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Luo Q, Qiu J, Chen M, Yang N, Li X, Huang S, Ma Q, Li Z, Lou D, Du Y, Chen L, Shen Q, Chen F, Li C, Qiu P. Vine tea (Ampelopsis grossedentata) ameliorates chronic alcohol-induced hepatic steatosis, oxidative stress, and inflammation via YTHDF2/PGC-1α/SIRT3 axis. Food Res Int 2025; 209:116321. [PMID: 40253212 DOI: 10.1016/j.foodres.2025.116321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/21/2025]
Abstract
For over a millennium, the leaves of Ampelopsis grossedentata (Hand.-Mazz.) W. T. Wang, commonly known as vine tea, have been revered as a popular tea and traditional herbal remedy, possessing antioxidant, anti-inflammatory, hepatoprotective, and antiviral properties. In recent years, the incidence of alcohol-related liver injury has been on the rise, imposing a significant public health burden worldwide. Previous studies have indicated that extracts of vine tea (AGE) can ameliorate alcoholic liver disease (ALD), yet the pharmacological mechanisms underlying this effect remain poorly understood. In this study, we first employed UPLC-Q-TOF-MS to analyze the chemical constituents of AGE. Subsequently, an ALD model was established in mice fed with Lieber-DeCarli diet, and the hepatoprotective benefits of AGE were assessed by measuring biochemical indicators and hepatic pathological changes. Moreover, a suite of bioinformatics tools, including transcriptomics, weighted gene co-expression network analysis, and single-cell data mining, were utilized to reveal that the YTHDF2/PGC-1α/SIRT3 signaling axis may be the potential mechanism by which AGE exerts its anti-ALD effects. Additionally, Western blotting and immunofluorescence staining techniques were employed to further substantiate the aforementioned mechanism. Our findings demonstrate that administration of vine tea significantly alleviated chronic ethanol-induced hepatic lipid accumulation, oxidative stress, and inflammation. Notably, knockdown of YTHDF2 partially protected the liver from ethanol-induced injury. Mechanistically, bioinformatics analysis and in vitro and in vivo experiments identified YTHDF2 as a key pharmacological target of AGE in treating ALD, acting through the downstream PGC-1α/SIRT3 pathway. In summary, in this study, we provide the first evidence that AGE mitigates ethanol-induced liver injury by inhibiting YTHDF2 and enhancing the expression of PGC-1α and SIRT3. Vine tea, as a tea food with unique medicinal value, shows significant potential and value in the treatment of ALD.
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Affiliation(s)
- Qihan Luo
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiang Qiu
- Department of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Minxia Chen
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Na Yang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xinyue Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuo Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qing Ma
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zongyuan Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dayong Lou
- Zhuji People's Hospital of Zhejiang Province, Shaoxing, China
| | - Yu Du
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qing Shen
- Collaborative Innovation Center of Seafood Deep Processing, Zhejiang Province Joint Key Laboratory of Aquatic Products Processing, Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China.
| | - Fangming Chen
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Changyu Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Ping Qiu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
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Shi J, Peng X, Huang J, Zhang M, Wang Y. Dihydromyricetin Alleviated Acetaminophen-Induced Acute Kidney Injury via Nrf2-Dependent Anti-Oxidative and Anti-Inflammatory Effects. Int J Mol Sci 2025; 26:2365. [PMID: 40076982 PMCID: PMC11899924 DOI: 10.3390/ijms26052365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/04/2025] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Acute kidney injury (AKI) is a common side effect of acetaminophen (APAP) overdose. Dihydromyricetin (DHM) is the most abundant flavonoid in rattan tea, which has a wide range of pharmacological effects. In the current study, APAP-induced AKI models were established both in vivo and in vitro. The results showed that DHM pretreatment remarkably alleviated APAP-induced AKI by promoting antioxidant capacity through the nuclear factor erythroid-related factor 2 (Nrf2) signaling pathway in vivo. In addition, DHM reduced ROS production and mitochondrial dysfunction, thereby alleviating APAP-induced cytotoxicity in HK-2 cells. The way in which DHM improved the antioxidant capacity of HK-2 cells was through promoting the activation of the Nrf2-mediated pathway and inhibiting the expression levels of inflammation-related proteins. Furthermore, Nrf2 siRNA partially canceled out the protective effect of DHM against the cytotoxicity caused by APAP in HK-2 cells. Altogether, the protective effect of DHM on APAP-induced nephrotoxicity was related to Nrf2-dependent antioxidant and anti-inflammatory effects.
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Affiliation(s)
| | | | | | | | - Yuqin Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226019, China; (J.S.); (X.P.); (J.H.); (M.Z.)
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Wang Y, Yuan M, Li S, Tang J, Wan Y, Liang X, Guo Y, Guo L. Multifunctional Liposome Delivery System Based on Ursodeoxycholic Acid Sodium for the Encapsulation of Silibinin and Combined Treatment of Alcoholic Liver Injury. Mol Pharm 2025; 22:1480-1497. [PMID: 39931930 DOI: 10.1021/acs.molpharmaceut.4c01197] [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] [Indexed: 03/04/2025]
Abstract
Alcohol liver disease (ALD) is a chronic liver disorder resulting from long-term heavy alcohol consumption. The pathogenesis of ALD is multifactorial, and existing therapeutic agents primarily target specific aspects of the disease while presenting significant side effects, including drug-induced liver injury and hepatobiliary disease. Silibinin (SLB) has attracted widespread attention for its hepatoprotective effects and favorable safety profile. However, inherent limitations associated with SLB, such as poor solubility and bioavailability, have significantly limited its clinical application. Drug delivery systems, including liposomes, offer promising potential for the delivery of hydrophobic drugs. However, the selection of an appropriate delivery vehicle requires optimization. Ursodeoxycholic acid sodium (UAS) serves as a promising alternative to cholesterol in liposomal formulations, offering a potential strategy to mitigate the health risks associated with cholesterol. In this study, UAS was employed as the liposomal membrane material to prepare a UAS liposome loaded with SLB (SUL), and its efficacy and mechanism of action in alcoholic-induced liver injury were subsequently evaluated. The experimental results demonstrated that SUL exhibited a uniform particle size distribution, good stability, and an effective release profile in vitro. Following oral administration, SUL effectively inhibited alcohol-induced liver damage, oxidative stress, and fat accumulation. In addition, SUL regulated the expression of the kelch-1ike ECH- associated protein l (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) proteins, thereby exerting antioxidative stress effects. Furthermore, it also modulated apoptosis-related factors, including B-cell lymphoma-2 (Bcl-2), BCL-2-associated X (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), and cleaved caspase-3, to mitigate hepatocyte apoptosis. In summary, SUL demonstrates enhanced therapeutic efficacy against ALD, offering a novel approach for the clinical application of SLB in the prevention and treatment of ALD.
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Affiliation(s)
- Yulu Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Minghao Yuan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Sihui Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Jiamei Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Yan Wan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Xue Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Yiping Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
| | - Li Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611100, China
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Wen M, Sun X, Pan L, Jing S, Zhang X, Liang L, Xiao H, Liu P, Xu Z, Zhang Q, Huang H. Dihydromyricetin ameliorates diabetic renal fibrosis via regulating SphK1 to suppress the activation of NF-κB pathway. Eur J Pharmacol 2024; 978:176799. [PMID: 38945289 DOI: 10.1016/j.ejphar.2024.176799] [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: 12/12/2023] [Revised: 03/19/2024] [Accepted: 06/28/2024] [Indexed: 07/02/2024]
Abstract
Dihydromyricetin (DHM) is a flavonoid from vine tea with broad pharmacological benefits, which improve inflammation by blocking the NF-κB pathway. A growing body of research indicates that chronic kidney inflammation is vital to the pathogenesis of diabetic renal fibrosis. Sphingosine kinase-1 (SphK1) is a key regulator of diabetic renal inflammation, which triggers the NF-κB pathway. Hence, we evaluated whether DHM regulates diabetic renal inflammatory fibrosis by acting on SphK1. Here, we demonstrated that DHM effectively suppressed the synthesis of fibrotic and inflammatory adhesion factors like ICAM-1, and VCAM-1 in streptozotocin-treated high-fat diet-induced diabetic mice and HG-induced glomerular mesangial cells (GMCs). Moreover, DHM significantly suppressed NF-κB pathway activation and reduced SphK1 activity and protein expression under diabetic conditions. Mechanistically, the results of molecular docking, molecular dynamics simulation, and cellular thermal shift assay revealed that DHM stably bound to the binding pocket of SphK1, thereby reducing sphingosine-1-phosphate content and SphK1 enzymatic activity, which ultimately inhibited NF-κB DNA binding, transcriptional activity, and nuclear translocation. In conclusion, our data suggested that DHM inhibited SphK1 phosphorylation to prevent NF-κB activation thus ameliorating diabetic renal fibrosis. This supported the clinical use and further drug development of DHM as a potential candidate for treating diabetic renal fibrosis.
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Affiliation(s)
- Min Wen
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou, 510801, China
| | - Xiaohong Sun
- Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, 518026, China
| | - Linjie Pan
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Shujin Jing
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xuting Zhang
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Liyin Liang
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Haiming Xiao
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Peiqing Liu
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Zhanchi Xu
- Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
| | - Qun Zhang
- Good Clinical Practice Development, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China.
| | - Heqing Huang
- Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou, 510801, China.
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Emad D, Bayoumi AMA, Gebril SM, Ali DME, Waz S. Modulation of keap-1/Nrf2/HO-1 and NF-ĸb/caspase-3 signaling pathways by dihydromyricetin ameliorates sodium valproate-induced liver injury. Arch Biochem Biophys 2024; 758:110084. [PMID: 38971420 DOI: 10.1016/j.abb.2024.110084] [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: 05/30/2024] [Revised: 06/30/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
Nuclear factor erythroid factor 2 (Nrf2) is the key regulatory of the antioxidant response elements. Also, Nrf2 interacts with nuclear factor kappa B (NF-ĸB) to inhibit subsequent inflammatory cascade. Activation of Nrf2 signaling ameliorates drug-induced liver injury. Sodium valproate (SVP) is an anti-epilepsy drug with a hepatotoxic adverse effect that restricts its clinical use. In this study, coadministration of Dihydromyricetin (DHM), a natural flavonoid, with SVP to rats upregulated gene expression of Nrf2 and its downstream gene, heme oxygenase 1 (HO-1), while suppressed the Nrf2 repressor, Keap-1. Additionally, DHM led to downregulation of proinflammatory factors in liver tissues, including NF-ĸB, interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α). This was accompanied by a decrease in the proapoptotic protein (cleaved caspase-3) expression level. Furthermore, biochemical and histopathological studies showed that DHM treatment improved liver function and lipid profile while decreased inflammatory cell infiltration, congestion, and hepatocellular damage. According to our knowledge, prior research has not examined the protective effect of DHM on the liver injury induced by SVP. Consequently, this study provides DHM as a promising herbal medication that, when used with SVP, can prevent its induced hepatotoxicity owing to its potential anti-oxidative, anti-inflammatory, and anti-apoptotic properties.
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Affiliation(s)
- Doaa Emad
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag, Egypt.
| | - Asmaa M A Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 61511, Egypt.
| | - Sahar M Gebril
- Department of Histology and Cell biology, Faculty of Medicine, Sohag University, Sohag, Egypt.
| | | | - Shaimaa Waz
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 61511, Egypt.
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Zeng X, Lin GX, Zeng X, Zheng J, Ren C, Luo Z, Xiao K, Sun N, Zhang L, Rui G, Chen X. Penfluridol regulates p62 / Keap1 / Nrf2 signaling pathway to induce ferroptosis in osteosarcoma cells. Biomed Pharmacother 2024; 177:117094. [PMID: 38996707 DOI: 10.1016/j.biopha.2024.117094] [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: 02/06/2024] [Revised: 06/24/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
The cure rate for patients with osteosarcoma (OS) has stagnated over the past few decades. Penfluridol, a first-generation antipsychotic, has demonstrated to prevent lung and esophageal malignancies from proliferation and metastasis. However, the effect of penfluridol on OS and its underlying molecular mechanism remains unclear. This study revealed that penfluridol effectively inhibited cell proliferation and migration, and induced G2/M phase arrest in OS cells. In addition, penfluridol treatment was found to increased reactive oxygen species (ROS) levels in OS cells. Combined with the RNA-Seq results, the anti-OS effect of penfluridol was hypothesized to be attributed to the induction of ferroptosis. Western blot results showed that penfluridol promoted intracellular Fe2+ concentration, membrane lipid peroxidation, and decreased intracellular GSH level to induce ferroptosis. Further studies showed that p62/Keap1/Nrf2 signaling pathway was implicated in penfluridol-induced ferroptosis in OS cells. Overexpression of p62 effectively reversed penfluridol-induced ferroptosis. In vivo, penfluridol effectively inhibited proliferation and prolonged survival in xenograft tumor model. Therefore, penfluridol is a promising drug targeting OS in the future.
