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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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Yin H, Yan Q, Li Y, Tang H. Dihydromyricetin Nanoparticles Alleviate Lipopolysaccharide-Induced Acute Kidney Injury by Decreasing Inflammation and Cell Apoptosis via the TLR4/NF-κB Pathway. J Funct Biomater 2024; 15:249. [PMID: 39330225 PMCID: PMC11433252 DOI: 10.3390/jfb15090249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
Acute kidney injury (AKI) is the most severe and fatal complication of sepsis resulting from infectious trauma. Currently, effective treatment options are still lacking. Dihydromyricetin is the main component extracted from Vine tea (Ampelopsis megalophylla Diels et Gilg). In our previous research, chitosan-tripolyphosphate-encapsulated nanoparticles of dihydromyricetin (CS-DMY-NPs) have been proven to have potential protective effects against cisplatin-induced AKI. Here, we investigated the protective effects and mechanisms of DMY and its nano-formulations against LPS-induced AKI by assessing pathological and inflammatory changes in mice. In mice with LPS-AKI treated with 300 mg/kg CS-DMY-NPs, the levels of creatinine (Cr), blood urea nitrogen (BUN), and KIM-1 were significantly reduced by 56%, 49%, and 88%, respectively. CS-DMY-NPs can upregulate the levels of GSH, SOD, and CAT by 47%, 7%, and 14%, respectively, to inhibit LPS-induced oxidative stress. Moreover, CS-DMY-NPs decreased the levels of IL-6, IL-1β, and MCP-1 by 31%, 49%, and 35%, respectively, to alleviate the inflammatory response. TUNEL and immunohistochemistry showed that CS-DMY-NPs reduced the number of apoptotic cells, increased the Bcl-2/Bax ratio by 30%, and attenuated renal cell apoptosis. Western blot analysis of renal tissue indicated that CS-DMY-NPs inhibited TLR4 expression and downregulated the phosphorylation of NF-κB p65 and IκBα. In summary, DMY prevented LPS-induced AKI by increasing antioxidant capacity, reducing inflammatory responses, and blocking apoptosis, and DMY nanoparticles were shown to have a better protective effect for future applications.
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Affiliation(s)
- Hongmei Yin
- School of Animal Science, Xichang University, Xichang 615012, China
- School of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Qiaohua Yan
- School of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yinglun Li
- School of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Huaqiao Tang
- School of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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Medeiros M, Guenka S, Bastos D, Oliveira KL, Brassesco MS. Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity. Pharmaceuticals (Basel) 2024; 17:734. [PMID: 38931401 PMCID: PMC11206879 DOI: 10.3390/ph17060734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the "omics" era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/β-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.
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Affiliation(s)
- Mariana Medeiros
- Cell Biology Department, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900-Vila Monte Alegre, Ribeirão Preto 14040-900, São Paulo, Brazil;
| | - Sophia Guenka
- Biology Department, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900-Vila Monte Alegre, Ribeirão Preto 14040-900, São Paulo, Brazil; (S.G.); (D.B.)
| | - David Bastos
- Biology Department, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900-Vila Monte Alegre, Ribeirão Preto 14040-900, São Paulo, Brazil; (S.G.); (D.B.)
| | - Karla Laissa Oliveira
- Regional Blood Center, University of São Paulo, Avenida Bandeirantes, 3900-Vila Monte Alegre, Ribeirão Preto 14051-140, São Paulo, Brazil;
| | - María Sol Brassesco
- Biology Department, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900-Vila Monte Alegre, Ribeirão Preto 14040-900, São Paulo, Brazil; (S.G.); (D.B.)
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Chen P, Huang M, Cui H, Feng L, Hayat K, Zhang X, Ho CT. Mechanism of Dihydromyricetin-Induced Reduction of Furfural Derived from the Amadori Compound: Formation of Adducts between Dihydromyricetin and Furfural or Its Precursors. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:6554-6564. [PMID: 38498924 DOI: 10.1021/acs.jafc.4c01388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
Dihydromyricetin (DMY) was employed to reduce the yield of furfural derived from the Amadori rearrangement product of l-threonine and d-xylose (Thr-ARP) by trapping Thr-ARP, 3-deoxyxyosone (3-DX), and furfural to form adducts. The effect of different concentrations of DMY at different pH values and temperatures on the reduction of furfural production was studied, and the results showed that DMY could significantly reduce furfural production at higher pH (pH 5-7) and lower temperature (110 °C). Through the surface electrostatic potential analysis by Gaussian, a significant enhancement of the C6 nucleophilic ability at higher pH (pH ≥ 5) was observed on DMY with hydrogen-dissociated phenol hydroxyl. The nucleophilic ability of DMY led to its trapping of Thr-ARP, 3-DX, and furfural with the generation of the adducts DMY-Thr-ARP, DMY-3-DX, and DMY-furfural. The formation of the DMY-Thr-ARP adduct slowed the degradation of Thr-ARP, caused the decrease of the 3-DX yield, and thereby inhibited the conversion of 3-DX to furfural. Therefore, DMY-Thr-ARP was purified, and the structure was identified by nuclear magnetic resonance (NMR). The results confirmed that C6 or C8 of DMY and carbonyl carbon in Thr-ARP underwent a nucleophilic addition reaction to form the DMY-Thr-ARP adduct. In combination with the analysis results of Gaussian, most of the DMY-Thr-ARP adducts were calculated to be C6-DMY-Thr-ARP. Furthermore, the formation of DMY-furfural caused furfural consumption. The formation of the adducts also shunted the pathway of both Thr-ARP and 3-DX conversion to furfural, resulting in a decrease in the level of furfural production.
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Affiliation(s)
- Pusen Chen
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Meigui Huang
- College of Food Science and Technology, Southwest Minzu University, Chengdu, Sichuan 610041, People's Republic of China
| | - Heping Cui
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Linhui Feng
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Khizar Hayat
- Department of Kinesiology, Nutrition, and Health, Miami University, Oxford, Ohio 45056, United States
| | - Xiaoming Zhang
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Chi-Tang Ho
- Department of Food Science, Rutgers, The State University of New Jersey, 65 Dudley Road, New Brunswick, New Jersey 08901, United States
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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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Wu D, Xia M, Yan A, Jiang H, Fan J, Zhou S, Wei X, Liu S, Chen B. Carvacrol attenuated lipopolysaccharide-induced intestinal injury by down-regulating TLRs gene expression and regulating the gut microbiota in rabbit. Sci Rep 2023; 13:11447. [PMID: 37454126 PMCID: PMC10349838 DOI: 10.1038/s41598-023-38577-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023] Open
Abstract
Carvacrol (CAR) is a plant extract that has been reported to enhance antioxidant activity in animals. However, the effect of CAR on the intestinal health of rabbits is poorly understood. Here, we investigated whether CAR exerts protective effects on the intestinal health of rabbits following lipopolysaccharide (LPS) challenge and whether these effects were mediated via the reduction of intestinal inflammation and the regulation of the intestinal flora. Intestinal damage was assessed in LPS-challenged rabbits treated or not with CAR. The serum levels of inflammatory factors were assessed by enzyme-linked immunosorbent assay. Histopathological changes in the ileum and cecum were examined using hematoxylin and eosin staining. The relative gene expression levels of inflammatory factors and tight junction proteins in the rabbit cecum were determined by qRT-PCR. High-throughput sequencing analysis of the microbial 16S rRNA gene was performed using the Illumina NovaSeq Platform. The results showed that CAR can prevent intestinal inflammation and damage as well as mitigate gut dysbiosis in rabbits following LPS challenge. Our study provides a theoretical reference for the application of dietary CAR in rabbit production.
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Affiliation(s)
- Diange Wu
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - Miao Xia
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - An Yan
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - Haotian Jiang
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - Jiaqi Fan
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - Siyuan Zhou
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - Xu Wei
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China
| | - Shudong Liu
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China.
| | - Baojiang Chen
- College of Animal Science and Technology, Hebei Agricultural University, No 2596, Lekai South Street Nanshi District, Baoding, 071000, China.
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Yang Z, Li T, Wang C, Meng M, Tan S, Chen L. Dihydromyricetin Inhibits M1 Macrophage Polarization in Atherosclerosis by Modulating miR-9-Mediated SIRT1/NF- κB Signaling Pathway. Mediators Inflamm 2023; 2023:2547588. [PMID: 37234960 PMCID: PMC10208763 DOI: 10.1155/2023/2547588] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 04/05/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Dihydromyricetin (DMY), a natural flavonoid compound extracted from the stems and leaves of Ampelopsis grossedentata, has been found as a potential therapeutic chemical for treating atherosclerosis. This study explores the underlying mechanism of DMY repressing M1 macrophage polarization in atherosclerosis. We showed that DMY treatment markedly decreased M1 macrophage markers (e.g., Tnf-α and IL-1β) and p65-positive macrophage numbers in the vessel wall of Apoe-deficient (Apoe-/-) mice. Overexpression of miR-9 or knockdown of SIRT1 in macrophages reversed the effect of DMY on M1 macrophage polarization. The data we presented in the study indicate that the miR-9-mediated SIRT1/NF-κB pathway plays a pivotal role in M1 macrophage polarization and is one of the molecular mechanisms underlying the anti-atherosclerosis effects of DMY. We provide new solid evidence that DMY may be explored as a potential therapeutic adjuvant for treating atherosclerosis.
