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1
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Li X, Li S, Li N. Research Progress on Natural Products Alleviating Liver Inflammation and Fibrosis via NF-κB Pathway. Chem Biodivers 2025; 22:e202402248. [PMID: 39576739 DOI: 10.1002/cbdv.202402248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/21/2024] [Accepted: 11/21/2024] [Indexed: 11/24/2024]
Abstract
Liver fibrosis is a key pathological process in chronic liver diseases, regulated by various cytokines and signaling pathways. Among these, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway plays a significant role in the initiation and progression of liver fibrosis. Recently, natural products have garnered attention as potential anti-fibrotic agents. This review highlights recent studies on how natural products, including flavonoids, terpenoids, polysaccharides, phenols, alkaloids, quinones, phenylpropanoids, steroids, and nitrogen compounds, mitigate liver fibrosis by modulating the NF-κB signaling pathway. Specifically, it examines how these natural products influence NF-κB activation, nuclear translocation, and downstream signaling, thereby inhibiting inflammatory responses, reducing apoptosis, and regulating hepatic stellate cell (HSC) activity, ultimately achieving therapeutic effects against liver fibrosis. A deeper understanding of the mechanisms by which natural products regulate the NF-κB signaling pathway can provide crucial theoretical foundations and valuable insights for the development of novel anti-fibrotic drugs.
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Affiliation(s)
- Xiaoying Li
- Department of Pathology, Henan Medical College, Zhengzhou, Henan, China
| | - Saifei Li
- Department of Pharmacy, Henan Medical College, Zhengzhou, Henan, China
| | - Ningning Li
- Department of Pathology, Henan Medical College, Zhengzhou, Henan, China
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2
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Luo K, Geng Y, Oosterhuis D, de Meijer VE, Olinga P. Evaluating the antifibrotic potential of naringenin, asiatic acid, and icariin using murine and human precision-cut liver slices. Physiol Rep 2024; 12:e16136. [PMID: 39501714 PMCID: PMC11538472 DOI: 10.14814/phy2.16136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 11/09/2024] Open
Abstract
Liver fibrosis is an exaggerated wound healing response defined by the excessive accumulation of extracellular matrix. This study investigated the antifibrotic potential of naringenin (NRG), asiatic acid (AA), and icariin (ICA) using murine and human precision-cut liver slices (PCLS). These natural products have shown promise in animal models, but human data are lacking. In this study, PCLS prepared from male mouse liver tissue (mPCLS), healthy human liver tissue (hhPCLS), and cirrhotic human liver tissue (chPCLS) were cultured for 48 h with varying concentrations of the three compounds. Our findings indicate that NRG reduced collagen type 1 (COL1A1) expression in a concentration-dependent manner in both mPCLS and chPCLS, decreased fibrosis-related gene expression, and significantly lowered pro-collagen type 1 (PCOL1A1) levels in the culture medium by 54 ± 21% (mPCLS) and 78 ± 35% (chPCLS). Furthermore, NRG effectively inhibited IL-1β and TNF-α in mPCLS and IL-1β in chPCLS on both gene and protein levels. AA specifically reduced COL1A1 and PCOL1A1 in chPCLS, while ICA selectively downregulated Col1a1 and Acta2 gene expression in mPCLS. This study suggests NRG's potential as an effective antifibrotic agent, warranting further investigation into its mechanisms and therapeutic applications in liver fibrosis.
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Affiliation(s)
- Ke Luo
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Yana Geng
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Dorenda Oosterhuis
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, University of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
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3
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Muralidharan J, Romain C, Chung L, Alcaraz P, Martínez-Noguera FJ, Keophiphath M, Lelouvier B, Ancel P, Gaborit B, Cases J. Effect of Sinetrol ® Xpur on metabolic health and adiposity by interactions with gut microbiota: a randomized, open label, dose-response clinical trial. Nutr Metab (Lond) 2024; 21:83. [PMID: 39415279 PMCID: PMC11484468 DOI: 10.1186/s12986-024-00851-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 09/16/2024] [Indexed: 10/18/2024] Open
Abstract
BACKGROUND Sinetrol® Xpur is a polyphenolic ingredient rich in citrus flavonoids that has shown weight loss effects in previous studies. The dose dependent nature, gut microbial actions of this product has not been explored previously, thus presented in this study. METHODS In this open label study, we evaluated the effect of Sinetrol® Xpur supplementation on healthy but overweight/obese adults (20-50 yrs) for 16 weeks. Participants (n = 20) were randomly allocated to a high dose group (HD, 1800 mg/day) or low dose group (LD, 900 mg/day) of the product for 16 weeks. Fat composition, gut microbial composition, were evaluated using MRI and 16S rDNA sequencing respectively at week 1 and 16. RESULTS We observed HDL, HbA1C, LDL and leptin improved significantly over 16 weeks, irrespective of the dosage. There was a trend for decrease in visceral adipose tissue (VAT), BMI over time and body weight displayed a trend for dose dependent decrease. Eubacterium xylanophilum, Ruminococcacea UCG-004 genus which increased in HD and LD respectively were negatively associated to VAT. Both doses increased butyrate producers such as Eubacterium ruminantium and Ruminococcaceae NK4A214 genus. CONCLUSIONS Overall chronic supplementation of Sinetrol® Xpur, irrespective of their dose improved HDL, HbA1c, LDL and leptin and tended to decrease visceral adipose tissue via changes in gut microbiota. Trial registration number NCT03823196.
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Affiliation(s)
| | - Cindy Romain
- Fytexia, ZAE via Europa-3 rue d'Athènes, 34350, Vendres, France
| | - Linda Chung
- Research Center for High Performance Sport-UCAM Universidad Católica de Murcia, Murcia, Spain
| | - Pedro Alcaraz
- Research Center for High Performance Sport-UCAM Universidad Católica de Murcia, Murcia, Spain
| | | | - Mayoura Keophiphath
- DIVA Expertise, Centre Pierre Potier, 1 place Pierre Potier, 31100, Toulouse, France
| | | | - Patricia Ancel
- INSERM, INRA, C2VN, Aix Marseille Univ, Marseille, France
| | | | - Julien Cases
- Fytexia, ZAE via Europa-3 rue d'Athènes, 34350, Vendres, France.
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Chowdhury A, Mitra Mazumder P. Unlocking the potential of flavonoid-infused drug delivery systems for diabetic wound healing with a mechanistic exploration. Inflammopharmacology 2024:10.1007/s10787-024-01561-5. [PMID: 39217278 DOI: 10.1007/s10787-024-01561-5] [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: 08/05/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024]
Abstract
Diabetes is one of the common endocrine disorders generally characterized by elevated levels of blood sugar. It can originate either from the inability of the pancreas to synthesize insulin, which is considered as an autoimmune disorder, or the reduced production of insulin, considered as insulin resistivity. A wound can be defined as a condition of damage to living tissues including skin, mucous membrane and other organs as well. Wounds get complicated with respect to time based on specific processes like diabetes mellitus, obesity and immunocompromised conditions. Proper growth and functionality of the epidermis gets sustained due to impaired diabetic wound healing which shows a sign of dysregulated wound healing process. In comparison with synthetic medications, phytochemicals like flavonoids, tannins, alkaloids and glycosides have gained enormous importance relying on their distinct potential to heal diabetic wounds. Flavonoids are one of the most promising and important groups of natural compounds which can be used to treat acute as well as chronic wounds. Flavonoids show excellent properties due to the presence of hydroxyl groups in their chemical structure, which makes this class of compounds different from others. Based on the novel principles of nanotechnology via utilizing suitable drug delivery systems, the delivery of bioactive constituents from plant source amplifies the wound-healing mechanism, minimizes complexities and enhances bioavailability. Hence, the encapsulation and applicability of flavonoids with an emphasis on mechanistic route and wound-healing therapeutics have been highlighted in the subsequent study with focus on multiple drug delivery systems.
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Affiliation(s)
- Ankit Chowdhury
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Papiya Mitra Mazumder
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
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Yashmi F, Fakhri S, Shiri Varnamkhasti B, Amin MN, Khirehgesh MR, Mohammadi-Noori E, Hosseini M, Khan H. Defining the mechanisms behind the hepatoprotective properties of curcumin. Arch Toxicol 2024; 98:2331-2351. [PMID: 38837048 DOI: 10.1007/s00204-024-03758-7] [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: 01/26/2024] [Accepted: 04/09/2024] [Indexed: 06/06/2024]
Abstract
As a critical cause of human dysfunctionality, hepatic failure leads to approximately two million deaths per year and is on the rise. Considering multiple inflammatory, oxidative, and apoptotic mechanisms behind hepatotoxicity, it urges the need for finding novel multi-targeting agents. Curcumin is a phenolic compound with anti-inflammatory, antioxidant, and anti-apoptotic roles. Curcumin possesses auspicious health benefits and protects against several diseases with exceptional safety and tolerability. This review focused on the hepatoprotective mechanisms of curcumin. The need to develop novel delivery systems of curcumin (e.g., nanoparticles, self-micro emulsifying, lipid-based colloids, solid lipid nanoparticles, cyclodextrin inclusion, phospholipid complexes, and nanoemulsions) is also considered.
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Affiliation(s)
- Farinam Yashmi
- Department of Pharmacy, Acibadem University, Istanbul, Turkey
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Behrang Shiri Varnamkhasti
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammed Namiq Amin
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Reza Khirehgesh
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ehsan Mohammadi-Noori
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahsa Hosseini
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, 23200, Pakistan.
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Liu L, Lv L, Dai W, Nie J. The effect of naringenin-phospholipid complex on thermal oxidative stability of soybean oil under heating condition. Food Chem 2024; 444:138631. [PMID: 38325079 DOI: 10.1016/j.foodchem.2024.138631] [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: 10/28/2023] [Revised: 01/15/2024] [Accepted: 01/28/2024] [Indexed: 02/09/2024]
Abstract
Naringenin (NGE), a typical flavanone abundant in citrus fruits, exhibits remarkable antioxidant activities. However, its low solubility in oil restricts its widespread use in inhibiting lipid oxidation. In this study, we present a novel and effective approach to address this limitation by developing a naringenin-phospholipid complex (NGE-PC COM). Comprehensive analytical techniques including Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were employed to confirm the formation of the NGE-PC COM and elucidate the interaction mechanism between NGE and phospholipids molecules. Notably, the oil-solubility of NGE was significantly enhanced by approximately 2700-fold when formulated as a phospholipid complex in soybean oil. The improved oil-solubility of NGE-PC COM enabled effective inhibition of oil thermal oxidation under high temperature conditions. Generally, this investigation proposed a novel and promising strategy for employing flavanones with strong antioxidant activities to enhance the thermal oxidative stability of edible oil during heating processes.
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Affiliation(s)
- Liyao Liu
- College of Basic Science, Tianjin Agriculture University, Tianjin 300392, PR China
| | - Lifei Lv
- College of Basic Science, Tianjin Agriculture University, Tianjin 300392, PR China
| | - Wenjie Dai
- College of Basic Science, Tianjin Agriculture University, Tianjin 300392, PR China
| | - Jinju Nie
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong 264000, PR China.
