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Hu L, Luo Y, Yang J, Cheng C. Botanical Flavonoids: Efficacy, Absorption, Metabolism and Advanced Pharmaceutical Technology for Improving Bioavailability. Molecules 2025; 30:1184. [PMID: 40076406 PMCID: PMC11902153 DOI: 10.3390/molecules30051184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/04/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Flavonoids represent a class of natural plant secondary metabolites with multiple activities including antioxidant, antitumor, anti-inflammatory, and antimicrobial properties. However, due to their structural characteristics, they often exhibit low bioavailability in vivo. In this review, we focus on the in vivo study of flavonoids, particularly the effects of gut microbiome on flavonoids, including common modifications such as methylation, acetylation, and dehydroxylation, etc. These modifications aim to change the structural characteristics of the original substances to enhance absorption and bioavailability. In order to improve the bioavailability of flavonoids, we discuss two feasible methods, namely dosage form modification and chemical modification, and hope that these approaches will offer new insights into the application of flavonoids for human health. In this article, we also introduce the types, plant sources, and efficacy of flavonoids. In conclusion, this is a comprehensive review on how to improve the bioavailability of flavonoids.
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Affiliation(s)
- Lei Hu
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
| | - Yiqing Luo
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
| | - Jiaxin Yang
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
| | - Chunsong Cheng
- Jiangxi Key Laboratory for Sustainable Utilization of Chinese Materia Medica Resources, Lushan Botanical Garden, Chinese Academy of Sciences, Jiujiang 332900, China; (L.H.); (Y.L.); (J.Y.)
- Lushan Xinglin Institute for Medicinal Plants, Jiujiang Xinglin Key Laboratory for Traditional Chinese Medicines, Jiujiang 332900, China
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2
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Ahmed H, Ijaz MU, Riaz M, Ullah F, Samir H, Shuaib M, Swelum AA. Taxifolin: A flavonoid in the freezing medium augments post-thaw semen quality and in vivo fertility potential of buffalo bull spermatozoa. Cryobiology 2024; 117:104980. [PMID: 39426473 DOI: 10.1016/j.cryobiol.2024.104980] [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: 07/04/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 10/21/2024]
Abstract
This comprehensive study was carried out to investigate the effects of taxifolin in the freezing medium on post-thaw semen quality, and fertility potential of buffalo bull spermatozoa. Taxifolin was also evaluated for radical scavenging activity through DPPH (2, 2-diphenyl-1-picrylhydrazyl), and Nitric oxide (NO) inhibition (%) during in vitro conditions. Collected semen samples from four buffalo bulls were initially evaluated (consistency, volume, motility, and concentrations); the accepted samples were pooled, and diluted in extenders containing different doses of taxifolin (0 μM [control], 2 μM, 5 μM, 10 μM, and 20 μM). Diluted semen was gradually cooled (2 h, 4 °C), equilibrated (4 h, 4 °C), and then frozen in liquid nitrogen (-196 °C). Data analysis revealed that taxifolin supplementation (10 μM) displayed the highest DPPH-scavenging ability, and NO inhibition compared to the control (% DPPH, 67.31 vs. 13.50; and % NO, 78.25 vs. 21.25) respectively. Moreover, taxifolin supplementation (10 μM) significantly (P < 0.05) improved progressive motility (%), average path velocity (μm/sec), straight-line velocity (μm/sec), and seminal plasma glutathione peroxidase (μM), and superoxide dismutase (U/mL) of buffalo bull spermatozoa than control. Sperm plasma membrane integrity, mitochondrial transmembrane potential, acrosome integrity (%) and seminal plasma adenosine triphosphate (nmol/million), and total antioxidant capacity (μM/L) were enhanced significantly with taxifolin (10 and 20 μM) supplementing group. Lastly, taxifolin supplementation significantly improved the fertility rate (%, 69.09 vs. 40.38) compared to the control. Further studies to assess mechanisms by which taxifolin improves semen quality and fertility of buffalo spermatozoa are warranted.
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Affiliation(s)
- Hussain Ahmed
- Department of Zoology, University of Buner, Khyber Pakhtunkhwa (KP), Pakistan; Centre of Animal Sciences and Fisheries, University of Swat, KP, Pakistan.
| | - Muhammad Umar Ijaz
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
| | - Mehreen Riaz
- Centre of Animal Sciences and Fisheries, University of Swat, KP, Pakistan
| | - Farhad Ullah
- Department of Zoology, Islamia College, Peshawar, KP, Pakistan
| | - Haney Samir
- Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Japan; Department of Theriogenology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Muhammad Shuaib
- Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Ayman A Swelum
- Department of Animal Production, College of Food and Agriculture Science, King Saud University, P.O. Box 2460, Riyadh, 11451, Saudi Arabia.
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Sarg NH, Hersi FH, Zaher DM, Hamouda AO, Ibrahim SI, El-Seedi HR, Omar HA. Unveiling the therapeutic potential of Taxifolin in Cancer: From molecular mechanisms to immune modulation and synergistic combinations. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155934. [PMID: 39128306 DOI: 10.1016/j.phymed.2024.155934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/21/2024] [Accepted: 08/02/2024] [Indexed: 08/13/2024]
Abstract
BACKGROUND Taxifolin (TAX), a flavonoid abundant in various medicinal plants, has gained attention for its multifaceted role in cancer therapy and cytoprotection against chemotherapy-induced toxicities. TAX modulates key signaling pathways to regulate several processes within tumors, thus potentially playing an important role in tumor suppression. PURPOSE This review aims to explore the current understanding of TAX's role in cancer therapy including its antitumor mechanisms, synergistic combinations, and cytoprotective effects. The review also addresses the safety profile of TAX, highlights its pharmacokinetic (PK) properties limiting its use, and summarizes the suggested pharmaceutical and chemical solutions to overcome these limitations. METHODOLOGY A literature review was conducted through searching online databases such as PubMed and Google Scholar using several combinations of relevant keywords related to TAX's potential in anticancer therapy. A total of 84 articles published within the last 15 years were included in this review and analyzed following the PRISMA guidelines. RESULTS TAX inhibits tumor proliferation, migration, and invasion via the cGMP-PKG pathway, inducing G1-phase arrest and apoptosis. TAX's anti-angiogenic and pro-apoptotic effects are mediated by downregulating Hif1-α, VEGF, and AKT. Additionally, it can synergize the conventional chemotherapeutic agents, enhancing their efficacy and mitigating drug resistance by inhibiting P-glycoprotein expression. Additionally, TAX demonstrates cytoprotective effects against cisplatin-induced nephrotoxicity and neurotoxicity, cyclophosphamide/pazopanib-induced hepatotoxicity, methotrexate-induced oral mucositis, and doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. TAX further has immunomodulatory effects in the tumor microenvironment, enhancing immune responses and sensitizing tumors to immune checkpoint inhibitors. Advancements in TAX's anticancer effects include introducing novel drug delivery systems and chemical modifications to generate derivatives with improved pharmacological effects. CONCLUSION Clinical trials are needed to confirm TAX's safety and effectiveness in cancer therapy, optimize formulations, and investigate synergistic combinations. Overall, TAX holds promise as a versatile anticancer agent, offering direct anticancer effects and protective benefits against chemotherapy-induced toxicities.
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Affiliation(s)
- Nadin H Sarg
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Fatema H Hersi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Dana M Zaher
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Alaa O Hamouda
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sara I Ibrahim
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Hesham R El-Seedi
- Chemistry Department, Faculty of Science, Islamic University of Madinah, P. O. Box: 170, Madinah 42351, Saudi Arabia; Pharmacognosy Group, Department of Pharmaceutical Biosciences, Biomedical Centre, Uppsala University, Box 591 751 24 Uppsala, Sweden
| | - Hany A Omar
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.
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Okoye CO, Jiang H, Wu Y, Li X, Gao L, Wang Y, Jiang J. Bacterial biosynthesis of flavonoids: Overview, current biotechnology applications, challenges, and prospects. J Cell Physiol 2024; 239:e31006. [PMID: 37025076 DOI: 10.1002/jcp.31006] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/17/2023] [Accepted: 03/15/2023] [Indexed: 04/08/2023]
Abstract
Flavonoids are secondary metabolites present in plant organs and tissues. These natural metabolites are the most prevalent and display a wide range of beneficial physiological effects, making them usually intriguing in several scientific fields. Due to their safety for use and protective attributes, including antioxidant, anti-inflammatory, anticancer, and antimicrobial functions, flavonoids are broadly utilized in foods, pharmaceuticals, and nutraceuticals. However, conventional methods for producing flavonoids, such as plant extraction and chemical synthesis, entailed dangerous substances, and laborious procedures, with low product yield. Recent studies have documented the ability of microorganisms, such as fungi and bacteria, to synthesize adequate amounts of flavonoids. Bacterial biosynthesis of flavonoids from plant biomass is a viable and environmentally friendly technique for producing flavonoids on a larger scale and has recently received much attention. Still, only a few bacteria species, particularly Escherichia coli, have been extensively studied. The most recent developments in bacterial biosynthesis of flavonoids are reviewed and discussed in this article, including their various applications as natural food biocontrol agents. In addition, the challenges currently faced in bacterial flavonoid biosynthesis and possible solutions, including the application of modern biotechnology approaches for developing bacterial strains that could successfully produce flavonoids on an industrial scale, were elucidated.
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Affiliation(s)
- Charles O Okoye
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
- Department of Zoology & Environmental Biology, University of Nigeria, Nsukka, Nigeria
| | - Huifang Jiang
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Yanfang Wu
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Xia Li
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Lu Gao
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Yongli Wang
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
| | - Jianxiong Jiang
- Biofuels Institute, School of Environment & Safety Engineering, Jiangsu University, Zhenjiang, China
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Hu M, Yuan L, Zhu J. The Dual Role of NRF2 in Colorectal Cancer: Targeting NRF2 as a Potential Therapeutic Approach. J Inflamm Res 2024; 17:5985-6004. [PMID: 39247839 PMCID: PMC11380863 DOI: 10.2147/jir.s479794] [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: 05/24/2024] [Accepted: 08/22/2024] [Indexed: 09/10/2024] Open
Abstract
Colorectal cancer (CRC), as the third most common bisexual cancer worldwide, requires urgent research on its underlying mechanisms and intervention methods. NRF2 is an important transcription factor involved in the regulation of redox homeostasis, protein degradation, DNA repair, and other cancer processes, playing an important role in cancer. In recent years, the complex role of NRF2 in CRC has been continuously revealed: on the one hand, it exhibits a chemopreventive effect on cancer by protecting normal cells from oxidative stress, and on the other hand, it also exhibits a protective effect on malignant cells. Therefore, this article explores the dual role of NRF2 and its related signaling pathways in CRC, including their chemical protective properties and promoting effects in the occurrence, development, metastasis, and chemotherapy resistance of CRC. In addition, this article focuses on exploring the regulation of NRF2 in CRC ferroptosis, as well as NRF2 drug modulators (activators and inhibitors) targeting CRC, including natural products, compounds, and traditional Chinese medicine formulations.
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Affiliation(s)
- Mengyun Hu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Lingling Yuan
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Jie Zhu
- Hospital of Chengdu University of Traditional Chinese Medicine, Oncology Department II, Chengdu, People's Republic of China
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Zhang XZ, Mo XC, Wang ZT, Sun R, Sun DQ. N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway. World J Gastrointest Oncol 2024; 16:2769-2780. [PMID: 38994173 PMCID: PMC11236237 DOI: 10.4251/wjgo.v16.i6.2769] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Wnt/FZD-mediated signaling pathways are activated in more than 90% of hepatocellular carcinoma (HCC) cell lines. As a well-known secretory glycoprotein, Wnt3 can interact with FZD receptors on the cell surface, thereby activating the Wnt/β-catenin signaling pathway. However, the N-glycosylation modification site of Wnt3 and the effect of this modification on the biological function of the protein are still unclear. AIM To investigate the effect of Wnt3 N-glycosylation on the biological function of HCC cells. METHODS Site-directed mutagenesis was used to verify the Wnt3 N-glycosylation sites, actinomycin D treatment was used to detect the stability of Wnt3 after site-directed mutation, the binding of the N-glycosylation site-directed mutant Wnt3 to FZD7 was observed by laser confocal microscopy, and the effects of the N-glycosylation site-directed mutation of Wnt3 on the Wnt/β-catenin signaling pathway and the progression of HCC cells were detected by western blot and cell function experiments. RESULTS Wnt3 has two N-glycosylation-modified sites (Asn90 and Asn301); when a single site at amino acid 301 is mutated, the stability of Wnt3 is weakened; the binding ability of Wnt3 to FZD7 decreases when both sites are mutated simultaneously; and the level of proteins related to the Wnt/β-catenin signaling pathway is downregulated. Cell proliferation, migration and invasion are also weakened in the case of single 301 site and double-site mutations. CONCLUSION These results indicate that by inhibiting the N-glycosylation of Wnt3, the proliferation, migration, invasion and colony formation abilities of liver cancer cells can be weakened, which might provide new therapeutic strategies for clinical liver cancer in the future.
