|
1
|
Zhang L, Zheng Y, Shao M, Chen A, Liu M, Sun W, Li T, Fang Y, Dong Y, Zhao S, Luo H, Feng J, Wang Q, Li L, Zheng Y. AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease. Pharmacol Res 2025; 212:107617. [PMID: 39832686 DOI: 10.1016/j.phrs.2025.107617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/12/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF's effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF's mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5'-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.
Collapse
Affiliation(s)
- Lulu Zhang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, China
| | - Yi Zheng
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mingyan Shao
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Aiping Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Meiyi Liu
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255000, China
| | - Tianxing Li
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yini Fang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yang Dong
- Monitoning and Statistical Research Center, National Administration of Traditional Chinese Medicine, Beijing 100600, China
| | - Shipeng Zhao
- Graduate School of China Academy of Chinese Medical Sciences, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Hui Luo
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Juan Feng
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen 518118, China.
| | - Qi Wang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Lingru Li
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Yanfei Zheng
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| |
Collapse
|
|
2
|
Dos Santos BG, Klein CP, August PM, Crestani MS, Hozer RM, Saccomori AB, Dal Magro BM, Rodrigues KS, Matté C. Naringin supplementation during pregnancy alters rat offspring's brain redox system and mitochondrial function. Brain Res 2025; 1847:149317. [PMID: 39515745 DOI: 10.1016/j.brainres.2024.149317] [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: 04/26/2024] [Revised: 10/24/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Naringin supplementation is known to ameliorate oxidative stress in the central nervous system (CNS) and improve cognitive function in disease models using adult rodents. However, if this supplementation is applied during critical periods of development, would it still be beneficial? To address this question, we used pregnant Wistar rats that were supplemented daily with naringin (100 mg/kg) during gestation. After delivery, pups were euthanized on postnatal day (PND) 1, 7, and 21. The prefrontal cortex, hippocampus, striatum, and cerebellum were dissected for redox system and mitochondrial function evaluation. Our data demonstrated that naringin supplementation to pregnant rats during gestation differentially affected the brain structures analyzed, inducing a dysregulation in the redox homeostasis, mainly on PND1. Redox and mitochondrial alterations found in offspring's cerebellum on PND1 were also observed on PND7, and persisted up to PND21, indicating a higher susceptibility of this structure to the effects triggered by maternal naringin supplementation. In contrast to what was observed in the cerebellum, we found a progressive decline in the number of alterations in the prefrontal cortex, hippocampus, and striatum from PND1 up to PND21, suggesting that these brain structures are not as susceptible as the cerebellum to the naringin's effects. Thus, our findings demonstrate a possible negative programming effect triggered by maternal naringin supplementation during pregnancy in the offspring's brain, especially in the cerebellum.
Collapse
Affiliation(s)
- B G Dos Santos
- Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - C P Klein
- Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - P M August
- Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - M S Crestani
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - R M Hozer
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - A B Saccomori
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - B M Dal Magro
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - K S Rodrigues
- Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - C Matté
- Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
| |
Collapse
|
|
3
|
Priya K, Roy AC, Prasad A, Kumar P, Ghosh I. Naringenin Against Cadmium Toxicity in Fibroblast Cells: An Integrated Network Pharmacology and In Vitro Metabolomics Approach. ENVIRONMENTAL TOXICOLOGY 2024; 39:5124-5139. [PMID: 39105392 DOI: 10.1002/tox.24388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/28/2024] [Accepted: 07/08/2024] [Indexed: 08/07/2024]
Abstract
Cadmium, a heavy metal, disrupts cellular homeostasis and is highly toxic, with no effective treatments currently available against its toxicity. According to studies, phytochemicals provide a promising strategy for mitigating cadmium toxicity. Naringenin (NG), a potent antioxidant found primarily in citrus fruits, showed protective properties against cadmium toxicity in rats. Nonetheless, the precise mechanism of cadmium cytotoxicity in fibroblasts remains unknown. This study evaluated NG against cadmium (CdCl2) toxicity utilizing network pharmacology and in silico molecular docking, and was further validated experimentally in rat fibroblast F111 cells. Using network pharmacology, 25 possible targets, including the top 10 targets of NG against cadmium, were identified. Molecular docking of interleukin 6 (IL6), the top potential target with NG, showed robust binding with an inhibition constant (Ki) of 58.76 μM, supporting its potential therapeutic potential. Pathway enrichment analysis suggested that "response to reactive oxygen species" and "negative regulation of small molecules metabolic process" were the topmost pathways targeted by NG against cadmium. In vitro analysis showed that NG (10 μM) attenuated CdCl2-induced oxidative stress by reducing altered intracellular ROS, mitochondrial mass, and membrane potential. Also, NG reversed CdCl2-mediated nuclear damage, G2/M phase arrest, and apoptosis. GC/MS-based metabolomics of F111 cells revealed CdCl2 reduced cholesterol levels, which led to alterations in primary bile acid, steroid and steroid hormone biosynthesis pathways, whereas, NG restored these alterations. In summary, combined in silico and in vitro analysis suggested that NG protected cells from CdCl2 toxicity by mitigating oxidative stress and metabolic pathway alterations, providing a comprehensive understanding of its protective mechanisms against cadmium-induced toxicity.