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Affiliation(s)
- Xiangchen Zeng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Guang-Xun Lin
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Xianhui Zeng
- Department of Infectious Diseases, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou 570206, China
| | - Jiyuan Zheng
- The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Chong Ren
- School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhong Luo
- School of Medicine, Xiamen University, Xiamen 361102, China
| | - Keyi Xiao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Naikun Sun
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Long Zhang
- Department of Pain, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
| | - Gang Rui
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China.
| | - Xiaohui Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China.
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Ding Q, Liu X, Zhang S, Chai G, Ma S, Sun S, Shen L, Gao Y, Ding C, Zhao T, Liu W. Chitosan-modified dihydromyricetin liposomes promote the repair of liver injury in mice suffering from diabetes mellitus. Int J Biol Macromol 2024; 273:133040. [PMID: 38857721 DOI: 10.1016/j.ijbiomac.2024.133040] [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: 02/04/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/12/2024]
Abstract
Liver injury caused by type-II diabetes mellitus (DM) is a significant public-health concern worldwide. We used chitosan (CS) to modify dihydromyricetin (DHM)-loaded liposomes (DL) through charge interaction. The effect of CS-modified DL (CDL) on liver injury in mice suffering from DM was investigated in vivo and in vitro. CDL exhibited superior antioxidant capacity and stability. Pharmacokinetic analyses revealed a 3.23- and 1.92-fold increase in the drug concentration-time curve (953.60 ± 122.55 ng/mL/h) in the CDL-treated group as opposed to the DHM-treated group (295.15 ± 25.53 ng/mL/h) and DL-treated group (495.31 ± 65.21 ng/mL/h). The maximum drug concentration in blood (Tmax) of the CDL group saw a 2.26- and 1.21-fold increase compared with that in DHM and DL groups. We observed a 1.49- and 1.31-fold increase in the maximum drug concentration in blood (Cmax) in the CDL group compared with that in DHM and DL groups. Western blotting suggested that CDL could alleviate liver injury in mice suffering from DM by modulating inflammatory factors and the transforming growth factor-β1/Smad2/Smad3 signaling pathway. In conclusion, modification of liposomes using CS is a viable approach to address the limitations of conventional liposomes and insoluble drugs.
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Affiliation(s)
- Qiteng Ding
- College of traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
| | - Xinglong Liu
- College of Traditional Chinese Medicine, Jilin Agriculture Science and Technology College, Jilin 132101, China
| | - Shuai Zhang
- College of traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
| | - Guodong Chai
- College of traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
| | - Shuang Ma
- College of traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
| | - Shuwen Sun
- College of traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
| | - Liqian Shen
- Jilin Jianwei Natural Biotechnology Co., Ltd., Linjiang 134600, China
| | - Yang Gao
- Jilin Jianwei Natural Biotechnology Co., Ltd., Linjiang 134600, China
| | - Chuanbo Ding
- College of Traditional Chinese Medicine, Jilin Agriculture Science and Technology College, Jilin 132101, China; Scientific and Technological Innovation Center of Health Products and Medical Materials with Characteristic Resources of Jilin Province, Changchun 130118, China
| | - Ting Zhao
- College of Traditional Chinese Medicine, Jilin Agriculture Science and Technology College, Jilin 132101, China.
| | - Wencong Liu
- School of Food and Pharmaceutical Engineering, Wuzhou University, Wuzhou 543002, China.
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Alexander M, Cho E, Gliozheni E, Salem Y, Cheung J, Ichii H. Pathology of Diabetes-Induced Immune Dysfunction. Int J Mol Sci 2024; 25:7105. [PMID: 39000211 PMCID: PMC11241249 DOI: 10.3390/ijms25137105] [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: 04/28/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024] Open
Abstract
Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.
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Affiliation(s)
- Michael Alexander
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Eric Cho
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Eiger Gliozheni
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Yusuf Salem
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Joshua Cheung
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Hirohito Ichii
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
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Tao X, Pan X, Zhao G, Xue M, Rui Y. Dihydromyricetin regulates KEAP1-Nrf2 pathways to enhance the survival of ischemic flap. Food Sci Nutr 2024; 12:3893-3909. [PMID: 38873488 PMCID: PMC11167164 DOI: 10.1002/fsn3.4049] [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: 10/31/2023] [Revised: 02/02/2024] [Accepted: 02/07/2024] [Indexed: 06/15/2024] Open
Abstract
In clinical flap practice, there are a lot of studies being done on how to promote the survival of distal random flap necrosis in the hypoxic and ischemic state. As a traditional Chinese medicine, dihydromyricetin (DHM) is crucial in preventing oxidative stress and apoptosis in a number of disorders. In this work, we examined the impact of DHM on the ability to survive of ischemia flaps and looked into its fundamental mechanism. Our results showed that DHM significantly increased the ischemic flaps' survival area, encouraged angiogenesis and blood flow, reduced oxidative stress and apoptosis, and stimulated KEAP1-Nrf2 (Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor) signaling pathways. Adeno-associated virus (AAV) upregulation of KEAP1 expression also negated the favorable effects of DHM on flap survival. By activating KEAP1-Nrf2 signaling pathways, DHM therapy promotes angiogenesis while reducing oxidative stress and apoptosis.
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Affiliation(s)
- Xianyao Tao
- Suzhou Medical College of Soochow UniversitySuzhouJiangsuChina
- Department of Hand SurgeryWuxi Ninth People's Hospital Affiliated to Soochow UniversityWuxiJiangsuChina
| | - Xiaoyun Pan
- Department of Hand SurgeryWuxi Ninth People's Hospital Affiliated to Soochow UniversityWuxiJiangsuChina
| | - Gang Zhao
- Department of Hand SurgeryWuxi Ninth People's Hospital Affiliated to Soochow UniversityWuxiJiangsuChina
| | - Mingyu Xue
- Department of Hand SurgeryWuxi Ninth People's Hospital Affiliated to Soochow UniversityWuxiJiangsuChina
| | - Yongjun Rui
- Department of Hand SurgeryWuxi Ninth People's Hospital Affiliated to Soochow UniversityWuxiJiangsuChina
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Wang ZN, Ma JC, Xi MF, Yin D, Jiang LF, Qi J. Effects of Nanoparticle-Mediated Dihydromyricetin to Diabetic Wounds: An In Vivo Study. J Burn Care Res 2024; 45:644-654. [PMID: 38236154 DOI: 10.1093/jbcr/irae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Indexed: 01/19/2024]
Abstract
Diabetic wound is one of the serious complications of diabetes, and the wound is persistent and easily recurring, which seriously endangers the health and life of patients. How to effectively promote the healing of diabetic wounds has been a hot spot and difficult area of clinical research. Some previous studies have shown that dihydromyricetin has the effects of regulating blood glucose, controlling the severity, and inhibiting scarring. In the present study, we used polylactic-co-glycolic acid nanoparticles as a carrier to load dihydromyricetin to make drug-loaded nanoparticles and applied them dropwise (200 µL) to diabetic mice wounds by topical application to observe the healing and scar formation of diabetic wounds. We found that the healing rate of the diabetic mice was faster and the scar formation was less obvious. In addition, the elevated blood glucose level and weight loss of the mice in the treatment group were also reduced. Therefore, nanoparticle-mediated dihydromyricetin may be an effective treatment for diabetic wounds.
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Affiliation(s)
- Zhao-Nan Wang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
- Nantong University Medical School, Nantong, Jiangsu 226000, P.R. China
- Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, Jiangsu 223800, P.R. China
| | - Jiu-Cheng Ma
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
- Nantong University Medical School, Nantong, Jiangsu 226000, P.R. China
| | - Ming-Fan Xi
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
- Nantong University Medical School, Nantong, Jiangsu 226000, P.R. China
| | - Dong Yin
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
- Nantong University Medical School, Nantong, Jiangsu 226000, P.R. China
| | - Li-Fan Jiang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
- Nantong University Medical School, Nantong, Jiangsu 226000, P.R. China
| | - Jun Qi
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
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11
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He YX, Liu MN, Wang YY, Wu H, Wei M, Xue JY, Zou Y, Zhou X, Chen H, Li Z. Hovenia dulcis: a Chinese medicine that plays an essential role in alcohol-associated liver disease. Front Pharmacol 2024; 15:1337633. [PMID: 38650630 PMCID: PMC11033337 DOI: 10.3389/fphar.2024.1337633] [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: 11/13/2023] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
Globally, alcohol-associated liver disease (ALD) has become an increased burden for society. Disulfirams, Benzodiazepines (BZDs), and corticosteroids are commonly used to treat ALD. However, the occurrence of side effects such as hepatotoxicity and dependence, impedes the achievement of desirable and optimal therapeutic efficacy. Therefore, there is an urgent need for more effective and safer treatments. Hovenia dulcis is an herbal medicine promoting alcohol removal clearance, lipid-lowering, anti-inflammatory, and hepatoprotective properties. Hovenia dulcis has a variety of chemical components such as dihydromyricetin, quercetin and beta-sitosterol, which can affect ALD through multiple pathways, including ethanol metabolism, immune response, hepatic fibrosis, oxidative stress, autophagy, lipid metabolism, and intestinal barrier, suggesting its promising role in the treatment of ALD. Thus, this work aims to comprehensively review the chemical composition of Hovenia dulcis and the molecular mechanisms involved in the process of ALD treatment.
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Affiliation(s)
- Yi-Xiang He
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Meng-Nan Liu
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Yang-Yang Wang
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Hao Wu
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Mei Wei
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Jin-Yi Xue
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Yuan Zou
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Xin Zhou
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Hui Chen
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhi Li
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
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12
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Yi M, Cruz Cisneros L, Cho EJ, Alexander M, Kimelman FA, Swentek L, Ferrey A, Tantisattamo E, Ichii H. Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities. Int J Mol Sci 2024; 25:821. [PMID: 38255895 PMCID: PMC10815857 DOI: 10.3390/ijms25020821] [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: 11/29/2023] [Revised: 12/27/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads to these comorbidities, of which increased oxidative stress in diabetic patients has been strongly implicated. Limited knowledge of antioxidative antidiabetic drugs and substances that can address diabetic comorbidities through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway calls for detailed investigation. This review will describe how diabetes increases oxidative stress, the general impact of that oxidative stress, and how oxidative stress primarily contributes to diabetic comorbidities. It will also address how treatments for diabetes, especially focusing on their effects on the Nrf2 antioxidative pathway, have been shown to similarly affect the Nrf2 pathway of the heart, kidney, and liver systems. This review demonstrates that the Nrf2 pathway is a common pathogenic component of diabetes and its associated comorbidities, potentially identifying this pathway as a target to guide future treatments.
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Affiliation(s)
- Michelle Yi
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
| | - Leslie Cruz Cisneros
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
| | - Eric J. Cho
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
| | - Francesca A. Kimelman
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
| | - Lourdes Swentek
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
| | - Antoney Ferrey
- Department of Medicine, University of California Irvine, Irvine, CA 92697, USA; (A.F.); (E.T.)
| | - Ekamol Tantisattamo
- Department of Medicine, University of California Irvine, Irvine, CA 92697, USA; (A.F.); (E.T.)
| | - Hirohito Ichii
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (L.C.C.); (E.J.C.); (M.A.); (F.A.K.); (L.S.)