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Affiliation(s)
- Xin-Zhan Zhang
- Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Xiao-Chuan Mo
- Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Zhu-Ting Wang
- Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Rong Sun
- Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Da-Quan Sun
- Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
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7
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Bruić M, Pirković A, Borozan S, Nacka Aleksić M, Jovanović Krivokuća M, Spremo-Potparević B. Antioxidative and anti-inflammatory effects of taxifolin in H 2O 2-induced oxidative stress in HTR-8/SVneo trophoblast cell line. Reprod Toxicol 2024; 126:108585. [PMID: 38574953 DOI: 10.1016/j.reprotox.2024.108585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/06/2024]
Abstract
Oxidative stress has been implicated in numerous pregnancy-related disorders. Biologically active plant secondary metabolites, which are present in everyday diet, could prove effective therapeutic agents in preventing these disorders. This study evaluated effects of taxifolin (dihydroquercetin) on ROS production, markers of oxidative damage to lipids and proteins, activity of antioxidant enzymes and production of pro-inflammatory cytokines in H2O2-induced oxidative stress in trophoblast HTR-8/SVneo cells. Taxifolin in 10 µM and 100 µM concentrations attenuated oxidative damage to lipids and proteins, as evidenced by a decrease in MDA content, extracellular LDH activity, carbonyl groups and nitrite contents. A reduction in the activity of antioxidant enzymes SOD, CAT and GPx in cells pre-treated with taxifolin, prior to H2O2 exposure, was also observed, along with a reduction in intracellular ROS production. Both evaluated concentrations of taxifolin showed anti-inflammatory activity in trophoblast cells, by reducing production of pro-inflammatory cytokines IL-1β and IL-6. In this model of H2O2-induced oxidative stress, taxifolin showed marked antioxidative and anti-inflammatory activities in trophoblast cells, adding further evidence of its protective effects and showing potential as a therapeutic agent in preventing adverse pregnancy outcomes.
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Affiliation(s)
- Marija Bruić
- University of Belgrade, Faculty of Pharmacy, Department of Pathobiology, Belgrade, Serbia.
| | - Andrea Pirković
- University of Belgrade, INEP Institute for Application of Nuclear Energy, Department for Biology of Reproduction, Belgrade, Serbia
| | - Sunčica Borozan
- University of Belgrade - Faculty of Veterinary Medicine, Department of Chemistry, Belgrade, Serbia
| | - Mirjana Nacka Aleksić
- University of Belgrade, INEP Institute for Application of Nuclear Energy, Department for Biology of Reproduction, Belgrade, Serbia
| | - Milica Jovanović Krivokuća
- University of Belgrade, INEP Institute for Application of Nuclear Energy, Department for Biology of Reproduction, Belgrade, Serbia
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Fu Y, Yuan P, Zeng M, Zhang Q, Hou Y, Gao L, Wei Y, Zheng Y, Feng W, Zheng X. Dihydroquercetin regulates HIF-1α/AKT/NR2B signalling to improve impaired brain function in rats with metabolic syndrome. Heliyon 2024; 10:e29807. [PMID: 38737244 PMCID: PMC11088260 DOI: 10.1016/j.heliyon.2024.e29807] [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: 08/01/2023] [Revised: 03/19/2024] [Accepted: 04/15/2024] [Indexed: 05/14/2024] Open
Abstract
Dihydroquercetin (DHQ) is commonly used as a dietary additive, but its activity in improving brain injury with metabolic syndrome (MS) remains known. In present study, the MS rat model was induced using 10 % fructose water. The apoptosis rate of primary brain cells was detected. The HIF-1α/AKT/NR2B signalling pathway, levels of KEAP1/NRF2, HO-1 and NQO-1 were detected. In vitro experiments were performed using H2O2-stimulated PC-12 cells. The effect of DHQ on rates of cell survival and apoptosis were detected. After silencing HIF-1α, we further elucidate the mechanism of action of DHQ. The results indicated that DHQ reduced the hyperactivity and inhibited oxidative stress via increasing the levels of HIF-1α/AKT/NR2B signalling pathway, whereas regulated KEAP1/NRF2 pathway. In vitro experiments showed that the HIF-1α plays an important role in this process. Overall, DHQ may improve impaired brain function in rats with metabolic syndrome by regulating the HIF-1α/AKT/NR2B signalling pathway.
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Affiliation(s)
- Yang Fu
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
| | - PeiPei Yuan
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
| | - Mengnan Zeng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
| | - Qi Zhang
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying Hou
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Liyuan Gao
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yaxin Wei
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yajuan Zheng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Weisheng Feng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
| | - Xiaoke Zheng
- Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China
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Culletta G, Buttari B, Arese M, Brogi S, Almerico AM, Saso L, Tutone M. Natural products as non-covalent and covalent modulators of the KEAP1/NRF2 pathway exerting antioxidant effects. Eur J Med Chem 2024; 270:116355. [PMID: 38555855 DOI: 10.1016/j.ejmech.2024.116355] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 04/02/2024]
Abstract
By controlling several antioxidant and detoxifying genes at the transcriptional level, including NAD(P)H quinone oxidoreductase 1 (NQO1), multidrug resistance-associated proteins (MRPs), UDP-glucuronosyltransferase (UGT), glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, glutathione S-transferase (GST), sulfiredoxin1 (SRXN1), and heme-oxygenase-1 (HMOX1), the KEAP1/NRF2 pathway plays a crucial role in the oxidative stress response. Accordingly, the discovery of modulators of this pathway, activating cellular signaling through NRF2, and targeting the antioxidant response element (ARE) genes is pivotal for the development of effective antioxidant agents. In this context, natural products could represent promising drug candidates for supplementation to provide antioxidant capacity to human cells. In recent decades, by coupling in silico and experimental methods, several natural products have been characterized to exert antioxidant effects by targeting the KEAP1/NRF2 pathway. In this review article, we analyze several natural products that were investigated experimentally and in silico for their ability to modulate KEAP1/NRF2 by non-covalent and covalent mechanisms. These latter represent the two main sections of this article. For each class of inhibitors, we reviewed their antioxidant effects and potential therapeutic applications, and where possible, we analyzed the structure-activity relationship (SAR). Moreover, the main computational techniques used for the most promising identified compounds are detailed in this survey, providing an updated view on the development of natural products as antioxidant agents.
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Affiliation(s)
- Giulia Culletta
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy
| | - Brigitta Buttari
- Department of Cardiovascular, Endocrine-metabolic Diseases, and Aging, Italian National Institute of Health, 00161, Rome, Italy
| | - Marzia Arese
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, 00185, Rome, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy; Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.
| | - Anna Maria Almerico
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Marco Tutone
- Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
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10
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Jiang H, Lin C, Cai T, Jiang L, Lou C, Lin S, Wang W, Yan Z, Pan X, Xue X. Taxifolin-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of glucocorticoid-induced osteonecrosis of the femoral head. Phytother Res 2024; 38:156-173. [PMID: 37846877 DOI: 10.1002/ptr.8031] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/27/2023] [Accepted: 09/23/2023] [Indexed: 10/18/2023]
Abstract
Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long-term or excessive use of glucocorticoids (GCs). Taxifolin (TAX) is a natural antioxidant with various pharmacological effects, such as antioxidative stress and antiapoptotic properties. The purpose of this study was to explore whether TAX could regulate oxidative stress and apoptosis in GIONFH by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. We conducted qRT-PCR, Western blotting, TUNEL assays, flow cytometry, and other experiments in vitro. Microcomputed tomography analysis, hematoxylin-eosin staining, and immunohistochemical staining were performed to determine the therapeutic effect of TAX in vivo. TAX mitigated the overexpression of ROS and NOX gene expression induced by DEX, effectively reducing oxidative stress. Additionally, TAX could alleviate DEX-induced osteoblast apoptosis, as evidenced by qRT-PCR, Western blotting, and other experimental techniques. Our in vivo studies further demonstrated that TAX mitigates the progression of GIONFH in rats by combating oxidative stress and apoptosis. Mechanistic exploration revealed that TAX thwarts the progression of GIONFH through the activation of the Nrf2 pathway. Overall, our research herein reports that TAX-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of GIONFH.
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Affiliation(s)
- Hongyi Jiang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Chihao Lin
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Tingwen Cai
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Liting Jiang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Chao Lou
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Shida Lin
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Weidan Wang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Zijian Yan
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China
- The Second Clinical School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Xiaoyun Pan
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xinghe Xue
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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11
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Woon CK, Ahmad FB, Zamakshshari NH. Chemical Constituents and Biological Activities of Piper as Anticancer Agents: A Review. Chem Biodivers 2023; 20:e202300166. [PMID: 37515318 DOI: 10.1002/cbdv.202300166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 07/30/2023]
Abstract
Cancer has become the primary cause of death worldwide, and anticancer drugs are used to combat this disease. Synthesis of anticancer drugs has limited success due to adverse side effects has made compounds from natural products with minimal toxicity gain much popularity. Piper species are known to have a biological effect on human health. The biological activity is due to Piper species rich with active secondary metabolites that can combat most diseases, including cancer. This review will discuss the phytochemistry of Piper species and their anticancer activity. The identification and characterization of ten active metabolites isolated from Piper species were discussed in detail and their anticancer mechanism. These metabolites were mainly found could inhibit anticancer through caspase and P38/JNK pathways. The findings discussed in this review support the therapeutic potential of Piper species against cancer due to their rich source of active metabolites with demonstrated anticancer activity.
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Affiliation(s)
- Choy Ker Woon
- Department of Anatomy, Faculty of Medicine, Universiti Teknologi Mara, Malaysia
| | | | - Nor Hisam Zamakshshari
- Chemistry Department, Faculty of Resource Science and Technology, Universiti Malaysia Sarawak, Malaysia
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12
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Caamaño JN, Santiago-Moreno J, Martínez-Pastor F, Tamargo C, Salman A, Fernández Á, Merino MJ, Lacalle E, Toledano-Díaz A, Hidalgo CO. Use of the flavonoid taxifolin for sperm cryopreservation from the threatened Bermeya goat breed. Theriogenology 2023; 206:18-27. [PMID: 37172535 DOI: 10.1016/j.theriogenology.2023.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 04/24/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023]
Abstract
Taxifolin is a plant flavonoid effective as an antioxidant. This study aimed to assess the effect of adding taxifolin to the semen extender during the cooling period before freezing on the overall post-thawing sperm variables of Bermeya goats. In the first experiment, a dose-response experiment was performed with four experimental groups: Control, 10, 50, and 100 μg/ml of taxifolin using semen from 8 Bermeya males. In the second experiment, semen from 7 Bermeya bucks was collected and extended at 20 °C using a Tris-citric acid-glucose medium supplemented with different concentrations of taxifolin and glutathione (GSH): control, 5 μM taxifolin, 1 mM GSH, and both antioxidants. In both experiments, two straws per buck were thawed in a water bath (37 °C, 30 s), pooled, and incubated at 38 °C. Motility (CASA) was assessed at 0, 2, and 5 h, and sperm physiology was assessed at 0 and 5 h by flow cytometry (viability, intact acrosome membrane, mitochondria membrane potential, capacitation, intracellular reactive oxygen species -ROS-, mitochondrial superoxide, and chromatin status). In experiment 2, an artificial insemination trial (AI) was included with 29 goats for testing the taxifolin 5-μM treatment on fertility. Data were analyzed with the R statistical environment using linear mixed-effects models. In experiment 1 and compared to the control, T10 increased progressive motility (P < 0.001) but taxifolin decreased total and progressive motility at higher concentrations (P < 0.001), both post-thawing and after the incubation. Viability decreased post-thawing in the three concentrations (P < 0.001). Cytoplasmic ROS decreased at 0 and 5 h at T10 (P = 0.049), and all doses decreased mitochondrial superoxide post-thawing (P = 0.024). In experiment 2, 5 μM taxifolin or 1 mM GSH (alone or combined) increased total and progressive motility vs. the control (P < 0.01), and taxifolin increased kinematic parameters such as VCL, ALH, and DNC (P < 0.05). Viability was not affected by taxifolin in this experiment. Both antioxidants did not significantly affect other sperm physiology parameters. The incubation significantly affected all the parameters (P < 0.004), overall decreasing sperm quality. Fertility after artificial insemination with doses supplemented with 5 μM taxifolin was 76.9% (10/13), not significantly different from the control group (69.2%, 9/13). In conclusion, taxifolin showed a lack of toxicity in the low micromolar range and could benefit goat semen cryopreservation.