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Affiliation(s)
- Zhousheng Yang
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
| | - Tianyu Li
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China 410011
- Institute of Clinical Pharmacy, Central South University, Changsha, China 410011
| | - Chunyan Wang
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China 410011
- Institute of Clinical Pharmacy, Central South University, Changsha, China 410011
| | - Mingyu Meng
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
| | - Shenglan Tan
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China 410011
- Institute of Clinical Pharmacy, Central South University, Changsha, China 410011
| | - Lei Chen
- Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning 530021, China
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China 410011
- Institute of Clinical Pharmacy, Central South University, Changsha, China 410011
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8
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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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9
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Dihydromyricetin Inhibits Pseudorabies Virus Multiplication In Vitro by Regulating NF-κB Signaling Pathway and Apoptosis. Vet Sci 2023; 10:vetsci10020111. [PMID: 36851415 PMCID: PMC9961748 DOI: 10.3390/vetsci10020111] [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: 11/30/2022] [Revised: 01/12/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Pseudorabies virus (PRV) infections have caused huge economic losses to the breeding industry worldwide, especially pig husbandry. PRV could threaten human health as an easily ignored zoonotic pathogen. The emergence of new mutants significantly reduced the protective effect of vaccination, indicating an urgent need to develop specific therapeutic drugs for PRV infection. In this study, we found that dihydromyricetin (DMY) could dose-dependently restrain PRV infection in vitro with an IC50 of 161.34 μM; the inhibition rate of DMY at a concentration of 500 μM was 92.16 %. Moreover, the mode of action showed that DMY directly inactivated PRV virion and inhibited viral adsorption and cellular replication. DMY treatment could improve PRV-induced abnormal changes of the NF-κB signaling pathway and excessive inflammatory response through regulation of the contents of IκBα and p-P65/P65 and the transcriptional levels of cytokines (TNF-α, IL-1β and IL-6). Furthermore, DMY promoted the apoptosis of PRV-infected cells through the regulation of the expressions of Bax and Bcl-xl and the transcriptional levels of Caspase-3, Bax, Bcl-2 and Bcl-xl, thereby limiting the production of progeny virus. These findings indicated that DMY could be a candidate drug for the treatment of PRV infection.
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Wei C, Chen X, Chen D, He J, Zheng P, Chen H, Yan H, Yu B, Luo Y, Huang Z. Effects of dietary dihydromyricetin supplementation on intestinal barrier and humoral immunity in growing-finishing pigs. Anim Biotechnol 2022; 33:1398-1406. [PMID: 35838495 DOI: 10.1080/10495398.2022.2099881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
In this study, we investigated the effect of dietary dihydromyricetin (DHM) supplementation on intestinal barrier and humoral immunity in growing-finishing pigs. The data showed that dietary DHM supplementation improved jejunal barrier function by upregulating the protein expressions of Occludin and Claudin-1 and the mRNA levels of MUC1 and MUC2. Dietary DHM supplementation increased the amylase, lipase, sucrase and maltase activities and the mRNA expression of nutrient transporter (SGLT1, GLUT2, PepT1) in the jejunum mucosa. Dietary DHM supplementation significantly reduced the E. coli population in the cecum and colon and increased the Lactobacillus population in the cecum. In addition, dietary DHM supplementation increased the contents of butyric acid and valeric acid in cecum and colon. In serum, dietary DHM supplementation reduced interleukin-1β (IL-1β) content and increased interleukin-10 (IL-10), Immunoglobulin M (IgM) and Immunoglobulin A (IgA) contents (p < 0.05). In addition, compared with the control group, dietary DHM supplementation improved secretory immunoglobulin A (sIgA) and interleukin-10 (IL-10) contents and down-regulated TNF-α protein expression in jejunum mucosa (p < 0.05). Together, this study demonstrated that dietary DHM supplementation improved intestinal barrier function, digestion and absorption capacity and immune function in growing-finishing pigs.
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Affiliation(s)
- Chuan Wei
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Hong Chen
- College of Food Science, Sichuan Agricultural University, Yaan, P. R. China
| | - Hui Yan
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, P. R. China
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Zhou L, Li H, Hou G, Wang J, Zhou H, Wang D. Effects of Vine Tea Extract on Meat Quality, Gut Microbiota and Metabolome of Wenchang Broiler. Animals (Basel) 2022; 12:ani12131661. [PMID: 35804560 PMCID: PMC9265100 DOI: 10.3390/ani12131661] [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] [Received: 05/16/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 11/16/2022] Open
Abstract
This study investigates the effects of vine tea (Ampelopsis grossedentata) extract (AGE) on meat quality, gut microbiota and cecal content metabolites of Wenchang broilers. A total of 240 female Wenchang broilers aged 70 days were randomly allocated into four groups with five replicates of twelve broilers each. Broilers were fed a corn-soybean basal diet supplemented with AGE at 0 (T1), 0.2% (T2), 0.4% (T3) and 0.6% (T4) until 124 days of age. The whole feeding trial lasted 54 days. Results suggest that the content of total triglycerides and low-density lipoprotein cholesterol in serum of broilers are linearly reduced with dietary AGE supplementation (p < 0.05). The T3 and T4 groups had higher (p < 0.05) a* value in thigh and breast muscles than the T1 group. Additionally, the dietary supplementation of AGE decreased the shear force and drip loss of both thigh and breast muscles linearly (p < 0.05). Compared with the T1 group, AGE supplementation increased the levels of inosine monophosphate (IMP) significantly (p < 0.05) in both the thigh and breast muscles. Furthermore, an increase (p < 0.05) in the total unsaturated fatty acid (USFA), polyunsaturated fatty acids (PUFA) and the ratio of unsaturated fatty acids to saturated fatty acid (USFA: SFA) in both the thigh and breast muscles in the T3 group was observed. Higher abundance of Bacteroidota (p < 0.05) and lower abundance of Firmicutes (p < 0.05) were observed in the T3 group. The abundance of Faecalibacterium was significantly decreased (p < 0.05) in the T3 group compared with the T1 group. Cholesterol sulfate and p-cresol sulfate were identified as differential metabolites between the T1 and T3 groups. It suggested that 0.4% of AGE supplementation significantly downregulated the levels of p-cresol sulfate and cholesterol sulfate (p < 0.05) and the hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity compared with the control. Our present study demonstrates that dietary supplementation with AGE can improve the quality and flavor by increasing the IMP and PUFA content in the muscle of Wenchang broilers. Furthermore, dietary AGE supplementation with 0.4% can regulate the cholesterol metabolism of Wenchang broilers.
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Affiliation(s)
- Luli Zhou
- Tropical Crops Genetic Resources Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (L.Z.); (G.H.)
| | - Hui Li
- College of Animal Science and Technology, Hainan University, Haikou 570228, China; (H.L.); (J.W.)
| | - Guanyu Hou
- Tropical Crops Genetic Resources Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (L.Z.); (G.H.)
| | - Jian Wang
- College of Animal Science and Technology, Hainan University, Haikou 570228, China; (H.L.); (J.W.)
| | - Hanlin Zhou
- Zhanjiang Experimental Station, Chinese Academy of Tropical Agricultural Sciences, Zhanjiang 524013, China
- Correspondence: (H.Z.); (D.W.)
| | - Dingfa Wang
- Tropical Crops Genetic Resources Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (L.Z.); (G.H.)
- Correspondence: (H.Z.); (D.W.)
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Wrońska N, Szlaur M, Zawadzka K, Lisowska K. The Synergistic Effect of Triterpenoids and Flavonoids-New Approaches for Treating Bacterial Infections? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030847. [PMID: 35164112 PMCID: PMC8838219 DOI: 10.3390/molecules27030847] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 11/16/2022]
Abstract
Currently, the pharmaceutical industry is well-developed, and a large number of chemotherapeutics are being produced. These include antibacterial substances, which can be used in treating humans and animals suffering from bacterial infections, and as animal growth promoters in the agricultural industry. As a result of the excessive use of antibiotics and emerging resistance amongst bacteria, new antimicrobial drugs are needed. Due to the increasing trend of using natural, ecological, and safe products, there is a special need for novel phytocompounds. The compounds analysed in the present study include two triterpenoids ursolic acid (UA) and oleanolic acid (OA) and the flavonoid dihydromyricetin (DHM). All the compounds displayed antimicrobial activity against Gram-positive (Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, and Listeria monocytogenes ATCC 19115) and Gram-negative bacteria (Escherichia coli ATCC 25922, Proteus hauseri ATCC 15442, and Campylobacter jejuni ATCC 33560) without adverse effects on eukaryotic cells. Both the triterpenoids showed the best antibacterial potential against the Gram-positive strains. They showed synergistic activity against all the tested microorganisms, and a bactericidal effect with the combination OA with UA against both Staphylococcus strains. In addition, the synergistic action of DHM, UA, and OA was reported for the first time in this study. Our results also showed that combination with triterpenoids enhanced the antimicrobial potential of DHM.
