X, Wang J, Deng Y, Liao L, Zhou M, Peng C, Li Y. Quercetin as a protective agent for liver diseases: A comprehensive descriptive review of the molecular mechanism. Phytother Res 2021; 35:4727-4747. [PMID: 34159683 DOI: 10.1002/ptr.7104] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/12/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Quercetin is the major representative of the flavonoid subgroup of flavones, with good pharmacological activities for the treatment of liver diseases, including liver steatosis, fatty hepatitis, liver fibrosis, and liver cancer. It can significantly influence the development of liver diseases via multiple targets and multiple pathways via antifat accumulation, anti-inflammatory, and antioxidant activity, as well as the inhibition of cellular apoptosis and proliferation. Despite extensive research on understanding the mechanism of quercetin in the treatment of liver diseases, there are still no targeted therapies available. Thus, we have comprehensively searched and summarized the different targets of quercetin in different stages of liver diseases and concluded that quercetin inhibited inflammation of the liver mainly through NF-κB/TLR/NLRP3, reduced PI3K/Nrf2-mediated oxidative stress, mTOR activation in autophagy, and inhibited the expression of apoptotic factors associated with the development of liver diseases. In addition, quercetin showed different mechanisms of action at different stages of liver diseases, including the regulation of PPAR, UCP, and PLIN2-related factors via brown fat activation in liver steatosis. The compound inhibited stromal ECM deposition at the liver fibrosis stage, affecting TGF1β, endoplasmic reticulum stress (ERs), and apoptosis. While at the final liver cancer stage, inhibiting cancer cell proliferation and spread via the hTERT, MEK1/ERK1/2, Notch, and Wnt/β-catenin-related signaling pathways. In conclusion, quercetin is an effective liver protectant. We hope to explore the pathogenesis of quercetin in different stages of liver diseases through the review, so as to provide more accurate targets and theoretical basis for further research of quercetin in the treatment of liver diseases.
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Affiliation(s)
- Xingtao Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ying Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mengting Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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15
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Quercetin and non-alcoholic fatty liver disease: A review based on experimental data and bioinformatic analysis. Food Chem Toxicol 2021; 154:112314. [PMID: 34087406 DOI: 10.1016/j.fct.2021.112314] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/18/2021] [Accepted: 05/29/2021] [Indexed: 02/08/2023]
Abstract
Quercetin, a polyphenol widely present in the plant kingdom, has received great interest due to pleiotropic effects. As evidenced by animal and cellular studies, quercetin exerts hepatoprotection against non-alcoholic fatty liver disease (NAFLD), particularly in hepatic steatosis and hepatitis. Mechanically, various hypotheses of such protective effects have been actively proposed, including improving fatty acid metabolism, anti-inflammation, anti-oxidant, modulating gut microbiota and bile acid, etc. Here, the role of quercetin in NAFLD was summarized. With a particular focus on molecular mechanism, we comprehensively discussed the pathways of quercetin on NAFLD based on the analysis from Gene Expression Omnibus (GEO) database and experimental evidence.
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16
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Banerjee S, Katiyar P, Kumar L, Kumar V, Saini SS, Krishnan V, Sircar D, Roy P. Black pepper prevents anemia of inflammation by inhibiting hepcidin over-expression through BMP6-SMAD1/ IL6-STAT3 signaling pathway. Free Radic Biol Med 2021; 168:189-202. [PMID: 33771600 DOI: 10.1016/j.freeradbiomed.2021.03.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/14/2021] [Accepted: 03/17/2021] [Indexed: 01/03/2023]
Abstract
Hepcidin, a circulatory hepatic peptide hormone, is associated with systemic iron homeostasis. Inflammation leads to an increase in hepcidin expression, which dysregulates body iron level. The related disorder, anemia of inflammation, is the second most prevalent anemia-related disorder worldwide. In the present study, we conducted in vitro and in vivo studies to evaluate the effect of black pepper (BP) and its major bioactive alkaloid, piperine, on anemia of inflammation. The initial in vitro study using human hepatocyte cell line, HepG2, confirmed that among different black pepper extracts: methanol (BPME), ethanol (BPEE) and aqueous (BPAE), BPME to be most effective in downregulating transcription of hepcidin gene. Further, BPME and piperine significantly downregulated hepcidin protein expression at 200 μg/ml and 100 μM concentrations, respectively. In the next phase, BPME and piperine were found to significantly attenuate BMP-6 and IL-6 induced hepcidin overexpression by downregulating the increased level of pSMAD1 and pSTAT3 proteins, respectively. For in vivo study, we first subcutaneously injected male BALB/c mice with oil of turpentine, thrice within a period of two weeks, in order to enhance the expression of hepcidin. After that, the intraperitoneal administration of BPME and piperine at 70 and 25 mg/kg body weight, respectively, on alternate days for a period of another two weeks resulted in downregulation of hepcidin overexpression in diseased mice, as confirmed by RT-PCR and immunoblot analysis. The histopathology of liver tissue confirmed increased iron bioavailability in BPME and piperine treated animals. The molecular docking-based interaction studies demonstrated the binding potential of piperine with SMAD1 and STAT3 proteins. The binding patterns supported the proposed inhibition of hepcidin activating proteins. All together, these findings suggest black pepper as a therapeutic candidate for the treatment of anemia of inflammation.