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Affiliation(s)
- J N Caamaño
- Department of Animal Selection and Reproduction, Regional Service for Agrifood Research and Development (SERIDA), Gijón, Asturias, Spain.
| | | | - F Martínez-Pastor
- INDEGSAL, Universidad de León, León, Spain; Molecular Biology (Cell Biology), Universidad de León, León, Spain
| | - C Tamargo
- Department of Animal Selection and Reproduction, Regional Service for Agrifood Research and Development (SERIDA), Gijón, Asturias, Spain
| | - A Salman
- INDEGSAL, Universidad de León, León, Spain
| | - Á Fernández
- Department of Animal Selection and Reproduction, Regional Service for Agrifood Research and Development (SERIDA), Gijón, Asturias, Spain
| | - M J Merino
- Department of Animal Selection and Reproduction, Regional Service for Agrifood Research and Development (SERIDA), Gijón, Asturias, Spain
| | - E Lacalle
- INDEGSAL, Universidad de León, León, Spain
| | | | - C O Hidalgo
- Department of Animal Selection and Reproduction, Regional Service for Agrifood Research and Development (SERIDA), Gijón, Asturias, Spain
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13
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Abid N, Hamad E, Ibrahim M, Abid H. Antibacterial and antibiofilm activities of taxifolin against vancomycin-resistant S. aureus (VRSA). BAGHDAD JOURNAL OF BIOCHEMISTRY AND APPLIED BIOLOGICAL SCIENCES 2022. [DOI: 10.47419/bjbabs.v3i04.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background and objective: The medicinal effects of flavonoids are widely described in the literature; however, their antimicrobial effects against antibiotic resistant bacteria are yet to be highlighted. This study was aimed at investigating the growth and biofilm inhibitory effects of taxifolin, a flavonoid, against vancomycin-resistant Staphylococcus aureus (VRSA).
Methods: Seven VRSA isolates were used to assess the antimicrobial and antibiofilm influence of taxifolin. The agar-well diffusion method was used to determine the zones of inhibition caused by taxifolin, and resazurin-based microdilution technique was used to assess the minimum inhibitory concentration. Crystal violet staining technique was used to assess the biomass of biofilms formed by the microorganisms. GraphPad Prism software was used to present the data in figures.
Results: Taxifolin inhibited bacterial growth in a dose-dependent fashion and reduced bacterial viability. It similarly attenuated the biofilm production activity of bacterial isolates in a dose-dependent manner.
Conclusions: Current findings suggest the antibacterial and antibiofilm influence of taxifolin against VRSA in a dose-dependent manner.
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Schmitt F, Eckert GP. Caenorhabditis elegans as a Model for the Effects of Phytochemicals on Mitochondria and Aging. Biomolecules 2022; 12:1550. [PMID: 36358900 PMCID: PMC9687847 DOI: 10.3390/biom12111550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 09/08/2024] Open
Abstract
The study of aging is an important topic in contemporary research. Considering the demographic changes and the resulting shifts towards an older population, it is of great interest to preserve youthful physiology in old age. For this endeavor, it is necessary to choose an appropriate model. One such model is the nematode Caenorhabditis elegans (C. elegans), which has a long tradition in aging research. In this review article, we explore the advantages of using the nematode model in aging research, focusing on bioenergetics and the study of secondary plant metabolites that have interesting implications during this process. In the first section, we review the situation of aging research today. Conventional theories and hypotheses about the ongoing aging process will be presented and briefly explained. The second section focuses on the nematode C. elegans and its utility in aging and nutrition research. Two useful genome editing methods for monitoring genetic interactions (RNAi and CRISPR/Cas9) are presented. Due to the mitochondria's influence on aging, we also introduce the possibility of observing bioenergetics and respiratory phenomena in C. elegans. We then report on mitochondrial conservation between vertebrates and invertebrates. Here, we explain why the nematode is a suitable model for the study of mitochondrial aging. In the fourth section, we focus on phytochemicals and their applications in contemporary nutritional science, with an emphasis on aging research. As an emerging field of science, we conclude this review in the fifth section with several studies focusing on mitochondrial research and the effects of phytochemicals such as polyphenols. In summary, the nematode C. elegans is a suitable model for aging research that incorporates the mitochondrial theory of aging. Its living conditions in the laboratory are optimal for feeding studies, thus enabling bioenergetics to be observed during the aging process.
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Affiliation(s)
| | - Gunter P. Eckert
- Laboratory for Nutrition in Prevention and Therapy, Biomedical Research Center Seltersberg (BFS), Institute of Nutritional Science, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany
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Taxifolin and Lucidin as Potential E6 Protein Inhibitors: p53 Function Re-Establishment and Apoptosis Induction in Cervical Cancer Cells. Cancers (Basel) 2022; 14:cancers14122834. [PMID: 35740499 PMCID: PMC9221127 DOI: 10.3390/cancers14122834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/29/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Human papillomavirus (HPV)-related cancers continue to be a major medical concern, and there exists an urgent need to improve the current therapeutic approaches by combining strategies or proposing new compounds to offer more specific and less invasive treatments. The aim of this work was to discover potential inhibitors of the E6/E6AP/p53 complex formation. We started this work with an initial in silico approach including molecular docking and molecular dynamics simulations, and these tools allowed us to select potential inhibitors, using E6 protein as a target. In addition, we found that lucidin and taxifolin were able to selectively decrease the viability of HPV-positive cells to re-establish p53 protein levels and to induce apoptosis. These findings represent a promising starting point for the development of anti-HPV drugs. Abstract Cervical cancer is the fourth leading cause of death in women worldwide, with 99% of cases associated with a human papillomavirus (HPV) infection. Given that HPV prophylactic vaccines do not exert a therapeutic effect in individuals previously infected, have low coverage of all HPV types, and have poor accessibility in developing countries, it is unlikely that HPV-associated cancers will be eradicated in the coming years. Therefore, there is an emerging need for the development of anti-HPV drugs. Considering HPV E6’s oncogenic role, this protein has been proposed as a relevant target for cancer treatment. In the present work, we employed in silico tools to discover potential E6 inhibitors, as well as biochemical and cellular assays to understand the action of selected compounds in HPV-positive cells (Caski and HeLa) vs. HPV-negative (C33A) and non-carcinogenic (NHEK) cell lines. In fact, by molecular docking and molecular dynamics simulations, we found three phenolic compounds able to dock in the E6AP binding pocket of the E6 protein. In particular, lucidin and taxifolin were able to inhibit E6-mediated p53 degradation, selectively reduce the viability, and induce apoptosis in HPV-positive cells. Altogether, our data can be relevant for discovering promising leads for the development of specific anti-HPV drugs.
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16
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Yuan L, Sun Y, Zhou N, Wu W, Zheng W, Wang Y. Dihydroquercetin Attenuates Silica-Induced Pulmonary Fibrosis by Inhibiting Ferroptosis Signaling Pathway. Front Pharmacol 2022; 13:845600. [PMID: 35645837 PMCID: PMC9133504 DOI: 10.3389/fphar.2022.845600] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 04/27/2022] [Indexed: 01/25/2023] Open
Abstract
Silicosis is a fatal occupational lung disease which currently has no effective treatment. Dihydroquercetin (DHQ) is a flavonoid compound known for its anti-inflammatory, anti-oxidant and anti-cancer bioactivity. However, whether DHQ protects against silica-induced lung fibrosis remains unknown. Therefore, we aimed to investigate the effect of DHQ on silica-induced lung fibrosis and the underlying molecular mechanism in vivo and in vitro. Our results demonstrated that DHQ treatment markedly attenuated SiO2-induced inflammation and fibrosis degree of lung tissues in the C57BL/6 mice. Additionally, experiments in vitro also confirmed that conditioned medium from DHQ-treated human bronchial epithelial (HBE) cells significantly decreased expression of fibrosis markers of human fetal lung fibroblast cells (MRC-5), such as α-SMA, collagen1 and fibronectin. Interestingly, HBE cells treated by DHQ showed few morphological features of ferroptosis compared with SiO2-treated cells. Furthermore, DHQ treatment remarkably inhibited ferroptosis in activated HBE cells by decreasing the accumulation of iron and lipid peroxidation products, and increasing levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4), whereas stimulation of ferroptosis by specific inducer erastin deeply impaired anti-fibrosis effect of DHQ in vitro. More importantly, our results showed that DHQ also evidently suppressed ferritinophagy by down-regulation of microtubule-associated protein 1A/1B-light chain 3 (LC3), and up-regulation of ferritin heavy chain 1 (FTH1), nuclear receptor co-activator 4 (NCOA4) in activated HBE cells. Nevertheless, activation of ferritinophagy by specific inducer rapamycin (Rapa) evidently blocked DHQ-inhibited HBE cells ferritinophagy and anti-fibrosis effect of DHQ. Overall, our research revealed that inhibition of ferritinophagy-mediated HBE cells ferroptosis was responsible for DHQ to ameliorate SiO2-induced lung fibrosis, which provided a preliminary theoretical basis for the clinical application of DHQ in the treatment of silicosis.
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Affiliation(s)
- Leyong Yuan
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Yan Sun
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Ning Zhou
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Weipeng Wu
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Weidong Zheng
- Department of Laboratory Medicine, Shenzhen University General Hospital, Shenzhen, China
- *Correspondence: Weidong Zheng, ; Yukun Wang,
| | - Yukun Wang
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Shenzhen, China
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- *Correspondence: Weidong Zheng, ; Yukun Wang,
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17
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The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions. Biomolecules 2022; 12:biom12030367. [PMID: 35327559 PMCID: PMC8945214 DOI: 10.3390/biom12030367] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer is a complex disease resulting from the genetic and epigenetic disruption of normal cells. The mechanistic understanding of the pathways involved in tumor transformation has implicated a priori predominance of epigenetic perturbations and a posteriori genetic instability. In this work, we aimed to explain the mechanistic involvement of epigenetic pathways in the cancer process, as well as the abilities of natural bioactive compounds isolated from medicinal plants (flavonoids, phenolic acids, stilbenes, and ketones) to specifically target the epigenome of tumor cells. The molecular events leading to transformation, angiogenesis, and dissemination are often complex, stochastic, and take turns. On the other hand, the decisive advances in genomics, epigenomics, transcriptomics, and proteomics have allowed, in recent years, for the mechanistic decryption of the molecular pathways of the cancerization process. This could explain the possibility of specifically targeting this or that mechanism leading to cancerization. With the plasticity and flexibility of epigenetic modifications, some studies have started the pharmacological screening of natural substances against different epigenetic pathways (DNA methylation, histone acetylation, histone methylation, and chromatin remodeling) to restore the cellular memory lost during tumor transformation. These substances can inhibit DNMTs, modify chromatin remodeling, and adjust histone modifications in favor of pre-established cell identity by the differentiation program. Epidrugs are molecules that target the epigenome program and can therefore restore cell memory in cancerous diseases. Natural products isolated from medicinal plants such as flavonoids and phenolic acids have shown their ability to exhibit several actions on epigenetic modifiers, such as the inhibition of DNMT, HMT, and HAT. The mechanisms of these substances are specific and pleiotropic and can sometimes be stochastic, and their use as anticancer epidrugs is currently a remarkable avenue in the fight against human cancers.
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18
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Oliveira LFS, Predes D, Borges HL, Abreu JG. Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14020403. [PMID: 35053565 PMCID: PMC8774030 DOI: 10.3390/cancers14020403] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is an emerging public health problem and the second leading cause of death worldwide, with a significant socioeconomic impact in several countries. The 5-year survival rate is only 12% due to the lack of early diagnosis and resistance to available treatments, and the canonical Wnt signaling pathway is involved in this process. This review underlines the importance of understanding the fundamental roles of this pathway in physiological and pathological contexts and analyzes the use of naturally occurring small molecules that inhibits the Wnt/β-catenin pathway in experimental models of CRC. We also discuss the progress and challenges of moving these small molecules off the laboratory bench into the clinical platform. Abstract Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.