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13
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Wei L, Li X, Yao Y, Wang S, Ai X, Liu S. Study on the molecular mechanism of dihydromyricetin in alleviating liver cirrhosis based on network pharmacology. Chem Biol Drug Des 2024; 103:e14421. [PMID: 38230771 DOI: 10.1111/cbdd.14421] [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: 02/13/2023] [Revised: 08/31/2023] [Accepted: 12/03/2023] [Indexed: 01/18/2024]
Abstract
Dihydromyricetin (DHM) is a bioactive flavonoid extracted from Hovenia dulcis, which has various activities. In the present study, the molecular mechanism of dihydromyricetin (DHM) in relieving liver cirrhosis was investigated through network pharmacology and experimental verification. The cell model was induced by TGF-β1 activating the human hepatic stellate cell line (HSC; LX-2). The protein levels of α-SMA, collagen I, and collagen III and pathway-related proteins within LX-2 cells were detected using Western blot. EdU staining was conducted to detect cell proliferation. Immunofluorescence staining was performed to detect the expression levels of α-SMA and collagen I. Next, the drug targets of DHM were screened from the PubChem database. The differentially expressed genes in the liver cirrhosis dataset GSE14323 were identified. The expression of the identified drug targets in LX-2 cells was verified using qRT-PCR. The results showed that TGF-β1 treatment notably increased LX-2 cell viability, promoted cell proliferation, and elevated α-SMA, collagen I, and collagen III protein contents. DHM treatment could partially eliminate TGF-β1 effects, as evidenced by the inhibited cell viability and proliferation and reduced α-SMA, collagen I, and collagen III contents. After network pharmacology analysis, nine differentially expressed target genes (MMP2, PDGFRB, PARP1, BCL2L2, ABCB1, TYR, CYP2E1, SQSTM1, and IL6) in liver cirrhosis were identified. According to qRT-PCR verification, DHM could inhibit the expression of MMP2, PDGFRB, PARP1, CYP2E1, SQSTM1, and IL6, and enhance ABCB1 expression levels within LX-2 cells. Moreover, DHM inhibited mTOR and MAPK signaling pathways in TGF-β1-induced HSCs. In conclusion, DHM could inhibit HSC activation, which may be achieved via acting on MMP2, PDGFRB, PARP1, CYP2E1, SQSTM1, IL6, and ABCB1 genes and their downstream signaling pathways, including mTOR and MAPK signaling pathway.
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Affiliation(s)
- Lin Wei
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Hunan, China
| | - Xiaoying Li
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of biology and food engineering, Huaihua University, Huaihua, Hunan, China
| | - Yuanzhi Yao
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of biology and food engineering, Huaihua University, Huaihua, Hunan, China
| | - Siqi Wang
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Hunan, China
| | - Xinghui Ai
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Hunan, China
| | - Shenggui Liu
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of biology and food engineering, Huaihua University, Huaihua, Hunan, China
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Chervet A, Nehme R, Decombat C, Longechamp L, Habanjar O, Rousset A, Fraisse D, Blavignac C, Filaire E, Berthon JY, Delort L, Caldefie-Chezet F. Exploring the Therapeutic Potential of Ampelopsis grossedentata Leaf Extract as an Anti-Inflammatory and Antioxidant Agent in Human Immune Cells. Int J Mol Sci 2023; 25:416. [PMID: 38203587 PMCID: PMC10779184 DOI: 10.3390/ijms25010416] [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: 12/05/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammation is a vital protective response to threats, but it can turn harmful if chronic and uncontrolled. Key elements involve pro-inflammatory cells and signaling pathways, including the secretion of pro-inflammatory cytokines, NF-κB, reactive oxygen species (ROS) production, and the activation of the NLRP3 inflammasome. Ampelopsis grossedentata, or vine tea, contains dihydromyricetin (DHM) and myricetin, which are known for their various health benefits, including anti-inflammatory properties. Therefore, the aim of this study is to assess the impact of an extract of A. grossedentata leaves (50 µg/mL) on inflammation factors such as inflammasome, pro-inflammatory pathways, and macrophage polarization, as well as its antioxidant properties, with a view to combating the development of low-grade inflammation. Ampelopsis grossedentata extract (APG) significantly decreased ROS production and the secretion of pro-inflammatory cytokines (IFNγ, IL-12, IL-2, and IL-17a) in human leukocytes. In addition, APG reduced LPS/IFNγ -induced M1-like macrophage polarization, resulting in a significant decrease in the expression of the pro-inflammatory cytokines TNF-α and IL-6, along with a decrease in the percentage of M1 macrophages and an increase in M0 macrophages. Simultaneously, a significant decrease in NF-κB p65 phosphorylation and in the expression of inflammasome genes (NLRP3, IL-1β and Caspase 1) was observed. The results suggest that Ampelopsis grossedentata could be a promising option for managing inflammation-related chronic diseases. Further research is needed to optimize dosage and administration methods.
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Affiliation(s)
- Arthur Chervet
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Rawan Nehme
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Caroline Decombat
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Lucie Longechamp
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Amandine Rousset
- Greentech, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France (J.-Y.B.)
| | - Didier Fraisse
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Christelle Blavignac
- Centre Imagerie Cellulaire Santé, Université Clermont Auvergne, 63000 Clermont-Ferrand, France;
| | - Edith Filaire
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Jean-Yves Berthon
- Greentech, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France (J.-Y.B.)
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France; (A.C.); (R.N.); (C.D.); (L.L.); (O.H.); (D.F.); (E.F.); (F.C.-C.)
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15
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Zeng T, Song Y, Qi S, Zhang R, Xu L, Xiao P. A comprehensive review of vine tea: Origin, research on Materia Medica, phytochemistry and pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116788. [PMID: 37343650 DOI: 10.1016/j.jep.2023.116788] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/24/2023] [Accepted: 06/13/2023] [Indexed: 06/23/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Vine tea is a popular folk tea that has been consumed in China for more than 1200 years. It is often used in ethnic medicine by ethnic groups in southwest China with at least 35 aliases in 10 provinces. In coastal areas, vine tea is mostly used to treat heatstroke, aphtha, aphonia, toothache, etc. In contrast, in the southwest inland regions, vine tea is mostly used to clear away heat and toxic materials, antiphlogosis and relieving sore-throat, lowering blood pressure and lipid levels, and alleviating fatigue. Three main species have been used as the source of vine tea, Nekemias grossedentata, Nekemias cantonensis and Nekemias megalophylla. Among them, the leaves of Nekemias grossedentata were considered as new food resource in complicance with regulations, according to the Food Safety Standards published by the Monitoring and Evaluation Department of the National Health and Family Planning Commission in China. AIM OF THE STUDY At present, the comprehensively summary of Materia Medica on the history and source of vine tea is currently unavailable. The current article summed up the Materia Medica, species origin and pharmacological effects of all 3 major species used in vine tea to fill the knowledge gaps. We also aim to provide a reference for future research on historical textual, resource development and medicinal utilization of vine tea. MATERIALS AND METHODS Adhering to the literature screening methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this review encompasses 148 scholarly research papers from three database, paper ancient books, local chronicles and folklore through field investigations. We then comprehensively summarized and discussed research progresses in scientific and application studies of vine tea. RESULTS The historical records indicated that vine tea could have been used as early as Southern and Northern Dynasties (AC 420-589). Nekemias grossedentata, Nekemias cantonensis and Nekemias megalophylla, were used to considered as vine tea in the ethnic medicine. The main phytochemicals found in three plants are flavonoids, polyphenols and terpenoids, among which dihydromyricetin (DHM) is the most important and most studied active substance. The key words "Ampelopsis grossedentata" (Synonym of Nekemias grossedentata) and "dihydromyricetin/DHM" showed the highest frequency over the last 27 year based on the research trend analysis. And the ethnopharmacology studies drawn the main activities of vine tea are antioxidant, antibacterial, hepatoprotective, neuroprotective and anti-atherosclerosis activities. CONCLUSIONS This review systematically summarized and discussed vine tea from the following five aspects, history, genetic relationship, phytochemistry, research trend and ethnopharmacology. Vine tea has a long historical usage in Chinese ethnic medicine. Its outstanding therapeutic efficacies have attracted extensive attention in other places in the world at present. Nekemias cantonensis and Nekemias megalophylla are quite similar to Nekemias grossedentata in terms of many aspects. However, the current research has a narrow focus on mainly Nekemias grossedentata and DHM. We propose that future studies could be carried out to determine the synergistic effect of multi-components and multi-targets of vine tea including all 3 species to provide valuable knowledge.
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Affiliation(s)
- Tiexin Zeng
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Yanjun Song
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Shunyao Qi
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Ruyue Zhang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Lijia Xu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
| | - Peigen Xiao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, 100193, China.
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16
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Lu M, Liu R, Chen Z, Su C, Pan L. Effects of dietary dihydromyricetin on growth performance, antioxidant capacity, immune response and intestinal microbiota of shrimp (Litopenaeus vannamei). FISH & SHELLFISH IMMUNOLOGY 2023; 142:109086. [PMID: 37722436 DOI: 10.1016/j.fsi.2023.109086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/31/2023] [Accepted: 09/16/2023] [Indexed: 09/20/2023]
Abstract
A 56-day culture trial was conducted to evaluate the effects of dietary dihydromyricetin (DMY) on growth performance, antioxidant capacity, immune response and intestinal microbiota of shrimp (Litopenaeus vannamei). 840 healthy shrimp (1.60 ± 0.21 g) in total were fed with four different levels of DMY diets at 0 (Control), 100 (D1), 200 (D2), and 300 (D3) mg/kg, respectively. Samples were collected after the culture trial, and then, a 7-day challenge experiment against Vibrio parahaemolyticus was conducted. The results demonstrated that DMY significantly enhanced the activity of protease, amylase and lipase as well as the expression of lipid and protein transport-related genes (P < 0.05). The results of plasma lipid parameters indicated that DMY reduced lipid deposition, manifested by significantly (P < 0.05) decreased plasma total cholesterol (T-CHO), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). The expression of genes involved in fatty acid β-oxidation and triglyceride catabolism was significantly up-regulated (P < 0.05), and genes involved in triglyceride synthesis were significantly down-regulated in DMY groups when compared to control group (P < 0.05). Moreover, dietary DMY also significantly (P < 0.05) increased the total antioxidant capacity (T-AOC), antioxidant enzymes activity and glutathione (GSH) content of shrimp, and a significant increase of total hemocytes count (THC), phagocytic rate (PR), antibacterial activity (AA) and bacteriolytic activity (BA) was observed in DMY groups (P < 0.05). The addition of DMY to the diet significantly augmented immune response by up-regulating the expression of genes related to toll-like receptors (Toll) signaling pathway, immune deficiency (IMD) signaling pathway and intestinal mucin. Furthermore, dietary DMY could modulate the composition and abundance of intestinal microbiota. In conclusion, DMY showed promising potential as a functional feed additive for shrimp to improve the growth performance and physiological health.
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Affiliation(s)
- Mingxiang Lu
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Renzhi Liu
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Zhifei Chen
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Chen Su
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Luqing Pan
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China.
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Han W, Li H, Jiang H, Xu H, Lin Y, Chen J, Bi C, Liu Z. Progress in the mechanism of autophagy and traditional Chinese medicine herb involved in alcohol-related liver disease. PeerJ 2023; 11:e15977. [PMID: 37727691 PMCID: PMC10506582 DOI: 10.7717/peerj.15977] [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: 04/28/2023] [Accepted: 08/07/2023] [Indexed: 09/21/2023] Open
Abstract
Alcohol-related liver disease (ALD) is chronic liver damage caused by long-term heavy drinking with, extremely complicated pathogenesis. The current studies speculated that excessive alcohol and its metabolites are the major causes of liver cell toxicity. Autophagy is evolutionarily conserved in eukaryotes and aggravates alcoholic liver damage, through various mechanisms, such as cellular oxidative stress, inflammation, mitochondrial damage and lipid metabolism disorders. Therefore, autophagy plays an critical role in the occurrence and development of ALD. Some studies have shown that traditional Chinese medicine extracts improve the histological characteristics of ALD, as reflected in the improvement of oxidative stress and lipid droplet clearance, which might be achieved by inducing autophagy. This article reviews the mechanisms of quercetin, baicalin, glycycoumarin, salvianolic acid A, resveratrol, ginsenoside rg1, and dihydromyricetin inducing autophagy and their participation in the inhibition of ALD. The regulation of autophagy in ALD by these traditional Chinese medicine extracts provides novel ideas for the treatment of the disease; however, its molecular mechanism needs to be elucidated further.