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Sun Y, Liu S, Yang S, Chen C, Yang Y, Lin M, Liu C, Wang W, Zhou X, Ai Q, Wang W, Chen N. Mechanism of Dihydromyricetin on Inflammatory Diseases. Front Pharmacol 2022; 12:794563. [PMID: 35115939 PMCID: PMC8804380 DOI: 10.3389/fphar.2021.794563] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
Inflammation plays a crucial role in a variety of diseases, including diabetes, arthritis, asthma, Alzheimer’s disease (AD), acute cerebral stroke, cancer, hypertension, and myocardial ischemia. Therefore, we need to solve the problem urgently for the study of inflammation-related diseases. Dihydromyricetin (DHM) is a flavonoid mainly derived from Nekemias grossedentata (Hand.-Mazz.) J.Wen and Z.L.Nie (N.grossedentata). DHM possesses many pharmacological effects, including anti-inflammatory (NLRP-3, NF-κB, cytokines, and neuroinflammation), antioxidant, improving mitochondrial dysfunction, and regulating autophagy and so on. In this review, we consulted the studies in the recent 20 years and summarized the mechanism of DHM in inflammation-related diseases. In addition, we also introduced the source, chemical structure, chemical properties, and toxicity of DHM in this review. We aim to deepen our understanding of DHM on inflammation-related diseases, clarify the relevant molecular mechanisms, and find out the problems and solutions that need to be solved urgently. Providing new ideas for DHM drug research and development, as well as broaden the horizons of clinical treatment of inflammation-related diseases in this review. Moreover, the failure of clinical transformation of DHM poses a great challenge for DHM as an inflammation related disease.
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Affiliation(s)
- Yang Sun
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces and College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Shasha Liu
- Pharmacy Department, Xiangtan Central Hospital, Xiangtan, China
| | - Songwei Yang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces and College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Chen Chen
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yantao Yang
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces and College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Meiyu Lin
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces and College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Chao Liu
- Zhangjiajie Meicha Technology Research Center, Hunan Qiankun Biotechnology Co., Ltd, Zhangjiajie, China
| | - Wenmao Wang
- Zhangjiajie Meicha Technology Research Center, Hunan Qiankun Biotechnology Co., Ltd, Zhangjiajie, China
| | - Xudong Zhou
- TCM and Ethnomedicine Innovation and Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Qidi Ai
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces and College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Qidi Ai, ; Wei Wang, ; Naihong Chen,
| | - Wei Wang
- TCM and Ethnomedicine Innovation and Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Qidi Ai, ; Wei Wang, ; Naihong Chen,
| | - Naihong Chen
- Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces and College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Qidi Ai, ; Wei Wang, ; Naihong Chen,
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14
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Sklenarova R, Svrckova M, Hodek P, Ulrichova J, Frankova J. Effect of the natural flavonoids myricetin and dihydromyricetin on the wound healing process in vitro. J Appl Biomed 2021; 19:149-158. [PMID: 34907758 DOI: 10.32725/jab.2021.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 07/20/2021] [Indexed: 11/05/2022] Open
Abstract
Myricetin (MYR) and dihydromyricetin (DHM) are classified as natural flavonoids. Both substances are known for their anti-inflammatory and antioxidant properties. In this study, an in vitro model of inflammation was demonstrated on monolayers of scratched fibroblasts or keratinocytes exposed to LPS from Pseudomonas aeruginosa for six hours. MYR and DHM were subsequently applied to the cells for 24 hours at sub toxic concentrations (5-15 µM). Inflammatory parameters were analysed in collected cell medium and lysate after the incubation period using the Enzyme-Linked ImmuneSorbent Assay (ELISA) and Western blot. Both flavonoids inhibit the production of pro-inflammatory cytokines (IL-6, IL-8) in LPS-stimulated skin cells as well as the decreased level of MMP-1 in fibroblasts. However, the application of MYR and DHM dose dependently increased the level of MMP-1 in keratinocytes. In our experiments, we focused on the anti-glycation activity of MYR and DHM, where the higher concentration of MYR seems to be more effective.
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Affiliation(s)
- Renata Sklenarova
- Palacky University Olomouc, Faculty of Medicine and Dentistry, Department of Medical Chemistry and Biochemistry, Olomouc, Czech Republic
| | - Marika Svrckova
- Palacky University Olomouc, Faculty of Medicine and Dentistry, Department of Medical Chemistry and Biochemistry, Olomouc, Czech Republic
| | - Petr Hodek
- Charles University, Faculty of Science, Department of Biochemistry, Prague 2, Czech Republic
| | - Jitka Ulrichova
- Palacky University Olomouc, Faculty of Medicine and Dentistry, Department of Medical Chemistry and Biochemistry, Olomouc, Czech Republic
| | - Jana Frankova
- Palacky University Olomouc, Faculty of Medicine and Dentistry, Department of Medical Chemistry and Biochemistry, Olomouc, Czech Republic
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15
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Feng L, Que D, Li Z, Zhong X, Yan J, Wei J, Zhang X, Yang P, Ou C, Chen M. Dihydromyricetin ameliorates vascular calcification in chronic kidney disease by targeting AKT signaling. Clin Sci (Lond) 2021; 135:2483-2502. [PMID: 34643227 DOI: 10.1042/cs20210259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 12/29/2022]
Abstract
Vascular calcification is highly prevalent in chronic kidney disease (CKD), and is characterized by transdifferentiation from contractile vascular smooth muscle cells (VSMCs) into an osteogenic phenotype. However, no effective and therapeutic option to prevent vascular calcification is yet available. Dihydromyricetin (DMY), a bioactive flavonoid isolated from Ampelopsis grossedentata, has been found to inhibit VSMCs proliferation and the injury-induced neointimal formation. However, whether DMY has an effect on osteogenic differentiation of VSMCs and vascular calcification is still unclear. In the present study, we sought to investigate the effect of DMY on vascular calcification in CKD and the underlying mechanism. DMY treatment significantly attenuated calcium/phosphate-induced calcification of rat and human VSMCs in a dose-dependent manner, as shown by Alizarin Red S staining and calcium content assay, associated with down-regulation of osteogenic markers including type I collagen (COL I), Runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2) and osteocalcin (OCN). These results were further confirmed in aortic rings ex vivo. Moreover, DMY ameliorated vascular calcification in rats with CKD. Additionally, we found that AKT signaling was activated during vascular calcification, whereas significantly inhibited by DMY administration. DMY treatment significantly reversed AKT activator-induced vascular calcification. Furthermore, inhibition of AKT signaling efficiently attenuated calcification, which was similar to that after treatment with DMY alone, and DMY had a better inhibitory effect on calcification as compared with AKT inhibitor. The present study demonstrated that DMY has a potent inhibitory role in vascular calcification partially by inhibiting AKT activation, suggesting that DMY may act as a promising therapeutic candidate for patients suffering from vascular calcification.
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MESH Headings
- Animals
- Aorta/drug effects
- Aorta/enzymology
- Aorta/pathology
- Aortic Diseases/enzymology
- Aortic Diseases/etiology
- Aortic Diseases/pathology
- Aortic Diseases/prevention & control
- Cells, Cultured
- Disease Models, Animal
- Flavonols/pharmacology
- Humans
- Male
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/enzymology
- Myocytes, Smooth Muscle/pathology
- Osteogenesis/drug effects
- Phosphorylation
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Rats, Sprague-Dawley
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/enzymology
- Renal Insufficiency, Chronic/pathology
- Signal Transduction
- Vascular Calcification/enzymology
- Vascular Calcification/etiology
- Vascular Calcification/pathology
- Vascular Calcification/prevention & control
- Rats
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Affiliation(s)
- Liyun Feng
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Dongdong Que
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Zehua Li
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Xinglong Zhong
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Jing Yan
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Jintao Wei
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Xiuli Zhang
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Pingzhen Yang
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Caiwen Ou
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Minsheng Chen
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, P.R. China
- Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, P.R. China
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IgE-Induced Mast Cell Activation Is Suppressed by Dihydromyricetin through the Inhibition of NF-κB Signaling Pathway. Molecules 2021; 26:molecules26133877. [PMID: 34201934 PMCID: PMC8270306 DOI: 10.3390/molecules26133877] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 12/03/2022] Open
Abstract
Mast cells play a crucial role in the pathogenesis of type 1 allergic reactions by binding to IgE and allergen complexes and initiating the degranulation process, releasing pro-inflammatory mediators. Recently, research has focused on finding a stable and effective anti-allergy compound to prevent or treat anaphylaxis. Dihydromyricetin (DHM) is a flavonoid compound with several pharmacological properties, including free radical scavenging, antithrombotic, anticancer, and anti-inflammatory activities. In this study, we investigated the anti-allergic inflammatory effects and the underlying molecular mechanism of DHM in the DNP-IgE-sensitized human mast cell line, KU812. The cytokine levels and mast cell degranulation assays were determined by enzyme-linked immunosorbent assay (ELISA). The possible mechanism of the DHM-mediated anti-allergic signaling pathway was analyzed by western blotting. It was found that treatment with DHM suppressed the levels of inflammatory cytokines TNF-α and IL-6 in DNP-IgE-sensitized KU812 cells. The anti-allergic inflammatory properties of DHM were mediated by inhibition of NF-κB activation. In addition, DHM suppressed the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and mast cell-derived tryptase production. Our study shows that DHM could mitigate mast cell activation in allergic diseases.