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19
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Wang L, Gao M, Kang G, Huang H. The Potential Role of Phytonutrients Flavonoids Influencing Gut Microbiota in the Prophylaxis and Treatment of Inflammatory Bowel Disease. Front Nutr 2021; 8:798038. [PMID: 34970585 PMCID: PMC8713745 DOI: 10.3389/fnut.2021.798038] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/25/2021] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel disease (IBD), characterized by the chronic inflammation of the gastrointestinal tract, is comprised of two idiopathic chronic intestinal inflammatory diseases. As the incidence of IBD increases, so does the need for safe and effective treatments. Trillions of microorganisms are colonized in the mammalian intestine, coevolve with the host in a symbiotic relationship. Gut microbiota has been reported to be involved in the pathophysiology of IBD. In this regard, phytonutrients flavonoids have received increasing attention for their anti-oxidant and anti-inflammatory activities. In this review, we address recent advances in the interactions among flavonoids, gut microbiota, and IBD. Moreover, their possible potential mechanisms of action in IBD have been discussed. We conclude that there is a complex interaction between flavonoids and gut microbiota. It is expected that flavonoids can change or reshape the gut microbiota to provide important considerations for developing treatments for IBD.
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Affiliation(s)
- Lina Wang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin, China
| | - Mengxue Gao
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin, China
| | - Guangbo Kang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin, China
| | - He Huang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin, China
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20
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Wan F, Han H, Zhong R, Wang M, Tang S, Zhang S, Hou F, Yi B, Zhang H. Dihydroquercetin supplement alleviates colonic inflammation potentially through improved gut microbiota community in mice. Food Funct 2021; 12:11420-11434. [PMID: 34673859 DOI: 10.1039/d1fo01422f] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The purpose of the current study was to investigate the effect of dietary dihydroquercetin (DHQ) supplementation on dextran sodium sulfate (DSS)-induced colitis in mice. Mice were given DHQ supplementation (3 g kg-1) throughout the study, starting 14 days prior to DSS treatment for 1 week followed by 2 days without DSS. The results showed that dietary DHQ supplementation restored DSS-induced disease activity index (DAI), colon length and histopathology scores of the colon tissue. Additionally, supplementation with DHQ reduced the pro-inflammatory cytokine levels, and enhanced the level of IL-10 in the serum. qPCR results indicated that DHQ supplementation significantly downregulated IL-1β, IL-6, and TNF-α, and upregulated IL-10 gene mRNA expression. Western blot results proved that DHQ supplementation upregulated ZO-1 and occludin levels. Using amplicon sequencing technology, 16S rRNA sequencing results showed that DHQ supplementation increased the fecal Firmicutes/Bacteroidetes ratio and the relative abundance of Lactobacillus and Dubosiella, and decreased the relative abundance of Bacteroidetes. Additionally, DHQ supplementation restored the decreased fecal acetic acid and butyric acid concentrations in DSS-induced colitis mice. Besides, Spearman's correlation analysis showed that Dubosiella was positively correlated with the butyric acid level and Bacteroidetes was positively correlated with the mRNA expression of IL-1β and IL-6. Both Lactobacillus and Dubosiella showed a negative correlation with the mRNA expression of IL-1β, IL-6, and TNF-α, and Dubosiella was positively correlated with IL-10. In summary, it was found that DHQ supplementation alleviated DSS-induced colitis which may be potentially associated with altered fecal microbiota communities in mice.
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Affiliation(s)
- Fan Wan
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. .,State Key Laboratory of Grassland Agro-Ecosystem, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Hui Han
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Mengyu Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Shanlong Tang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Shunfen Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Fujiang Hou
- State Key Laboratory of Grassland Agro-Ecosystem, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Bao Yi
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. .,State Key Laboratory of Grassland Agro-Ecosystem, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
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21
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Ajjarapu SM, Tiwari A, Taj G, Singh DB, Singh S, Kumar S. Simulation studies, 3D QSAR and molecular docking on a point mutation of protein kinase B with flavonoids targeting ovarian Cancer. BMC Pharmacol Toxicol 2021; 22:68. [PMID: 34727985 PMCID: PMC8564994 DOI: 10.1186/s40360-021-00512-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/09/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Ovarian cancer is the world's dreaded disease and its prevalence is expanding globally. The study of integrated molecular networks is crucial for the basic mechanism of cancer cells and their progression. During the present investigation, we have examined different flavonoids that target protein kinases B (AKT1) protein which exerts their anticancer efficiency intriguing the role in cross-talk cell signalling, by metabolic processes through in-silico approaches. METHOD Molecular dynamics simulation (MDS) was performed to analyze and evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. This investigation revealed the effect of a point mutation (W80R), considered based on their frequency of occurrence, with AKT1 protein. RESULTS The ligand with high docking scores and favourable behaviour on dynamic simulations are proposed as potential W80R inhibitors. A virtual screening analysis was performed with 12,000 flavonoids satisfying Lipinski's rule of five according to which drug-likeness is predicted based on its pharmacological and biological properties to be active and taken orally. The pharmacokinetic ADME (adsorption, digestion, metabolism, and excretion) studies featured drug-likeness. Subsequently, a statistically significant 3D-QSAR model of high correlation coefficient (R2) with 0.822 and cross-validation coefficient (Q2) with 0.6132 at 4 component PLS (partial least square) were used to verify the accuracy of the models. Taxifolin holds good interactions with the binding domain of W80R, highest Glide score of - 9.63 kcal/mol with OH of GLU234 and H bond ASP274 and LEU156 amino acid residues and one pi-cation interaction and one hydrophobic bond with LYS276. CONCLUSION Natural compounds have always been a richest source of active compounds with a wide variety of structures, therefore, these compounds showed a special inspiration for medical chemists. The present study has aimed molecular docking and molecular dynamics simulation studies on taxifolin targeting W80R mutant protein of protein kinase B/serine- threonine kinase/AKT1 (EC:2.7.11.1) protein of ovarian cancer for designing therapeutic intervention. The expected result supported the molecular cause in a mutant form which resulted in a gain of ovarian cancer. Here we discussed validations computationally and yet experimental evaluation or in vivo studies are endorsed for further study. Several of these compounds should become the next marvels for early detection of ovarian cancer.
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Affiliation(s)
- Suchitra Maheswari Ajjarapu
- Bioinformatics Sub-DIC, Department of Molecular Biology & Genetic Engineering, College of Basic Science and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar, Udham Singh Nagar, 263145, Uttarakhand, India
- Department of Biotechnology, Andhra University, Vishakhapatnam, 530003, Andhra Pradesh, India
| | - Apoorv Tiwari
- Bioinformatics Sub-DIC, Department of Molecular Biology & Genetic Engineering, College of Basic Science and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar, Udham Singh Nagar, 263145, Uttarakhand, India
- Department of Computational Biology and Bioinformatics, Jacob Institute of Biotechnology and Bio-Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, Uttar Pradesh, 211007, India
| | - Gohar Taj
- Bioinformatics Sub-DIC, Department of Molecular Biology & Genetic Engineering, College of Basic Science and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar, Udham Singh Nagar, 263145, Uttarakhand, India
| | - Dev Bukhsh Singh
- Department of Biotechnology, Siddharth University, Kapilvastu, Siddharth Nagar, 272202, Uttar Pradesh, India
| | - Sakshi Singh
- Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India
| | - Sundip Kumar
- Bioinformatics Sub-DIC, Department of Molecular Biology & Genetic Engineering, College of Basic Science and Humanities, Govind Ballabh Pant University of Agriculture and Technology, Pantnagar, Udham Singh Nagar, 263145, Uttarakhand, India.
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Kabel AM, Arab HH, Abd Elmaaboud MA. Attenuation of diethyl nitrosamine-induced hepatocellular carcinoma by taxifolin and/or alogliptin: The interplay between toll-like receptor 4, transforming growth factor beta-1, and apoptosis. Hum Exp Toxicol 2021; 40:1710-1720. [PMID: 33840231 DOI: 10.1177/09603271211008496] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver malignancies worldwide. Alogliptin is an anti-diabetic that may have effective anticancer properties against many types of malignancies. Taxifolin is a flavonoid that has potent antioxidant, and anti-inflammatory properties. The objective of this study was to explore the impact of alogliptin and/or taxifolin on diethyl nitrosamine-induced HCC in rats. One hundred male Wistar rats were divided into five equal groups as follows: Control; HCC; HCC + Alogliptin; HCC + Taxifolin; and HCC + Alogliptin + Taxifolin group. The survival rate, liver function tests, tissue antioxidant enzymes, malondialdehyde (MDA), nuclear factor (erythroid derived 2)-like 2 (Nrf2), transforming growth factor beta 1 (TGF-β1), interleukin 1 alpha (IL-1α), and toll-like receptor 4 (TLR4) were measured. Also, hepatic caspase 3, caspase 9, beclin-1, and c-Jun NH2-terminal kinase (JNK) in addition to serum alpha-fetoprotein (AFP) and α-L-Fucosidase (AFU) were assessed. Specimens of the liver were subjected to histopathological examination. Alogliptin and/or taxifolin induced significant improvement of liver function tests with significant increase in the survival rate, tissue antioxidant enzymes, Nrf2, caspase 3, caspase 9, Beclin-1 and JNK activities associated with significant decrease in serum AFP and AFU, tissue MDA, TGF-β1, IL-1α and TLR4 expression compared to HCC group. These results were significant with taxifolin/alogliptin combination when compared to the use of each of these agents alone. In conclusion, taxifolin/alogliptin combination might be used as adjuvant therapy for attenuation of HCC.
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Affiliation(s)
- A M Kabel
- Pharmacology Department, 68782Faculty of Medicine, Tanta University, Tanta, Egypt
| | - H H Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, 125895Taif University, Taif, Saudi Arabia
| | - M A Abd Elmaaboud
- Pharmacology Department, 68782Faculty of Medicine, Tanta University, Tanta, Egypt
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Kabel AM, Salama SA. Effect of taxifolin/dapagliflozin combination on colistin-induced nephrotoxicity in rats. Hum Exp Toxicol 2021; 40:1767-1780. [PMID: 33882723 DOI: 10.1177/09603271211010906] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Colistin is an antimicrobial agent that is used in resistant gram-negative infections. Its most common dose-limiting adverse effect is nephrotoxicity. The objective of our study was to explore the possible effects of each of taxifolin and dapagliflozin alone and in combination on colistin-induced nephrotoxicity in rats. Sixty male rats were randomized into six groups: Control; colistin; colistin + taxifolin; colistin + dapagliflozin; colistin + carboxymethyl cellulose (CMC) and colistin + taxifolin + dapagliflozin. Dapagliflozin, taxifolin, and CMC were given daily for 7 days, 4 hours before colistin injection. Kidney weight/body weight ratio and renal function tests were determined. Renal tissue nerve growth factor-β (NGF-β), transforming growth factor beta 1 (TGF-β1), proinflammatory cytokines, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) p65, signal transducer and activator of transcription 3 (STAT3), oxidative stress parameters, beclin-1 and c-Jun NH2-terminal kinase (JNK) activities were measured. Kidneys were examined histopathologically and immunohistochemically. Taxifolin and/or dapagliflozin induced significant improvement in the renal functions and oxidative stress parameters with significant increase in tissue Nrf2, STAT3 and NGF-β accompanied with significant decrease in kidney weight/body weight ratio, tissue proinflammatory cytokines, TGF-β1, NF-κB (p65), TLR4, beclin-1 and JNK activities and improved the histopathological picture when compared to rats treated with colistin alone. This improvement was significant with taxifolin/dapagliflozin combination compared to rats treated with each of these agents alone. So, we concluded that the combined use of taxifolin and dapagliflozin may confer a therapeutic tool for attenuation of colistin-induced nephrotoxicity.