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7
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Singh B, Semwal BC. A Compressive Review on Source, Toxicity and Biological Activity of Flavonoid. Curr Top Med Chem 2024; 24:2093-2116. [PMID: 39108008 DOI: 10.2174/0115680266316032240718050055] [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: 04/02/2024] [Revised: 06/05/2024] [Accepted: 06/25/2024] [Indexed: 10/22/2024]
Abstract
Flavonoids are biologically active chemicals in various fruits, plants, vegetables, and leaves, which have promising uses in medicinal science. The health properties of these natural chemicals are widely accepted, and efforts are underway to extract the specific components referred to as flavonoids. Flavonoids demonstrate a diverse range of bio-activities, anticancer, antioxidant activity, anti-cholinesterase activity, antiinflammatory activity, antimalarial activity, antidiabetic activity, neurodegenerative disease, cardiovascular effect, hepatoprotective effects, and antiviral and antimicrobial activity. This study aims to examine the prevailing trends in flavonoid investigation studies, elucidate the activity of flavonoids, examine their various functions and uses, assess the potential of flavonoids as preventive medications for chronic diseases, and outline future research opportunities in this field. This review explores the diverse functions of flavonoids in preventing and managing various diseases.
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Affiliation(s)
- Bhoopendra Singh
- Department of Pharmacology, GLA University, NH#2 Delhi Mathura Highway, Uttar Pradesh, India
| | - Bhupesh Chander Semwal
- Department of Pharmacology, GLA University, NH#2 Delhi Mathura Highway, Uttar Pradesh, India
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Madiha S, Batool Z, Shahzad S, Tabassum S, Liaquat L, Afzal A, Sadir S, Sajid I, Mehdi BJ, Ahmad S, Haider S. Naringenin, a Functional Food Component, Improves Motor and Non-Motor Symptoms in Animal Model of Parkinsonism Induced by Rotenone. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2023; 78:654-661. [PMID: 37796415 DOI: 10.1007/s11130-023-01103-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/26/2023] [Indexed: 10/06/2023]
Abstract
Parkinson's disease (PD) and other age-related neurodegenerative ailments have a strong link to oxidative stress. Bioflavonoid naringenin has antioxidant properties. The effects of pre- and post-naringenin supplementation on a rotenone-induced PD model were examined in this work. Naringenin (50 mg/kg, p.o.) was administered to rats for two weeks before the administration of rotenone in the pre-treatment phase. In contrast, rotenone (1.5 mg/kg, s.c.) was administered for eight days before naringenin (50 mg/kg, p.o.) was supplemented for two weeks in the post-treatment phase. During behavioral investigation, the motor and non-motor signs of PD were observed. Additionally, estimation of neurochemical and biochemical parameters was also carried out. Compared to controls, rotenone treatment substantially increased oxidative stress, altered neurotransmitters, and caused motor and non-motor impairments. Rotenone-induced motor and non-motor impairments were considerably reduced by naringenin supplementation. The supplementation also increased antioxidant enzyme activities and restored the changes in neurotransmitter levels. The findings of this work strongly imply that daily consumption of flavonoids such as naringenin may have a therapeutic potential to combat PD.
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Affiliation(s)
- Syeda Madiha
- Neurochemistry and Biochemical Neuropharmacology Research Unit, Department of Biochemistry, University of Karachi, Karachi, 75270, Pakistan
| | - Zehra Batool
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
| | - Sidrah Shahzad
- Pakistan Navy Medical Training School and College, PNS Shifa, Karachi, Pakistan
| | - Saiqa Tabassum
- Department of Biosciences, Shaheed Zuifiqar Ali Bhutto Institute of Science and Technology, Karachi, Pakistan
| | - Laraib Liaquat
- Multidisciplinary Research Lab, Bahria University Health Sciences Campus, Bahria University, Karachi, Pakistan
| | - Asia Afzal
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Sadia Sadir
- Department of Biosciences, Shaheed Zuifiqar Ali Bhutto Institute of Science and Technology, Karachi, Pakistan
| | - Irfan Sajid
- Department of Biochemistry, Federal Urdu University of Arts, Sciences & Technology, Karachi, Pakistan
| | - Bushra Jabeen Mehdi
- Department of Biomedical Engineering, Sir Syed University of Engineering and Technology, Karachi, Pakistan
| | - Saara Ahmad
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - Saida Haider
- Neurochemistry and Biochemical Neuropharmacology Research Unit, Department of Biochemistry, University of Karachi, Karachi, 75270, Pakistan
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9
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Peng C, Li J, Ke X, Liu F, Huang KE. In silico and in vivo demonstration of the regulatory mechanism of Qi-Ge decoction in treating NAFLD. Ann Med 2023; 55:2200258. [PMID: 37096878 DOI: 10.1080/07853890.2023.2200258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD), a chronic and progressive liver disease, often causes steatosis and steatohepatitis. Qi-Ge decoction (QGD) shows a good effect against NAFLD in the clinic. But the molecular mechanism for QGD in improving NAFLD is unknown. PURPOSE This study explored the molecular mechanism of QGD in NAFLD model rats using comprehensive network pharmacology, molecular docking and in vivo verification strategies. METHODS Active components and targets of QGD were obtained from public database. The overlapped genes between QGD and NAFLD targets were analyzed by enrichment analysis. Active components and targets were used to predict molecular docking analysis. Finally, seven key targets were screened out and the gene expression were verified in the NAFLD rat's liver tissues after QGD treatment. RESULTS Fifty-eight common QGD therapeutic targets were associated with NAFLD. Molecular docking demonstrated that seven targets had strong binding ability for the corresponding active ingredients. GO analysis identified 18 biological process entries, which were mainly related to regulation of lipid storage, lipid localization and peptide transport. KEGG analysis identified multiple signaling pathways, which were mainly associated with tumor necrosis factor signaling and NAFLD. In vivo data confirmed that the effect of QGD in the treatment of NAFLD was mainly exerted through improving liver steatosis and inflammatory cell infiltration. Additionally, QGD upregulated the expression of MAPK8 and ESR1 and downregulated the transcriptional expression of IL6, VEGFA, CASP3, EGFR and MYC. These targets may affect lipid metabolism by regulating lipid storage and inflammation. CONCLUSION The integration of results obtained in silico and in vivo indicated that QGD regulates multiple targets, biological processes and signaling pathways in NAFLD, which may represent a complex molecular mechanism by which QGD improves NAFLD.Key messagesQGD intervention is related to multiple biological processes such as inflammation, oxidation and cell apoptosis in NAFLD.Lipid and atherosclerosis, TNF signaling pathway, IL-17 signaling pathway, non-alcoholic fatty liver disease and AGE-RAGE signaling pathway in diabetic complications are the main pathways for QGD intervention NAFLD.The active components of QGD can form good binding with relevant target proteins through intermolecular forces, exhibiting excellent docking activity.
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Affiliation(s)
- Chong Peng
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Postdoctoral Research Station, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jing Li
- Postdoctoral Research Station, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Integrative Cancer Centre, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xuehong Ke
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Fengbin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ke-Er Huang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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10
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Wang Y, Li Z, Wang B, Li K, Zheng J. Naringenin attenuates inflammation and apoptosis of osteoarthritic chondrocytes via the TLR4/TRAF6/NF-κB pathway. PeerJ 2023; 11:e16307. [PMID: 37953787 PMCID: PMC10638912 DOI: 10.7717/peerj.16307] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 09/26/2023] [Indexed: 11/14/2023] Open
Abstract
Naringenin is a flavonoid extracted from the seed coat of Anacardiaceae plants. Increasing evidence indicates that it has several properties of biological significance, such as anti-infection, sterilization, anti-allergy, antioxidant free radical, and anti-tumor. However, its effect on osteoarthritis has not been elucidated properly. In this study, the treatment of primary chondrocytes with interleukin (IL)-1β was found to increase the secretions of IL-6, tumor necrosis factor (TNF)-α, and cyclooxygenase-2 (COX-2). Further, the mRNA expression of matrix metalloproteinase ((MMP)3, MMP9, and MMP13), the protein expression of Recombinant A Disintegrin And Metalloproteinase With Thrombospondin 5 (ADAMTS5), and cell apoptosis increased; the protein expression of Collagen II decreased. The injury of primary chondrocytes induced by IL-1β was reversed under the intervention of naringenin; this reversal was dose-dependent. The mechanistic study showed that naringenin inhibited the toll-like receptor 4 (TLR4)/TNF receptor-associated factor 6 (TRAF6)/NF-κB pathway in IL-1β-stimulated primary cells, and LPS, a TLR4 activator, reversed this inhibitory effect. In addition, a mouse model of osteoarthritis was established and treated with naringenin. The results revealed that naringenin alleviated the pathological symptoms of osteoarthritis in mice, reduced the expression of TLR4 and TRAF6, and the phosphorylation of NF-κB in knee cartilage tissue. It also inhibited the secretion of inflammatory factors, reduced extracellular matrix degradation, and decreased the protein expression of cleaved caspase3. In conclusion, the findings of this study suggest that naringenin may be a potential option for the treatment of osteoarthritis.
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Affiliation(s)
- Yan Wang
- Department of Hand Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Zhengzhao Li
- Department of Emergency Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Bo Wang
- Department of Sports Medicine, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Ke Li
- Department of Sports Medicine, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
| | - Jiaxuan Zheng
- Department of Pathology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China
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11
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Uçar K, Göktaş Z. Biological activities of naringenin: A narrative review based on in vitro and in vivo studies. Nutr Res 2023; 119:43-55. [PMID: 37738874 DOI: 10.1016/j.nutres.2023.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/21/2023] [Accepted: 08/21/2023] [Indexed: 09/24/2023]
Abstract
Naringenin (4',5,7-trihydroxyflavonone) is a phytochemical mainly found in citrus fruits. It is a promising phytochemical for human health because of its beneficial effects. This review aims to present comprehensive information on naringenin biological activities along with its action mechanisms and explain the pharmacokinetic properties of naringenin. This study involves a comprehensive literature review of in vitro and in vivo studies examining the effects of naringenin. Naringenin has antidiabetic, anticancer, antimicrobial, antiobesity, gastroprotective, immunomodulator, cardioprotective, nephroprotective, and neuroprotective properties. These properties are primarily attributed to its antioxidant and anti-inflammatory activities. The most important antioxidant activities of naringenin including free radical scavenging and preventing lipid peroxidation. Naringenin can increase the concentration of antioxidant enzymes and inhibit metal chelation and various pro-oxidant enzymes. Anti-inflammatory activities of naringenin are associated with decreased mitogen-activated protein kinase activities and nuclear factor kappa B by modulating the expression and release of proinflammatory cytokine and enzymes. In vitro and in vivo studies show that naringenin has promising biological activities for a variety of diseases. More research must be conducted on the bioactivities of naringenin, and to determine its optimum dose. In addition, the efficiency of naringenin must be examined with enhanced bioavailability methods to be able to increase its therapeutic effect.
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Affiliation(s)
- Kübra Uçar
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye
| | - Zeynep Göktaş
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye.
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12
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Cao Y, Fang X, Sun M, Zhang Y, Shan M, Lan X, Zhu D, Luo H. Preventive and therapeutic effects of natural products and herbal extracts on nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Phytother Res 2023; 37:3867-3897. [PMID: 37449926 DOI: 10.1002/ptr.7932] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/21/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common condition that is prevalent in patients who consume little or no alcohol, and is characterized by excessive fat accumulation in the liver. The disease is becoming increasingly common with the rapid economic development of countries. Long-term accumulation of excess fat can lead to NAFLD, which represents a global health problem with no effective therapeutic approach. NAFLD is a complex, multifaceted pathological process that has been the subject of extensive research over the past few decades. Herbal medicines have gained attention as potential therapeutic agents to prevent and treat NAFLD due to their high efficacy and low risk of side effects. Our overview is based on a PubMed and Web of Science database search as of Dec 22 with the keywords: NAFLD/NASH Natural products and NAFLD/NASH Herbal extract. In this review, we evaluate the use of herbal medicines in the treatment of NAFLD. These natural resources have the potential to inform innovative drug research and the development of treatments for NAFLD in the future.