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Affiliation(s)
- Wenwen Han
- Department of Medical Laboratory, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Haiyu Li
- Department of Medical Laboratory, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Hanqi Jiang
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Hang Xu
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Yifeng Lin
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Jiahuan Chen
- Department of Medical Laboratory, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Chenchen Bi
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Zheng Liu
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
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Zhu X, Liu S, Pei H, Chen W, Zong Y, Zhao Y, Li J, Du R, He Z. Study on Dihydromyricetin Improving Aflatoxin Induced Liver Injury Based on Network Pharmacology and Molecular Docking. TOXICS 2023; 11:760. [PMID: 37755770 PMCID: PMC10535947 DOI: 10.3390/toxics11090760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/26/2023] [Accepted: 08/31/2023] [Indexed: 09/28/2023]
Abstract
Aflatoxin B1 (AFB1) is a toxic food/feed contaminant and the liver is its main target organ, thus it poses a great danger to organisms. Dihydromyricetin (DHM), a natural flavonoid compound, can be used as a food additive with high safety and has been shown to have strong hepatoprotective effects. In this experiment, PPI network and KEGG pathway analysis were constructed by network pharmacological analysis technique using software and platforms such as Swiss, String, and David and Cytoscape. We screened AFB1 and DHM cross-targets and pathways of action, followed by molecular docking based on the strength of binding affinity of genes to DHM. In addition, we exposed AFB1 (200 μg/kg) to mice to establish a liver injury model. Histological observation, biochemical assay, oxidative stress indicator assay, TUNEL staining and Western blot were used to evaluate the liver injury. Network pharmacological results were screened to obtain 25 cross-targets of action and 20 pathways of action. It was found that DHM may exert anti-hepatic injury effects by inhibiting the overexpression of Caspase-3 protein and increasing the expression of Bcl-2 protein. DHM (200 mg/kg) was found to reduce AFB1-induced liver indices such as alanine aminotransferase (ALT) and aspartate acyltransferase (AST), and attenuate hepatic histopathological damage through animal models. Importantly, DHM inhibited malondialdehyde (MDA) formation in liver tissue and attenuated AFB1-induced oxidative stress injury by increasing glutathione-S-transferase (GST) glutathione (GPX) catalase (CAT) and superoxide dismutase (SOD). Meanwhile, DHM also restored the expression of anti-apoptotic protein Bcl-2 and antioxidant proteins, Nrf2, Keap1 and its downstream HO-1, and down-regulated the expression of pro-apoptotic proteins Bax and Caspase-3 in AFB1-induced liver tissues. The results confirmed that liver injury caused by AFB1 exposure could be alleviated by DHM, providing valuable guidance for in-depth study of DHM in the treatment of liver-related diseases, and laying the foundation for in-depth development and utilization of DHM.
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Affiliation(s)
- Xiaoying Zhu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
| | - Silu Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
| | - Hongyan Pei
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
| | - Weijia Chen
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
- Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Jilin Agricultural University, Changchun 130118, China
| | - Ying Zong
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
- Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Jilin Agricultural University, Changchun 130118, China
| | - Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
- Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Jilin Agricultural University, Changchun 130118, China
| | - Jianming Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
- Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Jilin Agricultural University, Changchun 130118, China
| | - Rui Du
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
- Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Jilin Agricultural University, Changchun 130118, China
- Key Laboratory of Animal Production and Product Quality and Safety, Ministry of Education, Jilin Agricultural University, Changchun 130118, China
| | - Zhongmei He
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; (X.Z.); (S.L.); (Y.Z.); (Y.Z.)
- Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Jilin Agricultural University, Changchun 130118, China
- Key Laboratory of Animal Production and Product Quality and Safety, Ministry of Education, Jilin Agricultural University, Changchun 130118, China
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Salete-Granado D, Carbonell C, Puertas-Miranda D, Vega-Rodríguez VJ, García-Macia M, Herrero AB, Marcos M. Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications. Antioxidants (Basel) 2023; 12:1425. [PMID: 37507963 PMCID: PMC10376811 DOI: 10.3390/antiox12071425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.
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Affiliation(s)
- Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
| | - Cristina Carbonell
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - David Puertas-Miranda
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Víctor-José Vega-Rodríguez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Marina García-Macia
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Instituto de Biología Funcional y Genómica (IBFG), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana Belén Herrero
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
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Jung UJ. Sarcopenic Obesity: Involvement of Oxidative Stress and Beneficial Role of Antioxidant Flavonoids. Antioxidants (Basel) 2023; 12:antiox12051063. [PMID: 37237929 DOI: 10.3390/antiox12051063] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Sarcopenic obesity, which refers to concurrent sarcopenia and obesity, is characterized by decreased muscle mass, strength, and performance along with abnormally excessive fat mass. Sarcopenic obesity has received considerable attention as a major health threat in older people. However, it has recently become a health problem in the general population. Sarcopenic obesity is a major risk factor for metabolic syndrome and other complications such as osteoarthritis, osteoporosis, liver disease, lung disease, renal disease, mental disease and functional disability. The pathogenesis of sarcopenic obesity is multifactorial and complicated, and it is caused by insulin resistance, inflammation, hormonal changes, decreased physical activity, poor diet and aging. Oxidative stress is a core mechanism underlying sarcopenic obesity. Some evidence indicates a protective role of antioxidant flavonoids in sarcopenic obesity, although the precise mechanisms remain unclear. This review summarizes the general characteristics and pathophysiology of sarcopenic obesity and focuses on the role of oxidative stress in sarcopenic obesity. The potential benefits of flavonoids in sarcopenic obesity have also been discussed.
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Affiliation(s)
- Un Ju Jung
- Department of Food Science and Nutrition, Pukyong National University, 45 Yongso-ro, Nam-gu, Busan 48513, Republic of Korea
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21
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Matouk AI, Awad EM, El-Tahawy NFG, El-Sheikh AAK, Anter A. Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity. Pharmaceuticals (Basel) 2023; 16:ph16040481. [PMID: 37111238 PMCID: PMC10145727 DOI: 10.3390/ph16040481] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/03/2023] [Accepted: 03/20/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. METHODS Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. RESULTS Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1β, and TGF-β1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. CONCLUSION This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.
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Affiliation(s)
- Asmaa I Matouk
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
| | - Eman M Awad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
| | - Nashwa F G El-Tahawy
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Azza A K El-Sheikh
- Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Aliaa Anter
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
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WANG J, JIN QG, LIU RP, WANG XQ, LI YH, KIM NH, XU YN. Dihydromyricetin supplementation during in vitro culture improves porcine oocyte developmental competence by regulating oxidative stress. J Reprod Dev 2023; 69:10-17. [PMID: 36403957 PMCID: PMC9939282 DOI: 10.1262/jrd.2022-031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Dihydromyricetin (DHM), a dihydroflavonoid compound, exhibits a variety of biological activities, including antitumor activity. However, the effects of DHM on mammalian reproductive processes, especially during early embryonic development, remain unclear. In this study, we added DHM to porcine zygotic medium to explore the influence and underlying mechanisms of DHM on the developmental competence of parthenogenetically activated porcine embryos. Supplementation with 5 μM DHM during in vitro culture (IVC) significantly improved blastocyst formation rate and increased the total number of cells in porcine embryos. Further, DHM supplementation also improved glutathione levels and mitochondrial membrane potential; reduced natural reactive oxygen species levels in blastomeres and apoptosis rate; upregulated Nanog, Oct4, SOD1, SOD2, Sirt1, and Bcl2 expression; and downregulated Beclin1, ATG12, and Bax expression. Collectively, DHM supplementation regulated oxidative stress during IVC and could act as a potential antioxidant during in vitro porcine oocytes maturation.
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Affiliation(s)
- Jing WANG
- College of Agriculture, Yanbian University, Yanji 133000, China,Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529000,
China
| | - Qing-Guo JIN
- College of Agriculture, Yanbian University, Yanji 133000, China
| | - Rong-Ping LIU
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529000,
China
| | - Xin-Qin WANG
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529000,
China
| | - Ying-Hua LI
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529000,
China
| | - Nam-Hyung KIM
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529000,
China
| | - Yong-Nan XU
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529000,
China
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Fan G, Li F, Wang P, Jin X, Liu R. Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases. Int J Mol Sci 2022; 23:ijms232315109. [PMID: 36499429 PMCID: PMC9739742 DOI: 10.3390/ijms232315109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/11/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022] Open
Abstract
Autophagy is essential for the maintenance of hepatic homeostasis, and autophagic malfunction has been linked to the pathogenesis of substantial liver diseases. As a popular source of drug discovery, natural products have been used for centuries to effectively prevent the progression of various liver diseases. Emerging evidence has suggested that autophagy regulation is a critical mechanism underlying the therapeutic effects of these natural products. In this review, relevant studies are retrieved from scientific databases published between 2011 and 2022, and a novel scoring system was established to critically evaluate the completeness and scientific significance of the reviewed literature. We observed that numerous natural products were suggested to regulate autophagic flux. Depending on the therapeutic or pathogenic role autophagy plays in different liver diseases, autophagy-regulative natural products exhibit different therapeutic effects. According to our novel scoring system, in a considerable amount of the involved studies, convincing and reasonable evidence to elucidate the regulatory effects and underlying mechanisms of natural-product-mediated autophagy regulation was missing and needed further illustration. We highlight that autophagy-regulative natural products are valuable drug candidates with promising prospects for the treatment of liver diseases and deserve more attention in the future.
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Affiliation(s)
- Guifang Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Fanghong Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Ping Wang
- Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xuejing Jin
- Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
- Correspondence: (X.J.); (R.L.); Tel.: +86-15632374331 (X.J.); +86-10-53912122 (R.L.)
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
- Correspondence: (X.J.); (R.L.); Tel.: +86-15632374331 (X.J.); +86-10-53912122 (R.L.)
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Matouk AI, Awad EM, El-Tahawy NF, El-Sheikh AA, Waz S. Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis. Biomed Pharmacother 2022; 155:113752. [DOI: 10.1016/j.biopha.2022.113752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/13/2022] [Accepted: 09/23/2022] [Indexed: 11/02/2022] Open
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Xie J, Zhang T, Li P, Wang D, Liu T, Xu S. Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis. Drug Des Devel Ther 2022; 16:3071-3085. [PMID: 36118165 PMCID: PMC9477154 DOI: 10.2147/dddt.s378786] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
Background Dihydromyricetin (DHM) exerts protective effects in various brain diseases. The aim of this research was to investigate the biological role of DHM in cerebral ischemia reperfusion (I/R) injury. Methods We generated a rat model of cerebral I/R injury by performing middle cerebral artery occlusion/reperfusion (MCAO/R). The neurological score and brain water content of the experimental rats was then evaluated. The infarct volume and extent of apoptosis in brain tissues was then assessed by 2,3,5-triphenyltetrazolium (TTC) and TdT-mediated dUTP nick end labeling (TUNEL) staining. Hippocampal neuronal cells (HT22) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) and cell counting kit-8 (CCK-8) assays and flow cytometry were performed to detect cell viability and apoptosis. The levels of lipid reactive oxygen species (ROS) and iron were detected and the expression levels of key proteins were assessed by Western blotting. Results DHM obviously reduced neurological deficits, brain water content, infarct volume and cell apoptosis in the brain tissues of MCAO/R rats. DHM repressed ferroptosis and inhibited the sphingosine kinase 1 (SPHK1)/mammalian target of rapamycin (mTOR) pathway in MCAO/R rats. In addition, DHM promoted cell viability and repressed apoptosis in OGD/R-treated HT22 cells. DHM also suppressed the levels of lipid ROS and intracellular iron in OGD/R-treated HT22 cells. The expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM. Moreover, the influence conferred by DHM was abrogated by the overexpression of SPHK1 or treatment with MHY1485 (an activator of mTOR). Conclusion This research demonstrated that DHM repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral I/R injury. Our findings suggest that DHM may be a candidate drug for cerebral I/R injury treatment.