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Affiliation(s)
- A M Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - S A Salama
- Division of Biochemistry, Department of Pharmacology, College of Pharmacy, Taif University, Taif, Saudi Arabia
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Lektemur Alpan A, Bakar O, Kızıldağ A, Özdede M, Topsakal Ş, Özmen Ö. Effects of taxifolin on bone formation and apoptosis in experimental periodontitis in diabetic rats. Biotech Histochem 2021; 97:306-314. [PMID: 34547962 DOI: 10.1080/10520295.2021.1977997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
We investigated the therapeutic potential of taxifolin for treatment of alveolar bone loss (ABL) in experimental periodontitis in diabetic rats. Diabetes mellitus (DM) was induced by streptozotocin. Rats were divided into six groups: untreated control; DM only (D) group; ligature only (P) group; DM + ligature (DP) group; DM + ligature + 5 mg/kg/day taxifolin (Taxi-5) group; DM + ligature + 10 mg/kg/day taxifolin (Taxi-10) group. Experimental periodontitis was induced by ligation of the first molar and allowed to progress for 30 days before performing cone-beam computed tomographic (CBCT), histomorphometric and immunohistochemical analyses of periodontal tissue destruction. ABL was assessed using CBCT. ABL was greatest in the P and DP groups. Decreased ABL was observed in the Taxi-5 and Taxi-10 groups. Bone morphogenic protein (BMP-2), osteocalcin (OCN), receptor activator of nuclear factor kappa-Β ligand (RANKL), alkaline phosphatase (ALP), type I collagen, B cell lymphoma-associated X (Bax), and B-cell lymphoma 2 (Bcl-2) levels were investigated using immunohistochemistry. The Taxi-5 and Taxi-10 groups exhibited decreased RANKL expression, but increased BMP-2, ALP, type I collagen and OCN levels compared to the P and DP groups. Bax activity was increased in the D, P and DP groups. Taxi-5 and Taxi-10 groups exhibited increased Bcl-2 activity. Our findings suggest that taxifolin can reduce apoptosis and improve alveolar bone formation in diabetic rats with periodontitis.
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Affiliation(s)
- Aysan Lektemur Alpan
- Department of Periodontology, Faculty of Dentistry, Pamukkale University, Denizli, Turkey
| | | | - Alper Kızıldağ
- Department of Periodontology, Faculty of Dentistry, Pamukkale University, Denizli, Turkey
| | - Melih Özdede
- Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Pamukkale University, Denizli, Turkey
| | - Şenay Topsakal
- Department of Endocrinology and Metabolism, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Özlem Özmen
- Department of Pathology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
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Papierska K, Krajka-Kuźniak V, Paluszczak J, Kleszcz R, Skalski M, Studzińska-Sroka E, Baer-Dubowska W. Lichen-Derived Depsides and Depsidones Modulate the Nrf2, NF-κB and STAT3 Signaling Pathways in Colorectal Cancer Cells. Molecules 2021; 26:molecules26164787. [PMID: 34443375 PMCID: PMC8400444 DOI: 10.3390/molecules26164787] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/29/2021] [Accepted: 08/05/2021] [Indexed: 01/14/2023] Open
Abstract
The study aimed to evaluate the possible modulation of Nrf2, NF-ĸB and STAT3 signaling pathways in the colorectal cancer (CRC) cells line DLD-1 and HCT116 by secondary metabolites of lichens. An attempt was made to indicate the most promising targets in these signaling pathways. Attention was also paid to the effects of the compounds tested on CRC cells using anakoinosis-that is, simultaneous analysis of several signaling pathways. The effects of the tested natural compounds on the activity of selected transcriptional factors related to CRC were analyzed by Western blot and RT-PCR assays. The highest activity against CRC cells was shown by physodic and salazinic acids from the studied secondary metabolites of lichens. As a result, an increase in the activation of transcription factor Nrf2 and the expression of its selected target genes was observed. Physodic and salazinic acids induced the opposite effect in relation to the NF-κB and STAT3 pathways. These results confirmed our earlier observations that lichen-derived compounds have the ability to modulate signaling pathway networks. While caperatic acid affected Wnt/β-catenin to the most extent, salazinic acid was the most potent modulator of Nrf2, NF-κB and STAT3 pathways. Physodic acid seemed to affect all the investigated pathways.
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Affiliation(s)
- Katarzyna Papierska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland; (K.P.); (J.P.); (R.K.); (M.S.); (W.B.-D.)
| | - Violetta Krajka-Kuźniak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland; (K.P.); (J.P.); (R.K.); (M.S.); (W.B.-D.)
- Correspondence: ; Tel.: +48-61-854-66-21
| | - Jarosław Paluszczak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland; (K.P.); (J.P.); (R.K.); (M.S.); (W.B.-D.)
| | - Robert Kleszcz
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland; (K.P.); (J.P.); (R.K.); (M.S.); (W.B.-D.)
| | - Marcin Skalski
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland; (K.P.); (J.P.); (R.K.); (M.S.); (W.B.-D.)
| | - Elżbieta Studzińska-Sroka
- Department of Pharmacognosy, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland;
| | - Wanda Baer-Dubowska
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcicki Str., 60-781 Poznań, Poland; (K.P.); (J.P.); (R.K.); (M.S.); (W.B.-D.)
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Rathod B, Chak S, Patel S, Shard A. Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents. RSC Med Chem 2021; 12:1121-1141. [PMID: 34355179 PMCID: PMC8292966 DOI: 10.1039/d1md00045d] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer cells and is expressed in most human tumors. It is essential in indiscriminate proliferation, survival, and tackling apoptosis in cancer cells. This positions PKM2 as a hot target in cancer therapy. Despite its well-known structure and several reported modulators targeting PKM2 as activators or inhibitors, a comprehensive review focusing on such modulators is lacking. Herein we summarize modulators of PKM2, the assays used to detect their potential, the preferable tense (T) and relaxed (R) states in which the enzyme resides, lacunae in existing modulators, and several strategies that may lead to effective anticancer drug development targeting PKM2.
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Affiliation(s)
- Bhagyashri Rathod
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad Opposite Air Force Station Gandhinagar Gujarat 382355 India
| | - Shivam Chak
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad Opposite Air Force Station Gandhinagar Gujarat 382355 India
| | - Sagarkumar Patel
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad Opposite Air Force Station Gandhinagar Gujarat 382355 India
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad Opposite Air Force Station Gandhinagar Gujarat 382355 India
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Butt SS, Khan K, Badshah Y, Rafiq M, Shabbir M. Evaluation of pro-apoptotic potential of taxifolin against liver cancer. PeerJ 2021; 9:e11276. [PMID: 34113483 PMCID: PMC8162243 DOI: 10.7717/peerj.11276] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 03/24/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the second most common cause of cancer-induced deaths worldwide. Liver cirrhosis and cancer are a consequence of the abnormal angio-architecture formation of liver and formation of new blood vessels. This angiogenesis is driven by overexpression of hypoxia-inducible factor 1-alpha (Hif1-α) and vascular endothelial growth factor (VEGF). Apart from this, protein kinase B (Akt) is also impaired in liver cancer. Despite the advancement in conventional treatments, liver cancer remains largely incurable. Nowadays, the use of naturally occurring anticancer agents particularly flavonoids is subject to more attention due to their enhanced physicochemical properties. Therefore, this study underlines the use of a natural anticancer agent taxifolin in the treatment of liver cancer using hepatocellular carcinoma cell line HepG2 and Huh7. The aim of our study is to devise a natural and efficient solution for the disease prevalent in Pakistan. The study involved the assessment of binding of ligand taxifolin using molecular docking. The binding of taxifolin with the proteins (Hif1-α, VEGF and Akt) was calculated by docking using Vina and Chimera. Further evaluation was performed by cell viability assay (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Assay), colony formation assay, cell migration assay, DNA ladder assay and flow cytometry. To see whether taxifolin directly affected expression levels, analysis of gene expression of Hif1-α, VEGF and Akt was performed using real-time polymerase chain reaction (qPCR) and western blotting. In silico docking experiments revealed that these proteins showed favorable docking scores with taxifolin. Treatment with taxifolin resulted in the inhibition of the liver cancer growth and migration, and induced apoptosis in HepG2 and Huh7 cell lines at an inhibitory concentration (IC50) value of 0.15 µM and 0.22 µM, respectively. The expression of HIF1-α, VEGF and Akt was significantly reduced in a dose- dependent manner. The inhibitory effect of taxifolin on hepatic cells suggested its chemopreventive and therapeutic potential. The studied compound taxifolin exhibited pronounced pro-apoptotic and hepatoprotective potential. Our study has confirmed the pro-apoptotic potential of taxifolin in liver cancer cell lines and will pave a way to the use of taxifolin as a chemotherapeutic agent after its further validation on the animal models and humans based epidemiological studies.
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Affiliation(s)
- Sania Safdar Butt
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Yasmin Badshah
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Mehak Rafiq
- Research Centre for Modelling and Simulation, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maria Shabbir
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
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Targeting the crosstalk between canonical Wnt/β-catenin and inflammatory signaling cascades: A novel strategy for cancer prevention and therapy. Pharmacol Ther 2021; 227:107876. [PMID: 33930452 DOI: 10.1016/j.pharmthera.2021.107876] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 04/05/2021] [Indexed: 02/06/2023]
Abstract
Emerging scientific evidence indicates that inflammation is a critical component of tumor promotion and progression. Most cancers originate from sites of chronic irritation, infections and inflammation, underscoring that the tumor microenvironment is largely orchestrated by inflammatory cells and pro-inflammatory molecules. These inflammatory components are intimately involved in neoplastic processes which foster proliferation, survival, invasion, and migration, making inflammation the primary target for cancer prevention and treatment. The influence of inflammation and the immune system on the progression and development of cancer has recently gained immense interest. The Wnt/β-catenin signaling pathway, an evolutionarily conserved signaling strategy, has a critical role in regulating tissue development. It has been implicated as a major player in cancer development and progression with its regulatory role on inflammatory cascades. Many naturally-occurring and small synthetic molecules endowed with inherent anti-inflammatory properties inhibit this aberrant signaling pathway, making them a promising class of compounds in the fight against inflammatory cancers. This article analyzes available scientific evidence and suggests a crosslink between Wnt/β-catenin signaling and inflammatory pathways in inflammatory cancers, especially breast, gastrointestinal, endometrial, and ovarian cancer. We also highlight emerging experimental findings that numerous anti-inflammatory synthetic and natural compounds target the crosslink between Wnt/β-catenin pathway and inflammatory cascades to achieve cancer prevention and intervention. Current challenges, limitations, and future directions of research are also discussed.
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Biologically Active Compounds in Stizolophus balsamita Inflorescences: Isolation, Phytochemical Characterization and Effects on the Skin Biophysical Parameters. Int J Mol Sci 2021; 22:ijms22094428. [PMID: 33922647 PMCID: PMC8122880 DOI: 10.3390/ijms22094428] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/20/2022] Open
Abstract
Three germacranolides, as well as five flavonoids, natural steroid and simple phenolic compounds, were isolated from the inflorescence of Stizolophus balsamita growing in Iran. The paper presents active compounds found for the first time in the inflorescence of this species. The flavonoids, simple phenolic compounds and natural steroids have been isolated for the first time in the genus Stizolophus. The MTT assay was employed to study in vitro cytotoxic effects of the taxifolin against human fibroblasts. We also evaluate the possible biological properties/cosmetic effects of Stizolophus balsamita extract and taxifolin on the human skin. Sixty healthy Caucasian adult females with no dermatological diseases were investigated. We evaluate the effects of S. balsamita extract and taxifolin on skin hydration and transepidermal water loss (TEWL). It was revealed that S. balsamita extract might decrease TEWL level and fixed the barrier function of the epidermis. The presence of bioactive phytochemical constituents in S. balsamita inflorescences makes them a valuable and safe source for creating new cosmetics and medicines.
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Ponte LGS, Pavan ICB, Mancini MCS, da Silva LGS, Morelli AP, Severino MB, Bezerra RMN, Simabuco FM. The Hallmarks of Flavonoids in Cancer. Molecules 2021; 26:2029. [PMID: 33918290 PMCID: PMC8038160 DOI: 10.3390/molecules26072029] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Flavonoids represent an important group of bioactive compounds derived from plant-based foods and beverages with known biological activity in cells. From the modulation of inflammation to the inhibition of cell proliferation, flavonoids have been described as important therapeutic adjuvants against several diseases, including diabetes, arteriosclerosis, neurological disorders, and cancer. Cancer is a complex and multifactor disease that has been studied for years however, its prevention is still one of the best known and efficient factors impacting the epidemiology of the disease. In the molecular and cellular context, some of the mechanisms underlying the oncogenesis and the progression of the disease are understood, known as the hallmarks of cancer. In this text, we review important molecular signaling pathways, including inflammation, immunity, redox metabolism, cell growth, autophagy, apoptosis, and cell cycle, and analyze the known mechanisms of action of flavonoids in cancer. The current literature provides enough evidence supporting that flavonoids may be important adjuvants in cancer therapy, highlighting the importance of healthy and balanced diets to prevent the onset and progression of the disease.