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Affiliation(s)
- Yiming Cao
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Xiaoxue Fang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Mingyang Sun
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Yegang Zhang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Mengyao Shan
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Xintian Lan
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Difu Zhu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
| | - Haoming Luo
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Effective Components of Traditional Chinese Medicine, Changchun, China
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Fang X, Song J, Zhou K, Zi X, Sun B, Bao H, Li L. Molecular Mechanism Pathways of Natural Compounds for the Treatment of Non-Alcoholic Fatty Liver Disease. Molecules 2023; 28:5645. [PMID: 37570615 PMCID: PMC10419790 DOI: 10.3390/molecules28155645] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/21/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and its incidence continues to increase each year. Yet, there is still no definitive drug that can stop its development. This review focuses mainly on lipotoxicity, oxidative stress, inflammation, and intestinal flora dysbiosis to understand NAFLD's pathogenesis. In this review, we used NCBI's PubMed database for retrieval, integrating in vivo and in vitro experiments to reveal the therapeutic effects of natural compounds on NAFLD. We also reviewed the mechanisms by which the results of these experiments suggest that these compounds can protect the liver from damage by modulating inflammation, reducing oxidative stress, decreasing insulin resistance and lipid accumulation in the liver, and interacting with the intestinal microflora. The natural compounds discussed in these papers target a variety of pathways, such as the AMPK pathway and the TGF-β pathway, and have significant therapeutic effects. This review aims to provide new possible therapeutic lead compounds and references for the development of novel medications and the clinical treatment of NAFLD. It offers fresh perspectives on the development of natural compounds in preventing and treating NAFLD.
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Affiliation(s)
| | | | | | | | | | | | - Lijing Li
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.F.)
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Liga S, Paul C, Péter F. Flavonoids: Overview of Biosynthesis, Biological Activity, and Current Extraction Techniques. PLANTS (BASEL, SWITZERLAND) 2023; 12:2732. [PMID: 37514347 PMCID: PMC10384615 DOI: 10.3390/plants12142732] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/17/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023]
Abstract
Recently, increased attention has been paid to natural sources as raw materials for the development of new added-value products. Flavonoids are a large family of polyphenols which include several classes based on their basic structure: flavanones, flavones, isoflavones, flavonols, flavanols, and anthocyanins. They have a multitude of biological properties, such as anti-inflammatory, antioxidant, antiviral, antimicrobial, anticancer, cardioprotective, and neuroprotective effects. Current trends of research and development on flavonoids relate to identification, extraction, isolation, physico-chemical characterization, and their applications to health benefits. This review presents an up-to-date survey of the most recent developments in the natural flavonoid classes, the biological activity of representative flavonoids, current extraction techniques, and perspectives.
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Affiliation(s)
- Sergio Liga
- Biocatalysis Group, Department of Applied Chemistry and Engineering of Organic and Natural Compounds, Faculty of Industrial Chemistry and Environmental Engineering, Politehnica University Timisoara, Carol Telbisz 6, 300001 Timisoara, Romania
| | - Cristina Paul
- Biocatalysis Group, Department of Applied Chemistry and Engineering of Organic and Natural Compounds, Faculty of Industrial Chemistry and Environmental Engineering, Politehnica University Timisoara, Carol Telbisz 6, 300001 Timisoara, Romania
| | - Francisc Péter
- Biocatalysis Group, Department of Applied Chemistry and Engineering of Organic and Natural Compounds, Faculty of Industrial Chemistry and Environmental Engineering, Politehnica University Timisoara, Carol Telbisz 6, 300001 Timisoara, Romania
- Research Institute for Renewable Energies, Politehnica University Timisoara, Gavril Muzicescu 138, 300501 Timisoara, Romania
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Gao S, Chen X, Yu Z, Du R, Chen B, Wang Y, Cai X, Xu J, Chen J, Duan H, Cai Y, Zheng G. Progress of research on the role of active ingredients of Citri Reticulatae Pericarpium in liver injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 115:154836. [PMID: 37119760 DOI: 10.1016/j.phymed.2023.154836] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND Liver is a vital organ responsible for metabolizing and detoxifying both endogenous and exogenous substances in the body. However, it is susceptible to damage from chemical and natural toxins. The high incidence and mortality rates of liver disease and its associated complications impose a significant economic burden and survival pressure on patients and their families. Various liver diseases exist, including cholestasis, viral and non-viral hepatitis, fatty liver disease, drug-induced liver injury, alcoholic liver injury, and severe end-stage liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and cholangiocellular carcinoma (CCA). Recent research has shown that flavonoids found in Citri Reticulatae Pericarpium (CRP) have the potential to normalize blood glucose, cholesterol levels, and liver lipid levels. Additionally, these flavonoids exhibit anti-inflammatory properties, prevent oxidation and lipid peroxidation, and reduce liver toxicity, thereby preventing liver injury. Given these promising findings, it is essential to explore the potential of active components in CRP for developing new drugs to treat liver diseases. OBJECTIVE Recent studies have revealed that flavonoids, including hesperidin (HD), hesperetin (HT), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangerine (TN), and erodcyol (ED), are the primary bioactive components in CRP. These flavonoids exhibit various therapeutic effects on liver injury, including anti-oxidative stress, anti-cytotoxicity, anti-inflammatory, anti-fibrosis, and anti-tumor mechanisms. In this review, we have summarized the research progress on the hepatoprotective effects of HD, HT, NIN, NOB, NRG, TN, ED and limonene (LIM), highlighting their underlying molecular mechanisms. Despite their promising effects, the current clinical application of these active ingredients in CRP has some limitations. Therefore, further studies are needed to explore the full potential of these flavonoids and develop new therapeutic strategies for liver diseases. METHODS For this review, we conducted a systematic search of three databases (ScienceNet, PubMed, and Science Direct) up to July 2022, using the search terms "CRP active ingredient," "liver injury," and "flavonoids." The search data followed the PRISMA standard. RESULTS Our findings indicate that flavonoids found in CRP can effectively reduce drug-induced liver injury, alcoholic liver injury, and non-alcoholic liver injury. These therapeutic effects are mainly attributed to the ability of flavonoids to improve liver resistance to oxidative stress and inflammation while normalizing cholesterol and liver lipid levels by exhibiting anti-free radical and anti-lipid peroxidation properties. CONCLUSION Our review provides new insights into the potential of active components in CRP for preventing and treating liver injury by regulating various molecular targets within different cell signaling pathways. This information can aid in the development of novel therapeutic strategies for liver disease.
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Affiliation(s)
- Shuhan Gao
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xiaojing Chen
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhiqian Yu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Rong Du
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Baizhong Chen
- Guangdong Xinbaotang Biological Technology Co., Ltd, Guangdong Jiangmen, 529000, China
| | - Yuxin Wang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xiaoting Cai
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jiepei Xu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jiamin Chen
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Huiying Duan
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yi Cai
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Guodong Zheng
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
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Li Z, Ouyang H, Zhu J. Traditional Chinese medicines and natural products targeting immune cells in the treatment of metabolic-related fatty liver disease. Front Pharmacol 2023; 14:1195146. [PMID: 37361209 PMCID: PMC10289001 DOI: 10.3389/fphar.2023.1195146] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
MAFLD stands for metabolic-related fatty liver disease, which is a prevalent liver disease affecting one-third of adults worldwide, and is strongly associated with obesity, hyperlipidemia, and type 2 diabetes. It encompasses a broad spectrum of conditions ranging from simple liver fat accumulation to advanced stages like chronic inflammation, tissue damage, fibrosis, cirrhosis, and even hepatocellular carcinoma. With limited approved drugs for MAFLD, identifying promising drug targets and developing effective treatment strategies is essential. The liver plays a critical role in regulating human immunity, and enriching innate and adaptive immune cells in the liver can significantly improve the pathological state of MAFLD. In the modern era of drug discovery, there is increasing evidence that traditional Chinese medicine prescriptions, natural products and herb components can effectively treat MAFLD. Our study aims to review the current evidence supporting the potential benefits of such treatments, specifically targeting immune cells that are responsible for the pathogenesis of MAFLD. By providing new insights into the development of traditional drugs for the treatment of MAFLD, our findings may pave the way for more effective and targeted therapeutic approaches.
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Sun M, Ye H. Natural Foods for the Treatment of Nonalcoholic Fatty Liver Disease. J Med Food 2023; 26:1-13. [PMID: 36579939 DOI: 10.1089/jmf.2022.k.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The etiology of NAFLD is highly heterogeneous, which occurs and develops under the joint action of metabolism, inflammation, genetics, environment, and gut microbiota. At present, the principal therapeutic modalities targeting NAFLD are lifestyle interventions such as weight loss through diet and exercise. At present, there is no established therapy for the treatment of NAFLD, and many therapies are associated with a variety of side effects. A great number of in vitro and in vivo experiments have indicated that there are many natural foods that have therapeutic potential for NAFLD. This review summarizes the natural foods and their mechanisms that were found in recent years, furthermore, provides further information relevant to the treatment of NAFLD.
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Affiliation(s)
- Mengxia Sun
- The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Hua Ye
- The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
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D’Abadia PL, Lemes SR, de Melo-Reis PR, Lino RDS, Gonçalves PJ, Reis DDS, Caixeta GAB, Amaral VCS, Almeida LM. Tissue healing changes on wounds in rats after treatment with Hancornia speciosa latex in cream-gel formulation. Acta Cir Bras 2022; 37:e371001. [PMID: 36542039 PMCID: PMC9762431 DOI: 10.1590/acb371001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/03/2022] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Hancornia speciosa latex has shown pharmacological potential in wound healing processes due to its angiogenic, osteogenic, and anti-inflammatory activities. The aims of this study were to carry out a cream-gel formulation with 5, 10 and 25% of H. speciosa serum latex and to evaluate its potential to stimulate the skin regeneration in rats' wounds. METHODS One hundred and twenty rats were divided into five groups: neutral control with saline (G1), cream-gel based on H. speciosa latex serum at 5% m/v (G2), cream-gel at 15% m/v (G3), cream-gel at 25% m/v (G4), and cream-gel (G5). The animals were euthanized at three, seven, 14 and 21 days after the injury induction, and some parameters were analyzed: wound contraction, necrosis, fibrin, polymorphonuclear and mononuclear infiltrates, fibroblast, angiogenesis, hemorrhage, and collagen. RESULTS The therapeutic treatment with cream-gel at 15 and 25% is beneficial in the inflammatory phase of healing processes since it increased the angiogenesis and proliferation of mononuclear infiltrations in wounds. Regarding wound contraction, the treatment with cream-gel (5 and 15%) induced a higher rate of contraction in the proliferative phase. The 15% cream-gel formulation stimulated a greater production of collagen in the injured tissues. CONCLUSIONS H. speciosa cream-gel is a low-cost herbal medicine which can aid in tissue repair.