Collapse
Affiliation(s)
- Komal Priya
- Biochemistry and Environmental Toxicology Laboratory, Lab. #103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Ashim Chandra Roy
- Biochemistry and Environmental Toxicology Laboratory, Lab. #103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Abhinav Prasad
- Biochemistry and Environmental Toxicology Laboratory, Lab. #103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Prabhat Kumar
- Biochemistry and Environmental Toxicology Laboratory, Lab. #103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Ilora Ghosh
- Biochemistry and Environmental Toxicology Laboratory, Lab. #103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India
| |
Collapse
|
|
4
|
Calabrese EJ, Pressman P, Hayes AW, Dhawan G, Kapoor R, Agathokleous E, Manes P, Calabrese V. Naringin commonly acts via hormesis. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 896:164728. [PMID: 37295528 DOI: 10.1016/j.scitotenv.2023.164728] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/05/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
The present paper provides the first integrative assessment of the capacity of naringin and its metabolite, naringenin, to induce hormetic dose responses within a broad range of experimental biomedical models. The findings indicate that these agents commonly induced protective effects that are typically mediated via hormetic mechanisms leading to biphasic dose-response relationships. The maximum protective effects are generally modest, 30-60 % greater than control group values. The range of experimental findings with these agents has been reported for models with various neurodegenerative diseases, nucleus pulpous cells (NPCs) located within intravertebral discs, several types of stem cells (i.e., bone marrow, amniotic fluid, periodontal, endothelial) as well as cardiac cells. These agents also were effective within preconditioning protocols protecting against environmental toxins such as ultraviolet radiation (UV), cadmium, and paraquat. The mechanism(s) by which the hormetic responses mediates these biphasic dose responses is complex but commonly involves the activation of nuclear factor erythroid 2-related factor (Nrf2), an increasingly recognized regulator of cellular resistance to oxidants. Nrf2 appears to play a role in controlling the basal and induced expression of an array of antioxidant response element-dependent genes to regulate oxidant exposure's physiological and pathophysiological outcomes. Hence its importance in the assessment of toxicologic and adaptive potential is likely to be significant.
Collapse
Affiliation(s)
- Edward J Calabrese
- Department of Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA.
| | - Peter Pressman
- University of Maine, 5728 Fernald Hall, Room 201, Orono, ME 04469, USA.
| | - A Wallace Hayes
- Center for Environmental Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, USA
| | | | - Rachna Kapoor
- Saint Francis Hospital and Medical Center, Hartford, CT, USA
| | - Evgenios Agathokleous
- Department of Ecology, School of Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing 210044, China.
| | | | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, School of Medicine University of Catania, Via Santa Sofia 97, Catania 95123, Italy.
| |
Collapse
|
|
5
|
Požgajová M, Navrátilová A, Kovár M. Curative Potential of Substances with Bioactive Properties to Alleviate Cd Toxicity: A Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:12380. [PMID: 36231680 PMCID: PMC9566368 DOI: 10.3390/ijerph191912380] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 06/16/2023]
Abstract
Rapid urbanization and industrialization have led to alarming cadmium (Cd) pollution. Cd is a toxic heavy metal without any known physiological function in the organism, leading to severe health threat to the population. Cd has a long half-life (10-30 years) and thus it represents serious concern as it to a great extent accumulates in organs or organelles where it often causes irreversible damage. Moreover, Cd contamination might further lead to certain carcinogenic and non-carcinogenic health risks. Therefore, its negative effect on population health has to be minimalized. As Cd is able to enter the body through the air, water, soil, and food chain one possible way to defend and eliminate Cd toxicities is via dietary supplements that aim to eliminate the adverse effects of Cd to the organism. Naturally occurring bioactive compounds in food or medicinal plants with beneficial, mostly antioxidant, anti-inflammatory, anti-aging, or anti-tumorigenesis impact on the organism, have been described to mitigate the negative effect of various contaminants and pollutants, including Cd. This study summarizes the curative effect of recently studied bioactive substances and mineral elements capable to alleviate the negative impact of Cd on various model systems, supposing that not only the Cd-derived health threat can be reduced, but also prevention and control of Cd toxicity and elimination of Cd contamination can be achieved in the future.