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Liu X, Xing Y, Li M, Zhang Z, Wang J, Ri M, Jin C, Xu G, Piao L, Jin H, Zuo H, Ma J, Jin X. Licochalcone A inhibits proliferation and promotes apoptosis of colon cancer cell by targeting programmed cell death-ligand 1 via the NF-κB and Ras/Raf/MEK pathways. JOURNAL OF ETHNOPHARMACOLOGY 2021; 273:113989. [PMID: 33677006 DOI: 10.1016/j.jep.2021.113989] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/10/2021] [Accepted: 03/01/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Glycyrrhiza glabra L., a traditional medicinal, has a history of thousands of years. It is widely used in clinic and has been listed in Chinese Pharmacopoeia. Licochalcone A is a phenolic chalcone compound and a characteristic chalcone of Glycyrrhiza glabra L. It has many pharmacological activities, such as anti-cancer, anti-inflammatory, anti-viral and anti-angiogenic activities. AIM OF THE STUDY In this study, we explored the anti-tumor activity and potential mechanism of licochalcone A in vitro and in vivo. MATERIALS AND METHODS In vitro, the mechanism of licochalcone A at inhibiting PD-L1 expression was investigated by molecular docking, western blotting, RT-PCR, flow cytometry, immunofluorescence and immunoprecipitation assays. The co-culture model of T cells and tumor cells was used to detect the activity of cytotoxic T lymphocytes. Colony formation, EdU labelling and apoptosis assays were used to detect changes in cellular proliferation and apoptosis. In vivo, anti-tumor activity of licochalcone A was assessed in a xenograft model of HCT116 cells. RESULTS In the present study, we found that licochalcone A suppressed the expression of programmed cell death ligand-1 (PD-L1), which plays a key role in regulating the immune response. In addition, licochalcone A inhibited the expressions of p65 and Ras. Immunoprecipitation experiment showed that licochalcone A suppressed the expression of PD-L1 by blocking the interaction between p65 and Ras. In the co-culture model of T cells and tumor cells, licochalcone A pretreatment enhanced the activity of cytotoxic T lymphocytes and restored the ability to kill tumor cells. In addition, we showed that licochalcone A inhibited cell proliferation and promoted cell apoptosis by targeting PD-L1. In vivo xenograft assay confirmed that licochalcone A inhibited the growth of tumor xenografts. CONCLUSION In general, these results reveal the previously unknown properties of licochalcone A and provide new insights into the anticancer mechanism of this compound.
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Affiliation(s)
- Xueshuang Liu
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Yue Xing
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Mingyue Li
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Zhihong Zhang
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Jingying Wang
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - MyongHak Ri
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Chenghua Jin
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Guanghua Xu
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Lianxun Piao
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Honglan Jin
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Hongxiang Zuo
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
| | - Juan Ma
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
| | - Xuejun Jin
- Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
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Xie W, Du Y, Yuan S, Pang J. Dihydromyricetin incorporated active films based on konjac glucomannan and gellan gum. Int J Biol Macromol 2021; 180:385-391. [PMID: 33652043 DOI: 10.1016/j.ijbiomac.2021.02.185] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 11/27/2022]
Abstract
Active composite films were developed by incorporating different concentration of dihydromyricetin (DMY) into konjac glucomannan (KGM)/gellan gum (GG) matrix. Physicochemical, mechanical, released behaviour, antioxidant and antimicrobial properties of composite films were investigated. The results from the Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) indicated that DMY which well-dispersed in the KGM/GG matrix interacted with matrix through hydrogen bonds. The obtained films presented predominant thermostability, good water resistance property, excellent ultraviolet light barrier ability and sustained controlled release behaviour. In particular, the incorporation of DMY remarkably enhanced the antioxidant and antimicrobial activities of the films. Overall, the fabricated KGM/GG-DMY composite films have a promising application in the fields of food packaging.
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Affiliation(s)
- Wanzhen Xie
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China
| | - Yu Du
- School of Food Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510641, China
| | - Shuyi Yuan
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China
| | - Jie Pang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China.
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19
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Deng X, Hou Y, Zhou H, Li Y, Xue Z, Xue X, Huang G, Huang K, He X, Xu W. Hypolipidemic, anti-inflammatory, and anti-atherosclerotic effects of tea before and after microbial fermentation. Food Sci Nutr 2021; 9:1160-1170. [PMID: 33598200 PMCID: PMC7866600 DOI: 10.1002/fsn3.2096] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Microbial fermentation significantly affects the flavor and efficacy of tea. It is generally believed that fermented tea is more effective in lowering lipids, while unfermented tea can more effectively inhibit inflammation. However, there is not sufficient evidence to support this claim. To systematically compare the hypolipidemic, anti-inflammatory, and anti-atherosclerotic effects of tea before and after microbial fermentation, hyperlipidemic rats and inflammatory injury cells were treated with Monascus purpureus-fermented pu-erh tea water extract (MPT) and sun-dried green tea water extract (SGT), respectively. RESULTS MPT, with higher levels of theabrownins, flavonoids, gallic acid (GA), and lovastatin, was more effective in reducing serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and inflammatory cytokines (TNF-α, IL-1β, and IL-6), while SGT, with higher levels of tea polyphenols, amino acids, (-)-epigallocatechin gallate (EGCG), and theaflavins, was more effective in increasing serum high-density lipoprotein cholesterol (HDL-C) in hyperlipidemic rats. The foam cells on the arterial wall of the rats in the MPT group were visibly less, and the thrombosis time was longer than that in the SGT group. Cell experiments showed that MPT was more effective in protecting endothelial cells from damage than SGT. CONCLUSION Surprisingly, Monascus purpureus-fermented pu-erh tea not only had better hypolipidemic and anti-atherosclerotic effects than its raw material (sun-dried green tea), but also was superior in anti-inflammatory effects to the latter, which was possibly attributable to the great changes in functional ingredients during microbial fermentation.
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Affiliation(s)
- Xiujuan Deng
- College of Food Science and TechnologyYunnan Agricultural UniversityKunmingChina
| | - Yan Hou
- College of Long Run Pu‐erh TeaYunnan Agricultural UniversityKunmingChina
| | - Hongjie Zhou
- College of Long Run Pu‐erh TeaYunnan Agricultural UniversityKunmingChina
| | - Yali Li
- College of Long Run Pu‐erh TeaYunnan Agricultural UniversityKunmingChina
| | - Zhiqiang Xue
- College of Long Run Pu‐erh TeaYunnan Agricultural UniversityKunmingChina
| | - Xiaoting Xue
- College of Long Run Pu‐erh TeaYunnan Agricultural UniversityKunmingChina
| | - Ganghua Huang
- College of Long Run Pu‐erh TeaYunnan Agricultural UniversityKunmingChina
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food QualityDepartment of Nutrition and HealthChina Agricultural UniversityBeijingChina
| | - Xiaoyun He
- Key Laboratory of Precision Nutrition and Food QualityDepartment of Nutrition and HealthChina Agricultural UniversityBeijingChina
| | - Wentao Xu
- Key Laboratory of Precision Nutrition and Food QualityDepartment of Nutrition and HealthChina Agricultural UniversityBeijingChina
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20
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Govindarajulu M, Ramesh S, Neel L, Fabbrini M, Buabeid M, Fujihashi A, Dwyer D, Lynd T, Shah K, Mohanakumar KP, Smith F, Moore T, Dhanasekaran M. Nutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease. Neurochem Int 2021; 144:104958. [PMID: 33444675 DOI: 10.1016/j.neuint.2021.104958] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 12/21/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, and its incidence is increasing worldwide with increased lifespan. Currently, there is no effective treatment to cure or prevent the progression of AD, which indicates the need to develop novel therapeutic targets and agents. Sirtuins, especially SIRT3, a mitochondrial deacetylase, are NAD-dependent histone deacetylases involved in aging and longevity. Accumulating evidence indicates that SIRT3 dysfunction is strongly associated with pathologies of AD, hence, therapeutic modulation of SIRT3 activity may be a novel application to ameliorate the pathologies of AD. Natural products commonly used in traditional medicine have wide utility and appear to have therapeutic benefits for the treatment of neurodegenerative diseases such as AD. The present review summarizes the currently available natural SIRT3 activators and their potentially neuroprotective molecular mechanisms of action that make them a promising agent in the treatment and management of neurodegenerative diseases such as AD.
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Affiliation(s)
- Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Logan Neel
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Mary Fabbrini
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Manal Buabeid
- Clinical Pharmacy Department, College of Pharmacy and Health Sciences, Ajman University, United Arab Emirates
| | - Ayaka Fujihashi
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Darby Dwyer
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Tyler Lynd
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Karishma Shah
- Department of Ophthalmology, D.Y. Patil Medical College and Research Hospital, Mumbai, India
| | | | - Forrest Smith
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Timothy Moore
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA.