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Affiliation(s)
- Patrícia Lima D’Abadia
- Graduate student. Universidade Estadual de Goiás – Programa Recursos Naturais do Cerrado – Biotechnology Laboratory – Anápolis (GO), Brazil
| | - Susy Ricardo Lemes
- PhD, Assistant professor. Centro Universitário Goyazes – Department of Agricultural Science – Trindade (GO), Brazil
| | - Paulo Roberto de Melo-Reis
- PhD, Assistant professor. Pontifícia Universidade Católica de Goiás – Biomedicine Department – Laboratory of Experimental and Biotechnological Studies – Goiânia (GO), Brazil
| | - Ruy de Souza Lino
- PhD, Associate professor. Universidade Federal de Goiás – Experimental Pathology Laboratory – Institute of Tropical Pathology and Public Health – Goiânia (GO), Brazil
| | - Pablo José Gonçalves
- PhD, Associate professor. Universidade Federal de Goiás – Institute of Physics – Goiânia (GO), Brazil
| | - Diego dos Santos Reis
- Graduate student. Universidade Estadual de Goiás – Laboratory of Pharmacology and Toxicology of Natural and Synthetic Products – Anápolis (GO), Brazil
| | - Graziele Alícia Batista Caixeta
- Graduate student. Universidade Estadual de Goiás – Sciences Applied to Health Products – Laboratory of Pharmacology and Toxicology of Natural and Synthetic Products – Anápolis (GO), Brazil
| | - Vanessa Cristine Santana Amaral
- PhD, Full professor. Universidade Estadual de Goiás – Laboratory of Pharmacology and Toxicology of Natural and Synthetic Products – Anápolis (GO), Brazil
| | - Luciane Madureira Almeida
- PhD, Full professor. Universidade Estadual de Goiás – Biotechnology Laboratory – Anápolis (GO), Brazil.,Corresponding author:
- (55 62) 3328-1115
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Wang S, Du Q, Meng X, Zhang Y. Natural polyphenols: a potential prevention and treatment strategy for metabolic syndrome. Food Funct 2022; 13:9734-9753. [PMID: 36134531 DOI: 10.1039/d2fo01552h] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Metabolic syndrome (MS) is the term for a combination of hypertension, dyslipidemia, insulin resistance, and central obesity as factors leading to cardiovascular and metabolic disease. Epidemiological investigation has shown that polyphenol intake is negatively correlated with the incidence of MS. Natural polyphenols are widely found in cocoa beans, tea, vegetables, fruits, and some Chinese herbal medicines; they are a class of plant compounds containing a variety of phenolic structural units, which are potent antioxidants and anti-inflammatory agents in plants. Polyphenols are composed of flavonoids (such as flavanols, anthocyanidins, anthocyanins, isoflavones, etc.) and non-flavonoids (such as phenolic acids, stilbenes, and lignans). Modern pharmacological studies have proved that polyphenols can reduce blood pressure, improve lipid metabolism, lower blood glucose, and reduce body weight, thereby preventing and improving MS. Due to the unique characteristics and potential development and application value of polyphenols, this review summarizes some natural polyphenols that could treat MS, including their chemical properties, plant sources, and pharmacological action against MS, to provide a basis for the further study of polyphenols in MS.
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Affiliation(s)
- Shaohui Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Qinyun Du
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Flavonoids regulate tumor-associated macrophages - From structure-activity relationship to clinical potential (Review). Pharmacol Res 2022; 184:106419. [PMID: 36041653 DOI: 10.1016/j.phrs.2022.106419] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/13/2022] [Accepted: 08/25/2022] [Indexed: 11/23/2022]
Abstract
In recent years, the strategy for tumor therapy has changed from focusing on the direct killing effect of different types of therapeutic agents on cancer cells to the new mainstream of multi-mode and -pathway combined interventions in the microenvironment of the developing tumor. Flavonoids, with unique tricyclic structures, have diverse and extensive immunomodulatory and anti-cancer activities in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the TME. The regulation of macrophages to fight cancer is a promising immunotherapeutic strategy. This study covers the most comprehensive cognition of flavonoids in regulating TAMs so far. Far more than a simple list of studies, we try to dig out evidence of crosstalk at the molecular level between flavonoids and TAMs from literature, in order to discuss the most relevant chemical structure and its possible relationship with the multimodal pharmacological activity, as well as systematically build a structure-activity relationship between flavonoids and TAMs. Additionally, we point out the advantages of the macro-control of flavonoids in the TME and discuss the potential clinical implications as well as areas for future research of flavonoids in regulating TAMs. These results will provide hopeful directions for the research of antitumor drugs, while providing new ideas for the pharmaceutical industry to develop more effective forms of flavonoids.
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Cardoso LM, Pansani TN, de Souza Costa CA, Basso FG. Regulation of interleukin-6 and matrix metalloproteinases syntheses by bioflavonoids and photobiomodulation in human gingival fibroblasts. Lasers Med Sci 2022; 37:2973-2987. [PMID: 35612681 DOI: 10.1007/s10103-022-03579-z] [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: 09/16/2021] [Accepted: 05/16/2022] [Indexed: 11/25/2022]
Abstract
This study aimed to evaluate the separately effects of bioflavonoids proanthocyanidins, from grape seed extract (GSE) and synthetic naringenin (NA), as well as photobiomodulation (PBM) by low-level laser therapy on interleukin (IL)-6 and matrix metalloproteinases (MMPs) syntheses by human gingival fibroblasts (HGF). For this purpose, a connective tissue exposure (ulceration) model of HGF, stimulated with tumor necrosis factor-alpha (TNF-α), was used. Initially, the highest non-cytotoxic and non-genotoxic concentrations of bioflavonoids were determined by cell viability and micronuclei formation assays. Then, HGF were exposed to different stimuli: culture medium (negative control), dimethyl sulfoxide (DMSO), TNF-α, NA, GSE, TNF-α + NA, TNF-α + GSE, PBM (3 J/cm2, 0.025 W, 780 nm), and TNF-α + PBM. Next, IL-6, MMP-2, and MMP-9 syntheses were assessed. The concentration of 10 μg/mL of bioflavonoids increased cell viability at 24 and 48 h and did not present cytotoxic or genotoxic effects on HGF after 24, 48, and 72 h of contact. This concentration was selected for the assessment of bioflavonoids potential in modulating inflammatory mediators. TNF-α exposure enhanced IL-6 (170%), MMP-2 (10%), and MMP-9 (20%) syntheses, while a decrease of MMP-2 by 55% after exposure to TNF-α + GSE and 20% after TNF-α + NA and TNF-α + PBM was observed. MMP-9 synthesis was decreased by 35% after TNF-α + NA, 20% after TNF-α + GSE, and 30% after PBM. IL-6 was down-regulated by GSE in the presence of TNF-α (80%). In conclusion, TNF-α up-regulated IL-6 and MMPs, while bioflavonoids and PBM down-regulated MMP-2 and MMP-9 syntheses; GSE also decreased IL-6 synthesis, demonstrating the individual promising potential of these therapies for ulceration management.
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Affiliation(s)
- Laís Medeiros Cardoso
- Department of Dental Materials and Prosthodontics, School of Dentistry, São Paulo State University (UNESP, 1680 Humaitá Street, Araraquara, São Paulo, 14801-903, Brazil
| | - Taisa Nogueira Pansani
- Department of Dental Materials and Prosthodontics, School of Dentistry, São Paulo State University (UNESP, 1680 Humaitá Street, Araraquara, São Paulo, 14801-903, Brazil
| | - Carlos Alberto de Souza Costa
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University (UNESP, 1680 Humaitá Street, Araraquara, São Paulo, 14801-903, Brazil
| | - Fernanda Gonçalves Basso
- Department of Dentistry, Ribeirão Preto University (UNAERP), 2201 Costábile Romano Avenue, Ribeirão Preto, São Paulo, 14096-900, Brazil.
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22
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Naringenin Improves Ovalbumin-Induced Allergic Asthma in Rats through Antioxidant and Anti-Inflammatory Effects. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9110798. [PMID: 35419072 PMCID: PMC9001106 DOI: 10.1155/2022/9110798] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/12/2022] [Accepted: 03/07/2022] [Indexed: 11/17/2022]
Abstract
Asthma is a chronic disease with eosinophilic inflammation and oxidative damages leading to airway obstruction. Naringenin is a phytochemical possessing strong antioxidant and anti-inflammatory activities against chronic destructive conditions. The current study is devoted to evaluating naringenin's effects on the attenuation of inflammation and oxidative stress in lung tissue in a rat model of ovalbumin-induced asthma. Male Wistar rats were allocated to five groups of six: normal control (NC, receiving 1 ml/day of normal saline, orally), asthmatic (AS, receiving ovalbumin (1 mg/mL), and alum (1 mg/mL in saline) on days 0 and 14. Then, on days 21, 22, and 23, they were sensitized with the inhalation of ovalbumin), AS treated with dexamethasone (AS, 1 mg/kg/day, orally) [AS + D1], AS treated with naringenin (20 mg/kg/day, orally) [AS + N20], and AS treated with naringenin (40 mg/kg/day, orally) [AS + N40]. All the groups received associated drugs/agents for 28 days. Finally, bronchoalveolar lavage fluid (BALF) and lung tissue samples were taken off from the animals. The eosinophil count in BALF and malondialdehyde (MDA), glutathione (GSH), interleukin-13 and -4 (IL-13 and IL-4) levels were measured. Besides, the expression of urocortin (UCN) and surfactant protein-D (SP-D) were evaluated in the lung tissue using immunohistochemistry (IHC) and western blotting methods, respectively. Hematoxylin and eosin (H&E) staining were utilized to conduct histopathological analysis. Naringenin treatment significantly reduced MDA, remarkably increased GSH, and meaningfully reduced IL-4 and IL-13 levels in lung tissue. The count of eosinophils in the BALF of AS + N20 and AS + N40 was significantly reduced in comparison with the AS group. The UCN and SP-D protein levels were significantly decreased in the AS + N20 and AS + N40 groups compared to the AS group, using the IHC and western blot methods, respectively. Histopathological analysis data also confirm the results. Naringenin improves the symptoms of allergic asthma through antioxidant and anti-inflammatory effects.
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Das R, Mitra S, Tareq AM, Emran TB, Hossain MJ, Alqahtani AM, Alghazwani Y, Dhama K, Simal-Gandara J. Medicinal plants used against hepatic disorders in Bangladesh: A comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114588. [PMID: 34480997 DOI: 10.1016/j.jep.2021.114588] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/19/2021] [Accepted: 08/29/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Liver disease is a major cause of illness and death worldwide which accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma. That's why it is seeking the researchers' attention to find out the effective treatment strategies. Phytochemicals from natural resources are the main leads for the development of noble hepatoprotective drugs. The majority of the natural sources whose active compounds are currently employed actually have an ethnomedical use. Ethnopharmacological research is essential for the development of these bioactive compounds. These studies not only provide scientific evidence on medicinal plants utilized for particular therapeutic purposes, but they also ensure cultural heritage preservation. Plenty of experimental studies have been well-documented that the ethnomedicinal plants are of therapeutics' interest for the advanced pharmacological intervention in terms of hepatic disorders. AIM OF THE STUDY This study summarizes the processes of hepatotoxicity induced by various toxins and explores identified hepatoprotective plants and their phytoconstituents, which can guide the extraction of novel phytochemical constituents from plants to treat liver injury. This review aimed to summarize the hepatoprotective activity of Bangladeshi medicinal plants where the bioactive compounds may be leads for the drug discovery in future. MATERIALS AND METHODS Literature searches in electronic databases, such as Web of Science, Science Direct, SpringerLink, PubMed, Google Scholar, Semantic Scholar, Scopus, BanglaJOL, and so on, were performed using the keywords 'Bangladesh', 'ethnomedicinal plants', 'Hepatoprotective agents' as for primary searches, and secondary search terms were used as follows, either alone or in combination: traditional medicine, medicinal plants, folk medicine, liver, hepatitis, therapeutic uses, and anti-inflammatory. Besides, several books, including the book entitled "Medicinal plants of Bangladesh: chemical constituents and uses" authored by Abdul Ghani, were carefully considered, which contained pharmacological properties and phytoconstituents of many medicinal plants growing and traditionally available in Bangladesh. Among them, the most promising plant species with their latest therapeutic effects against hepatic disorders were deeply considered in this review. RESULTS The results of this study revealed that in most cases, therapy using plant extracts stabilized altered hepatic biochemical markers induced by hepatotoxins. Initially, we investigated 32 plant species for hepatoprotective activity, however after extensive literature searching; we observed that 20 plants offer good pharmacological evidence of hepatoprotective function. Consequently, most bioactive compounds derived from the herbs including berberine, thymoquinone, andrographolide, ursolic acid, luteolin, naringenin, genistein, quercetin, troxerutin, morin, epigallocatechin-3-gallate, chlorogenic acid, emodin, curcumin, resveratrol, capsaicin, ellagic acid, etc. are appeared to be effective against hepatic disorders. CONCLUSIONS Flavonoids, phenolic acids, monoterpenoids, diterpenoids, triterpenoids, alkaloids, chromenes, capsaicinoids, curcuminoids, and anthraquinones are among the phytoconstituents were appraised to have hepatoprotective activities. All the actions displayed by these ethnomedicinal plants could make them serve as leads in the formulation of drugs with higher efficacy to treat hepatic disorders.