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Affiliation(s)
- Somesh Banerjee
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
| | - Parul Katiyar
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
| | - Lokesh Kumar
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
| | - Vijay Kumar
- Laboratory of Structural Microbiology, Regional Centre for Biotechnology, Faridabad, 121001, Haryana, India.
| | - Shashank Sagar Saini
- Plant Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
| | - Vengadesan Krishnan
- Laboratory of Structural Microbiology, Regional Centre for Biotechnology, Faridabad, 121001, Haryana, India.
| | - Debabrata Sircar
- Plant Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
| | - Partha Roy
- Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
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17
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Ding H, Chen L, Hong Z, Yu X, Wang Z, Feng J. Network pharmacology-based identification of the key mechanism of quercetin acting on hemochromatosis. Metallomics 2021; 13:6271328. [PMID: 33960370 DOI: 10.1093/mtomcs/mfab025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 04/21/2021] [Accepted: 04/24/2021] [Indexed: 02/07/2023]
Abstract
Hemochromatosis is an iron overload disease, which lacks nutritional intervention strategies. This study explored the protective effect of quercetin on hemochromatosis and its possible mechanism through network pharmacology. We used Online Mendelian Inheritance in Man to screen the disease targets of hemochromatosis, and further constructed a potential protein interaction network through STITCH. The above-mentioned targets revealed by Gene enrichment analysis have played a significant role in ferroptosis, mineral absorption, basal cell carcinoma, and related signal pathways. Besides, the drug likeness of quercetin obtained by Comparative Toxicogenomics Database was evaluated by Traditional Chinese Medicine Systems Pharmacology, and potential drug targets identified by PharmMapper and similar compounds identified by PubChem were selected for further research. Moreover, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed the relationship between quercetin and glycosylation. Furthermore, we performed experiments to verify that the protective effect of quercetin on iron overload cells is to inhibit the production of reactive oxygen species, limit intracellular iron, and degrade glycosaminoglycans. Finally, iron-induced intracellular iron overload caused ferroptosis, and quercetin and fisetin were potential ferroptosis inhibitors. In conclusion, our study revealed the correlation between hemochromatosis and ferroptosis, provided the relationship between the target of quercetin and glycosylation, and verified that quercetin and its similar compounds interfere with iron overload related disease. Our research may provide novel insights for quercetin and its structurally similar compounds as a potential nutritional supplement for iron overload related diseases.
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Affiliation(s)
- Haoxuan Ding
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Lingjun Chen
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Zuopeng Hong
- Research Center of Zhejiang Weifeng Biotechnology Co., Ltd, Hangzhou 310000, China
| | - Xiaonan Yu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Zhonghang Wang
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Jie Feng
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
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18
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Bloomer SA, Brown KE. Hepcidin and Iron Metabolism in Experimental Liver Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1165-1179. [PMID: 33891874 DOI: 10.1016/j.ajpath.2021.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/25/2021] [Accepted: 04/06/2021] [Indexed: 11/18/2022]
Abstract
The liver plays a pivotal role in the regulation of iron metabolism through its ability to sense and respond to iron stores by release of the hormone hepcidin. Under physiologic conditions, regulation of hepcidin expression in response to iron status maintains iron homeostasis. In response to tissue injury, hepcidin expression can be modulated by other factors, such as inflammation and oxidative stress. The resulting dysregulation of hepcidin is proposed to account for alterations in iron homeostasis that are sometimes observed in patients with liver disease. This review describes the effects of experimental forms of liver injury on iron metabolism and hepcidin expression. In general, models of acute liver injury demonstrate increases in hepcidin mRNA and hypoferremia, consistent with hepcidin's role as an acute-phase reactant. Conversely, diverse models of chronic liver injury are associated with decreased hepcidin mRNA but with variable effects on iron status. Elucidating the reasons for the disparate impact of different chronic injuries on iron metabolism is an important research priority, as is a deeper understanding of the interplay among various stimuli, both positive and negative, on hepcidin regulation. Future studies should provide a clearer picture of how dysregulation of hepcidin expression and altered iron homeostasis impact the progression of liver diseases and whether they are a cause or consequence of these pathologies.