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21
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A deep insight into mechanism for inclusion of 2R,3R-dihydromyricetin with cyclodextrins and the effect of complexation on antioxidant and lipid-lowering activities. Food Hydrocoll 2020. [DOI: 10.1016/j.foodhyd.2020.105718] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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22
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Chang Y, Yuan L, Liu J, Muhammad I, Cao C, Shi C, Zhang Y, Li R, Li C, Liu F. Dihydromyricetin attenuates Escherichia coli lipopolysaccharide-induced ileum injury in chickens by inhibiting NLRP3 inflammasome and TLR4/NF-κB signalling pathway. Vet Res 2020; 51:72. [PMID: 32448367 PMCID: PMC7247275 DOI: 10.1186/s13567-020-00796-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/10/2020] [Indexed: 12/15/2022] Open
Abstract
Lipopolysaccharide (LPS) as a major component of Escherichia coli cell wall can cause inflammation and cell death. Dihydromyricetin (ampelopsin, DHM) is a natural flavonoid compound with anti-inflammatory, anti-oxidant and anti-bacterial effects. The preventive effects of DHM against ileum injury remain unclear. Here, we explored the protective role of DHM against LPS-induced ileum injury in chickens. In this study, DHM significantly attenuated LPS-induced alteration in diamine oxidase, malondialdehyde, reduced glutathione, glutathione peroxidase and superoxide dismutase levels in chicken plasma and ileum. Histology evaluation showed that the structure of blood vessels in ileum was seriously fragmented and presence of necrotic tissue in the lumen in the LPS group. Scanning electron microscopic observation revealed that the surface of the villi was rough and uneven, the structure was chaotic, and the normal finger shape was lost in the LPS group. In contrast, 0.05% and 0.1% DHM treatment partially alleviated the abnormal morphology. Additionally, DHM maintained the barrier function by restoring the protein expression of occludin, claudin-1 and zonula occludens protein-1. DHM inhibited apoptosis through the reduction of the expression of bax and caspase-3 and restored the expression of bcl-2. Importantly, DHM could reduce ileum NLR family pyrin domain-containing 3 (NLRP3), caspase-1, interleukin (IL)-1β and IL-18 expression to protect tissues from pyroptosis and inhibited toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signalling pathway. In summary, DHM attenuated the ileum mucosal damage, oxidative stress and apoptosis, maintained barrier function, inhibited NLRP3 inflammasome and TLR4/NF-κB signalling pathway activation triggered by Escherichia coli LPS.
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Affiliation(s)
- Yicong Chang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Liang Yuan
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Jiarui Liu
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Ishfaq Muhammad
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Chuanbao Cao
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Chenxi Shi
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Yuanyuan Zhang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Rui Li
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.,Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China
| | - Changwen Li
- Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China
| | - Fangping Liu
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China. .,Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China.
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23
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Mu HQ, He YH, Wang SB, Yang S, Wang YJ, Nan CJ, Bao YF, Xie QP, Chen YH. MiR-130b/TNF-α/NF-κB/VEGFA loop inhibits prostate cancer angiogenesis. Clin Transl Oncol 2020; 22:111-121. [PMID: 31667686 DOI: 10.1007/s12094-019-02217-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Angiogenesis is a critical biological process essential for solid cancer growth and metastasis. It has been shown that microRNAs (miRNAs) play a vital role in a variety of biological processes in cancers. However, whether miR-130b is involved in prostate cancer angiogenesis remains ill-defined. METHODS We performed the miRNA microarray to analyze miRNA expression in human prostate cancer specimens. In vitro gain-of-function assays and loss-of-function assays were conducted to explore the potential functions of miR-130b in human prostate cancer cells. Correlation analysis and dual-luciferase reporter assay were performed to validate whether tumor necrosis factor-α (TNF-α) was a direct target of miR-130b. The Matrigel plug and tumor vascular imaging assays were performed to confirm the anti-angiogenic activity of miR-130b in nude mice. RESULTS We found that miR-130b was one of the miRNAs being most significantly downregulated. Subsequently, we found that miR-130b expression was markedly downregulated in human prostate cancer cell lines. Down-regulation of miR-130b in prostate cancer cells significantly promoted the proliferation, invasion and tubule formation of human umbilical vein endothelial cells (HUVECs), while ectopic expression of miR-130b blocked prostate cancer angiogenesis in vitro and in vivo. Mechanistic analyses indicated that tumor necrosis factor-α (TNF-α) was regulated by miR-130b directly. MiR-130b attenuated nuclear factor-κB (NF-κB) signaling and its downstream gene vascular endothelial growth factor-A (VEGFA) by directly inhibiting TNF-α expression. Additionally, subsequent investigations identified that the ectopic level of VEGFA markedly abrogated the anti-angiogenic effect induced by miR-130b. Interestingly, VEGFA could in turn decrease the expression of miR-130b, thus forming a negative feedback loop that drives the angiogenesis of prostate cancer. CONCLUSION These findings show that miR-130b/TNF-α/NF-κB/VEGFA feedback loop is significantly correlated with angiogenesis in prostate cancer and miR-130b could be regarded as potential therapeutic target for prostate cancer anti-angiogenesis treatment.
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Affiliation(s)
- H Q Mu
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Y H He
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - S B Wang
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - S Yang
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Y J Wang
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - C J Nan
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Y F Bao
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Q P Xie
- Clinical Laboratory, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Y H Chen
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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24
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Martínez-Coria H, Mendoza-Rojas MX, Arrieta-Cruz I, López-Valdés HE. Preclinical Research of Dihydromyricetin for Brain Aging and Neurodegenerative Diseases. Front Pharmacol 2019; 10:1334. [PMID: 31780947 PMCID: PMC6859532 DOI: 10.3389/fphar.2019.01334] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/18/2019] [Indexed: 12/11/2022] Open
Abstract
Brain aging and neurodegenerative diseases share the hallmarks of slow and progressive loss of neuronal cells. Flavonoids, a subgroup of polyphenols, are broadly present in food and beverage and numerous studies have suggested that it could be useful for preventing or treating neurodegenerative diseases in humans. Dihydromyricetin (DHM) is one of the main flavonoids of some Asian medicinal plants that are used to treat diverse illness. The effects of DHM have been studied in different in vitro systems of oxidative damage and neuroinflammation, as well as in animal models of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Here we analyzed the most important effects of DHM, including its antioxidant, anti-inflammatory, and neuroprotective effects, as well as its ability to restore GABA neurotransmission and improve motor and cognitive behavior. We propose new areas of research that might contribute to a better understanding of the mechanism of action of this flavonoid, which could help develop a new therapy for aging and age-related brain diseases.
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Affiliation(s)
- Hilda Martínez-Coria
- Division de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
- Laboratorio Experimental de Enfermedades Neurodegenerativas, UNAM-INNyN, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”,Ciudad de México, Mexico
| | - Martha X. Mendoza-Rojas
- Unidad Periférica de Neurociencias, UNAM-INNyN, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”,Ciudad de México, Mexico
| | - Isabel Arrieta-Cruz
- Departamento de Investigación Básica, Instituto Nacional de Geriatría,Ciudad de México, Mexico
| | - Héctor E. López-Valdés
- Division de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
- Unidad Periférica de Neurociencias, UNAM-INNyN, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”,Ciudad de México, Mexico
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25
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Liu D, Mao Y, Ding L, Zeng XA. Dihydromyricetin: A review on identification and quantification methods, biological activities, chemical stability, metabolism and approaches to enhance its bioavailability. Trends Food Sci Technol 2019; 91:586-597. [PMID: 32288229 PMCID: PMC7127391 DOI: 10.1016/j.tifs.2019.07.038] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/21/2019] [Accepted: 07/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Dihydromyricetin (DMY) is an important plant flavonoid, which has received great attention due to its health-benefiting activities, including antioxidant, antimicrobial, anti-inflammatory, anticancer, antidiabetic and neuroprotective activities. DMY capsules have been sold in US as a nutraceutical supplement to prevent alcoholic hangovers. The major disadvantage associated with DMY is its chemical instability and poor bioavailability caused by the combined effects of its low solubility and poor membrane permeability. This limits its practical use in the food and pharmaceutical fields. SCOPE AND APPROACH The present paper gives an overview of the current methods for the identification and quantification of DMY. Furthermore, recent findings regarding the main biological properties and chemical stability of DMY, the metabolism of DMY as well as different approaches to increase DMY bioavailability in both aqueous and lipid phases are discussed. KEY FINDINGS AND CONCLUSIONS Current trends on identification and quantification of DMY have been focused on spectral and chromatographic techniques. Many factors such as heat, pH, metal ions, could affect the chemical stability of DMY. Despite the diverse biological effects of DMY, DMY faces with the problem of poor bioavailability. Utilization of different delivery systems including solid dispersion, nanocapsule, microemuslion, cyclodextrin inclusion complexes, co-crystallization, phospholipid complexes, and chemical or enzymatic acylation has the potential to improve both the solubility and bioavailability. DMY digested in laboratory animals undergoes reduction, dehydroxylation, methylation, glucuronidation, and sulfation. Novel DMY delivery systems and basic pharmacokinetic studies of encapsulated DMY on higher animals and humans might be required in the future.