Collapse
Affiliation(s)
- Miroslava Požgajová
- AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 94976 Nitra, Slovakia
| | - Alica Navrátilová
- Institute of Nutrition and Genomics, Faculty of Agrobiology and Food Resources, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 94976 Nitra, Slovakia
| | - Marek Kovár
- Institute of Plant and Environmental Science, Faculty of Agrobiology and Food Resources, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 94976 Nitra, Slovakia
| |
Collapse
|
|
6
|
Exploration of the Protective Mechanism of Naringin in the Acetaminophen-Induced Hepatic Injury by Metabolomics. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7138194. [PMID: 36160708 PMCID: PMC9507767 DOI: 10.1155/2022/7138194] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/23/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022]
Abstract
Naringin is a dihydroflavone which was found in citrus fruits. Previous studies have indicated the antiapoptotic, antioxidative stress, and anti-inflammatory effects of naringin. It can improve many common diseases, including fibrosis or hepatotoxicity, cardiovascular disease, and diabetes. Acetaminophen (APAP) is a frequently used painkiller, and hepatotoxic side effects limit its use. The purpose of the current examination is to find the impact of naringin on APAP-induced hepatic injury. Firstly, we pretreated mice model groups with naringin. Then, the liver injury model was established by injecting intraperitoneally into mice with APAP. After the mice were euthanized, we obtained serum and liver tissue samples from the mice. Finally, these samples were analyzed using a metabolomics approach to find the underlying mechanism of the effects of naringin on APAP-induced liver injury and provide a new treatment strategy for APAP-induced liver injury. Our data indicate that naringin significantly improves APAP-induced liver injury in mice and reduces the expression levels of liver injury markers in a dose-dependent manner. Furthermore, analysis of differential metabolites in mice with liver injury showed that naringin reduced APAP-induced hepatotoxicity due to reversing multiple metabolite expression levels and the rescue of energy, amino acid, and purine metabolism.
Collapse
|
|
7
|
Ashrafizadeh M, Ahmadi Z, Farkhondeh T, Samarghandian S. Back to Nucleus: Combating with Cadmium Toxicity Using Nrf2 Signaling Pathway as a Promising Therapeutic Target. Biol Trace Elem Res 2020; 197:52-62. [PMID: 31786752 DOI: 10.1007/s12011-019-01980-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/06/2019] [Indexed: 12/25/2022]
Abstract
There are concerns about the spread of heavy metals in the environment, and human activities are one of the most important factors in their spread. These agents have the high half-life resulting in their persistence in the environment. So, prevention of their spread is the first step. However, heavy metals are an inevitable part of modern and industrial life and they are applied in different fields. Cadmium is one of the heavy metals which has high carcinogenesis ability. Industrial waste, vehicle emissions, paints, and fertilizers are ways of exposing human to cadmium. This potentially toxic agent harmfully affects the various organs and systems of body such as the liver, kidney, brain, and cardiovascular system. Oxidative stress is one of the most important pathways of cadmium toxicity. So, improving the antioxidant defense system can be considered as a potential target. On the other hand, the Nrf2 signaling pathway involves improving the antioxidant capacity by promoting the activity of antioxidant enzymes such as catalase and superoxide dismutase. At the present review, we demonstrate how Nrf2 signaling pathway can be modulated to diminish the cadmium toxicity.