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Affiliation(s)
- Steven A Bloomer
- Division of Science and Engineering, Penn State Abington, Abington, Pennsylvania
| | - Kyle E Brown
- Iowa City Veterans Administration Medical Center, Iowa City, Iowa; Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Program in Free Radical and Radiation Biology, Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
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19
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Cotoraci C, Ciceu A, Sasu A, Hermenean A. Natural Antioxidants in Anemia Treatment. Int J Mol Sci 2021; 22:ijms22041883. [PMID: 33668657 PMCID: PMC7918704 DOI: 10.3390/ijms22041883] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/07/2021] [Accepted: 02/11/2021] [Indexed: 01/03/2023] Open
Abstract
Anemia, characterized by a decrease of the hemoglobin level in the blood and a reduction in carrying capacity of oxygen, is a major public health problem which affects people of all ages. The methods used to treat anemia are blood transfusion and oral administration of iron-based supplements, but these treatments are associated with a number of side effects, such as nausea, vomiting, constipation, and stomach pain, which limit its long-term use. In addition, oral iron supplements are poorly absorbed in the intestinal tract, due to overexpression of hepcidin, a peptide hormone that plays a central role in iron homeostasis. In this review, we conducted an analysis of the literature on biologically active compounds and plant extracts used in the treatment of various types of anemia. The purpose of this review is to provide up-to-date information on the use of these compounds and plant extracts, in order to explore their therapeutic potential. The advantage of using them is that they are available from natural resources and can be used as main, alternative, or adjuvant therapies in many diseases, such as various types of anemia.
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Affiliation(s)
- Coralia Cotoraci
- Department of Hematology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania;
- Correspondence:
| | - Alina Ciceu
- “Aurel Ardelean” Institute of Life Sciences, Vasile Godis Western University of Arad, Rebreanu 86, 310414 Arad, Romania; (A.C.); (A.H.)
| | - Alciona Sasu
- Department of Hematology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania;
| | - Anca Hermenean
- “Aurel Ardelean” Institute of Life Sciences, Vasile Godis Western University of Arad, Rebreanu 86, 310414 Arad, Romania; (A.C.); (A.H.)
- Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, Rebreanu 86, 310414 Arad, Romania
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20
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An Overview of the Mechanism of Penthorum chinense Pursh on Alcoholic Fatty Liver. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:4875764. [PMID: 33014105 PMCID: PMC7519454 DOI: 10.1155/2020/4875764] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 08/13/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022]
Abstract
Alcohol liver disease (ALD) caused by excessive alcohol consumption is a progressive disease, and alcohol fatty liver disease is the primary stage. Currently, there is no approved drug for its treatment. Abstinence is the best way to heal, but patients' compliance is poor. Unlike other chronic diseases, alcohol fatty liver disease is not caused by nutritional deficiencies; it is caused by the molecular action of ingested alcohol and its metabolites. More and more studies have shown the potential of Penthorum chinense Pursh (PCP) in the clinical use of alcohol fatty liver treatment. The purpose of this paper is to reveal from the essence of PCP treatment of alcohol liver mechanism mainly by the ethanol dehydrogenase (ADH) and microsomal ethanol oxidation system-dependent cytochrome P4502E1 (CYP2E1) to exert antilipogenesis, antioxidant, anti-inflammatory, antiapoptotic, and autophagy effects, with special emphasis on its mechanisms related to SIRT1/AMPK, KEAP-1/Nrf2, and TLR4/NF-κB. Overall, data from the literature shows that PCP appears to be a promising hepatoprotective traditional Chinese medicine (TCM).