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Affiliation(s)
- Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Abu Montakim Tareq
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh.
| | - Md Jamal Hossain
- Department of Pharmacy, State University of Bangladesh, 77 Satmasjid Road, Dhanmondi, Dhaka, 1205, Bangladesh
| | - Ali M Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Yahia Alghazwani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareil-ly, 243122, Uttar Pradesh, India
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E32004, Ourense, Spain.
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Naringenin: A Promising Therapeutic Agent against Organ Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1210675. [PMID: 34804359 PMCID: PMC8601819 DOI: 10.1155/2021/1210675] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023]
Abstract
Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-β1/small mother against decapentaplegic protein 3 (TGF-β1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.
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Raghu SV, Kudva AK, Rao S, Prasad K, Mudgal J, Baliga MS. Dietary agents in mitigating chemotherapy-related cognitive impairment (chemobrain or chemofog): first review addressing the benefits, gaps, challenges and ways forward. Food Funct 2021; 12:11132-11153. [PMID: 34704580 DOI: 10.1039/d1fo02391h] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Chemobrain or chemofog is one of the important but less investigated side effects, where the cancer survivors treated with chemotherapy develop long-term cognitive impairments, affecting their quality of life. The biological mechanisms triggering the development of chemobrain are largely unknown. However, a literature study suggests the generation of free radicals, oxidative stress, inflammatory cytokines, epigenetic chromatin remodeling, decreased neurogenesis, secretion of brain-derived neurotropic factor (BDNF), dendritic branching, and neurotransmitter release to be the cumulative contributions to the ailment. Unfortunately, there is no means to prevent/mitigate the development and intensity of chemobrain. Given the lack of effective prevention strategies or treatments, preclinical studies have been underway to ascertain the usefulness of natural products in mitigating chemobrain in the recent past. Natural products used in diets have been shown to provide beneficial effects by inhibition of free radicals, oxidative stress, inflammatory processes, and/or concomitant upregulation of various cell survival proteins. For the first time, this review focuses on the published effects of astaxanthin, omega-3 fatty acids, ginsenoside, cotinine, resveratrol, polydatin, catechin, rutin, naringin, curcumin, dehydrozingerone, berberine, C-phycocyanin, the higher fungi Cordyceps militaris, thyme (Thymus vulgaris) and polyherbal formulation Mulmina™ in mitigating cognitive impairments in preclinical models of study, and also addresses their potential neuro-therapeutic mechanisms and applications in preventing/ameliorating chemobrain.
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Affiliation(s)
- Shamprasad Varija Raghu
- Neurogenetics Laboratory, Department of Applied Zoology, Mangalore University, Mangalagangotri, Karnataka 574199, India
| | - Avinash Kundadka Kudva
- Department of Biochemistry, Mangalore University, Mangalagangotri, Karnataka 574199, India
| | - Suresh Rao
- Radiation Oncology, Mangalore Institute of Oncology, Mangalore, Karnataka 575002, India
| | - Krishna Prasad
- Medical Oncology, Mangalore Institute of Oncology, Mangalore, Karnataka 575002, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
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Zhang S, Xu M, Zhang W, Liu C, Chen S. Natural Polyphenols in Metabolic Syndrome: Protective Mechanisms and Clinical Applications. Int J Mol Sci 2021; 22:ijms22116110. [PMID: 34204038 PMCID: PMC8201163 DOI: 10.3390/ijms22116110] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/29/2021] [Accepted: 06/02/2021] [Indexed: 12/14/2022] Open
Abstract
Metabolic syndrome (MetS) is a chronic disease, including abdominal obesity, dyslipidemia, hyperglycemia, and hypertension. It should be noted that the occurrence of MetS is closely related to oxidative stress-induced mitochondrial dysfunction, ectopic fat accumulation, and the impairment of the antioxidant system, which in turn further aggravates the intracellular oxidative imbalance and inflammatory response. As enriched anti-inflammatory and antioxidant components in plants, natural polyphenols exhibit beneficial effects, including improving liver fat accumulation and dyslipidemia, reducing blood pressure. Hence, they are expected to be useful in the prevention and management of MetS. At present, epidemiological studies indicate a negative correlation between polyphenol intake and MetS incidence. In this review, we summarized and discussed the most promising natural polyphenols (including flavonoid and non-flavonoid drugs) in the precaution and treatment of MetS, including their anti-inflammatory and antioxidant properties, as well as their regulatory functions involved in glycolipid homeostasis.
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Affiliation(s)
| | | | | | | | - Siyu Chen
- Correspondence: ; Tel./Fax: +86-25-86185645
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Li J, Wang T, Liu P, Yang F, Wang X, Zheng W, Sun W. Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD. Food Funct 2021; 12:3898-3918. [PMID: 33977953 DOI: 10.1039/d0fo02736g] [Citation(s) in RCA: 243] [Impact Index Per Article: 60.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Dietary supplementation has become a promising strategy for managing NAFLD. Hesperetin, a citrus flavonoid, is mainly found in citrus fruits (oranges, grapefruit, and lemons) and possesses multiple pharmacological properties, including anti-cancer, anti-Alzheimer and anti-diabetic effects. However, the anti-NAFLD effect and mechanisms of hesperetin remain unclear. In this study, we investigated the therapeutic effect of hesperetin against NAFLD and the underlying mechanism in vitro and in vivo. In oleic acid (OA)-induced HepG2 cells, hesperetin upregulated antioxidant levels (SOD/GPx/GR/GCLC/HO-1) by triggering the PI3 K/AKT-Nrf2 pathway, alleviating OA-induced reactive oxygen species (ROS) overproduction and hepatotoxicity. Furthermore, hesperetin suppressed NF-κB activation and reduced inflammatory cytokine secretion (TNF-α and IL-6). More importantly, we revealed that this anti-inflammatory effect is attributed to reduced ROS overproduction by the Nrf2 pathway, as pre-treatment with Nrf2 siRNA or an inhibitor of superoxide dismutase (SOD) or/and glutathione peroxidase (GPx) abolished hesperetin-induced NF-κB inactivation and reductions in inflammatory cytokine secretion. In a rat model of high-fat diet (HFD)-induced NAFLD, we confirmed that hesperetin relieved hepatic steatosis, oxidative stress, inflammatory cell infiltration and fibrosis. Moreover, hesperetin activated the PI3 K/AKT-Nrf2 pathway in the liver, increasing antioxidant expression and inhibiting NF-κB activation and inflammatory cytokine secretion. In summary, our results demonstrate that hesperetin ameliorates hepatic oxidative stress through the PI3 K/AKT-Nrf2 pathway and that this antioxidative effect further suppresses NF-κB-mediated inflammation during NAFLD progression. Thus, our study suggests that hesperetin may be an effective dietary supplement for improving NAFLD by suppressing hepatic oxidative stress and inflammation.
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Affiliation(s)
- Jingda Li
- College of Life Science, Yangtze University, Jingzhou, Hubei, China.
| | - Tianqi Wang
- College of Agriculture, Yangtze University, Jingzhou, Hubei, China
| | - Panpan Liu
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, China.
| | - Fuyuan Yang
- Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Xudong Wang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Weilong Zheng
- Institute of Biomass Resources, Taizhou University, Taizhou, Zhejiang, China
| | - Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, China.
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D’Amore A, Gradogna A, Palombi F, Minicozzi V, Ceccarelli M, Carpaneto A, Filippini A. The Discovery of Naringenin as Endolysosomal Two-Pore Channel Inhibitor and Its Emerging Role in SARS-CoV-2 Infection. Cells 2021; 10:1130. [PMID: 34067054 PMCID: PMC8150892 DOI: 10.3390/cells10051130] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/01/2021] [Accepted: 05/04/2021] [Indexed: 12/23/2022] Open
Abstract
The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19.
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Affiliation(s)
- Antonella D’Amore
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 16 Via A. Scarpa, 00161 Rome, Italy; (A.D.); (F.P.)
| | - Antonella Gradogna
- Institute of Biophysics, National Research Council, Via De Marini 6, 16149 Genova, Italy
| | - Fioretta Palombi
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 16 Via A. Scarpa, 00161 Rome, Italy; (A.D.); (F.P.)
| | - Velia Minicozzi
- INFN and Department of Physics, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Roma, Italy;
| | - Matteo Ceccarelli
- Department of Physics, University of Cagliari, 09042 Monserrato, Italy;
- IOM-CNR Unità di Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy
| | - Armando Carpaneto
- Institute of Biophysics, National Research Council, Via De Marini 6, 16149 Genova, Italy
- Department of Earth, Environment and Life Sciences (DISTAV), University of Genoa, Viale Benedetto XV 5, 16132 Genova, Italy
| | - Antonio Filippini
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 16 Via A. Scarpa, 00161 Rome, Italy; (A.D.); (F.P.)
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El-Saad AMA, Abdel-Wahab WM. Naringenin Attenuates Toxicity and Oxidative Stress Induced by Lambda-cyhalothrin in Liver of Male Rats. Pak J Biol Sci 2021; 23:510-517. [PMID: 32363836 DOI: 10.3923/pjbs.2020.510.517] [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] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Extensive use of Lambda-cyhalothrin (LTC), a synthetic pyrethroid insecticide, has been associated with serious health problems to the non-target organisms including mammals. The present study investigated the protective effect of naringenin (NGN), an antioxidant flavonoid, against the toxicity induced LTC in the liver of male rats. MATERIALS AND METHODS Five groups of rats were assigned as follows; control group, LTC group (6.12 mg kg-1, 1/10 LD50), LTC-NGN group (6.12 mg kg-1 LTC and 50 mg kg-1 NGN), NGN-LTC group (50 mg kg-1 NGN and 6.12 mg kg-1 LTC) and NGN group (50 mg kg-1). Doses were administrated orally for 21 consecutive days. RESULTS Administration of LTC induced liver damage as indicated by the increase in the activities of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase and in the level of total bilirubin in serum. LTC also induced a significant elevation in the levels of serum total lipids, total cholesterol, triglycerides and low-density lipoproteins while high-density lipoproteins decreased. Furthermore, LTC significantly disturbed the oxidant/antioxidant balance in the liver as shown by the elevation in lipid peroxidation, lipid hydroperoxides, protein carbonyl content and conjugated dienes with a concomitant inhibition in the major antioxidants such as reduced glutathione and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase. Both post-treatment and pre-treatment with NGN significantly modulated the LTC-induced hepatotoxicity and oxidative stress in rat's liver and pretreatment was found to be more effective in improving most of the studied parameters in both serum and liver tissue. CONCLUSION NGN could be used as a safe dietary supplement to protect against the toxicity and oxidative stress associated with the use of LTC.