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Affiliation(s)
- Jiangbo Xie
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
- Department of Neurology, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China
| | - Tingting Zhang
- Department of Rehabilitation Medicine, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China
| | - Peichun Li
- Department of Rehabilitation Medicine, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China
| | - Dong Wang
- Department of Neurology, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China
| | - Tao Liu
- Department of Neurology, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China
| | - Shunliang Xu
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
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Sun Y, He L, Wang W, Xie Z, Zhang X, Wang P, Wang L, Yan C, Liu Z, Zhao J, Cui Z, Wang Y, Tang L, Zhang Z. Activation of Atg7-dependent autophagy by a novel inhibitor of the Keap1-Nrf2 protein-protein interaction from Penthorum chinense Pursh. attenuates 6-hydroxydopamine-induced ferroptosis in zebrafish and dopaminergic neurons. Food Funct 2022; 13:7885-7900. [PMID: 35776077 DOI: 10.1039/d2fo00357k] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The death of dopaminergic neurons is a dominant factor during the occurrence and development of Parkinson's disease (PD). Previous studies demonstrated that ferroptosis is implicated in the death of dopaminergic neurons. Besides, polyphenols have been proven to be effective in preventing the death of dopaminergic neurons. This work aims to explore the neuroprotective effect and mechanism of thonningianin A (Th A), a polyphenolic compound in natural plant foods, against 6-hydroxydopamine (6-OHDA)-induced ferroptosis in dopaminergic cells. The results of molecular docking and other binding assays collectively demonstrated that Th A can strongly target the Kelch domain of Keap1. Th A treatment significantly facilitated the nuclear factor erythroid 2-like 2 (Nrf2) nuclear translocation and subsequently increased the heme oxygenase-1 (HO-1) protein level through inhibiting the protein-protein interaction (PPI) of Keap1 and Nrf2. Compared with the nomifensine (Nomi) treatment, Th A had a more potent protective effect on 6-OHDA-induced ferroptosis during PD pathology in zebrafish, which was associated with assuaging the reduction of the total swimming distance, glutathione (GSH) depletion, iron accumulation, lipid peroxidation, and aggregation of α-synuclein (α-syn). Furthermore, Th A also exhibited a strong protective effect against 6-OHDA-induced ferroptosis in vitro in the human neuroblastoma cell line SH-SY5Y. Th A degraded Keap1 protein through activating Atg7-dependent autophagy. Additionally, Th A treatment facilitated the degradation of Keap1 protein by promoting the interaction between p62/SQSTM1 (sequestosome 1, hereafter referred to as p62) and Keap1. Taken together, our findings indicated that Th A protects dopaminergic cells against 6-OHDA-induced ferroptosis through activating the Nrf2-based cytoprotective system, thus enabling a potential application of Keap1-Nrf2 PPI inhibitors in the restraint of ferroptosis and treatment of PD.
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Affiliation(s)
- Yiran Sun
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Libo He
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China.
| | - Wang Wang
- School of Basic Medicine, Nanchang Medical College, Nanchang 330052, Jiangxi, China
| | - Zhishen Xie
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Xiaowei Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Pan Wang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Lan Wang
- College of Chemical and Food Engineering, Zhengzhou Institute of Technology, Zhengzhou 450044, China
| | - Chenchen Yan
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Zhiwen Liu
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Jie Zhao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Zhenghao Cui
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
| | - Yida Wang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China.
| | - Lin Tang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China.
| | - Zhenqiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China.
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Present Status, Challenges, and Prospects of Dihydromyricetin in the Battle against Cancer. Cancers (Basel) 2022; 14:cancers14143487. [PMID: 35884547 PMCID: PMC9317349 DOI: 10.3390/cancers14143487] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 12/14/2022] Open
Abstract
Dihydromyricetin (DHM) is a natural flavonoid compound extracted from Ampelopsis grossedentata that has been used for centuries in traditional Chinese medicine. DHM has attracted intensive attention due to its numerous beneficial activities, such as hepatoprotection, cardioprotection, antioxidant, and anti-inflammation. In addition, DHM inhibits the progression of cancers such as lung cancer, hepatocellular cancer, breast cancer, melanoma, and malignant reproductive systems through multiple mechanisms, including antiangiogenesis, antiproliferation, apoptosis, and inhibition of invasion and migration. Notably, DHM also activates autophagy at different levels, exerting a dual-regulatory effect on cancers. Mechanistically, DHM can effectively regulate mammalian target of rapamycin (mTOR), noncoding RNA-mediated signaling, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, nuclear factor-κB (NF-κB), p53, and endoplasmic reticulum stress (ER stress)-driven signaling in different types of cancers. DHM has also been shown to have inhibitory effects on various regulators that trigger epithelial–mesenchymal transition (EMT). Furthermore, DHM exhibits a remarkable anticancer reversal ability when used in combination with drugs such as adriamycin, nedaplatin, and other drugs. However, the low bioavailability of DHM limits its potential applications, which are improved through structural modification and the exploration of novel dosage forms. Therefore, DHM may become a promising candidate for treating malignancies alone or combined with conventional anticancer strategies used in clinical practice.
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Zhou Q, Zhang N, Hu T, Xu H, Duan X, Liu B, Chen F, Wang M. Dietary phenolic-type Nrf2-activators: implications in the control of toxin-induced hepatic disorders. Food Funct 2022; 13:5480-5497. [PMID: 35411358 DOI: 10.1039/d1fo04237h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Numerous studies have exemplified the importance of nuclear factor erythroid 2-related factor 2 (Nrf2) activation in the alleviation of toxin-induced hepatic disorders primarily through eliminating oxidative stress. Whereafter, increasingly more efforts have been contributed to finding Nrf2-activators, especially from dietary polyphenols. The present review summarized the phenolic-type Nrf2-activators published in the past few decades, analyzed their effectiveness based on their structural characteristics and outlined their related mechanisms. It turns out that flavonoids are the largest group of phenolic-type Nrf2-activators, followed by nonflavonoids and phenolic acids. When counting on subgroups, the top three types are flavonols, flavones, and hydroxycinnamic acids, with curcuminoids having the highest effective doses. Moreover, most polyphenols work through the phosphorylation of Nrf2. Besides, mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt) are the frequent targets of these Nrf2-activators, which indirectly mediate the behavior of Nrf2. However, current data are not sufficient to conclude any structure-activity relationship.
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Affiliation(s)
- Qian Zhou
- Institute for Advanced Study, Shenzhen University, Shenzhen, China. .,Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, China.
| | - Nana Zhang
- School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Tingyan Hu
- Institute for Advanced Study, Shenzhen University, Shenzhen, China. .,Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, China.
| | - Hui Xu
- Institute for Advanced Study, Shenzhen University, Shenzhen, China. .,Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, China.
| | - Xinxing Duan
- Schlegel Research Institute for Aging & Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Canada
| | - Bin Liu
- Institute for Advanced Study, Shenzhen University, Shenzhen, China. .,Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, China.
| | - Feng Chen
- Institute for Advanced Study, Shenzhen University, Shenzhen, China. .,Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, China.
| | - Mingfu Wang
- Institute for Advanced Study, Shenzhen University, Shenzhen, China. .,Institute for Innovative Development of Food Industry, Shenzhen University, Shenzhen, China.
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[Dihydromyricetin reduces lipid accumulation in LO2 cells via AMPK/mTOR-mediated lipophagy pathway and inhibits HepG2 cell proliferation in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:518-527. [PMID: 35527487 PMCID: PMC9085583 DOI: 10.12122/j.issn.1673-4254.2022.04.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To explore the mechanism underlying the hepatoprotective effect of dihydromyricetin (DMY) against lipid accumulation in light of the lipophagy pathway and the inhibitory effect of DMY on HepG2 cell proliferation. METHODS LO2 cells were cultured in the presence of 10% FBS for 24 h and treated with 100 μg/mL DMY, or exposed to 50% FBS for 24 h followed by treatment with 50, 100, or 200 μg/mL DMY; the cells in recovery group were cultured in 50% FBS for 24 h and then in 10% FBS for another 24 h. Oil red O staining was used to observe the accumulation of lipid droplets in the cells, and the levels of TC, TG, and LDL and activities of AST, ALT and LDH were measured. The expression of LC3 protein was detected using Western blotting. AO staining and transmission electron microscopy were used to determine the numbers of autophagolysosomes and autophagosomes, respectively. The formation of autophagosomes was observed with MDC staining, and the mRNA expression levels of LC3, ATG7, AMPK, mTOR, p62 and Beclin1 were determined with q-PCR. Flow cytometry was performed to analyze the effect of 50, 100, and 200 μg/mL DMY on cell cycle and apoptosis of HepG2 cells; DNA integrity in the treated cells was examined with cell DNA fragmentation test. RESULTS DMY treatment and pretreatment obviously inhibited lipid accumulation and reduced the levels of TC, TG, LDL and enzyme activities of AST, ALT and LDH in LO2 cells (P < 0.05). In routinely cultured LO2 cells, DMY significantly promoted the formation of autophagosomes and autophagolysosomes and upregulated the expression of LC3 protein. DMY obviously attenuated high FBS-induced inhibition of autophagosome formation in LO2 cells, up- regulated the mRNA levels of LC3, ATG7, Beclin1 and AMPK, and downregulated p62 and mTOR mRNA levels (P < 0.05 or 0.01). In HepG2 cells, DMY caused obvious cell cycle arrest, inhibited cell proliferation, and induced late apoptosis and DNA fragmentation. CONCLUSION DMY reduces lipid accumulation in LO2 cells by regulating the AMPK/ mTOR-mediated lipophagy pathway and inhibits the proliferation of HepG2 by causing cell cycle arrest and promoting apoptosis.
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Fan X, Fan Z, Yang Z, Huang T, Tong Y, Yang D, Mao X, Yang M. Flavonoids-Natural Gifts to Promote Health and Longevity. Int J Mol Sci 2022; 23:ijms23042176. [PMID: 35216290 PMCID: PMC8879655 DOI: 10.3390/ijms23042176] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/08/2022] [Accepted: 02/14/2022] [Indexed: 02/01/2023] Open
Abstract
The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.
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Affiliation(s)
- Xiaolan Fan
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Ziqiang Fan
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
| | - Ziyue Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
| | - Tiantian Huang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
| | - Yingdong Tong
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
| | - Deying Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Xueping Mao
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Mingyao Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China; (X.F.); (Z.F.); (Z.Y.); (T.H.); (Y.T.); (D.Y.); (X.M.)
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
- Correspondence:
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Mahmoud AM, Sayed AM, Ahmed OS, Abdel-Daim MM, Hassanein EHM. The role of flavonoids in inhibiting IL-6 and inflammatory arthritis. Curr Top Med Chem 2022; 22:746-768. [PMID: 34994311 DOI: 10.2174/1568026622666220107105233] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 11/22/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the synovial joints. RA has well-known clinical manifestations and can cause progressive disability and premature death along with socioeconomic burdens. Interleukin-6 (IL-6) has been implicated in the pathology of RA where it can stimulate pannus formation, osteoclastogenesis, and oxidative stress. Flavonoids are plant metabolites with beneficial pharmacological effects, including anti-inflammatory, antioxidant, antidiabetic, anticancer, and others. Flavonoids are polyphenolic compounds found in a variety of plants, vegetables, and fruits. Many flavonoids have demonstrated anti-arthritic activity mediated mainly through the suppression of pro-inflammatory cytokines. This review thoroughly discusses the accumulate data on the role of flavonoids on IL-6 in RA.