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Hu S, Li SW, Yan Q, Hu XP, Li LY, Zhou H, Pan LX, Li J, Shen CP, Xu T. Natural products, extracts and formulations comprehensive therapy for the improvement of motor function in alcoholic liver disease. Pharmacol Res 2019; 150:104501. [PMID: 31689520 DOI: 10.1016/j.phrs.2019.104501] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 10/08/2019] [Accepted: 10/15/2019] [Indexed: 02/07/2023]
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22
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Sajadi Hezaveh Z, Azarkeivan A, Janani L, Hosseini S, Shidfar F. The effect of quercetin on iron overload and inflammation in β-thalassemia major patients: A double-blind randomized clinical trial. Complement Ther Med 2019; 46:24-28. [PMID: 31519283 DOI: 10.1016/j.ctim.2019.02.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/06/2019] [Accepted: 02/25/2019] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVES The aim of this study was to determine whether quercetin can reduce iron overload and inflammation in thalassemic patients. METHODS Eighty four patients were recruited to this study and randomly assigned to two groups: 42 patients received a 500 mg/day quercetin tablet and 42 others took a 500 mg/day starch placebo for 12 weeks. Demographic, anthropometric and biochemical evaluation were performed. RESULTS ANCOVA analysis revealed that compared to the control group, quercetin could reduce high sensitivity C-reactive protein (hs-CRP) (P = 0.046), iron (p = 0.036), ferritin (p = 0.043), and transferrin saturation (TS) (p = 0.008) and increase transferrin (p = 0.045) significantly, but it had no significant effect on total iron binding capacity (TIBC) (p = 0.734) and tumor necrosis factor α (TNF-α) (p = 0.310). CONCLUSIONS Quercetin could ameliorate the iron status in thalassemia major, but its effect on inflammation is indistinctive.
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Affiliation(s)
- Zohreh Sajadi Hezaveh
- Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Azita Azarkeivan
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Leila Janani
- Department of Epidemiology and Biostatistics, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Sharieh Hosseini
- Department of Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Farzad Shidfar
- Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran.
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Gabr SA, Gabr NS, Elsaed WM. Protective Activity of Taurine and Molecular Fibrogenesis in Iron Overloaded Hepatic Tissues. INT J PHARMACOL 2019. [DOI: 10.3923/ijp.2019.418.427] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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24
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Jin L, Frazer DM, Lu Y, Wilkins SJ, Ayton S, Bush A, Anderson GJ. Mice overexpressing hepcidin suggest ferroportin does not play a major role in Mn homeostasis. Metallomics 2019; 11:959-967. [DOI: 10.1039/c8mt00370j] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Knockout mice with constitutively low ferroportin show that ferroportin does not make a major contribution to manganese homeostasis in vivo.
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Affiliation(s)
- Lian Jin
- Iron Metabolism Laboratory
- QIMR Berghofer Medical Research Institute
- Brisbane
- Australia
- Faculty of Medicine
| | - David M. Frazer
- Iron Metabolism Laboratory
- QIMR Berghofer Medical Research Institute
- Brisbane
- Australia
| | - Yan Lu
- Iron Metabolism Laboratory
- QIMR Berghofer Medical Research Institute
- Brisbane
- Australia
| | - Sarah J. Wilkins
- Iron Metabolism Laboratory
- QIMR Berghofer Medical Research Institute
- Brisbane
- Australia
| | - Scott Ayton
- Melbourne Dementia Research Centre
- Florey Institute of Neuroscience and Mental Health
- University of Melbourne
- Melbourne
- Australia
| | - Ashley Bush
- Melbourne Dementia Research Centre
- Florey Institute of Neuroscience and Mental Health
- University of Melbourne
- Melbourne
- Australia
| | - Gregory J. Anderson
- Iron Metabolism Laboratory
- QIMR Berghofer Medical Research Institute
- Brisbane
- Australia
- Faculty of Medicine
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Ma Y, Li R, Liu Y, Liu M, Liang H. Protective Effect of Aplysin Supplementation on Intestinal Permeability and Microbiota in Rats Treated with Ethanol and Iron. Nutrients 2018; 10:nu10060681. [PMID: 29861488 PMCID: PMC6024731 DOI: 10.3390/nu10060681] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/20/2018] [Accepted: 05/22/2018] [Indexed: 02/07/2023] Open