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Affiliation(s)
- Dan Liu
- Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China
| | - Yiqin Mao
- Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China
| | - Lijun Ding
- Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China
| | - Xin-An Zeng
- South China University of Technology, School of Food Science & Engineering, Guangzhou, 510640, Guangdong, PR China
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Zhu XH, Lang HD, Wang XL, Hui SC, Zhou M, Kang C, Yi L, Mi MT, Zhang Y. Synergy between dihydromyricetin intervention and irinotecan chemotherapy delays the progression of colon cancer in mouse models. Food Funct 2019; 10:2040-2049. [PMID: 30907395 DOI: 10.1039/c8fo01756e] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) is the third highest cause of cancer-related death and the main option for prolonged survival is chemotherapeutic intervention. There is increasing interest in dietary intervention using natural agents to enhance the sensitivity of such invasive chemical treatment. In this study, the chemotherapeutic efficacy of dihydromyricetin (DMY) intervention on treatments involving irinotecan (CPT-11) or gemcitabine (GM) was evaluated in an AOM/DSS-induced colitis-associated colon cancer model and a Min (Apc Min/+) mice model. Our data showed that DMY could promote the CPT-11 effect both in the mouse model of AOM/DSS and Apc Min/+ cancer and had no influence on the GM effect. In AOM/DSS cancer, tumors were sensitive to 100 mg kg-1 DMY chemotherapy under 100 mg kg-1 or 200 mg kg-1 CPT-11. DMY-driven CPT-11 chemotherapy induced enhanced IgG levels and the reduction of Fusobacterium abundance in the gut. In the Min model, CPT-11 with 20 mg kg-1 DMY prevented tumor formation but not with 100 mg kg-1 DMY. Mechanically, chloride ion-dependent CFTR, CLCN4, and CLIC4 signaling are not involved in DMY mediated chemotherapeutic colon tumorigenesis. These results suggested that a suitable dose of DMY could act as a coadjuvant to CPT-11 chemotherapy.
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Affiliation(s)
- Xiao-Hui Zhu
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Army Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Chongqing Medical Nutrition Research Center, Chongqing, P.R. China.
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27
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Xiao XN, Wang F, Yuan YT, Liu J, Liu YZ, Yi X. Antibacterial Activity and Mode of Action of Dihydromyricetin from Ampelopsis grossedentata Leaves against Food-Borne Bacteria. Molecules 2019; 24:molecules24152831. [PMID: 31382605 PMCID: PMC6695662 DOI: 10.3390/molecules24152831] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 07/24/2019] [Accepted: 07/31/2019] [Indexed: 12/28/2022] Open
Abstract
Dihydromyricetin (DMY) has recently attracted increased interest due to its considerable health-promoting activities but there are few reports on its antibacterial activity and mechanism. In this paper, the activity and mechanisms of DMY from Ampelopsis grossedentata leaves against food-borne bacteria are investigated. Moreover, the effects of pH, thermal-processing, and metal ions on the antibacterial activity of DMY are also evaluated. The results show that DMY exhibits ideal antibacterial activity on five types of food-borne bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella paratyphi, and Pseudomonas aeruginosa). The activities of DMY against bacteria are extremely sensitive to pH, thermal-processing, and metal ions. The morphology of the tested bacteria is changed and damaged more seriously with the exposure time of DMY. Furthermore, the results of the oxidative respiratory metabolism assay and the integrity of the cell membrane and wall tests revealed that the death of bacteria caused by DMY might be due to lysis of the cell wall, leakage of intracellular ingredients, and inhibition of the tricarboxylic acid cycle (TCA) pathway.
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Affiliation(s)
- Xiao-Nian Xiao
- OAI Sino-German United Research Institute, Nanchang University, Nanchang 330047, Jiangxi Province, China
| | - Fan Wang
- OAI Sino-German United Research Institute, Nanchang University, Nanchang 330047, Jiangxi Province, China
| | - Yi-Ting Yuan
- Sino-German Food Engineering Center, Nanchang University, Nanchang 330047, Jiangxi Province, China
| | - Jing Liu
- OAI Sino-German United Research Institute, Nanchang University, Nanchang 330047, Jiangxi Province, China
| | - Yue-Zhen Liu
- OAI Sino-German United Research Institute, Nanchang University, Nanchang 330047, Jiangxi Province, China
| | - Xing Yi
- Sino-German Food Engineering Center, Nanchang University, Nanchang 330047, Jiangxi Province, China.
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Wu J, Zhang ZH, Zhang LH, Jin XJ, Ma J, Piao HR. Design, synthesis, and screening of novel ursolic acid derivatives as potential anti-cancer agents that target the HIF-1α pathway. Bioorg Med Chem Lett 2019; 29:853-858. [DOI: 10.1016/j.bmcl.2018.12.060] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/25/2018] [Accepted: 12/27/2018] [Indexed: 11/16/2022]
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Zhang J, Chen Y, Luo H, Sun L, Xu M, Yu J, Zhou Q, Meng G, Yang S. Recent Update on the Pharmacological Effects and Mechanisms of Dihydromyricetin. Front Pharmacol 2018; 9:1204. [PMID: 30410442 PMCID: PMC6209623 DOI: 10.3389/fphar.2018.01204] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022] Open
Abstract
As the most abundant natural flavonoid in rattan tea, dihydromyricetin (DMY) has shown a wide range of pharmacological effects. In addition to the general characteristics of flavonoids, DMY has the effects of cardioprotection, anti-diabetes, hepatoprotection, neuroprotection, anti-tumor, and dermatoprotection. DMY was also applied for the treatment of bacterial infection, osteoporosis, asthma, kidney injury, nephrotoxicity and so on. These effects to some extent enrich the understanding about the role of DMY in disease prevention and therapy. However, to date, we still have no outlined knowledge about the detailed mechanism of DMY, which might be related to anti-oxidation and anti-inflammation. And the detailed mechanisms may be associated with several different molecules involved in cellular apoptosis, oxidative stress, and inflammation, such as AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), protein kinase B (Akt), nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-γ (PPARγ) and so on. Here, we summarized the current pharmacological developments of DMY as well as possible mechanisms, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application.
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Affiliation(s)
- Jingyao Zhang
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China.,Department of Pharmacology, School of Pharmacy, Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong University, Nantong, China
| | - Yun Chen
- Department of Pharmacology, School of Pharmacy, Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong University, Nantong, China
| | - Huiqin Luo
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China.,Department of Pharmacology, School of Pharmacy, Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong University, Nantong, China
| | - Linlin Sun
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China.,Department of Pharmacology, School of Pharmacy, Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong University, Nantong, China
| | - Mengting Xu
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China.,Department of Pharmacology, School of Pharmacy, Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong University, Nantong, China
| | - Jin Yu
- Department of Pharmacology, School of Pharmacy, Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong University, Nantong, China
| | - Qigang Zhou
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Guoliang Meng
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Shengju Yang
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, China
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Jia R, Ma J, Meng W, Wang N. Dihydromyricetin inhibits caerulin-induced TRAF3-p38 signaling activation and acute pancreatitis response. Biochem Biophys Res Commun 2018; 503:1696-1702. [PMID: 30055802 DOI: 10.1016/j.bbrc.2018.07.101] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 07/20/2018] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a common inflammatory disease in gastrointestinal tract. Our previous study has shown that caerulin induces TNF receptor-associated factor 3 (TRAF3)-p38 signaling activation and pro-inflammatory response in macrophages, causing damage to co-cultured pancreatic acinar cells. Dihydromyricetin (DHM) is a flavonoid extracted from Ampelopsis grossedentata, which has displayed anti-inflammation and anti-oxidant functions. Our results here show that DHM potently inhibited caerulin-induced expression and productions of multiple pro-inflammatory cytokines (IL-1β, TNF-α and IL-17) in murine bone marrow-derived macrophages (BMDMs). DHM significantly inhibited caerulin-induced TRAF3 protein stabilization, TRAF3-mitogen-activated protein kinase kinase 3 (MKK3) association and following MKK3-p38 activation in BMDMs. Significantly, DHM was ineffective against caerulin in TRAF3-silenced BMDMs. Importantly, DHM supplement attenuated the cytotoxicity of caerulin-activated BMDMs to co-cultured pancreatic acinar cells, resulting in significantly decreased acinar cell death and apoptosis. In vivo, DHM co-administration largely attenuated pancreatic and systemic inflammation in caerulin-injected AP mice. Together, DHM inhibits caerulin-induced TRAF3-p38 signaling activation and AP response. DHM could be further studied as a potential anti-AP agent.
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Affiliation(s)
- Rongrong Jia
- Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiali Ma
- Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenying Meng
- Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Na Wang
- Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Chu J, Wang X, Bi H, Li L, Ren M, Wang J. Dihydromyricetin relieves rheumatoid arthritis symptoms and suppresses expression of pro-inflammatory cytokines via the activation of Nrf2 pathway in rheumatoid arthritis model. Int Immunopharmacol 2018; 59:174-180. [PMID: 29656207 DOI: 10.1016/j.intimp.2018.04.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 03/09/2018] [Accepted: 04/04/2018] [Indexed: 12/17/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory and autoimmune disease. In this research, we estimated the protective effects of Dihydromyricetin (DMY) on RA induced by Complete Freund's Adjuvant (CFA). We found that DMY effectively relieved rheumatoid arthritis symptoms, such as body weight change, paw swelling and rheumatoid arthritis scores. In addition, we also observed that DMY significantly lowered the immune organ indexes (including thymus and spleen) and exhibited the anti-inflammatory effect in CFA-induced rheumatoid arthritis. The results demonstrated that the increased expression levels of interleukin-1β (IL-1β), interleukin-6(IL-6), tumor necrosis factor-α (TNF-α) were significantly inhibited by DMY. Furthermore, the key inflammatory mediator, cyclooxygenase-2 (COX-2) was markedly lowered after treatment with DMY. A mechanistic study indicated that DMY could up-regulate the down-regulation levels of the mRNA and protein of Nrf2, HO-1 and NQO1. Moreover, the Nrf2 activation of DMY was abolished by Nrf2 inhibitor brusatol. Thus, DMY inhibits the expressions of pro-inflammatory cytokines via activating Nrf2 pathway in RA model, which suggests that DMY has potential for further investigation as a candidate anti-arthritic agent in future.