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Mayengbam SS, Singh A, Pillai AD, Bhat MK. Influence of cholesterol on cancer progression and therapy. Transl Oncol 2021; 14:101043. [PMID: 33751965 PMCID: PMC8010885 DOI: 10.1016/j.tranon.2021.101043] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/24/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022] Open
Abstract
Abnormality in blood cholesterol level is significantly correlated with risk of different cancers. Majority of tumor tissue from cancer patient exhibits overexpression of LDLR and ACAT for supporting rapid cancer cell proliferation. Alteration of the cholesterol metabolism in cancer cells hampers therapeutic response. Targeting cholesterol metabolism for treatment of cancer with other conventional chemotherapeutic drugs appears to be beneficial. Cholesterol is a fundamental molecule necessary for the maintenance of cell structure and is vital to various normal biological functions. It is a key factor in lifestyle-related diseases including obesity, diabetes, cardiovascular disease, and cancer. Owing to its altered serum chemistry status under pathological states, it is now being investigated to unravel the mechanism by which it triggers various health complications. Numerous clinical studies in cancer patients indicate an alteration in blood cholesterol level (either decreased or increased) in comparison to normal healthy individuals. This article elaborates on our understanding as to how cholesterol is being hijacked in the malignancy for the development, survival, stemness, progression, and metastasis of cancerous cells. Also, it provides a glimpse of how cholesterol derived entities, alters the signaling pathway towards their advantage. Moreover, deregulation of the cholesterol metabolism pathway has been often reported to hamper various treatment strategies in different cancer. In this context, attempts have been made to bring forth its relevance in being targeted, in pre-clinical and clinical studies for various treatment modalities. Thus, understanding the role of cholesterol and deciphering associated molecular mechanisms in cancer progression and therapy are of relevance towards improvement in the management of various cancers.
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Affiliation(s)
| | - Abhijeet Singh
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India
| | - Ajay D Pillai
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India
| | - Manoj Kumar Bhat
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India.
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Multi-Therapeutic Potential of Naringenin (4',5,7-Trihydroxyflavonone): Experimental Evidence and Mechanisms. PLANTS 2020; 9:plants9121784. [PMID: 33339267 PMCID: PMC7766900 DOI: 10.3390/plants9121784] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 12/12/2022]
Abstract
Extensive research has been carried out during the last few decades, providing a detailed account of thousands of discovered phytochemicals and their biological activities that have the potential to be exploited for a wide variety of medicinal purposes. These phytochemicals, which are pharmacologically important for clinical use, primarily consist of polyphenols, followed by terpenoids and alkaloids. There are numerous published reports indicating the primary role of phytochemicals proven to possess therapeutic potential against several diseases. However, not all phytochemicals possess significant medicinal properties, and only some of them exhibit viable biological effects. Naringenin, a flavanone found in citrus fruits, is known to improve immunity, repair DNA damage, and scavenge free radicals. Despite the very low bioavailability of naringenin, it is known to exhibit various promising biological properties of medicinal importance, including anti-inflammatory and antioxidant activities. This review focuses on the various aspects related to naringenin, particularly its physicochemical, pharmacokinetic, and pharmacodynamic properties. Furthermore, various pharmacological activities of naringenin, such as anticancer, antidiabetic, hepatoprotective, neuroprotective, cardioprotective, nephroprotective, and gastroprotective effects, have been discussed along with their mechanisms of action.
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32
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Khan TH, Ganaie MA, Alharthy KM, Madkhali H, Jan BL, Sheikh IA. Naringenin prevents doxorubicin-induced toxicity in kidney tissues by regulating the oxidative and inflammatory insult in Wistar rats. Arch Physiol Biochem 2020; 126:300-307. [PMID: 30406686 DOI: 10.1080/13813455.2018.1529799] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
This study is undertaken to investigate the effects of naringenin on doxorubicin- (Dox) induced nephrotoxicity in Wistar rats. Dox 10 mg/kg body weight was administered intraperitoneally once and naringenin 50 and 100 mg/kg body weight was administered orally daily for 21 d. Dox-induced oxidative stress lead to steep elevation in blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and kidney injury molecule-1 (KIM-1), compared to control, treatment with naringenin preserved kidney functions. With Dox treatment significant decrease in antioxidant enzymes with increase in malondialdehyde (MDA) compared to control was observed. Naringenin treatment reversed these values compared to Dox in kidney tissue. Dox treatment showed increased tissue nitric oxide levels naringenin treatment decreased nitric oxide (NO) in kidney tissue. Furthermore, Dox-induced inflammatory burst as indicated by up-regulation of nuclear factor-κB (NF-κB), tumour necrosis factor-α (TNF-α) tissue levels and prostaglandin-E2 (PGE-2). All such events were normalised back to normal by naringenin treatment.
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Affiliation(s)
- Tajdar Husain Khan
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Majid Ahmad Ganaie
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Khalid Mofleh Alharthy
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Hassan Madkhali
- Department of Pharmacology, College of Pharmacy, Prince Sattan Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Basit Latief Jan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ishfaq Ahmad Sheikh
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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Rehman K, Khan II, Akash MSH, Jabeen K, Haider K. Naringenin downregulates inflammation-mediated nitric oxide overproduction and potentiates endogenous antioxidant status during hyperglycemia. J Food Biochem 2020; 44:e13422. [PMID: 32770581 DOI: 10.1111/jfbc.13422] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/13/2022]
Abstract
Nitric oxide is a key regulating factor for physiological functions, when elevated during inflammatory conditions, NO, can lower endogenous antioxidants level. Naringenin, a bioflavonoid has shown to possess anti-inflammatory action. However, its role in NO-mediated responses has not been elucidated till date. This study was designed to investigate antioxidant potential of naringenin against inflammation-mediated nitric oxide overproduction and antioxidant status with an improved glycemic profile in diabetic rats. From total rats, Group 1 received normal saline, while remaining received single intraperitoneal injection of alloxan and were then equally divided into group 2, 3, and 4, which latter received no-treatment, metformin (50 mg kg-1 day-1) and naringenin (50 mg kg-1 day-1), respectively, for 1 month. Results showed that naringenin significantly downregulated levels of glucose (p < .05), lipid profile, inflammatory biomarkers, and nitric oxide (p < .01) in alloxan-induced diabetic rats. It also improved SOD level as compared to that of metformin treatment. This work delivers that naringenin exerts antioxidant effect by downregulating inflammation-mediated nitric oxide overproduction. PRACTICAL APPLICATIONS: Naringenin is a well-recognized member of bioflavonoids and is commonly present in citrus fruits like oranges, grapes, and berries. The foremost property of naringenin is its antioxidant potential, which aids in decreasing the burden of oxidative stress by declining the generation of free radicals. The overproduction of these oxygen or nitrogen reactive species are considered as underlying cause of undesired biological activities likeO 2 - ∙ or nitrite-mediated inflammation and altered metabolic parameters. Hence, this study was designed to investigate the antioxidant potential of naringenin as natural flavone to downregulate the inflammation-mediated nitric oxide overproduction and improve glycemic profile. The therapeutic perspective of naringenin from current study against nitric oxide overproduction and to eradicate inflammation via controlling of levels of pro-inflammatory mediators suggests that naringenin holds the forthcoming vision as a supportive constituent alone or in combination with some other conventional medicinal agents against conditions like metabolic disorders.
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Affiliation(s)
- Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
| | - Ikram Ilahee Khan
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
| | | | - Komal Jabeen
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Kamran Haider
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
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Naeini F, Namkhah Z, Ostadrahimi A, Tutunchi H, Hosseinzadeh-Attar MJ. A Comprehensive Systematic Review of the Effects of Naringenin, a Citrus-Derived Flavonoid, on Risk Factors for Nonalcoholic Fatty Liver Disease. Adv Nutr 2020; 12:413-428. [PMID: 32879962 PMCID: PMC8009752 DOI: 10.1093/advances/nmaa106] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/08/2020] [Accepted: 08/06/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver dysfunction worldwide. Recently, some natural compounds have attracted growing interest in the treatment of NAFLD. In this context, most attention has been paid to natural products derived from fruits, vegetables, and medicinal herbs. Naringenin, a natural flavanone, has been revealed to have pharmacological effects in the treatment of obesity and associated metabolic disorders such as NAFLD. The aim of this study was to examine the therapeutic effects of naringenin and its possible mechanisms of action in the management of NAFLD and related risk factors. The current systematic review was performed according to the guidelines of the 2015 PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statements. We searched PubMed/Medline, Science Direct, Scopus, ProQuest, and Google Scholar databases up until February 2020. Of 1217 full-text articles assessed, 36 studies met the inclusion criteria. The evidence reviewed in the present study indicates that naringenin modulates several biological processes related to NAFLD including energy balance, lipid and glucose metabolism, inflammation, and oxidative stress by different mechanisms. Overall, the favorable effects of naringenin along with its more potency and efficacy, compared with other antioxidants, indicate that naringenin may be a promising therapeutic approach for the management of NAFLD and associated complications. However, due to the lack of clinical trials, future robust human randomized clinical trials that address the effects of naringenin on NAFLD and other liver-related diseases are crucial. Further careful human pharmacokinetic studies are also needed to establish dosage ranges, as well as addressing preliminary safety and tolerability of naringenin, before proceeding to larger-scale endpoint trials.
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Affiliation(s)
- Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran
| | - Zahra Namkhah
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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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.
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36
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Singh A, Yau YF, Leung KS, El-Nezami H, Lee JCY. Interaction of Polyphenols as Antioxidant and Anti-Inflammatory Compounds in Brain-Liver-Gut Axis. Antioxidants (Basel) 2020; 9:antiox9080669. [PMID: 32722619 PMCID: PMC7465954 DOI: 10.3390/antiox9080669] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023] Open
Abstract
Oxidative stress plays an important role in the onset as well as the progression of inflammation. Without proper intervention, acute inflammation could progress to chronic inflammation, resulting in the development of inflammatory diseases. Antioxidants, such as polyphenols, have been known to possess anti-oxidative properties which promote redox homeostasis. This has encouraged research on polyphenols as potential therapeutics for inflammation through anti-oxidative and anti-inflammatory pathways. In this review, the ability of polyphenols to modulate the activation of major pathways of inflammation and oxidative stress, and their potential to regulate the activity of immune cells are examined. In addition, in this review, special emphasis has been placed on the effects of polyphenols on inflammation in the brain–liver–gut axis. The data derived from in vitro cell studies, animal models and human intervention studies are discussed.