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Affiliation(s)
- Ayman M Mahmoud
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Egypt
| | - Ahmed M Sayed
- Biochemistry Laboratory, Chemistry Department, Faculty of Science, Assiut University, Egypt
| | - Osama S Ahmed
- Faculty of Pharmacy, Al-Azhar University-Assiut Branch, Egypt
| | - Mohamed M Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Egypt
| | - Emad H M Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University-Assiut Branch, Egypt
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Zhao Y, Liu X, Ding C, Gu Y, Liu W. Dihydromyricetin Reverses Thioacetamide-Induced Liver Fibrosis Through Inhibiting NF-κB-Mediated Inflammation and TGF-β1-Regulated of PI3K/Akt Signaling Pathway. Front Pharmacol 2021; 12:783886. [PMID: 34867416 PMCID: PMC8634482 DOI: 10.3389/fphar.2021.783886] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/27/2021] [Indexed: 01/07/2023] Open
Abstract
As a natural active substance, dihydromyricetin (DHM) has been proven to have good hepatoprotective activity. However, the therapeutic effect of DHM on liver fibrosis, which has become a liver disease threatening the health of people around the world, has not been studied to date. The purpose of this study was to investigate the effect of DHM as a new nutritional supplement on thioacetamide (TAA)-induced liver fibrosis. The liver fibrosis model was established by intraperitoneal injection of TAA (200 mg/kg, every 3 days) for 8 weeks, and oral administration of DHM (20 mg/kg and 40 mg/kg, daily) after 4 weeks of TAA-induced liver fibrosis. The results showed that DHM treatment significantly inhibited the activities of alanine aminotransferase (ALT) (37.81 ± 7.62 U/L) and aspartate aminotransferase (AST) (55.18 ± 10.94 U/L) in serum of liver fibrosis mice, and increased the levels of superoxide dismutase (SOD) and glutathione (GSH) while reversed the level of malondialdehyde (MDA). In addition, histopathological examination illustrated that TAA induced the inflammatory infiltration, apoptosis and fibroatherosclerotic deposition in liver, which was further confirmed by western-blot and immunofluorescence staining. Moreover, DHM inhibited hepatocyte apoptosis by regulating the phosphorylation level of phosphatidylinositol 3-kinase (PI3K), protein kinase-B (AKT) and its downstream apoptotic protein family. Interestingly, immunofluorescence staining showed that DHM treatment significantly inhibited alpha smooth muscle actin (α-SMA), which was a marker of hepatic stellate cell activation, and regulated the expression of transforming growth factor (TGF-β1). Importantly, supplementation with DHM significantly inhibited the release of nuclear factor kappa-B (NF-κB) signaling pathway and pro-inflammatory factors in liver tissue induced by TAA, and improved liver fiber diseases, such as tumor necrosis factor alpha (TNF-α) and recombinant rat IL-1β (IL-1β). In conclusion, the evidence of this study revealed that DHM is a potential hepatoprotective and health factor, and which also provides the possibility for the treatment of liver fibrosis.
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Affiliation(s)
- Yingchun Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Xinglong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Chuanbo Ding
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Yan Gu
- College of Agriculture, Jilin Agricultural University, Changchun, China
| | - Wencong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China.,National and Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun, China
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Selenomethionine-Dominated Selenium-Enriched Peanut Protein Ameliorates Alcohol-Induced Liver Disease in Mice by Suppressing Oxidative Stress. Foods 2021; 10:foods10122979. [PMID: 34945529 PMCID: PMC8700997 DOI: 10.3390/foods10122979] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/18/2021] [Accepted: 12/01/2021] [Indexed: 01/11/2023] Open
Abstract
Numerous natural compounds are considered as potential therapeutic agents against alcohol-induced liver disease (ALD). Research shows that selenium (Se) has a variety of bioactivities, including liver protecting ability. The present study based on in vitro cell culture models and in vivo mouse models was aimed at examining the contribution of selenomethionine (SeMet)-dominated Se-enriched peanut protein (SePP) to liver protection. SeMet and especially SePP reversed cell viability and cell death, inhibited ethanol induced CYP2E1 activation, decreased reactive oxygen species level, and restored GSH level. Hence, SeMet-dominated SePP alleviates alcohol-induced AML-12 cytotoxicity by suppressing oxidative stress. The p38-dependent mechanism was found to be responsible for SePP-induced Nrf-2 activation. Furthermore, supplementation with SePP and SeMet regulated lipid metabolism and reduced oxidative stress, minimizing liver damage in mice. Selenomethionine-dominated SePP possesses potential therapeutic properties and can be used to treat ALD through the suppression of oxidative stress.
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Zhang Q, Zhao Y, Zhang M, Zhang Y, Ji H, Shen L. Recent advances in research on vine tea, a potential and functional herbal tea with dihydromyricetin and myricetin as major bioactive compounds. J Pharm Anal 2021; 11:555-563. [PMID: 34765268 PMCID: PMC8572699 DOI: 10.1016/j.jpha.2020.10.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 10/07/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023] Open
Abstract
Vine tea has been used as an herbal tea by several ethnic minorities for hundreds of years in China. Flavonoids, a kind of indispensable component in a variety of nutraceutical, pharmaceutical and cosmetic applications, are identified to be the major metabolites and bioactive ingredients in vine tea. Interestingly, vine tea exhibits a wide range of significant bioactivities including anti-oxidant, anti-inflammatory, anti-tumor, antidiabetic, neuroprotective and other activities, but no toxicity. These bioactivities, to some extent, enrich the understanding about the role of vine tea in disease prevention and therapy. The health benefits of vine tea, particularly dihydromyricetin and myricetin, are widely investigated. However, there is currently no comprehensive review available on vine tea. Therefore, this report summarizes the most recent studies investigating bioactive constituents, pharmacological effects and possible mechanisms of vine tea, which will provide a better understanding about the health benefits and preclinical assessment of novel application of vine tea.
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Affiliation(s)
- Qili Zhang
- College of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Yanfang Zhao
- College of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Meiyan Zhang
- Department of Pharmacy, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Yalu Zhang
- Department of Pharmacy, The Affiliated Hospital of Jining Medical College, Jining, Shandong 272100, China
| | - Hongfang Ji
- College of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
| | - Liang Shen
- College of Life Sciences, Shandong University of Technology, Zibo, Shandong 255000, China
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Huang L, Zeng X, Li B, Wang C, Zhou M, Lang H, Yi L, Mi M. Dihydromyricetin attenuates palmitic acid-induced oxidative stress by promoting autophagy via SIRT3-ATG4B signaling in hepatocytes. Nutr Metab (Lond) 2021; 18:83. [PMID: 34503544 PMCID: PMC8428134 DOI: 10.1186/s12986-021-00612-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Oxidative stress in hepatocytes was important pathogenesis of nonalcoholic steatohepatitis (NASH). Autophagy was a cellular process that can remove damaged organelles under oxidative stress, and thus presented a potential therapeutic target against NASH. This work aimed to investigate whether autophagy was participated in the protective effects of dihydromyricetin (DHM) on palmitic acid (PA)-induced oxidative stress in hepatocytes and the underlying mechanism. METHODS HepG2 and HHL-5 cell lines were pretreated with DHM (20 μM) for 2 h, followed by PA (0.2 mM) treatment for 16 h. The oxidative stress was assessed by the quantification of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), mitochondrial membrane potential (MMP) and mitochondrial ultrastructural analyses. The protein expressions of SIRT3, LC3I/II, P62 and ATG4B, as well as the acetylation of AGT4B were determined by western blotting using HepG2 and HepG2/ATG4B± cells with heterozygous knockout of ATG4B. RESULTS Exposure to PA resulted in increased intracellular ROS and mtROS, decreased MMP and aggravated mitochondrial injury in HepG2 cells, which were notably attenuated by DHM treatment. DHM-induced inhibition of oxidative stress was associated with the induction of autophagy, characterized by upregulated ATG4B and LC3 II as well as downregulated P62 levels. Furthermore, the inhibitory effects of DHM on PA-induced autophagy arrest and oxidative stress were eliminated when pretreated with a SIRT3 inhibitor 3-TYP or conducted in HepG2/ATG4B± cells, suggesting that SIRT3 and ATG4B were involved in DHM-induced benefits. Moreover, DHM treatment increased the protein expression of SIRT3 and SIRT3-dependent deacetylation of ATG4B in HepG2 cells. CONCLUSION Our results demonstrated that DHM attenuated PA-induced oxidative stress in hepatocytes through induction of autophagy, which was mediated through the increased expression of SIRT3 and SIRT3-mediated ATG4B deacetylation following DHM treatment.
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Affiliation(s)
- Li Huang
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China
| | - Xianglong Zeng
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China.,General Hospital of Tibet Military Command Area, 850000, Lhasa, Tibet, People's Republic of China
| | - Bo Li
- Department of Blood Transfusion, 925 Hospital, Joint Logistics Support Force, PLA, 550009, Guiyang, People's Republic of China
| | - Cong Wang
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China
| | - Min Zhou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China
| | - Hedong Lang
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China
| | - Long Yi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China.
| | - Mantian Mi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, 400038, Chongqing, People's Republic of China.
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Zhao Y, Lu J, Mao A, Zhang R, Guan S. Autophagy Inhibition Plays a Protective Role in Ferroptosis Induced by Alcohol via the p62-Keap1-Nrf2 Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:9671-9683. [PMID: 34388345 DOI: 10.1021/acs.jafc.1c03751] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Binge alcohol consumption is a serious health concern. Ferroptosis is an iron-dependent lipid peroxidation mediated cell death. Activation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway has been shown to exert a protective effect by blunting the responses to ferroptosis inducers. The autophagy substrate p62 was demonstrated to modulate Nrf2 and contribute to the suppression of ferroptosis. Furthermore, autophagy inhibition resulted in the accumulation of p62, which is a specific substrate for this process. Therefore, we aimed to explore the protective effect of autophagy inhibition against alcohol-induced ferroptosis through activating the p62-Keap1-Nrf2 pathway. Our results demonstrated that alcohol induced ferroptosis, which could be significantly reduced by ferrostatin-1. Additionally, we found that autophagy inhibition could protect HepG2 cells against alcohol-induced ferroptosis by activating the p62-Keap1-Nrf2 pathway. Furthermore, inhibition of autophagy increased the expression of p62, which interacted with Keap1 to promote Nrf2 translocation into the nucleus and upregulation its target proteins ferritin heavy (FTH), ferroportin (FPN), and heme oxygenase-1 (HO-1). This study provides a theoretical basis for further elucidation of the relationship between autophagy and ferroptosis and lays a preliminary foundation for further research concerning dietary guidance in the prevention and treatment of diseases related to alcohol-induced ferroptosis.
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Affiliation(s)
- Yanan Zhao
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Jing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
- Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Ankang Mao
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Ranran Zhang
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Shuang Guan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China
- Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China
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Wang R, Mu J. Arbutin attenuates ethanol-induced acute hepatic injury by the modulation of oxidative stress and Nrf-2/HO-1 signaling pathway. J Biochem Mol Toxicol 2021; 35:e22872. [PMID: 34346143 DOI: 10.1002/jbt.22872] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/20/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats via the modulation of the Nrf-2/HO-1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf-2/HO-1 signaling proteins was studied by reverse-transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor-α and interleukin-6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf-2/HO-1 signaling cascade liver tissues of ethanol-provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol-challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.
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Affiliation(s)
- Rongsheng Wang
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Jinji Mu
- Department of Gastroenterology, People's Hospital of Tongchuan, Tongchuan, China
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Chen J, Wang X, Xia T, Bi Y, Liu B, Fu J, Zhu R. Molecular mechanisms and therapeutic implications of dihydromyricetin in liver disease. Biomed Pharmacother 2021; 142:111927. [PMID: 34339914 DOI: 10.1016/j.biopha.2021.111927] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 07/04/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023] Open
Abstract
Recent studies demonstrated that dihydromyricetin (DHM) has prominent therapeutic effects on liver injury and liver cancer. By summarizing the current preclinical in vitro and in vivo studies, the present review examines the preventive and therapeutic effects of DHM on liver disorders as well as its potential mechanisms. Briefly, in both chemical- and alcohol-induced liver injury models, DHM ameliorates hepatocyte necrosis and steatosis while promoting liver regeneration. In addition, DHM can alleviate nonalcoholic fatty liver disease (NAFLD) via regulating lipid/glucose metabolism, probably due to its anti-inflammatory or sirtuins-dependent mechanisms. Furthermore, DHM treatment inhibits cell proliferation, induces apoptosis and autophagy and regulates redox balance in liver cancer cells, thus exhibiting remarkable anti-cancer effects. The pharmacological mechanisms of DHM may be associated with its anti-inflammatory, anti-oxidative and apoptosis-regulatory benefits. With the accumulating interests in utilizing natural products to target common diseases, our work aims to improve the understanding of DHM acting as a novel drug candidate for liver diseases and to accelerate its translation from bench to bedside.
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Affiliation(s)
- Jingnan Chen
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China; Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, China
| | - Xitong Wang
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China; Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, China
| | - Tian Xia
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China; Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, China
| | - Yanhua Bi
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China
| | - Bin Liu
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, China.
| | - Junfen Fu
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China; Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, China.
| | - Runzhi Zhu
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China; Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, China; Cancer Center, Zhejiang University, China.