Collapse
Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Zahra Ahmadi
- Department of Basic Science, Shoushtar Branch, Islamic Azad University, Shoushtar, Iran
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
| |
Collapse
|
|
8
|
Flavonoids from Aurantii Fructus Immaturus and Aurantii Fructus: promising phytomedicines for the treatment of liver diseases. Chin Med 2020; 15:89. [PMID: 32863858 PMCID: PMC7449045 DOI: 10.1186/s13020-020-00371-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022] Open
Abstract
Background Liver diseases and related complications are major sources of morbidity and mortality, which places a huge financial burden on patients and lead to nonnegligible social problems. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently required. Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) are frequently used herbal medicines in traditional Chinese medicine (TCM) formulas for the treatment of diverse ailments. A variety of bioactive ingredients have been isolated and identified from AFI and AF, including alkaloids, flavonoids, coumarins and volatile oils. Main body Emerging evidence suggests that flavonoids, especially hesperidin (HD), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangeretin (TN), hesperetin (HT) and eriodictyol (ED) are major representative bioactive ingredients that alleviate diseases through multi-targeting mechanisms, including anti-oxidative stress, anti-cytotoxicity, anti-inflammation, anti-fibrosis and anti-tumor mechanisms. In the current review, we summarize the recent progress in the research of hepatoprotective effects of HD, NIN, NOB, NRG, TN, HT and ED and highlight the potential underlying molecular mechanisms. We also point out the limitations of the current studies and shed light on further in-depth pharmacological and pharmacokinetic studies of these bioactive flavonoids. Conclusion This review outlines the recent advances in the literature and highlights the potential of these flavonoids isolated from AFI and AF as therapeutic agents for the treatment of liver diseases. Further pharmacological studies will accelerate the development of natural products in AFI and AF and their derivatives as medicines with tantalizing prospects in the clinical application.
Collapse
|
|
9
|
Shirani K, Yousefsani BS, Shirani M, Karimi G. Protective effects of naringin against drugs and chemical toxins induced hepatotoxicity: A review. Phytother Res 2020; 34:1734-1744. [DOI: 10.1002/ptr.6641] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/16/2020] [Accepted: 01/31/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Kobra Shirani
- Department of Toxicology, Faculty of Medical SciencesTarbiat Modares University Tehran Iran
| | - Bahare Sadat Yousefsani
- Research Institute for Islamic and Complementary MedicineIran University of Medical Sciences Tehran Iran
- School of Persian MedicineIran University of Medical Sciences
| | - Maryam Shirani
- Department of Toxicology, Faculty of PharmacyAhvaz Jundishapur University of Medical Sciences Ahvaz Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of PharmacyMashhad University of Medical Sciences Mashhad Iran
- Pharmaceutical Research Center, Pharmaceutical Technology InstituteMashhad University of Medical Sciences Mashhad Iran
| |
Collapse
|
|
10
|
Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J Gastroenterol 2018; 24:1679-1707. [PMID: 29713125 PMCID: PMC5922990 DOI: 10.3748/wjg.v24.i16.1679] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/04/2018] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-β) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-β non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-β and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases.
Collapse
Affiliation(s)
- Erika Hernández-Aquino
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07000, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 07000, Mexico
| |
Collapse
|
|
11
|
Viswanatha GL, Shylaja H, Moolemath Y. The beneficial role of Naringin- a citrus bioflavonoid, against oxidative stress-induced neurobehavioral disorders and cognitive dysfunction in rodents: A systematic review and meta-analysis. Biomed Pharmacother 2017; 94:909-929. [PMID: 28810519 DOI: 10.1016/j.biopha.2017.07.072] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/04/2017] [Accepted: 07/17/2017] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES Naringin is a bioflavonoid, very abundantly found in citrus species. In literature, naringin has been scientifically well documented for its beneficial effects in various neurological disorders. In this systematic review and meta-analysis, we have made an attempt to correlate the protective role of naringin against oxidative stress-induced neurological disorders in rodents. METHODS The systematic search was performed using electronic databases; the search was mainly focused on the role of naringin in oxidative stress-induced neuropathological conditions in rodents. While, the meta-analysis was performed on the effect of naringin on oxidative stress markers [superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), lipid peroxidation (LPO)], nitrite, mitochondrial complexes (I to IV) and enzymes (acetylcholinesterase, Na+-K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase) in the rodent brain. The data was analyzed using Review Manager Software. THE RESULTS Based on the inclusion and exclusion criteria, twenty studies were selected. The meta-analysis revealed that, naringin could significantly inhibit various physical and chemical stimuli- induced neurological perturbances in the rodent brain, mediated through oxidative stress. Further, naringin also significantly restored the levels of all the oxidative stress markers (oxidative, nitrosative, enzymes, and mitochondrial complexes) in different parts of the rodent brain. SUMMARY This systematic review and meta-analysis supports the available scientific evidence on the beneficial role of naringin in the management of various neurological ailments. However, further studies involving human subjects is recommended to establish the safety and therapeutic efficacy in humans.
Collapse
Affiliation(s)
| | - H Shylaja
- Independent Researcher, Kengeri, Bangalore, 560060, Karnataka, India
| | - Yogananda Moolemath
- Vittarthaa Life Sciences, Bommasandra Industrial Area, Bangalore, 560099, Karnataka, India
| |
Collapse
|