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37
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Tutunchi H, Naeini F, Ostadrahimi A, Hosseinzadeh-Attar MJ. Naringenin, a flavanone with antiviral and anti-inflammatory effects: A promising treatment strategy against COVID-19. Phytother Res 2020; 34:3137-3147. [PMID: 32613637 PMCID: PMC7361426 DOI: 10.1002/ptr.6781] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/15/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022]
Abstract
At the end of 2019, a novel flu-like coronavirus named COVID-19 (coronavirus disease 2019) was recognized by World Health Organization. No specific treatments exist for COVID-19 at this time. New evidence suggests that therapeutic options focusing on antiviral agents may alleviate COVID-19 symptoms as well as those that lead to the decrease in the inflammatory responses. Flavonoids, as phenolic compounds, have attracted considerable attention due to their various biological properties. In this review, the promising effects and possible mechanisms of action of naringenin, a citrus-derived flavonoid, against COVID-19 were discussed. We searched PubMed/Medline, Science direct, Scopus, and Google Scholar databases up to March 2020 using the definitive keywords. The evidence reviewed here indicates that naringenin might exert therapeutic effects against COVID-19 through the inhibition of COVID-19 main protease, 3-chymotrypsin-like protease (3CLpro), and reduction of angiotensin converting enzyme receptors activity. One of the other mechanisms by which naringenin might exert therapeutic effects against COVID-19 is, at least partly, by attenuating inflammatory responses. The antiviral activity of the flavanone naringenin against some viruses has also been reported. On the whole, the favorable effects of naringenin lead to a conclusion that naringenin may be a promising treatment strategy against COVID-19.
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Affiliation(s)
- Helda Tutunchi
- Student Research Committee, Nutrition Research Center, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Naeini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Science, Tehran, Iran
| | - Alireza Ostadrahimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Inosine, an endogenous purine nucleoside, avoids early stages of atherosclerosis development associated to eNOS activation and p38 MAPK/NF-kB inhibition in rats. Eur J Pharmacol 2020; 882:173289. [PMID: 32565337 DOI: 10.1016/j.ejphar.2020.173289] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 06/03/2020] [Accepted: 06/16/2020] [Indexed: 01/22/2023]
Abstract
Atherosclerosis is a multifactorial chronic disease, initiated by an endothelial dysfunction. Adenosine and its analogs can change a variety of inflammatory diseases and has shown important effects at different disease models. Inosine is a stable analogous of adenosine, but its effects in inflammatory diseases, like atherosclerosis, have not yet been studied. The aim of this study was to evaluate the pharmacological properties of inosine, administered sub chronically in a hypercholesterolemic model. Male Wistar rats were divided into four groups: control group (C) and control + inosine (C + INO) received standard chow, hypercholesterolemic diet group (HCD) and HCD + inosine (HCD + INO) were fed a hypercholesterolemic diet. At 31st experimentation day, the treatment with inosine was performed for C + INO and HCD + INO groups once daily in the last 15 days. We observed that the hypercholesterolemic diet promoted an increase in lipid levels and inflammatory cytokines production, while inosine treatment strongly decreased these effects. Additionally, HCD group presented a decrease in maximum relaxation acetylcholine induced and an increase in contractile response phenylephrine induced when compared to the control group, as well as it has presented an enhancement in collagen and ADP-induced platelet aggregation. On the other hand, inosine treatment promoted a decrease in contractile response to phenylephrine, evoked an improvement in endothelium-dependent vasorelaxant response and presented antiplatelet properties. Moreover, inosine activated eNOS and reduced p38 MAPK/NF-κB pathway in aortic tissues. Taken together, the present results indicate inosine as a potential drug for the treatment of cardiovascular disorders such as atherosclerosis.
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Akintunde JK, Akintola TE, Aliu FH, Fajoye MO, Adimchi SO. Naringin regulates erectile dysfunction by abolition of apoptosis and inflammation through NOS/cGMP/PKG signalling pathway on exposure to Bisphenol-A in hypertensive rat model. Reprod Toxicol 2020; 95:123-136. [PMID: 32428650 DOI: 10.1016/j.reprotox.2020.05.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 12/13/2022]
Abstract
This study investigated the effect of naringin (NRG) on extracellular metabolism of ATP through the NOS/cGMP/PKG signaling pathway induced by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) on exposure to Bisphenol-A (BPA) in penis. Fifty-six adult male albino rats were randomly distributed into eight (n = 7) groups. Group I: control animals, Group II was treated with 40 mg/kg L-NAME, Group III was treated with 50 mg/kg BPA, Group IV was treated with 40 mg/kg L-NAME +50 mg/kg BPA. Group V was administered with 40 mg/kg L-NAME +80 mg/kg NRG. Group VI was administered with 50 mg/kg BPA + 80 mg/kg NRG. Group VII was administered with 40 mg/kg L-NAME+50 mg/kg BPA + 80 mg/kg NRG. Lastly, group VIII was treated with 80 mg/kg NRG for 14 days. NRG prevented hypertension and erectile dysfunction by inhibiting the activities of angiotensin-converting enzymes, arginase, and phosphodiesterase-51 (PDE-51) with corresponding down-regulation of inflammatory markers including TNF-α and IL-B. Additionally, hypertensive erectile dysfunction was remarkably prevented by NRG as manifested by the declined activities of AChE, MAO-A and enzymes of ATP hydrolysis (ATPase, ADPase, AMPase and ADA) with resultant increase in NO level. Also, penile expression of antigen presenting cells, CD43 transcript, caspace-9 and tumor suppressor P53 proteins were repressed on treatment with NRG. This study validates the hypothesis that NRG may be a valuable remedy in abrogating penile inflammatory markers, apoptosis and enzymes of ATP-hydrolysis via NOS/cGMP/PKG signaling pathways in hypertensive rat model on exposure to environmental toxicant.
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Affiliation(s)
- J K Akintunde
- Applied Biochemistry and Molecular Toxicology Research Group, Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria.
| | - T E Akintola
- Applied Biochemistry and Molecular Toxicology Research Group, Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - F H Aliu
- Applied Biochemistry and Molecular Toxicology Research Group, Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - M O Fajoye
- Applied Biochemistry and Molecular Toxicology Research Group, Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - S O Adimchi
- Applied Biochemistry and Molecular Toxicology Research Group, Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
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Madabhushi V, Tharappel J, Alluri S, Totten C, Roth JS. Hernia Repair Strength Enhanced With Antioxidants. J Surg Res 2020; 247:144-149. [PMID: 31761443 DOI: 10.1016/j.jss.2019.10.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 09/24/2019] [Accepted: 10/12/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Incisional hernia is one of the most common complications of abdominal surgery, and repairs are associated with significant recurrence rates. Mesh repairs are associated with the best outcomes, but failures are not uncommon. Doxycycline has been demonstrated to enhance mesh hernia repair outcomes with associated increases in collagen deposition and improved tensiometric strength. This study compares the outcomes of incisional hernia repair with doxycycline administration and the antioxidant tempol. MATERIALS AND METHODS Twenty-eight male Sprague Dawley rats underwent a midline hernia creation and an intraabdominal polypropylene mesh repair. The animals were administered saline, doxycycline, tempol, or both, daily for 8 wk. The abdominal wall was harvested at 8 wk and tensiometric strength and biochemical analysis was performed. RESULTS The tensiometric strength of the repair was increased in all experimental groups. Collagen type 1 deposition was increased, and collagen type 3 deposition was decreased in each of the experimental groups relative to control. There was no difference in MMP-2 and MMP-9 levels between control and experimental groups. CONCLUSIONS The hernia repair strength is equally enhanced with the administration of doxycycline or tempol. Dual therapy provided no benefit over treatment with either single agent. All treatment groups had an increase in collagen type 1:3 ratios, but the mechanism is not well understood. The benefits of antioxidant treatment following hernia repair are similar to treatment with doxycycline. Given the high frequency of incisional hernia repair failures, this study has implications for improving outcomes following ventral hernia repair through the use of either doxycycline or antioxidant therapy.
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Affiliation(s)
| | - Job Tharappel
- Division of General Surgery, University of Kentucky, Lexington, Kentucky
| | - Satya Alluri
- University of Kentucky College of Medicine, Lexington, Kentucky
| | - Crystal Totten
- Division of General Surgery, University of Kentucky, Lexington, Kentucky
| | - John Scott Roth
- Division of General Surgery, University of Kentucky, Lexington, Kentucky.
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Hernández-Aquino E, Quezada-Ramírez MA, Silva-Olivares A, Casas-Grajales S, Ramos-Tovar E, Flores-Beltrán RE, Segovia J, Shibayama M, Muriel P. Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways. Eur J Pharmacol 2019; 865:172730. [PMID: 31618621 DOI: 10.1016/j.ejphar.2019.172730] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/08/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023]
Abstract
There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.
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Affiliation(s)
| | - Marco A Quezada-Ramírez
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Angélica Silva-Olivares
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Sael Casas-Grajales
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Erika Ramos-Tovar
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Rosa E Flores-Beltrán
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - José Segovia
- Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico
| | - Pablo Muriel
- Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City, Mexico.
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Jack BU, Malherbe CJ, Mamushi M, Muller CJF, Joubert E, Louw J, Pheiffer C. Adipose tissue as a possible therapeutic target for polyphenols: A case for Cyclopia extracts as anti-obesity nutraceuticals. Biomed Pharmacother 2019; 120:109439. [PMID: 31590126 DOI: 10.1016/j.biopha.2019.109439] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/29/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
Obesity is a significant contributor to increased morbidity and premature mortality due to increasing the risk of many chronic metabolic diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle modifications such as energy restriction and increased physical activity are highly effective first-line treatment strategies used in the management of obesity. However, adherence to these behavioral changes is poor, with an increased reliance on synthetic drugs, which unfortunately are plagued by adverse effects. The identification of new and safer anti-obesity agents is thus of significant interest. In recent years, plants and their phenolic constituents have attracted increased attention due to their health-promoting properties. Amongst these, Cyclopia, an endemic South African plant commonly consumed as a herbal tea (honeybush), has been shown to possess modulating properties against oxidative stress, hyperglycemia, and obesity. Likewise, several studies have reported that some of the major phenolic compounds present in Cyclopia spp. exhibit anti-obesity effects, particularly by targeting adipose tissue. These phenolic compounds belong to the xanthone, flavonoid and benzophenone classes. The aim of this review is to assess the potential of Cyclopia extracts as an anti-obesity nutraceutical as underpinned by in vitro and in vivo studies and the underlying cellular mechanisms and biological pathways regulated by their phenolic compounds.