Abstract
Aplysin, a kind of phytochemicals or phytonutrients, is purified from red alga Laurencia tristicha. The present study aims to investigate the influence of aplysin on changes of intestinal permeability and microbiota induced by excessive ethanol and iron. Thirty male rats were randomly divided into three groups (10/group): control group (normal saline); ethanol + iron group as EI treated with ethanol (8–12 mL/kg/day) and iron (1000 mg/kg) in diet; EI supplemented with aplysin (150 mg/kg/day) group as AEI; the trial lasts for 12 weeks. The result showed that levels of plasma endotoxin, fatty acid-binding protein 2, D-lactic acid, diamine oxidase were increased in rats in the EI group; and significantly decreased by 14%, 17%, 26%, 16%, respectively (p < 0.05) in the AEI group after the 12-week aplysin treatment. Moreover, in the AEI group the amount of Escherichia coli and Bacteroides fragilis were higher, while the amount of Lactobacillus, Bifidobacterium and Clostridium were lower than those in the EI group. The expressions of iron transporters divalent-metal transporter 1(DMT1) and ferroportin 1(FPN1) were significantly upregulated in the EI group compared to those in the control group. In conclusion, aplysin could effectively improve intestinal permeability and intestinal flora disorder induced with excessive ethanol and iron.
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Affiliation(s)
- Yan Ma
- Department of Human Nutrition, College of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao 266021, China.
| | - Ruiying Li
- Department of Human Nutrition, College of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao 266021, China.
| | - Ying Liu
- Basic Medical College, Qingdao University of Medicine, 308 Ningxia Road, Qingdao 266071, China.
| | - Man Liu
- Department of Human Nutrition, College of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao 266021, China.
| | - Hui Liang
- Department of Human Nutrition, College of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao 266021, China.
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26
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Lesjak M, Balesaria S, Skinner V, Debnam ES, Srai SKS. Quercetin inhibits intestinal non-haem iron absorption by regulating iron metabolism genes in the tissues. Eur J Nutr 2018; 58:743-753. [PMID: 29594477 PMCID: PMC6437293 DOI: 10.1007/s00394-018-1680-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/27/2018] [Indexed: 01/24/2023]
Abstract
Purpose There is general agreement that some dietary polyphenols block non-haem iron uptake, but the mechanisms by which they achieve this action are poorly understood. Since the polyphenol quercetin is ingested daily in significant amounts, we have investigated the effect of quercetin on duodenal non-haem iron absorption in vivo, as well as its effect on factors known to be involved in systemic iron metabolism. Methods Rats were subject to gastric gavage and systemic quercetin administration. Treatments were followed with uptake studies using radiolabeled iron, serum iron and transferrin saturation measurements, LC-MS/MS analysis of quercetin metabolites in serum, determination of tissue non-haem iron content and analysis of gene expression of iron-related proteins. Results Both oral and intraperitoneal (IP) quercetin caused serum and tissue iron depletion by two means, first by increasing mucosal iron uptake and inhibiting iron efflux from duodenal mucosa, and second by decreasing levels of duodenal DMT1, Dcytb and FPN. Additionally, IP quercetin induced highly significant increased liver expression of hepcidin, a hormone known to inhibit intestinal iron uptake. Conclusions Oral quercetin significantly inhibited iron absorption, while IP quercetin significantly affected iron-related genes. These results could lead to development of new effective ways of preventing and treating iron deficiency anaemia, the most widespread nutritional disorder in the world. Electronic supplementary material The online version of this article (10.1007/s00394-018-1680-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marija Lesjak
- Division of Biosciences, Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK. .,Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, Novi Sad, 21000, Serbia.