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Affiliation(s)
- Luis Gustavo Saboia Ponte
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
| | - Isadora Carolina Betim Pavan
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
- Laboratory of Signal Mechanisms (LMS), School of Pharmaceutical Sciences (FCF), University of Campinas (UNICAMP), Campinas, São Paulo 13083-871, Brazil
| | - Mariana Camargo Silva Mancini
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
| | - Luiz Guilherme Salvino da Silva
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
| | - Ana Paula Morelli
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
| | - Matheus Brandemarte Severino
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
| | - Rosangela Maria Neves Bezerra
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil; (L.G.S.P.); (I.C.B.P.); (M.C.S.M.); (L.G.S.d.S.); (A.P.M.); (M.B.S.); (R.M.N.B.)
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Zhan X, Li J, Zhou T. Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas. Front Pharmacol 2021; 12:565748. [PMID: 33841137 PMCID: PMC8024532 DOI: 10.3389/fphar.2021.565748] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 02/12/2021] [Indexed: 12/27/2022] Open
Abstract
Oxidative stress and oxidative damage are the common pathophysiological characteristics in pituitary adenomas (PAs), which have been confirmed with many omics studies in PA tissues and cell/animal experimental studies. Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), the core of oxidative stress response, is an oxidative stress sensor. Nrf2 is synthesized and regulated by multiple factors, including Keap1, ERK1/2, ERK5, JNK1/2, p38 MAPK, PKC, PI3K/AKT, and ER stress, in the cytoplasm. Under the oxidative stress status, Nrf2 quickly translocates from cytoplasm into the nucleus and binds to antioxidant response element /electrophile responsive element to initiate the expressions of antioxidant genes, phases I and II metabolizing enzymes, phase III detoxifying genes, chaperone/stress response genes, and ubiquitination/proteasomal degradation proteins. Many Nrf2 or Keap1 inhibitors have been reported as potential anticancer agents for different cancers. However, Nrf2 inhibitors have not been studied as potential anticancer agents for PAs. We recommend the emphasis on in-depth studies of Nrf2 signaling and potential therapeutic agents targeting Nrf2 signaling pathways as new therapeutic strategies for PAs. Also, the use of Nrf2 inhibitors targeting Nrf2 signaling in combination with ERK inhibitors plus p38 activators or JNK activators targeting MAPK signaling pathways, or drugs targeting mitochondrial dysfunction pathway might produce better anti-tumor effects on PAs. This perspective article reviews the advances in oxidative stress and Nrf2-mediated oxidative stress response signaling pathways in pituitary tumorigenesis, and the potential of targeting Nrf2 signaling pathways as a new therapeutic strategy for PAs.
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Affiliation(s)
- Xianquan Zhan
- Shandong Key Laboratory of Radiation Oncology, Cancer Hospital of Shandong First Medical University, Jinan, China.,Science and Technology Innovation Center, Shandong First Medical University, Jinan, China.,Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jiajia Li
- Science and Technology Innovation Center, Shandong First Medical University, Jinan, China.,Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Tian Zhou
- Science and Technology Innovation Center, Shandong First Medical University, Jinan, China.,Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
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Dostal Z, Sebera M, Srovnal J, Staffova K, Modriansky M. Dual Effect of Taxifolin on ZEB2 Cancer Signaling in HepG2 Cells. Molecules 2021; 26:1476. [PMID: 33803107 PMCID: PMC7963166 DOI: 10.3390/molecules26051476] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/16/2022] Open
Abstract
Polyphenols, secondary metabolites of plants, exhibit different anti-cancer and cytoprotective properties such as anti-radical, anti-angiogenic, anti-inflammation, or cardioprotective. Some of these activities could be linked to modulation of miRNAs expression. MiRNAs play an important role in posttranscriptional regulation of their target genes that could be important within cell signalling or preservation of cell homeostasis, e.g., cell survival/apoptosis. We evaluated the influence of a non-toxic concentration of taxifolin and quercetin on the expression of majority human miRNAs via Affymetrix GeneChip™ miRNA 3.0 Array. For the evaluation we used two cell models corresponding to liver tissue, Hep G2 and primary human hepatocytes. The array analysis identified four miRNAs, miR-153, miR-204, miR-211, and miR-377-3p, with reduced expression after taxifolin treatment. All of these miRNAs are linked to modulation of ZEB2 expression in various models. Indeed, ZEB2 protein displayed upregulation after taxifolin treatment in a dose dependent manner. However, the modulation did not lead to epithelial mesenchymal transition. Our data show that taxifolin inhibits Akt phosphorylation, thereby diminishing ZEB2 signalling that could trigger carcinogenesis. We conclude that biological activity of taxifolin may have ambiguous or even contradictory outcomes because of non-specific effect on the cell.
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Affiliation(s)
- Zdenek Dostal
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, 77515 Olomouc, Czech Republic;
| | - Martin Sebera
- Faculty of Sport Studies, Masaryk University, 60177 Brno, Czech Republic;
| | - Josef Srovnal
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, 77515 Olomouc, Czech Republic; (J.S.); (K.S.)
| | - Katerina Staffova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, 77515 Olomouc, Czech Republic; (J.S.); (K.S.)
| | - Martin Modriansky
- Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, 77515 Olomouc, Czech Republic;
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Ren L, Guo HN, Yang J, Guo XY, Wei YS, Yang Z. Dissecting Efficacy and Metabolic Characteristic Mechanism of Taxifolin on Renal Fibrosis by Multivariate Approach and Ultra-Performance Liquid Chromatography Coupled With Mass Spectrometry-Based Metabolomics Strategy. Front Pharmacol 2021; 11:608511. [PMID: 33519473 PMCID: PMC7841412 DOI: 10.3389/fphar.2020.608511] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
Taxifolin (TFN) is an important natural compound with antifibrotic activity; however, its pharmacological mechanism is not clear. In this study, our aim is to gain insight into the effects of TFN and its potential mechanisms in unilateral ureteral obstruction (UUO) animal model using metabolomics approach to identify the metabolic biomarkers and perturbed pathways. Serum metabolomics analysis by UPLC-Q-TOF/MS was carried out to discover the changes in the metabolic profile. It showed that TFN has a significant protective effect on UUO-induced renal fibrosis and a total of 32 potential biomarkers were identified and related to RF progression. Of note, 27 biomarkers were regulated by TFN treatment, which participate in eight metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, and phenylalanine metabolism. It also showed that metabolomics was a promising strategy to better dissect metabolic characteristics and pharmacological mechanisms of natural compounds by multivariate approach and ultra-performance liquid chromatography coupled with mass spectrometry.
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Affiliation(s)
- Lei Ren
- Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guangxi, China
| | - Hao-Nan Guo
- Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guangxi, China
| | - Jun Yang
- Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guangxi, China
| | - Xiao-Ying Guo
- Department of Clinical Laboratory, Daqing Oilfield General Hospital, Daqing, China
| | - Ye-Sheng Wei
- Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guangxi, China
| | - Zhao Yang
- Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guangxi, China
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Feng E, Wang J, Wang X, Wang Z, Chen X, Zhu X, Hou W. Inhibition of HMGB1 Might Enhance the Protective Effect of Taxifolin in Cardiomyocytes via PI3K/AKT Signaling Pathway. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:316-332. [PMID: 34567165 PMCID: PMC8457741 DOI: 10.22037/ijpr.2020.113584.14384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cardiovascular diseases (CVD) affect millions of people and spend a lot of medical costs around the world each year. Taxifolin is a natural anti-oxidative reagent obtained from multiple plants and exhibits a wide range of pharmacological effects. High mobility group box protein 1 (HMGB1) is expressed in multiple types of cells in the extracellular environment, regulating the pro-inflammatory process. Here, we detected the viability of cells using MTT assay, and the expression of each target protein was detected using western blotting analysis. The expression of each target mRNA was detected using the qPCR method, and the concentration of each cytokine in serum samples was detected using the ELISA method. In this study, we found that taxifolin could decrease the expression of hypoxia-inducible factor-1α (HIF-1α) while increasing the expression of endothelial nitric oxide synthase (eNOS), presented a protective role. Besides, taxifolin could also increase the expression of vascular endothelial growth factor-α (VEGF-α), transforming growth factor-β (TGF-β) and fibroblast growth factor21 (FGF21), resulting in viability rate increasing. And these effects were mediated by phosphatidylinositol 3-hydroxy kinase (PI3K)/AKT/mTOR signaling pathway; a similar trend was also observed in HMGB1 knockdown mice. We also found that inhibition of HMGB1 could enhance the cardioprotective effect of taxifolin and might be a new therapeutic strategy for cardiovascular disease.
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Affiliation(s)
- Erjun Feng
- Department of Cardiology, Fourth Center Hospital of Tianjin, Tianjin, China, 300000.
- E. F. and J. W. and X. W. contributed equally to this work.
| | - Jian Wang
- Department of Cardiology, Fourth Center Hospital of Tianjin, Tianjin, China, 300000.
- E. F. and J. W. and X. W. contributed equally to this work.
| | - Xinwei Wang
- Oncology Department of Characteristic Medical Center of PAF, Tianjin, China, 300162.
- E. F. and J. W. and X. W. contributed equally to this work.
| | - Zhenguo Wang
- Medical Research Department of Characteristic Medical Center of PAF, Tianjin, China, 300162.
| | - Xiaochu Chen
- Medical Research Department of Characteristic Medical Center of PAF, Tianjin, China, 300162.
| | - Xu Zhu
- Second Department of Neurology, Central Hospital of Handan, Handan, China, 056000.
| | - Wenli Hou
- Cadre Ward of Characteristic Medical Center of PAF, Tianjin, China, 300162.
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Kalló G, Kunkli B, Győri Z, Szilvássy Z, Csősz É, Tőzsér J. Compounds with Antiviral, Anti-Inflammatory and Anticancer Activity Identified in Wine from Hungary's Tokaj Region via High Resolution Mass Spectrometry and Bioinformatics Analyses. Int J Mol Sci 2020; 21:E9547. [PMID: 33334025 PMCID: PMC7765363 DOI: 10.3390/ijms21249547] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/10/2020] [Accepted: 12/14/2020] [Indexed: 12/17/2022] Open
Abstract
(1) Background: Wine contains a variety of molecules with potential beneficial effects on human health. Our aim was to examine the wine components with high-resolution mass spectrometry including high-resolution tandem mass spectrometry in two wine types made from grapes with or without the fungus Botrytis cinerea, or "noble rot". (2) For LC-MS/MS analysis, 12 wine samples (7 without and 5 with noble rotting) from 4 different wineries were used and wine components were identified and quantified. (3) Results: 288 molecules were identified in the wines and the amount of 169 molecules was statistically significantly different between the two wine types. A database search was carried out to find the molecules, which were examined in functional studies so far, with high emphasis on molecules with antiviral, anti-inflammatory and anticancer activities. (4) Conclusions: A comprehensive functional dataset related to identified wine components is also provided highlighting the importance of components with potential health benefits.
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Affiliation(s)
- Gergő Kalló
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; (G.K.); (É.C.)
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - Balázs Kunkli
- Laboratory of Retroviral Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - Zoltán Győri
- Institute of Food Science, Faculty of Agricultural and Food Sciences and Environmental Management, University of Debrecen, Böszörményi út 128, 4032 Debrecen, Hungary;
| | - Zoltán Szilvássy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
| | - Éva Csősz
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; (G.K.); (É.C.)
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - József Tőzsér
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; (G.K.); (É.C.)