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Zhang P, Wang W, Mao M, Gao R, Shi W, Li D, Calderone R, Sui B, Tian X, Meng X. Similarities and Differences: A Comparative Review of the Molecular Mechanisms and Effectors of NAFLD and AFLD. Front Physiol 2021; 12:710285. [PMID: 34393826 PMCID: PMC8362097 DOI: 10.3389/fphys.2021.710285] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are the most prevalent metabolic liver diseases globally. Due to the complex pathogenic mechanisms of NAFLD and AFLD, no specific drugs were approved at present. Lipid accumulation, oxidative stress, insulin resistance, inflammation, and dietary habits are all closely related to the pathogenesis of NAFLD and AFLD. However, the mechanism that promotes disease progression has not been fully elucidated. Meanwhile, the gut microbiota and their metabolites also play an important role in the pathogenesis and development of NAFLD and AFLD. This article comparatively reviewed the shared and specific signaling pathways, clinical trials, and potential intervention effectors of NAFLD and AFLD, revealing their similarities and differences. By comparing the shared and specific molecular regulatory mechanisms, this paper provides mutual reference strategies for preventing and treating NAFLD, AFLD, and related metabolic diseases. Furthermore, it provides enlightenment for discovering novel therapies of safe and effective drugs targeting the metabolic liver disease.
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Affiliation(s)
- Pengyi Zhang
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Weiya Wang
- School of Sports and Health, Shandong Sport University, Jinan, China.,Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Min Mao
- Department of Allied Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ruolin Gao
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Wenting Shi
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Dongmei Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Richard Calderone
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bo Sui
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Xuewen Tian
- School of Sports and Health, Shandong Sport University, Jinan, China
| | - Xiangjing Meng
- Shandong Academy of Pharmaceutical Science, Jinan, China
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Hou R, Liu X, Wu X, Zheng M, Fu J. Therapeutic effect of natural melanin from edible fungus Auricularia auricula on alcohol-induced liver damage in vitro and in vivo. FOOD SCIENCE AND HUMAN WELLNESS 2021. [DOI: 10.1016/j.fshw.2021.04.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Ma L, Li C, Lian S, Xu B, Lv H, Liu Y, Lu J, Ji H, Li S, Guo J, Yang H. Procyanidin B2 alleviates liver injury caused by cold stimulation through Sonic hedgehog signalling and autophagy. J Cell Mol Med 2021; 25:8015-8027. [PMID: 34155807 PMCID: PMC8358862 DOI: 10.1111/jcmm.16733] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 05/20/2021] [Accepted: 05/29/2021] [Indexed: 12/13/2022] Open
Abstract
Procyanidin B2 (PB2), a naturally occurring flavonoid abundant in a wide range of fruits, has been shown to exert antioxidant, anti‐inflammatory and anticancer properties. However, the role of PB2 in the prevention of cold stimulation (CS)‐induced liver injury. The present study was undertaken to determine the effects of PB2 on liver injury induced by cold stimulation and its potential molecular mechanisms. The present study results showed that treatment with PB2 significantly reduced CS‐induced liver injury by alleviating histopathological changes and serum levels of alanine transaminase and aspartate transaminase. Moreover, treatment with PB2 inhibited secretion of inflammatory cytokines and oxidative stress in cold‐stimulated mice. PB2 reduced cold stimulation‐induced inflammation by inhibiting TLR4/NF‐κB and Txnip/NLRP3 signalling. Treatment with PB2 reduced oxidative stress by activating Nrf‐2/Keap1, AMPK/GSK3β signalling pathways and autophagy. Furthermore, simultaneous application of Shh pathway inhibitor cyclopamine proved that PB2 targets the Hh pathway. More importantly, co‐treatment with PB2 and cyclopamine showed better efficacy than monotherapy. In conclusion, our findings provide new evidence that PB2 has protective potential against CS‐induced liver injury, which might be closely linked to the inhibition of Shh signalling pathway.
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Affiliation(s)
- Li Ma
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Chengxu Li
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Shuai Lian
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Bin Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Hongming Lv
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yanzhi Liu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jingjing Lu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Hong Ji
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Shize Li
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jingru Guo
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Huanmin Yang
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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Zhou X, Yu L, Zhou M, Hou P, Yi L, Mi M. Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect. Nutr Metab (Lond) 2021; 18:64. [PMID: 34147124 PMCID: PMC8214786 DOI: 10.1186/s12986-021-00589-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/10/2021] [Indexed: 12/11/2022] Open
Abstract
Background This study investigated the mechanisms underlying the preventive effect of dihydromyricetin (DHM) against liver fibrosis involving hepatic stellate cells (HSCs) and hepatic natural killer (NK) cells. Methods A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 mice to study the antifibrotic effect of DHM based on serum biochemical parameters, histological and immunofluorescence stainings, and the expression of several fibrosis-related markers. Based on the immunoregulatory role of DHM, the effect of DHM on NK cell activation ex vivo was evaluated by flow cytometry. Then, we investigated whether DHM-induced autophagy was involved in HSCs inactivation using enzyme-linked immunosorbent assays, transmission electron microscopy, and western blot analysis. Thereafter, the role of DHM in NK cell-mediated killing was studied by in vitro coculture of NK cells and HSCs, with subsequent analysis by flow cytometry. Finally, the mechanism by which DHM regulates NK cells was studied by western blot analysis. Results DHM ameliorated liver fibrosis in C57BL/6 mice, as characterized by decreased serum alanine transaminase and aspartate transaminase levels, decreased expressions of collagen I alpha 1 (CoL-1α1), collagen I alpha 2 (CoL-1α2), tissue inhibitor of metalloproteinases 1 (TIMP-1), α-smooth muscle actin (α-SMA) and desmin, as well as increased expression of matrix metalloproteinase 1 (MMP1). Interestingly, HSCs activation was significantly inhibited by DHM in vivo and in vitro. As expected, DHM also upregulated autophagy-related indicators in liver from CCl4-treated mice. DHM also prevented TGF-β1-induced activation of HSCs in vitro by initiating autophagic flux. In contrast, the autophagy inhibitor 3-methyladenine markedly abolished the antifibrotic effect of DHM. Surprisingly, the frequency of activated intrahepatic NK cells was significantly elevated by DHM ex vivo. Furthermore, DHM enhanced NK cell-mediated killing of HSCs by increasing IFN-γ expression, which was abolished by an anti-IFN-γ neutralizing antibody. Mechanistically, DHM-induced IFN-γ expression was through AhR-NF-κB/STAT3 pathway in NK cells. Conclusion These results demonstrated that DHM can ameliorate the progression of liver fibrosis and inhibition of HSCs activation by inducing autophagy and enhancing NK cell-mediated killing through the AhR-NF-κB/STAT3-IFN-γ signaling pathway, providing new insights into the preventive role of DHM in liver fibrosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00589-6.
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Affiliation(s)
- Xi Zhou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Li Yu
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Min Zhou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Pengfei Hou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China
| | - Long Yi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
| | - Mantian Mi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University (Army Medical University), NO. 30th Gao Tan Yan Street, Shapingba District, Chongqing, 400038, People's Republic of China.
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Lu Q, Shu Y, Wang L, Li G, Zhang S, Gu W, Sun Y, Hua W, Huang L, Chen F, Tang L. The protective effect of Veronica ciliata Fisch. Extracts on relieving oxidative stress-induced liver injury via activating AMPK/p62/Nrf2 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113775. [PMID: 33406386 DOI: 10.1016/j.jep.2021.113775] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Veronica ciliata Fisch. existed in various Tibetan medicine prescriptions, which was recorded to treat liver diseases in the Tibetan medicine roll of Chinese materia medica. HYPOTHESIS/PURPOSE The current study aimed to examine the effect of active constituents from V.ciliata relieving oxidative stress-mediated liver injury and clarify the underlying mechanism. MATERIALS AND METHODS tert-Butyl hydroperoxide (BHP) induced liver injury in mice model was established to evaluate the hepatoprotective effect of ethyl acetate extract of V. ciliata (EAFVC). Serum and liver indicators, as well as the histopathological change of liver were examined. Next, the constituents of EAFVC were separated and characterized by high-speed countercurrent chromatography (HSCCC) and Ultra performance liquid chromatography-mass spectrometer (UPLC-MS), respectively. Based on the above, the antioxidant activity of EAFVC and two fractions was evaluated using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azino-bis (3-ethylbenzothiazoli- ne-6-sulfonic acid) (ABTS) free radical scavenging assays. The hepatoprotective activity of EAFVC and its fractions/compounds attenuating ethanol-induced hepatocyte damage in BRL-3A cells was evaluated using the MTT method. The effect of the fraction and compounds with the strongest protective activity on ethanol-induced cytotoxicity, reactive oxygen species (ROS) accumulation, and glutathione (GSH) depletion was investigated. mRNA expression of nuclear factor-E2-related factor 2 (Nrf2) and nuclear factor of κB (NF-κB), as well as their downstream target genes, was determined by RT-qPCR. Finally, the potential mechanism of fraction 1 and luteolin on the AMPK/p62/Nrf2 signal pathway was studied using western blotting. RESULTS Firstly, EAFVC could relieve liver impairment induced by t-BHP in mice. Next, fraction 1 enriched with polyphenolic compounds and luteolin derived from EAFVC were screened to yield the highest hepatoprotective activity against ethanol-induced hepatocyte damage. Further study demonstrated that fraction 1 and luteolin relieved BRL-3A cells damage by decreasing the aspartate aminotransferase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) activities, ROS accumulation, as well as the depletion of GSH. Also, we determined that fraction 1 and luteolin suppressed inflammation and apoptosis of BRL-3A cells. The mechanistic studies indicated that fraction 1 could attenuate oxidative stress, inflammation, and apoptosis by activating AMPK phosphorylation, which promotes autophagy associated protein expression (LC3-B, Beclin1 and p62) as well as promote phosphorylation of p62 -dependent autophagic degradation of Keap1, to induce Nrf2 dissociation from Keap1 and translocate to nuclear. Nrf2 in the nuclear activate cytoprotective related genes to exert hepatoprotective function. Finally, we found that luteolin activated the protein expression of p-AMPK, p-p62, p62, Nrf2, and its downstream target genes. CONCLUSIONS This study clarified that fraction 1 enriched phenolic compounds could attenuate ethanol-induced liver injury in BRL-3A cells via activating AMPK/p62/Nrf2 pathway. Luteolin could serve as the major bioactive component in the therapeutic effect of fraction 1. These active constituents in V. ciliata could be used as the potential drugs targeted activation of AMPK or p62 for relieving oxidative stress-mediated liver disorders.
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Affiliation(s)
- Qiuxia Lu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China; College of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Yueyue Shu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Li Wang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Guoxiu Li
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Shiyan Zhang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Wanqin Gu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Yiran Sun
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Wan Hua
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Lei Huang
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China
| | - Fang Chen
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Lin Tang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China.
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Silva J, Carry E, Xue C, Zhang J, Liang J, Roberge JY, Davies DL. A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice. Molecules 2021; 26:molecules26061791. [PMID: 33810134 PMCID: PMC8004700 DOI: 10.3390/molecules26061791] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these effects are limited by P-glycoprotein (Pgp/ABCB1) efflux. The current study tested the hypothesis that dihydromyricetin (DHM), a natural product suggested to inhibit Pgp, will enhance IVM potency as measured by changes in EtOH consumption. Using a within-subjects study design and two-bottle choice study, we tested the combination of DHM (10 mg/kg; i.p.) and IVM (0.5–2.5 mg/kg; i.p.) on EtOH intake and preference in male and female C57BL/6J mice. We also conducted molecular modeling studies of DHM with the nucleotide-binding domain of human Pgp that identified key binding residues associated with Pgp inhibition. We found that DHM increased the potency of IVM in reducing EtOH consumption, resulting in significant effects at the 1.0 mg/kg dose. This combination supports our hypothesis that inhibiting Pgp improves the potency of IVM in reducing EtOH consumption. Collectively, we demonstrate the feasibility of this novel combinatorial approach in reducing EtOH consumption and illustrate the utility of DHM in a novel combinatorial approach.
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Affiliation(s)
- Joshua Silva
- Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA; (J.S.); (C.X.); (J.Z.); (J.L.)
| | - Eileen Carry
- Molecular Design and Synthesis Group, Rutgers University Biomedical Research Innovation Core, Piscataway, NJ 08854, USA; (E.C.); (J.Y.R.)
| | - Chen Xue
- Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA; (J.S.); (C.X.); (J.Z.); (J.L.)
| | - Jifeng Zhang
- Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA; (J.S.); (C.X.); (J.Z.); (J.L.)
| | - Jing Liang
- Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA; (J.S.); (C.X.); (J.Z.); (J.L.)
| | - Jacques Y. Roberge
- Molecular Design and Synthesis Group, Rutgers University Biomedical Research Innovation Core, Piscataway, NJ 08854, USA; (E.C.); (J.Y.R.)
| | - Daryl L. Davies
- Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA; (J.S.); (C.X.); (J.Z.); (J.L.)