| | - Sara Balesaria
- Division of Biosciences, Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK
| | - Vernon Skinner
- Division of Biosciences, Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK
| | - Edward S Debnam
- Division of Biosciences, Research Department of Neuroscience, Physiology and Pharmacology, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Surjit Kaila S Srai
- Division of Biosciences, Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
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27
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Guo X, Chen M, Zeng H, Liu P, Zhu X, Zhou F, Liu J, Zhang J, Dong Z, Tang Y, Gao C, Yao P. Quercetin Attenuates Ethanol-Induced Iron Uptake and Myocardial Injury by Regulating the Angiotensin II-L-Type Calcium Channel. Mol Nutr Food Res 2018; 62. [PMID: 29266790 DOI: 10.1002/mnfr.201700772] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/19/2017] [Indexed: 01/19/2023]
Abstract
SCOPE Increased iron deposition in the myocardium in alcoholics may lead to increased risk of cardiac dysfunction. Quercetin has been demonstrated to quench production of intracellular free iron-induced -OH, but the effect of quercetin in ethanol-induced cardiac damage remains unclear. This study aims to explore whether quercetin attenuates ethanol-induced iron uptake and myocardial injury by regulating angiotensin II-L-type voltage-dependent Ca2+ channel (Ang II-LTCC). METHODS AND RESULTS Adult male C57BL/6J mice are isocalorically pair-fed either a regular or ethanol-containing Lieber De Carli liquid diets supplemented with either quercetin (100 mg kg-1 bw) or desferrioxamine mesylate (DFO, 100 mg kg-1 bw) for 15 weeks. Quercetin alleviated ethanol-induced histopathological changes, creatine kinase isoenzyme release, Ang II secretion, ROS generation, total cardiac iron, and labile iron level. Ethanol exposure or quercetin intervention fails to regulate traditional iron transporters except LTCC. LTCC is upregulated by ethanol and inhibited by quercetin. In H9C2 cell, LTCC is increased by ethanol (100 mm) and/or Ang II (1 μm) concomitant with iron disorders and oxidative stress. This effect is partially normalized by quercetin (50 μm), nifedipine (LTCC inhibitor, 15 μm), or losartan (Ang II receptor antagonist, 100 μm). CONCLUSION Alcohol-induced cardiac injury is associated with excessive NTBI uptake mediated by Ang II-LTCC activation which may be mediated by quercetin against ethanol cardiotoxicity.
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Affiliation(s)
- Xiaoping Guo
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Man Chen
- Wuhan Centers for Disease Prevention and Control, Wuhan, China
| | - Hongmei Zeng
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peiyi Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinghong Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingjing Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuangzhuang Dong
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhan Tang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao Gao
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Xiao L, Luo G, Tang Y, Yao P. Quercetin and iron metabolism: What we know and what we need to know. Food Chem Toxicol 2018; 114:190-203. [PMID: 29432835 DOI: 10.1016/j.fct.2018.02.022] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 01/18/2018] [Accepted: 02/07/2018] [Indexed: 12/14/2022]
Abstract
Iron is a life-supporting micronutrient that is required in the human diet, and is essential for maintaining physiological homeostasis. Properly harnessing a redox-active metal such as iron is a great challenge for cells and organisms because an excess of highly reactive iron catalyzes the formation of reactive oxygen species and can lead to cell and tissue damage. Quercetin is a typical flavonoid that is commonly found in fruits and vegetables and has versatile biological effects. From a classical viewpoint, owing to its unique chemical characteristics, quercetin has long been associated with iron metabolism only in the context of its iron-chelating and ROS-scavenging activities. However, within the field of human iron biology, expanding concepts of the roles of quercetin are flourishing, and great strides are being made in understanding the interactions between quercetin and iron. This progress highlights the varied roles of quercetin in iron metabolism, which involve much more than iron chelation alone. A review of these studies provides an ideal context to summarize recent progress and discuss compelling evidence for therapeutic opportunities that could arise from a better understanding of the underlying mechanisms.
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Affiliation(s)
- Lin Xiao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Gang Luo
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuhan Tang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Ping Yao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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29
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Imam MU, Zhang S, Ma J, Wang H, Wang F. Antioxidants Mediate Both Iron Homeostasis and Oxidative Stress. Nutrients 2017; 9:E671. [PMID: 28657578 PMCID: PMC5537786 DOI: 10.3390/nu9070671] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Revised: 06/20/2017] [Accepted: 06/22/2017] [Indexed: 12/18/2022] Open
Abstract
Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions.
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Affiliation(s)
- Mustapha Umar Imam
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Shenshen Zhang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Jifei Ma
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Hao Wang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
- Department of Nutrition, Nutrition Discovery Innovation Center, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Fudi Wang
- Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou 450001, China.