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Affiliation(s)
- Jianguo Chu
- Tangshan GongRen Hospital, Tangshan, Hebei, PR China
| | - Xiujun Wang
- Tangshan GongRen Hospital, Tangshan, Hebei, PR China
| | - Huanjie Bi
- Tangshan GongRen Hospital, Tangshan, Hebei, PR China
| | - Lifeng Li
- Tangshan GongRen Hospital, Tangshan, Hebei, PR China
| | - Mingguang Ren
- Tangshan GongRen Hospital, Tangshan, Hebei, PR China
| | - Jingwei Wang
- Tangshan GongRen Hospital, Tangshan, Hebei, PR China.
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Chen YL, Zhang YL, Dai YC, Tang ZP. Systems pharmacology approach reveals the antiinflammatory effects of Ampelopsis grossedentata on dextran sodium sulfate-induced colitis. World J Gastroenterol 2018; 24:1398-1409. [PMID: 29632421 PMCID: PMC5889820 DOI: 10.3748/wjg.v24.i13.1398] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 02/12/2018] [Accepted: 03/03/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the protective effects of Ampelopsis grossedentata (AMP) on dextran sulfate sodium (DSS)-induced colitis in mice based on systems pharmacology approach.
METHODS Systems pharmacology approach was used to predict the active ingredients, candidate targets and the efficacy of AMP on ulcerative colitis (UC) using a holistic process of active compound screening, target fishing, network construction and analysis. A DSS-induced colitis model in C57BL/6 mice (n = 10/group) was constructed and treated with 5-aminosalicylic acid (100 mg/kg/d) and AMP (400 mg/kg/d) to confirm the underlying mechanisms and effects of AMP on UC with western blot analyses, polymerase chain reaction, histological staining and immunohistochemistry.
RESULTS The therapeutic effects of AMP against DSS-induced colitis were determined in the beginning, and the results showed that AMP significantly improved the disease in general observations and histopathology analysis. Subsequent systems pharmacology predicted 89 corresponding targets for the four candidate compounds of AMP, as well as 123 candidate targets of UC, and protein-protein interaction networks were constructed for the interaction of putative targets of AMP against UC. Enrichment analyses on TNF-α and RANKL/RANK, a receptor activator of NF-κB signaling pathways, were then carried out. Experimental validation revealed that inflammation-related signaling pathways were activated in the DSS group, and AMP significantly suppressed DSS-induced high expression of IRAK1, TRAF6, IκB and NF-κB, and inhibited the elevated expression levels of TNF-α, IL-1β, IL-6 and IL-8.
CONCLUSION AMP could exert protective effects on UC via suppressing the IRAK1/TRAF6/NF-κB-mediated inflammatory signaling pathways.
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Affiliation(s)
- You-Lan Chen
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Department of Gastroenterology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ya-Li Zhang
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan-Cheng Dai
- Department of Gastroenterology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zhi-Peng Tang
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Department of Gastroenterology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Zeng Y, Peng Y, Tang K, Wang YQ, Zhao ZY, Wei XY, Xu XL. Dihydromyricetin ameliorates foam cell formation via LXRα-ABCA1/ABCG1-dependent cholesterol efflux in macrophages. Biomed Pharmacother 2018; 101:543-552. [PMID: 29505925 DOI: 10.1016/j.biopha.2018.02.124] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 02/16/2018] [Accepted: 02/23/2018] [Indexed: 02/04/2023] Open
Abstract
As the most abundant flavonoid in Ampelopsis grossedentata, the protective effects of dihydromyricetin on atherosclerosis have been well established, yet the detailed mechanisms are not fully understood. The aim of the present study was to examine the effect of dihydromyricetin on lipid accumulation and the underlying molecular mechanisms in macrophages and ApoE-/- mice. Incubation with dihydromyricetin significantly attenuated oxidized low-density lipoprotein (ox-LDL)-mediated cholesterol and lipid accumulation in THP-1-derived macrophages, which was due to increased cholesterol efflux. In addition, dihydromyricetin increased mRNA and protein expressions of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 but had no effect on the mRNA and protein expressions of SR-A, CD36, or SR-BI involved in cholesterol homeostasis. Furthermore, the upregulation of ABCA1 and ABCG1 by dihydromyricetin depended on liver X receptor α (LXRα), as evidenced by an increase in the nuclear level of LXRα and its prevention of the expression of ABCA1 and ABCG1 after inhibition of LXRα activity by knockdown of LXRα expression with small interfering RNA (siRNA). Accordingly, dihydromyricetin-mediated suppression of cholesterol and lipid accumulation in macrophages was also abrogated by LXRα siRNA. Moreover, the lesion size of atherosclerosis was smaller in dihydromyricetin-treated ApoE-/- mice compared with the vehicle-treated mice, and the protein expression of CD36, SR-A, ABCA1, ABCG1 and LXRα in aortas was modulated similar to that observed in THP-1-derived macrophages. These data suggest that promotion of LXRα-ABCA1/ABCG1-dependent cholesterol efflux is crucial event in suppression of lipid accumulation by dihydromyricetin in the transformation of macrophage foam cells.
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Affiliation(s)
- Yi Zeng
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Yi Peng
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Kun Tang
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Yu Qin Wang
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Zhe Yu Zhao
- Department of Pharmacy, Wuxi No. 2 People's Hospital, Wuxi, China
| | - Xin Yu Wei
- Department of Pharmacy, Wuxi Huishan District People's Hospital, Wuxi, China
| | - Xiao Le Xu
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China.
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Dihydromyricetin exerts a rapid antidepressant-like effect in association with enhancement of BDNF expression and inhibition of neuroinflammation. Psychopharmacology (Berl) 2018; 235:233-244. [PMID: 29058041 DOI: 10.1007/s00213-017-4761-z] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 10/11/2017] [Indexed: 12/19/2022]
Abstract
RATIONALE Major depressive disorder (MDD) is a highly prevalent illness that affects large populations across the world, and increasing evidence suggests that neuroinflammation and levels of brain-derived neurotrophic factor (BDNF) are closely related to depression. Dihydromyricetin (DHM) is a kind of flavonoid natural product that has been reported to display multiple pharmacological effects, including anti-inflammatory and anti-oxidative properties, and these may contribute to ameliorate MDD. OBJECTIVE This study investigated the effect of DHM on depression-related phenotypes in various experimental animal models. METHODS The antidepressant-like effect of DHM was validated via depression-related behavioral tests in naïve male C57BL/6 mice, as well as in the acute lipopolysaccharide-induced mouse model of depression. The chronic unpredicted mild stress (CUMS) mouse model of depression was also used to assess the rapid antidepressant-like effect of DHM by tail suspension test (TST), forced swimming test (FST), locomotor activity, and sucrose preference test (SPT). The expression of BDNF and inflammatory factors were determined through Western blotting and enzyme-linked immunosorbent assay, respectively. RESULTS DHM reduced immobility time in the TST and FST both in mice and the acute LPS-induced mouse model of depression. Seven days of DHM treatment ameliorated depression-related behaviors induced by CUMS, whereas similar treatment with the typical antidepressant venlafaxine did not. DHM activated the ERK1/2-CREB pathway and increased glycogen synthase kinase-3 beta (GSK-3β) phosphorylation at ser-9, with upregulation of BDNF expression, in both hippocampal tissues and cultured hippocampal cells. CONCLUSION The present data indicate that DHM exerts a more rapid antidepressant-like effect than does a typical antidepressant, in association with enhancement of BDNF expression and inhibition of neuroinflammation.
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Zhao L, Cai C, Wang J, Zhao L, Li W, Liu C, Guan H, Zhu Y, Xiao J. Dihydromyricetin Protects against Bone Loss in Ovariectomized Mice by Suppressing Osteoclast Activity. Front Pharmacol 2017; 8:928. [PMID: 29311931 PMCID: PMC5742133 DOI: 10.3389/fphar.2017.00928] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/07/2017] [Indexed: 12/21/2022] Open
Abstract
Dihydromyricetin (DMY), the main flavonoid component of Ampelopsis grossedentata, possesses pharmacological activities useful for treatment of diseases associated with inflammation and oxidative damage. Because osteoclasts are often involved in chronic low-grade systemic inflammation and oxidative damage, we hypothesized that DMY may be an effective treatment for osteoclast-related diseases. The effects of DMY on osteoclast formation and activity were examined in vitro. Female C57BL/6 mice were ovariectomized to mimic menopause-induced bone loss and treated with DMY, and femur samples were subjected to bone structure and histological analysis, serum biochemical indicators were also measured. DMY suppressed the activation of nuclear factor-κB, c-Fos and mitogen-activated protein kinase, and prevented production of reactive oxygen species. DMY decreased expression of osteoclast-specific genes, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. In addition, DMY prevented bone loss and decreased serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6, and with a decrease in the ratio between receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and osteoprotegerin (OPG) in vivo. These findings demonstrate that DMY attenuates bone loss and inhibits osteoclast formation and activity through modulation of multiple pathways both upstream and downstream of RANKL signaling. DMY may thus be a useful option for treatment of osteoclast-related diseases such as rheumatoid arthritis and osteoporosis.