- Correspondence: ; Tel.: +13-23-442-1427
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Lu Q, Gu W, Luo C, Wang L, Hua W, Sun Y, Tang L. Phytochemical characterization and hepatoprotective effect of active fragment from Adhatoda vasica Nees. against tert-butyl hydroperoxide induced oxidative impairment via activating AMPK/p62/Nrf2 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 266:113454. [PMID: 33065254 DOI: 10.1016/j.jep.2020.113454] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/29/2020] [Accepted: 10/06/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Adhatoda vasica Nees., which existed in a large; number of Tibetan medicine prescriptions for hepatopathy, used as an adjuvant to treat liver diseases. HYPOTHESIS/PURPOSE Oxidative stress is the key player in the development and progression of liver pathogenesis. In recent years, research is increasingly being focused on exploitation of the active components from medicinal plants to combat the liver oxidative injury. In our study, we aimed to screen the active principles from A. vasica and clarify whether they could relieve oxidative damage induced by tert-Butyl hydroperoxide (t-BHP) and its potential mechanism via activating AMPK/p62/Nrf2 pathway. MATERIALS AND METHODS Ultra performance liquid chromatography (UPLC) was adopted for analysis of chemical composition in the extracts. Furthermore, the antioxidant activity of the fractions was evaluated using DPPH, ABTS and reducing power assay. Along with this, the compounds in this fraction with highest antioxidant activity were analyzed using UPLC-MS. Based on this, the condition for extracting flavonoids of this subfraction was optimized via response surface method. CCK-8 assay was used to detect cell viability. Detection kits were used to measure the activity changes of AST, ALT, LDH and CAT as well as MDA and GSH levels induced by t-BHP. Detection of reactive oxygen species (ROS) production was used DCFH-DA probe. DAPI staining and flow cytometry was used to detect cell apoptosis. In terms of the mechanistic studies, the expression of proteins involved in AMPK/p62/Nrf2 pathway was measured using western blotting. RESULTS Eventually, 70% ethanol extract from leaf of A. vasica was chosen due to its highest active components compared with other extracts. Further, ethyl acetate fraction derived from 70% ethanol extract in A. vasica (AVEA) possess highest ability for scavenging DPPH and ABTS free radicals as well as strongest reducing power than other fractions. Chemical composition analysis showed that AVEA contained 17 compounds, including 1 quinazoline alkaloid, 12 flavonoid-C-glycosides and 4 flavonoid-O-glycosides. In addition, the conditions (ratio of solid-liquid 1:14, the concentration of ethanol 73%, and the temperature 65 °C) were selected to enrich the flavonoids in AVEA. Furthermore, AVEA could attenuate t-BHP induced hepatocyte damage via increasing the cell viability, restoring abnormal the activities of AST, ALT, LDH and CAT as well as the levels of MDA and GSH. ROS fluorescence intensity was reduced by AVEA. Meanwhile, it could inhibit the cell apoptosis of BRL 3 A cells, as evidenced by restoration of cell morphology and decreasing the number of apoptotic cells. Further mechanistic studies indicated AVEA could promote p-AMPK expression to further induce autophagy adaptor-p62 protein expression, which could autophagic degradation of Keap1, leading to Nrf2 release and translocation into nucleus to induce antioxidant genes (HO-1, NQO-1, GCLC and GCLM) expression. CONCLUSION In our study, AVEA was first to screen as the active fraction in A. vasica with alkaloids and abundant flavones. Moreover, the fraction potentiates its beneficial aspect by displaying the protective role on relieving t-BHP induced oxidative stress and activating AMPK/p62/Nrf2 pathway. AVEA helps maintain the redox homeostasis of hepatic cells and could be considered as an effective candidate against oxidative stress related liver disorders.
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Affiliation(s)
- Qiuxia Lu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Wanqin Gu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Chaomei Luo
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Li Wang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Wan Hua
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Yiran Sun
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Lin Tang
- National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China.
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Li G, Li H, Lyu Y, Zeng W, Zhou J. Enhanced Biosynthesis of Dihydromyricetin in Saccharomyces cerevisiae by Coexpression of Multiple Hydroxylases. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:14221-14229. [PMID: 33205970 DOI: 10.1021/acs.jafc.0c05261] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Dihydromyricetin (DHM) is a traditional plant-extracted flavonoid with some health benefits. This study aimed to metabolically engineer the strains for DHM bioproduction. Two strains of BK-11 and BQ-21 were integrated with flavonoid 3-hydroxylase (F3H) or both F3H and flavonoid 3'-hydroxylase (F3'H). The resulting strains have expressed the enzymes of GmCPR and SlF3'5'H, and then, the promoters of INO1p and TDH1p were used to enhance further the DHM production from naringenin in Saccharomyces cerevisiae. Through multiple-copy integration, 709.6 mg/L DHM was obtained by adding 2.5 g/L naringenin in a 5 L bioreactor, implying that the synergistic effect between F3'H and flavonoid 3'5'-hydroxylase is likely to promote the DHM production. An yield of 246.4 mg/L DHM was obtained from glucose by deleting genes for branch pathways and integrating PhCHS, MsCHI, Pc4CL, and FjTAL. To our knowledge, this is the highest production reported for the de novo biosynthesis of DHM.
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Affiliation(s)
- Guangjian Li
- Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- National Engineering Laboratory for Cereal Fermentation Technology (NELCF), Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Hongbiao Li
- Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- National Engineering Laboratory for Cereal Fermentation Technology (NELCF), Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Yunbin Lyu
- Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- National Engineering Laboratory for Cereal Fermentation Technology (NELCF), Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Weizhu Zeng
- Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
| | - Jingwen Zhou
- Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- National Engineering Laboratory for Cereal Fermentation Technology (NELCF), Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
- Jiangsu Provisional Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
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Cheng QC, Fan J, Deng XW, Liu HC, Ding HR, Fang X, Wang JW, Chen CH, Zhang WG. Dihydromyricetin ameliorates chronic liver injury by reducing pyroptosis. World J Gastroenterol 2020; 26:6346-6360. [PMID: 33244197 PMCID: PMC7656208 DOI: 10.3748/wjg.v26.i41.6346] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/30/2020] [Accepted: 08/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic liver injury (CLI) is now a worldwide disease. However, there is no effective treatment. Pyroptosis plays an essential role in CLI. Dihydromyricetin (DHM) resists oxidation and protects the liver. We hypothesize that the beneficial effect of DHM on CLI is related to its effect on the expression of pyroptosis-related molecules. Therefore, we studied the influence of DHM on CLI and pyroptosis.
AIM To study the role of pyroptosis in the pathogenesis of CLI and the therapeutic mechanism of DHM.
METHODS Thirty-two mice were randomly divided into four groups: The control group was injected with olive oil, the carbon tetrachloride (CCl4) group was injected with CCl4, the vehicle group was injected with hydroxypropyl-β-cyclodextrin while injecting CCl4 and the DHM group was injected with DHM while injecting CCl4. After four weeks of treatment, liver tissues from the mice were stained with hematoxylin and eosin, and oil red O. Blood was collected from the angular vein for serological analysis. The severity of CLI was estimated. Some liver tissue was sampled for immunohistochemistry, Western blotting and quantitative reverse transcription PCR to observe the changes in pyroptosis-related molecules.
RESULTS Serum total cholesterol, low density lipoprotein, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the CCl4 group were higher than those in the control group, and serum total cholesterol, low density lipoprotein, AST and ALT in the DHM group were lower than those in the vehicle group. Hematoxylin and eosin and oil red O staining showed that there were more lipid droplets in the CCl4 group than in the control group, and there were fewer lipid droplets in the DHM group than in the vehicle group. Western blotting showed that the expression of the pyroptosis-related molecules caspase-1, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and gasdermin D (GSDMD)-N in the CCl4 group was higher than that in the control group, while expression of these proteins in the DHM group was lower than that in the vehicle group. Quantitative reverse transcription PCR results showed that the expression of the pyroptosis-related genes caspase-1, NLRP3, GSDMD and interleukin-1β (IL-1β) in the CCl4 group was higher than that in the control group, while there was no significant change in NLRP3 and caspase-1 expression in the DHM group compared with that in the vehicle group, and the expression of GSDMD and IL-1β was decreased.
CONCLUSION DHM improves CCl4-induced CLI and regulates the pyroptosis pathway in hepatocytes. DHM may be a potential therapeutic agent for CLI.
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Affiliation(s)
- Quan-Cheng Cheng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jing Fan
- Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 202155, China
| | - Xin-Wei Deng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Huai-Cun Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Hui-Ru Ding
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xuan Fang
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jian-Wei Wang
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Chun-Hua Chen
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Wei-Guang Zhang
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
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Liu M, Guo H, Li Z, Zhang C, Zhang X, Cui Q, Tian J. Molecular Level Insight Into the Benefit of Myricetin and Dihydromyricetin Uptake in Patients With Alzheimer's Diseases. Front Aging Neurosci 2020; 12:601603. [PMID: 33192493 PMCID: PMC7645199 DOI: 10.3389/fnagi.2020.601603] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/06/2020] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease with a high incidence rate and complicated pathogenesis. Currently, all anti-AD drugs treat the symptoms of the disease, and with currently no cure for AD. Flavonoid containing natural products, Myricetin (MYR) and Dihydromyricetin (DMY), are abundant in fruits and vegetables, and have been approved as food supplements in some countries. Interestingly, MYR and DMY have been reported to have anti-AD effects. However, the underlying anti-AD mechanism of action of MYR and DMY is complex with many facets being identified. In this review, we explore the benefit of MYR and DMY in AD patients from a molecular level. Their mechanism of action are discussed from various aspects including amyloid β-protein (Aβ) imbalance, neuroinflammation, dyshomeostasis of metal ions, autophagy disorder, and oxidative stress.
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Affiliation(s)
- Miaomiao Liu
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hong Guo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhongyuan Li
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chenghua Zhang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoping Zhang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, China
| | - Qinghua Cui
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, China
| | - Jingzhen Tian
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
- Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, China
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Hu H, Luo F, Wang M, Fu Z, Shu X. New Method for Extracting and Purifying Dihydromyricetin from Ampelopsis grossedentata. ACS OMEGA 2020; 5:13955-13962. [PMID: 32566862 PMCID: PMC7301542 DOI: 10.1021/acsomega.0c01222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/19/2020] [Indexed: 05/15/2023]
Abstract
Dihydromyricetin (DMY) is a kind of flavone. It has a variety of physiological effects, and its content in Ampelopsis grossedentata is as high as 35%. There are two shortcomings in the traditional batch extraction process commonly used in a laboratory: long extraction time and low extraction rate. In this study, a new chelating extraction method was proposed, that is, Zn2+ was introduced into the extraction and purification process to chelate with DMY, and the yield and purity were taken as evaluation indices for a comparative study with the traditional batch extraction method. In addition, 1H NMR, single-crystal X-ray diffraction, IR, and UV were used to analyze the product structure; thermogravimetry and differential thermal analysis was utilized to examine the thermal stability of DMY. The results were shown as follows. Compared with the batch extraction method, the chelation extraction method could effectively avoid the oxidation of DMY by air during the extraction and purification process, and the yield of the DMY also increased. Furthermore, this method was time-saving. Through investigating the extraction process and characterizing the structure and thermal stability of DMY, the chelating extraction method could be considered to provide a reference for commercial applications of DMY.
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Affiliation(s)
- Hongchao Hu
- School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PRC
| | - Fan Luo
- School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PRC
| | - Mingjie Wang
- School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PRC
| | - Zhihuan Fu
- School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PRC
| | - Xugang Shu
- School of Chemistry and Chemical Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PRC
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Zeng Y, Hua YQ, Wang W, Zhang H, Xu XL. Modulation of SIRT1-mediated signaling cascades in the liver contributes to the amelioration of nonalcoholic steatohepatitis in high fat fed middle-aged LDL receptor knockout mice by dihydromyricetin. Biochem Pharmacol 2020; 175:113927. [DOI: 10.1016/j.bcp.2020.113927] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 03/19/2020] [Indexed: 02/08/2023]
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