- Department of Nutrition, Nutrition Discovery Innovation Center, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou 310058, China.
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Long-Term Sodium Ferulate Supplementation Scavenges Oxygen Radicals and Reverses Liver Damage Induced by Iron Overloading. Molecules 2016; 21:molecules21091219. [PMID: 27649133 PMCID: PMC6273935 DOI: 10.3390/molecules21091219] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 09/03/2016] [Accepted: 09/08/2016] [Indexed: 12/29/2022] Open
Abstract
Ferulic acid is a polyphenolic compound contained in various types of fruits and wheat bran. As a salt of the active ingredient, sodium ferulate (SF) has potent free radical scavenging activity and can effectively scavenge ROS. In this study, we examined the effect of SF on iron-overloaded mice in comparison to a standard antioxidant, taurine (TAU). We determined the protective role of SF against liver injury by examining liver-to-body ratio (%), transaminase and hepatocyte apoptosis in rats supplied with 10% dextrose intraperitoneal injection. In addition, antioxidative enzymes activities, ROS formation, mitochondrial swelling, and mitochondrial membrane potential (MMP) were all evaluated to clarify the mechanism of protective effect of SF associated with oxidative stress. After 15 weeks of SF treatment, we found a significant reduction in liver-to-body weight radio and elevation in both transaminase and hepatocyte apoptosis associated with iron-injected to levels comparable to those achieved with TAU. Both SF and TAU significantly attenuated the impaired liver function associated with iron-overloaded in mice, whereas neither showed any significant effect on the iron uptake. Furthermore, treatment with either SF or TAU in iron-overloaded mice attenuated oxidative stress, associated with elevated oxidant enzymes activities, decreased ROS production, prevented mitochondrial swelling and dissipation of MMP and then inhibited hepatic apoptosis. Taken together, the current study shows that, SF alleviated oxidative stress and liver damage associated with iron-overload conditions compared to the standard ROS scavenger (TAU), and potentially could encourage higher consumption and utilization as healthy and sustainable ingredients by the food and drink.
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Liu L, Hu Q, Wu H, Xue Y, Cai L, Fang M, Liu Z, Yao P, Wu Y, Gong Z. Protective role of n6/n3 PUFA supplementation with varying DHA/EPA ratios against atherosclerosis in mice. J Nutr Biochem 2016; 32:171-80. [DOI: 10.1016/j.jnutbio.2016.02.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 01/16/2016] [Accepted: 02/08/2016] [Indexed: 10/22/2022]
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Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin. Br J Nutr 2016; 115:1978-86. [PMID: 27080262 DOI: 10.1017/s0007114516001197] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatic Fe overload has often been reported in patients with advanced alcoholic liver disease. However, it is not known clearly whether it is the effect of alcohol that is responsible for such overload. To address this lacuna, a time-course study was carried out in mice in order to determine the effect of alcohol on Fe homoeostasis. Male Swiss albino mice were pair-fed Lieber-DeCarli alcohol diet (20 % of total energy provided as alcohol) for 2, 4, 8 or 12 weeks. Expression levels of duodenal and hepatic Fe-related proteins were determined by quantitative PCR and Western blotting, as were Fe levels and parameters of oxidative stress in the liver. Alcohol induced cytochrome P4502E1 and oxidative stress in the liver. Hepatic Fe levels and ferritin protein expression dropped to significantly lower levels after 12 weeks of alcohol feeding, with no significant effects at earlier time points. This was associated, at 12 weeks, with significantly decreased liver hepcidin expression and serum hepcidin levels. Protein expressions of duodenal ferroportin (at 8 and 12 weeks) and divalent metal transporter 1 (at 8 weeks) were increased. Serum Fe levels rose progressively to significantly higher levels at 12 weeks. Histopathological examination of the liver showed mild steatosis, but no stainable Fe in mice fed alcohol for up to 12 weeks. In summary, alcohol ingestion by mice in this study affected several Fe-related parameters, but produced no hepatic Fe accumulation. On the contrary, alcohol-induced decreases in hepatic Fe levels were seen and may contribute to alcohol-induced suppression of hepcidin.