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Affiliation(s)
- Babalwa U Jack
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa.
| | - Christiaan J Malherbe
- Plant Bioactives Group, Post-Harvest and Agro-processing Technologies, Agricultural Research Council, Infruitec-Nietvoorbij, Stellenbosch, South Africa
| | - Mokadi Mamushi
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
| | - Christo J F Muller
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; Department of Biochemistry and Microbiology, University of Zululand, Kwa-Dlangezwa, South Africa
| | - Elizabeth Joubert
- Plant Bioactives Group, Post-Harvest and Agro-processing Technologies, Agricultural Research Council, Infruitec-Nietvoorbij, Stellenbosch, South Africa; Department of Food Science, Stellenbosch University, Stellenbosch, South Africa
| | - Johan Louw
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Department of Biochemistry and Microbiology, University of Zululand, Kwa-Dlangezwa, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa
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43
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Hao Y, Wu B, Li C. Cardioprotective Efficacy of Naringenin Against Isoproterenol Induced Chronic Heart Failure in a Rat Model. INT J PHARMACOL 2019. [DOI: 10.3923/ijp.2019.759.765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Saha P, Talukdar AD, Nath R, Sarker SD, Nahar L, Sahu J, Choudhury MD. Role of Natural Phenolics in Hepatoprotection: A Mechanistic Review and Analysis of Regulatory Network of Associated Genes. Front Pharmacol 2019; 10:509. [PMID: 31178720 PMCID: PMC6543890 DOI: 10.3389/fphar.2019.00509] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/24/2019] [Indexed: 12/11/2022] Open
Abstract
The liver is not only involved in metabolism and detoxification, but also participate in innate immune function and thus exposed to frequent target Thus, they are the frequent target of physical injury. Interestingly, liver has the unique ability to regenerate and completely recoup from most acute, non-iterative situation. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease, long term alcohol abuse and chronic use of medications can cause persistent injury in which regenerative capacity eventually becomes dysfunctional resulting in hepatic scaring and cirrhosis. Despite the recent therapeutic advances and significant development of modern medicine, hepatic diseases remain a health problem worldwide. Thus, the search for the new therapeutic agents to treat liver disease is still in demand. Many synthetic drugs have been demonstrated to be strong radical scavengers, but they are also carcinogenic and cause liver damage. Present day various hepatic problems are encountered with number of synthetic and plant based drugs. Nexavar (sorafenib) is a chemotherapeutic medication used to treat advanced renal cell carcinoma associated with several side effects. There are a few effective varieties of herbal preparation like Liv-52, silymarin and Stronger neomin phages (SNMC) against hepatic complications. Plants are the huge repository of bioactive secondary metabolites viz; phenol, flavonoid, alkaloid etc. In this review we will try to present exclusive study on phenolics with its mode of action mitigating liver associated complications. And also its future prospects as new drug lead.
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Affiliation(s)
- Priyanka Saha
- Department of Life Science & Bioinformatics, Assam University, Silchar, India
| | - Anupam Das Talukdar
- Department of Life Science & Bioinformatics, Assam University, Silchar, India
| | - Rajat Nath
- Department of Life Science & Bioinformatics, Assam University, Silchar, India
| | - Satyajit D. Sarker
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Lutfun Nahar
- Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Jagajjit Sahu
- Department of Mycology and Plant Pathology, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, India
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Wang Y, Zhao H, Li X, Li N, Wang Q, Liu Y, Liang Q, Shao Z, Zhang N, Zhao T, Peng L, Li P. Tangshen Formula Alleviates Hepatic Steatosis by Inducing Autophagy Through the AMPK/SIRT1 Pathway. Front Physiol 2019; 10:494. [PMID: 31105592 PMCID: PMC6498888 DOI: 10.3389/fphys.2019.00494] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 04/08/2019] [Indexed: 01/26/2023] Open
Abstract
Tangshen formula (TSF), a formula of Chinese herbal medicine, improves lipid metabolism in humans and animals with diabetic kidney disease. However, the effect and mechanism of TSF on nonalcoholic fatty liver disease (NAFLD) remain unclear. The activation of autophagy appears to be a potential mechanism for improving NAFLD. In the present study, we examined the therapeutic effect of TSF on hepatic steatosis and sought to explore whether its effect is related to activating autophagy. Here, we showed that TSF treatment significantly attenuated hepatic steatosis in both high-fat diet (HFD) and methionine choline-deficient diet (MCDD)-fed mice. Meanwhile, TSF reduced lipid accumulation in palmitate (PA)-stimulated HepG2 cells and primary mouse hepatocytes. Furthermore, TSF increased Sirtuin 1 (SIRT1) expression and promoted autophagy activation in vivo. TSF also improved PA-induced suppression of both SIRT1 expression and SIRT1-dependent autophagy, thereby alleviating intracellular lipid accumulation in vitro. In addition, TSF increased SIRT1 expression and induced autophagy in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Moreover, SIRT1 knockdown abolished the autophagy-inducing and lipid-lowering effects of TSF. In conclusion, TSF improved lipid accumulation and hepatic steatosis by inducing the AMPK/SIRT1 pathway-mediated autophagy.
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Affiliation(s)
- Yan Wang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Hailing Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xin Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Nan Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Qian Wang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Beijing University of Chinese Medicine, Beijing, China
| | - Yanzhen Liu
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Beijing University of Chinese Medicine, Beijing, China
| | - Qionglin Liang
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China
| | - Zixing Shao
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, China
| | - Nannan Zhang
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Tingting Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Liang Peng
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
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Ahmed OM, Fahim HI, Ahmed HY, Al-Muzafar HM, Ahmed RR, Amin KA, El-Nahass ES, Abdelazeem WH. The Preventive Effects and the Mechanisms of Action of Navel Orange Peel Hydroethanolic Extract, Naringin, and Naringenin in N-Acetyl-p-aminophenol-Induced Liver Injury in Wistar Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2745352. [PMID: 31049130 PMCID: PMC6458942 DOI: 10.1155/2019/2745352] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/24/2018] [Indexed: 01/14/2023]
Abstract
N-Acetyl-p-aminophenol (APAP) or acetaminophen is the most common drug ingredient worldwide. It is found in more than 600 different over-the-counter and prescription medicines. Its long-term and overdose use is highly toxic and may result in liver injury. Thus, this study was designed to assess the preventive effects and to suggest the mechanisms of action of the navel orange peel hydroethanolic extract, naringin, and naringenin in APAP-induced hepatotoxicity in male Wistar rats. APAP was administered to male Wistar rats at a dose level of 0.5 g/kg body weight (b.w.) by oral gavage every other day for 4 weeks. APAP-administered rats were treated with the navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.), and naringenin (20 mg/kg b.w.) by oral gavage every other day during the same period of APAP administration. The treatments of APAP-administered rats with the peel extract, naringin, and naringenin produced a significant decrease in the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-α levels while they induced a significant increase in the lowered serum albumin and IL-4 levels. The treatments also resulted in a significant decrease in the elevated liver lipid peroxidation and enhanced the liver GSH content and SOD, GST, and GPx activities as compared with APAP-administered control; the peel extract was the most potent in improving the liver LPO, GSH content, and GPx activity. In addition, the three treatments significantly downregulated the elevated hepatic proapoptotic mediators p53, Bax, and caspase-3 and significantly upregulated the suppressed antiapoptotic protein, Bcl-2, in APAP-administered rats. In association, the treatments markedly amended the APAP-induced liver histopathological deteriorations that include hepatocyte steatosis, cytoplasmic vacuolization, hydropic degeneration, and necrosis together with mononuclear leucocytic and fibroblastic inflammatory cells' infiltration. In conclusion, the navel orange peel hydroethanolic extract, naringin, and naringenin may exert their hepatopreventive effects in APAP-administered rats via enhancement of the antioxidant defense system and suppression of inflammation and apoptosis.
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Affiliation(s)
- Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Hanaa I. Fahim
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Heba Y. Ahmed
- Rodents Division, Department of Harmful Animals, Plant Protection Research Institute, Agriculture Research Center, Egypt
| | - Hessah Mohammed Al-Muzafar
- Chemistry Department, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
| | - Rasha R. Ahmed
- Cell Biology, Histology and Genetics Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Kamal Adel Amin
- Chemistry Department, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
| | - El-Shaymaa El-Nahass
- Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Walaa H. Abdelazeem
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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Beneficial Effects of Citrus Flavonoids on Cardiovascular and Metabolic Health. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5484138. [PMID: 30962863 PMCID: PMC6431442 DOI: 10.1155/2019/5484138] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 01/06/2019] [Accepted: 01/30/2019] [Indexed: 12/20/2022]
Abstract
The prevalence of cardiovascular disease (CVD) is increasing over time. CVD is a comorbidity in diabetes and contributes to premature death. Citrus flavonoids possess several biological activities and have emerged as efficient therapeutics for the treatment of CVD. Citrus flavonoids scavenge free radicals, improve glucose tolerance and insulin sensitivity, modulate lipid metabolism and adipocyte differentiation, suppress inflammation and apoptosis, and improve endothelial dysfunction. The intake of citrus flavonoids has been associated with improved cardiovascular outcomes. Although citrus flavonoids exerted multiple beneficial effects, their mechanisms of action are not completely established. In this review, we summarized recent findings and advances in understanding the mechanisms underlying the protective effects of citrus flavonoids against oxidative stress, inflammation, diabetes, dyslipidemia, endothelial dysfunction, and atherosclerosis. Further studies and clinical trials to assess the efficacy and to explore the underlying mechanism(s) of action of citrus flavonoids are recommended.
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Bussmann AJC, Borghi SM, Zaninelli TH, Dos Santos TS, Guazelli CFS, Fattori V, Domiciano TP, Pinho-Ribeiro FA, Ruiz-Miyazawa KW, Casella AMB, Vignoli JA, Camilios-Neto D, Casagrande R, Verri WA. The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45 + hematopoietic cells. Inflammopharmacology 2019; 27:1229-1242. [PMID: 30612217 DOI: 10.1007/s10787-018-00561-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 12/31/2018] [Indexed: 01/28/2023]
Abstract
BACKGROUND Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored. METHODS The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7-150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated. RESULTS Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1β, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1β mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression). CONCLUSIONS Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.
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Affiliation(s)
- Allan J C Bussmann
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Sergio M Borghi
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Tiago H Zaninelli
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Telma S Dos Santos
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Carla F S Guazelli
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Victor Fattori
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Talita P Domiciano
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Felipe A Pinho-Ribeiro
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Kenji W Ruiz-Miyazawa
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil
| | - Antonio M B Casella
- Department of Clinical Medicine, Health Science Center, Londrina State University, University Hospital, 86039-440, Londrina, Paraná State, Brazil
| | - Josiane A Vignoli
- Department of Biochemistry and Biotechnology, Exact Sciences Center, Londrina State University, Londrina, 86057-970, Brazil
| | - Doumit Camilios-Neto
- Department of Biochemistry and Biotechnology, Exact Sciences Center, Londrina State University, Londrina, 86057-970, Brazil
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Health Science Center, Londrina State University, University Hospital, Londrina, Paraná State, 86039-440, Brazil
| | - Waldiceu A Verri
- Department of Pathology, Biological Science Center, Londrina State University, Rod. Celso Garcia Cid, PR 445, Km 380, Londrina, Paraná State, 86051-990, Brazil.
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A recent review of citrus flavanone naringenin on metabolic diseases and its potential sources for high yield-production. Trends Food Sci Technol 2018. [DOI: 10.1016/j.tifs.2018.06.012] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Abstract
Naringenin, a citrus flavonoid that possesses various biological activities, has emerged as a potential therapeutic agent for the management of a variety of diseases. Studies using cell culture system have shown that naringenin can inhibit inflammatory response in diverse cell types. Moreover, research using various animal models has further demonstrated therapeutic potentials of naringenin in the treatment of several inflammation-related disorders, such as sepsis, fulminant hepatitis, fibrosis and cancer. The mechanism of action of naringenin is not completely understood but recent mechanistic studies revealed that naringenin suppresses inflammatory cytokine production through both transcriptional and post-transcriptional mechanisms. Surprisingly, naringenin not only inhibits cytokine mRNA expression but also promotes lysosome-dependent cytokine protein degradation. This unique property of naringenin stands in sharp contrast with some widely-studied natural products such as apigenin and curcumin, which regulate cytokine production essentially at the transcriptional level. Therefore, naringenin may provide modality for the development of novel anti-inflammatory agent. This review article summarizes our recent studies in understanding how naringenin acts in cells and animal models. Particularly, we will discuss the anti-inflammatory activities of naringenin in various disease context and its potential use, as an immunomodulator, in the treatment of inflammatory related disease.
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