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
- Laboratory of Retroviral Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
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Akagunduz B, Ozer M, Ozcıcek F, Kara AV, Lacın S, Özkaraca M, Çoban A, Suleyman B, Mammadov R, Suleyman H. Protective effects of taxifolin on pazopanib-induced liver toxicity: an experimental rat model. Exp Anim 2020; 70:169-176. [PMID: 33239495 PMCID: PMC8150244 DOI: 10.1538/expanim.20-0103] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Pazopanib is a tyrosine kinase inhibitor that is generally used for the treatment of metastatic renal cell cancer and advanced soft tissue sarcoma. It can cause various degrees of hepatotoxicity. Our study aimed to investigate the effect of taxifolin on pazopanib-induced liver toxicity. A total of 18 rats were divided into three groups: the pazopanib (PP), pazopanib plus taxifolin (TPP), and control (C) group. Taxifolin was administered to the TPP (n=6) group with a dose of 50 mg/kg. Distilled water was orally admnistered to the C (n=6) and PP (n=6) groups as a solvent. Subsequently, pazopanib 200 mg/kg was administered to the TPP and PP groups via the stomach. This procedure was repeated once a day for four weeks. Then, all rats were sacrificed, and their livers were removed. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), and total antioxidant status (TAS) levels were evaluated. MDA and TOS levels were higher in the PP group compared with the levels of the other parameters (P<0.001). tGSH and TAS levels were lower in the PP group than in the TPP and C groups (P<0.001), and the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were higher. Furthermore, liver tissue damage, including hemorrhage, hydropic degeneration, and necrosis was observed in the PP group. Administration of taxifolin before pazopanib significantly improved degenerative changes. Our study demonstrated that the administration of taxifolin is significantly effective in preventing pazopanib-induced hepatotoxicity in rats.
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Affiliation(s)
- Baran Akagunduz
- Department of Medical Oncology, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
| | - Muhammet Ozer
- Department of Internal Medicine, Capital Health Regional Medical Center, 750 Brunswich Avenue, 08638, Trenton, NJ, USA
| | - Fatih Ozcıcek
- Department of Internal Medicine, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
| | - Ali Veysel Kara
- Department of Internal Medicine, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
| | - Sahin Lacın
- Department of Medical Oncology, Faculty of Medicine, Yeditepe University, 326 Atasehir, 34010, Istanbul, Turkey
| | - Mustafa Özkaraca
- Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, 12 Yakutiye Avenue, 25000, Erzurum, Turkey
| | - Abdulkadir Çoban
- Department of Biochemistry, Faculty of Medicine, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
| | - Bahadır Suleyman
- Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
| | - Renad Mammadov
- Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
| | - Halis Suleyman
- Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Fatih Street #124, 24030, Erzincan, Turkey
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He LJ, Yang DL, Chen HY, Huang JH, Zhang YJ, Qin HX, Wang JL, Tang DY, Chen ZZ. A Novel Imidazopyridine Derivative Exhibits Anticancer Activity in Breast Cancer by Inhibiting Wnt/β‑catenin Signaling. Onco Targets Ther 2020; 13:10111-10121. [PMID: 33116593 PMCID: PMC7553630 DOI: 10.2147/ott.s266752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background Breast cancer exhibits poor prognosis and high relapse rates following chemotherapy therapeutics. Thus, this study aims to develop effective novel agents regulating the core molecular pathway of breast cancer such as Wnt/β-catenin signaling. Methods The present study screened a novel inhibitor, called “C188”, using MTT assay. The molecular formula of C188 is C21H15FN4O3 and the molecular weight is 390. Flow cytometry and Western blotting were employed to assess cell cycle arrest after treatment with C188. Wound-healing and transwell assays were applied to measure the cell migration and invasion viability. The regulatory effects of C188 on Wnt/β‑catenin signaling and localization of β‑catenin in the nucleus were investigated by Western blotting and immunofluorescence. Results We found that C188 significantly suppressed proliferation and growth in a dose- and time-dependent manner in breast cancer cells, but not in normal breast cells. The inhibitory effect was caused by cell cycle arrest at the G1-phase which is induced by C188 treatment. Additionally, C188 dramatically inhibited cell migration of breast cancer cells in a dose-dependent manner. The migration inhibition was attributed to the suppression of Wnt/β‑catenin signaling and localization of β‑catenin in the nucleus mediated by regulating phosphorylation of β‑catenin and its subsequent stability. Furthermore, the target genes, including Axin 2, c-JUN, and c-Myc, were downregulated due to the decrease of β‑catenin in the nucleus after exposure to C188. Conclusion C188 treatment resulted in the downregulation of cyclin D which led to cell cycle arrest at the G1 phase, and the inhibition of cell migration, indicating that C188 may be an effective novel therapeutic candidate as a potential treatment for human breast cancer.
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Affiliation(s)
- Liu-Jun He
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - Dong-Lin Yang
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - He-Ying Chen
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China.,Division of Molecular Nephrology and the Creative Training Center for Undergraduates, The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China.,The Undergraduates Class of 2016 Entry the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Jiu-Hong Huang
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - Ya-Jun Zhang
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - Hong-Xia Qin
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - Juan-Li Wang
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - Dian-Yong Tang
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
| | - Zhong-Zhu Chen
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People's Republic of China
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Zhang D, Iwabuchi S, Baba T, Hashimoto SI, Mukaida N, Sasaki SI. Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone. Cancers (Basel) 2020; 12:3003. [PMID: 33081224 PMCID: PMC7602858 DOI: 10.3390/cancers12103003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.
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Affiliation(s)
- Di Zhang
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa 920-1192, Japan; (D.Z.); (T.B.); (N.M.)
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (S.I.); (S.-i.H.)
| | - Tomohisa Baba
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa 920-1192, Japan; (D.Z.); (T.B.); (N.M.)
| | - Shin-ichi Hashimoto
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (S.I.); (S.-i.H.)
| | - Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa 920-1192, Japan; (D.Z.); (T.B.); (N.M.)
| | - So-ichiro Sasaki
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa 920-1192, Japan; (D.Z.); (T.B.); (N.M.)
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Zhu Y, Yang Q, Liu H, Song Z, Chen W. Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer. Eur J Pharmacol 2020; 887:173588. [PMID: 32961170 DOI: 10.1016/j.ejphar.2020.173588] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) has become one of the major factors of tumor-related morbidity and mortality in the world because of its poor prognosis and consequences of metastatic spread. Currently, chemoprevention has been considered as a way of preventing cancer who takes advantage of plant phytochemicals and synthetic compounds. Phytochemical compounds are receiving much considerable attention for their ability in chemoprevention due to low toxicity and cost. For strategies of chemoprevention, keeping the balance of internal and external environment in cells or tissues is important. Hence, it is particularly important to eliminate overmuch carcinogens and carcinogenic metabolites by phase 2 detoxifying enzymes and antioxidant enzymes such as glutathione S-transferase (GST), heme oxygenase-1(HO-1) and so on. Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a key role in regulating these enzymes via mediating antioxidant response elements (ARE). In this review, we collected recent studies of phytochemical compounds targeting on Nrf2 in CRC treatment. We summarized the mechanisms of these compounds in activating Nrf2, and their effects on chemotherapeutic agents.
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Affiliation(s)
- Yuandong Zhu
- Department of Colorectal and Anal Surgery, Yiwu Central Hospital, Zhejiang Province, Yiwu, 322000, China.
| | - Qinghua Yang
- Department of Colorectal and Anal Surgery, Yiwu Central Hospital, Zhejiang Province, Yiwu, 322000, China
| | - Haiyuan Liu
- Department of Colorectal and Anal Surgery, Yiwu Central Hospital, Zhejiang Province, Yiwu, 322000, China
| | - Zhengming Song
- Department of Colorectal and Anal Surgery, Yiwu Central Hospital, Zhejiang Province, Yiwu, 322000, China
| | - Wenbin Chen
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, 310003, China
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Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals. Antioxidants (Basel) 2020; 9:antiox9090865. [PMID: 32938017 PMCID: PMC7555619 DOI: 10.3390/antiox9090865] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human NFE2L2/KEAP1 and murine Nfe2l2/Keap1 genes, acetylation of lysine residues in NRF2 and Nrf2, interaction with bromodomain and extraterminal domain (BET) acetyl “reader” proteins, and non-coding RNAs such as microRNA (miRNA) and long non-coding RNA (lncRNA). Phytochemicals documented to modulate NRF2 signaling act by reversing hypermethylated states in the CpG islands of NFE2L2 or Nfe2l2, via the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), through the induction of ten-eleven translocation (TET) enzymes, or by inducing miRNA to target the 3′-UTR of the corresponding mRNA transcripts. To date, fewer than twenty phytochemicals have been reported as NRF2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. This opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target NRF2 signaling with a view to beneficial interception of cancer and other chronic diseases.
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The effects of taxifolin on alveolar bone in experimental periodontitis in rats. Arch Oral Biol 2020; 117:104823. [PMID: 32593876 DOI: 10.1016/j.archoralbio.2020.104823] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE This study aimed to evaluate the effect of taxifolin, a powerful antioxidant, on the progression of periodontitis by immunohistochemical and cone-beam computed tomography (CBCT) examination. DESIGN This study was performed with 32 rats in four experimental groups: a non-ligated group (Control, n = 8), periodontitis group (Perio, n = 8), periodontitis with 1 mg/kg/day taxifolin group (Taxi-1, n = 8), and periodontitis with 10 mg/kg/day taxifolin group (Taxi-10, n = 8). A ligature-induced experimental periodontitis design was used. All rats were sacrificed at 30 days. Alveolar bone loss was determined by CBCT. Hematoxylin-eosin stained slides were examined. The expression levels of bone morphogenetic protein 2 (BMP-2), osteocalcin (OCN), alkaline phosphatase (ALP), collagen type I (Col 1), Bcl-2, Bax, and receptor activator of NF-κB ligand (RANKL) were determined immunohistochemically. RESULTS Both doses of taxifolin showed a decrease in alveolar bone loss. The inflammatory reaction was higher in the Perio group and lower in the taxifolin groups. BMP-2, OCN, ALP, and Col 1 expression were dose-dependently elevated in the taxifolin groups. RANKL immunoexpression decreased with both doses of taxifolin. Bcl-2 expression increased and Bax expression decreased in the taxifolin groups. CONCLUSION Taxifolin successfully reduced apoptosis and improved bone formation in alveolar bone in this experimental periodontitis model.
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Liu F, Ma Y, Xu Y. Taxifolin Shows Anticataractogenesis and Attenuates Diabetic Retinopathy in STZ-Diabetic Rats via Suppression of Aldose Reductase, Oxidative Stress, and MAPK Signaling Pathway. Endocr Metab Immune Disord Drug Targets 2020; 20:599-608. [PMID: 31656158 DOI: 10.2174/1871530319666191018122821] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/30/2019] [Accepted: 09/27/2019] [Indexed: 12/28/2022]
Abstract
Background:
Due to the increased prevalence of diabetes-associated complications of the
eye like diabetic retinopathy and cataract, the need for a novel therapeutic agent is urgent. Due to the
advantages that the polyphenolic compounds enjoy in diabetes and associated complications, we postulated
that Taxifolin (TXF), a poly-phenolic flavanol, could show anti-retinopathic and anti-cataract
effect in diabetes-induced rats.
Methods:
TXF at a dose of 10, 25, and 50 mg/kg was given by oral route to STZ mediated diabetic rats
for a time period of 10 weeks. The opacity of lens was studied after every 7 days of treatment till 10
weeks; evaluation of the severity of cataract and changes in the histology of lens as well as retina was
done. Tissue homogenates of lens isolated after the end of the study were evaluated for markers of
oxidative stress, levels of aldose reductase, p38MAPK, VEGF, and ERK1/2.
Results:
Outcomes suggested that TXF improved retinopathy and cataract in diabetes-induced rats.
The treatment of TXF also improved the status of oxidative stress and inhibited the levels of
p38MAPK, VEGF, and ERK1/2. The treatment also improved the lens opacity in diabetic rats. The
results suggest that the protective effect of TXF against cataract and retinopathy may be due to the
anti-oxidative potential of TXF and its inhibiting effect on VEGF, ERK1/2, p38MAPK, and aldose
reductase.
Conclusion:
The study confirms that TXF is a potential candidate showing a protective effect against
diabetic induced retinopathy and cataract..