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Boye A, Zou YH, Yang Y. Metabolic derivatives of alcohol and the molecular culprits of fibro-hepatocarcinogenesis: Allies or enemies? World J Gastroenterol 2016; 22:50-71. [PMID: 26755860 PMCID: PMC4698508 DOI: 10.3748/wjg.v22.i1.50] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/12/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis, steatohepatitis, hepatic fibrosis and cirrhosis. Subsequently, these initial pathological events are sustained and ushered into a more complex and progressive liver disease, increasing the risk of fibro-hepatocarcinogenesis. These coordinated pathological events mainly result from buildup of toxic metabolic derivatives of alcohol including but not limited to acetaldehyde (AA), malondialdehyde (MDA), CYP2E1-generated reactive oxygen species, alcohol-induced gut-derived lipopolysaccharide, AA/MDA protein and DNA adducts. The metabolic derivatives of alcohol together with other comorbidity factors, including hepatitis B and C viral infections, dysregulated iron metabolism, abuse of antibiotics, schistosomiasis, toxic drug metabolites, autoimmune disease and other non-specific factors, have been shown to underlie liver diseases. In view of the multiple etiology of liver diseases, attempts to delineate the mechanism by which each etiological factor causes liver disease has always proved cumbersome if not impossible. In the case of alcoholic liver disease (ALD), it is even more cumbersome and complicated as a result of the many toxic metabolic derivatives of alcohol with their varying liver-specific toxicities. In spite of all these hurdles, researchers and experts in hepatology have strived to expand knowledge and scientific discourse, particularly on ALD and its associated complications through the medium of scientific research, reviews and commentaries. Nonetheless, the molecular mechanisms underpinning ALD, particularly those underlying toxic effects of metabolic derivatives of alcohol on parenchymal and non-parenchymal hepatic cells leading to increased risk of alcohol-induced fibro-hepatocarcinogenesis, are still incompletely elucidated. In this review, we examined published scientific findings on how alcohol and its metabolic derivatives mount cellular attack on each hepatic cell and the underlying molecular mechanisms leading to disruption of core hepatic homeostatic functions which probably set the stage for the initiation and progression of ALD to fibro-hepatocarcinogenesis. We also brought to sharp focus, the complex and integrative role of transforming growth factor beta/small mothers against decapentaplegic/plasminogen activator inhibitor-1 and the mitogen activated protein kinase signaling nexus as well as their cross-signaling with toll-like receptor-mediated gut-dependent signaling pathways implicated in ALD and fibro-hepatocarcinogenesis. Looking into the future, it is hoped that these deliberations may stimulate new research directions on this topic and shape not only therapeutic approaches but also models for studying ALD and fibro-hepatocarcinogenesis.
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Lee HJ, Choi JS, Lee HJ, Kim WH, Park SI, Song J. Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction. J Nutr Biochem 2015; 26:1414-23. [DOI: 10.1016/j.jnutbio.2015.07.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 06/19/2015] [Accepted: 07/14/2015] [Indexed: 02/06/2023]
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Quercetin Alleviates High-Fat Diet-Induced Oxidized Low-Density Lipoprotein Accumulation in the Liver: Implication for Autophagy Regulation. BIOMED RESEARCH INTERNATIONAL 2015; 2015:607531. [PMID: 26697490 PMCID: PMC4678061 DOI: 10.1155/2015/607531] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 10/23/2015] [Accepted: 11/04/2015] [Indexed: 12/16/2022]
Abstract
A growing body of evidence has indicated that high-fat diet-induced nonalcoholic fatty liver disease is usually accompanied by oxidized low-density lipoprotein (ox-LDL) deposited in the liver. The current study aimed to investigate the effect of quercetin on high-fat diet-induced ox-LDL accumulation in the liver and to explore the potential underlying mechanisms. The results demonstrate that quercetin supplementation for 24 weeks significantly alleviated high-fat diet-induced liver damage and reduced hepatic cholesterol and ox-LDL level. Quercetin notably inhibited both mRNA and protein expression of CD36 (reduced by 53% and 71%, resp.) and MSR1 (reduced by 25% and 45%, resp.), which were upregulated by high-fat diet. The expression of LC3II was upregulated by 2.4 times whereas that of p62 and mTOR was downregulated by 57% and 63% by quercetin treatment. Therefore, the significantly improved autophagy lysosomal degradation capacity for ox-LDL may be implicated in the hepatoprotective effect of quercetin; scavenger receptors mediated ox-LDL uptake might also be involved.
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