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Affiliation(s)
- Libo Zhao
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Cai
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wang
- Department of Oncology, Renmin Hospital, Wuhan University, Wuhan, China
| | - Liming Zhao
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijin Li
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changyu Liu
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hanfeng Guan
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanli Zhu
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Xiao
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Moon NR, Kang S, Park S. Consumption of ellagic acid and dihydromyricetin synergistically protects against UV-B induced photoaging, possibly by activating both TGF-β1 and wnt signaling pathways. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2017; 178:92-100. [PMID: 29128706 DOI: 10.1016/j.jphotobiol.2017.11.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 10/30/2017] [Accepted: 11/02/2017] [Indexed: 01/31/2023]
Abstract
Ellagic acid (EGA) and dihydromyricetin (DHM) are both found in fruits and vegetables are used for anti-aging treatment for the skin. The anti-photoaging efficacy of EGA and DHM was investigated in UV-B irradiated skin in vivo and the involvement of transforming growth factor (TGF)-β1 and wnt signaling pathways were examined in vitro. HaCaT cells were treated with either 50μM EGA, 50μM DHM or 25μM EGA+25μM DHM before 100mJ/cm2 UV-B exposure, and then oxidative stress and inflammation was measured. The involvement of TGF-β1 and wnt signaling was measured using their inhibitors, respectively, in HaCaT cells. Mice were fed a high fat diet with either 0.7% cellulose, 0.7% EGA, 0.7% DHM or 0.35% EGA+0.35% DHM for 3weeks and the dorsal skin of the mice had UV-B irradiation. 3% cellulose, 3% EGA, 3% DHM or 1.5% EGA+1.5% DHM in 1,3-buthylene glycol was applied onto the dorsal skin at 30min before 1 MED UV-B exposure. In 100mJ/cm2 UVB irradiation, EGA and DHM mainly decreased oxidative stress and inflammation, respectively in HaCaT cells. Their activities were blocked by the TGF-β1 inhibitor, indicating their actions were mediated by TGF-β1 signaling (TGF-β1➔pSmad3➔Smad7). DHM enhanced wnt signaling by increasing β-catenin and decreasing Dickkopf-related protein-1. In mice, 1 MED UV-B exposure induced sunburn, redness, and blistering. EGA, DHM and especially EGA+DHM lessened their severity. UV-B increased epidermal thickness and damaged epidermal nucleus and cell structures. DHM and especially EGA+DHM prevented damage to the nucleus and cell structures. Expressions of circulating and dorsal skin IL-1β and TNF-α mRNA were lower in descending order of: control, EGA, DHM, EGA+DHM and normal-control. In conclusion, the consumption of EGA+DHM had a synergistically protective action against UV-B damage in the skin tissues of mice and HaCaT cells, and it may be associated with activating of both TGF-β1 and wnt signaling.
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Affiliation(s)
- Na Rang Moon
- Dept. of Food & Nutrition, Obesity/Diabetes Center, Hoseo University, Asan, South Korea
| | - Suna Kang
- Dept. of Food & Nutrition, Obesity/Diabetes Center, Hoseo University, Asan, South Korea
| | - Sunmin Park
- Dept. of Food & Nutrition, Obesity/Diabetes Center, Hoseo University, Asan, South Korea.
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The Versatile Effects of Dihydromyricetin in Health. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:1053617. [PMID: 28947908 PMCID: PMC5602609 DOI: 10.1155/2017/1053617] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 07/27/2017] [Indexed: 01/02/2023]
Abstract
Dihydromyricetin is a flavonoid isolated from Ampelopsis grossedentata, which is traditionally used in China. Dihydromyricetin exhibits health-benefiting activities with minimum adverse effects. Dihydromyricetin has been demonstrated to show antioxidative, anti-inflammatory, anticancer, antimicrobial, cell death-mediating, and lipid and glucose metabolism-regulatory activities. Dihydromyricetin may scavenge ROS to protect against oxidative stress or potentiate ROS generation to counteract cancer cells selectively without any effects on normal cells. However, the low bioavailability of dihydromyricetin limits its potential applications. Recent research has gained positive and promising data. This review will discuss the versatile effects and clinical prospective of dihydromyricetin.
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Shikonin suppresses proliferation and induces cell cycle arrest through the inhibition of hypoxia-inducible factor-1α signaling. Chem Biol Interact 2017; 274:58-67. [PMID: 28684144 DOI: 10.1016/j.cbi.2017.06.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 05/16/2017] [Accepted: 06/29/2017] [Indexed: 12/27/2022]
Abstract
Hypoxia enhances the development of solid tumors. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor of tumor regulation. HIF-1α regulates several target genes involved in many aspects of cancer progression, including angiogenesis, metastasis, and cell proliferation, as well as imparting resistance to cancer treatment. In this study, we assessed shikonin, which derives from the traditional medical herb Lithospermum erythrorhizon, for its anti-cancer effects in hypoxia-induced human colon cancer cell lines. Shikonin showed potent inhibitory activity against hypoxia-induced HIF-1α activation in various human cancer cell lines and efficient scavenging activity of hypoxia-induced reactive oxygen species in tumor cells. Further analysis revealed that shikonin inhibited HIF-1α protein synthesis without affecting the expression of HIF-1α mRNA or degrading HIF-1α protein. It was subsequently shown to attenuate the activation of downstream mTOR/p70S6K/4E-BP1/eIF4E kinase. Shikonin also dose-dependently caused the cell cycle arrest of activated HCT116 cells and inhibited the proliferation of HCT116 and SW620 cells. Moreover, it significantly inhibited tumor growth in a xenograft modal. These findings suggest that shikonin could be considered for use as a potential drug in human colon cancer therapy.
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Liu TT, Zeng Y, Tang K, Chen X, Zhang W, Xu XL. Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice. Atherosclerosis 2017; 262:39-50. [PMID: 28500865 DOI: 10.1016/j.atherosclerosis.2017.05.003] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 05/02/2017] [Accepted: 05/04/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr-/-) mice. METHODS Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied. RESULTS (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr-/- mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux. CONCLUSIONS These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation, amelioration of lipid profiles, anti-inflammatory action and anti-oxidative effect.
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Affiliation(s)
- Ting Ting Liu
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Yi Zeng
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Kun Tang
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - XueMeng Chen
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Wei Zhang
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China
| | - Xiao Le Xu
- Department of Pharmacology, Nantong University Pharmacy College, Nantong, China.
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Xu B, Huang S, Wang C, Zhang H, Fang S, Zhang Y. Anti‑inflammatory effects of dihydromyricetin in a mouse model of asthma. Mol Med Rep 2017; 15:3674-3680. [PMID: 28393183 PMCID: PMC5436282 DOI: 10.3892/mmr.2017.6428] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 02/01/2017] [Indexed: 01/17/2023] Open
Abstract
Dihydromyricetin (DHM) is a plant flavonoid and is the primary active ingredient isolated from the medicinal herb, Ampelopsis grossedentata. DHM has been shown to possess various pharmacological activities, including anti-inflammatory effects. However, the possible role of DHM in asthma treatment remains to be elucidated. The present study aimed to investigate its anti-inflammatory properties in mice with symptoms of allergic asthma. The C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. DHM or phosphate-buffered saline treatment was administered 1 h prior to the OVA challenge. The levels of interleukin (IL)-4, IL-5 and IL-13 in the bronchoalveolar lavage (BAL) fluid were measured by enzyme-linked immunosorbent assay (ELISA), and OVA-specific serum IgE and IgG1 levels were also determined by ELISA. Histopathological staining was performed to evaluate the infiltration of inflammatory cells into the BAL fluid, lung tissues and goblet cell hyperplasia. DHM treatment significantly reduced the total number of inflammatory cells, including eosinophils, neutrophils, lymphocytes and macrophages, in the BAL fluid. DHM also reduced the levels of IL-4, IL-5 and IL-13 in the BAL fluid, and reduced the secretion of OVA-specific IgE and IgG1 in the serum. The histological staining demonstrated that DHM treatment effectively suppressed the OVA-induced inflammatory cells in the lung tissues and in the mucus hypersecreted by goblet cells in the airway. These results showed that DHM had a potent anti-inflammatory effect in an OVA-induced mouse model of asthma, offering potential as an anti-inflammatory agent for the treatment of asthma.
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Affiliation(s)
- Bin Xu
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Shuran Huang
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Caiying Wang
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Haitao Zhang
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Shengcun Fang
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Yingming Zhang
- Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, P.R. China
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