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Affiliation(s)
- Fei Liu
- Department of Ophthalmology, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, PR, China
| | - Ying Ma
- Department of Ophthalmology, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, PR, China
| | - Yanli Xu
- Department of Ophthalmology, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, PR, China
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Fang W, Tang L, Wang G, Lin J, Liao W, Pan W, Xu J. Molecular Hydrogen Protects Human Melanocytes from Oxidative Stress by Activating Nrf2 Signaling. J Invest Dermatol 2020; 140:2230-2241.e9. [PMID: 32234461 DOI: 10.1016/j.jid.2019.03.1165] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 02/28/2019] [Accepted: 03/06/2019] [Indexed: 01/03/2023]
Abstract
Oxidative stress is proven to be critical for the initiation and progression of vitiligo. Molecular hydrogen (H2) possesses potent antioxidant activity and has been shown to protect against various oxidative stress-related diseases. In this study, we first investigated the effects and mechanisms of H2 in human melanocytes damaged by hydrogen peroxide. We initially found that H2 reduced intracellular ROS accumulation and malondialdehyde levels in both vitiligo specimens and hydrogen peroxide-treated melanocytes in vitro in a concentration- and time-dependent manner, concomitant with the enhancement of antioxidant enzyme activity. Correspondingly, H2 reversed hydrogen peroxide-induced apoptosis and dysfunction in both normal and vitiligo melanocytes. H2 protected mitochondrial morphology and function in melanocytes under stress and promoted the activation of Nrf2 signaling, whereas Nrf2 deficiency abolished the protective effect of H2 against hydrogen peroxide-induced oxidative damage. Furthermore, H2 positively modulated β-catenin in hydrogen peroxide-treated melanocytes, and the β-catenin pathway was implicated in H2-induced Nrf2 activation. Collectively, our results indicate that H2 could be a promising therapeutic agent for vitiligo treatment via attenuating oxidative damage, and its beneficial effect in human melanocytes might involve Wnt/β-catenin-mediated activation of Nrf2 signaling.
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Affiliation(s)
- Wei Fang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; The Shanghai Institute of Dermatology, Shanghai, China; Shanghai Key Laboratory of Molecular Medical Mycology, Department of Dermatology, Changzheng Hospital, Shanghai, China
| | - Luyan Tang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; The Shanghai Institute of Dermatology, Shanghai, China
| | - Guizhen Wang
- Emergency room, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Jinran Lin
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wanqing Liao
- Shanghai Key Laboratory of Molecular Medical Mycology, Department of Dermatology, Changzheng Hospital, Shanghai, China
| | - Weihua Pan
- Shanghai Key Laboratory of Molecular Medical Mycology, Department of Dermatology, Changzheng Hospital, Shanghai, China
| | - Jinhua Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; The Shanghai Institute of Dermatology, Shanghai, China.
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Paunkov A, Chartoumpekis DV, Ziros PG, Chondrogianni N, Kensler TW, Sykiotis GP. Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway. Curr Pharm Des 2020; 25:1828-1846. [PMID: 31267862 DOI: 10.2174/1381612825666190701165821] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 06/20/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Natural compounds with potential antioxidant properties have been used in the form of food supplements or extracts with the intent to prevent or treat various diseases. Many of these compounds can activate the cytoprotective Nrf2 pathway. Besides, some of them are known to impact the thyroid gland, often with potential side-effects, but in other instances, with potential utility in the treatment of thyroid disorders. OBJECTIVE In view of recent data regarding the multiple roles of Nrf2 in the thyroid, this review summarizes the current bibliography on natural compounds that can have an effect on thyroid gland physiology and pathophysiology, and it discusses the potential implication of the Nrf2 system in the respective mechanisms. METHODS & RESULTS Literature searches for articles from 1950 to 2018 were performed in PubMed and Google Scholar using relevant keywords about phytochemicals, Nrf2 and thyroid. Natural substances were categorized into phenolic compounds, sulfur-containing compounds, quinones, terpenoids, or under the general category of plant extracts. For individual compounds in each category, respective data were summarized, as derived from in vitro (cell lines), preclinical (animal models) and clinical studies. The main emerging themes were as follows: phenolic compounds often showed potential to affect the production of thyroid hormones; sulfur-containing compounds impacted the pathogenesis of goiter and the proliferation of thyroid cancer cells; while quinones and terpenoids modified Nrf2 signaling in thyroid cell lines. CONCLUSION Natural compounds that modify the activity of the Nrf2 pathway should be evaluated carefully, not only for their potential to be used as therapeutic agents for thyroid disorders, but also for their thyroidal safety when used for the prevention and treatment of non-thyroidal diseases.
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Affiliation(s)
- Ana Paunkov
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
| | - Dionysios V Chartoumpekis
- Department of Internal Medicine, Endocrinology Unit, Patras University Medical School, Patras, Greece
| | - Panos G Ziros
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
| | - Niki Chondrogianni
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Thomas W Kensler
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Gerasimos P Sykiotis
- Service of Endocrinology, Diabetology and Metabolism, University of Lausanne, Lausanne, Switzerland
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Kang HS, Kwon HY, Kim IK, Ban WH, Kim SW, Kang HH, Yeo CD, Lee SH. Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer. Sci Rep 2020; 10:1854. [PMID: 32024881 PMCID: PMC7002457 DOI: 10.1038/s41598-020-58906-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 01/02/2020] [Indexed: 02/07/2023] Open
Abstract
The purpose of this study was to evaluate whether obstructive sleep apnea (OSA)-related chronic intermittent hypoxia (CIH) influences lung cancer progression and to elucidate the associated mechanisms in a mouse model of lung cancer. C57/BL6 mice in a CIH group were exposed to intermittent hypoxia for two weeks after tumor induction and compared with control mice (room air). Hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF) and metastasis-related matrix metalloproteinases (MMP) were measured. The expression levels of several hypoxia-related pathway proteins including HIF-1α, Wnt/ß-catenin, the nuclear factor erythroid 2-related factor 2 (Nrf2) and mammalian target of rapamycin-ERK were measured by western blot. The number (P < 0.01) and volume (P < 0.05) of tumors were increased in the CIH group. The activity of MMP-2 was enhanced after CIH treatment. The level of VEGF was increased significantly in the CIH group (p < 0.05). ß-catenin and Nrf2 were translocated to the nucleus and the levels of downstream effectors of Wnt/ß-catenin signaling increased after IH exposure. CIH enhanced proliferative and migratory properties of tumors in a mouse model of lung cancer. ß-catenin and Nrf2 appeared to be crucial mediators of tumor growth.
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Affiliation(s)
- Hye Seon Kang
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hee Young Kwon
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - In Kyoung Kim
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Woo Ho Ban
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sei Won Kim
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyeon Hui Kang
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chang Dong Yeo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Haak Lee
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. .,Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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The anti-carcinogenesis properties of erianin in the modulation of oxidative stress-mediated apoptosis and immune response in liver cancer. Aging (Albany NY) 2019; 11:10284-10300. [PMID: 31754081 PMCID: PMC6914393 DOI: 10.18632/aging.102456] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 11/07/2019] [Indexed: 12/25/2022]
Abstract
In this study, erianin was found to reduce the viability of cancer cells, inhibit their proliferation and migration, induce G2/M phase arrest, enhance cancer cell apoptosis, promote an increase in levels of intracellular reactive oxygen species and a decrease in mitochondrial membrane potential, and regulate the expression levels of anti- and pro-apoptosis-related proteins in HepG2 and SMMC-7721 cells. Erianin inhibited tumor growth in HepG2- and SMMC-7721-xenograft tumor nude mouse models, reduced the expression levels of anti-apoptosis proteins and enhanced the expression levels of pro-apoptosis proteins in tumor tissues. Erianin inhibited tumor growth in immunosuppressed BALB/c mice bearing heterotopic tumors. Among 111 types of cytokines detected in proteome profiling of tumor tissues, erianin substantially influenced levels of 38 types of cytokines in HepG2-xenografted tumors and of 15 types of cytokines in SMMC-7721-xenografted tumors, most of which are related to immune functions. Erianin strongly affected the serum levels of cytokines, and regulated the activation of nuclear factor-kappa B (NF-κB), and the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins in spleen. The anti-liver cancer properties of erianin were found to be related mostly to its modulation of oxidative stress-mediated mitochondrial apoptosis and immune response.
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Antigenotoxic Effects of Biochaga and Dihydroquercetin (Taxifolin) on H 2O 2-Induced DNA Damage in Human Whole Blood Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5039372. [PMID: 31814882 PMCID: PMC6878777 DOI: 10.1155/2019/5039372] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/30/2019] [Accepted: 10/05/2019] [Indexed: 01/09/2023]
Abstract
The health benefits of natural products have long been recognized. Consumption of dietary compounds such as supplements provides an alternative source of natural products to those obtained from the diet. There is a growing concern regarding the possible side effects of using different food supplements simultaneously, since their possible interactions are less known. For the first time, we have tested genotoxic and antigenotoxic effects of Biochaga, in combination with dihydroquercetin. No genotoxic effect on whole blood cells was observed within individual treatment of Biochaga (250 μg/mL, 500 μg/mL and 1000 μg/mL) and dihydroquercetin (100 μg/mL, 250 μg/mL and 500 μg/mL), nor in combination. Afterwards, antigenotoxic potency of both supplements against hydrogen peroxide- (H2O2-) induced DNA damage to whole blood cells (WBC) was assessed, using the comet assay. Biochaga and dihydroquercetin displayed a strong potential to attenuate H2O2-induced damage on DNA in cells at all tested concentrations, with a statistical significance (p < 0.05), whereas Biochaga at the dose of 500 μg/mL in combination with dihydroquercetin 500 μg/mL was most prominent. Biochaga in combination with dihydroquercetin is able to protect genomic material from oxidative damage induced by hydrogen peroxide in vitro.
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Sunil C, Xu B. An insight into the health-promoting effects of taxifolin (dihydroquercetin). PHYTOCHEMISTRY 2019; 166:112066. [PMID: 31325613 DOI: 10.1016/j.phytochem.2019.112066] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/07/2019] [Accepted: 07/11/2019] [Indexed: 06/10/2023]
Abstract
Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®. This review focuses on taxifolin's biological activities and related molecular mechanisms. Published literatures were gathered from the scientific databases like PubMed, SciFinder, ScienceDirect, Wiley Online Library, Google Scholar, and Web of Science up to January 2019. Taxifolin showed promising pharmacological activities in the management of inflammation, tumors, microbial infections, oxidative stress, cardiovascular, and liver disorders. The anti-cancer activity was more prominent than other activities evaluated using different in vitro and in vivo models. Further research on the pharmacokinetics, in-depth molecular mechanisms, and safety profile using well-designed randomized clinical studies are suggested to develop a drug for human use.
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Affiliation(s)
- Christudas Sunil
- Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China
| | - Baojun Xu
- Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China.
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Huang D, Yang L, Li XL, Zou L, Ye B. A new electrochemical sensor for Taxifolin based on RGO-Co3S4@MoS2 modified electrode. J Electroanal Chem (Lausanne) 2019. [DOI: 10.1016/j.jelechem.2019.113473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Kim D, Lim JW, Kim H. β-carotene Inhibits Expression of c-Myc and Cyclin E in Helicobacter pylori-infected Gastric Epithelial Cells. J Cancer Prev 2019; 24:192-196. [PMID: 31624725 PMCID: PMC6786805 DOI: 10.15430/jcp.2019.24.3.192] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/25/2019] [Accepted: 09/01/2019] [Indexed: 12/11/2022] Open
Abstract
Background Helicobacter pylori infection is a major risk factor in the development of gastric cancer. H. pylori infection of gastric epithelial cells increases the levels of reactive oxygen species (ROS), activates oncogenes, and leads to β-catenin-mediated hyper-proliferation. β-Carotene reduces ROS levels, inhibits oxidant-mediated activation of inflammatory signaling and exhibits anticancer properties. The present study was carried out to determine if β-carotene inhibits H. pylori-induced cell proliferation and the expression of oncogenes c-myc and cyclin E by reducing the levels of β-catenin and phosphorylated glycogen synthase kinase 3β (p-GSK3β). Methods Gastric epithelial AGS cells were pre-treated with β-carotene (5 and 10 μM) for 2 hours prior to H. pylori infection and cultured for 6 hours (for determination of the levels of p-GSK3β, GSK3β, and β-catenin) and 24 hours (for determination of cell viability and protein levels of c-myc and cyclin E). Cell viability was determined by the MTT assay and protein levels were determined via western blot-based analysis. Results β-Carotene inhibited H. pylori-induced increases in the percentage of viable cells, phosphorylated GSK3β (p-GSK3β), and the levels of β-catenin, c-myc and cyclin E. Conclusions β-Carotene inhibits H. pylori-induced hyper-proliferation of gastric epithelial cells by suppressing β-catenin signaling and oncogene expression.
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Affiliation(s)
- Dahye Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea
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