Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols
Abstract
1. Introduction
2. Results
2.1. Time Course Cytokine Production Curves
2.2. Study of the Effects of Flavonoids in Cytokine Production in LPS-Stimulated Whole Blood
3. Discussion
4. Materials and Methods
4.1. Study Cohort, and Inclusion and Exclusion Criteria
4.2. Peripheral Blood Extraction
4.3. Selected Drugs
4.4. Assay of IL-1β, TNF-α, Il-6, and IL-8 Production in LPS-Stimulated Whole Blood
4.5. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Kaptoge, S.; Pennells, L.; De Bacquer, D.; Cooney, M.T.; Kavousi, M.; Stevens, G.; Riley, L.M.; Savin, S.; Khan, T.; Altay, S.; et al. World Health Organization cardiovascular disease risk charts: Revised models to estimate risk in 21 global regions. Lancet Glob. Health 2019, 7, e1332–e1345. [Google Scholar] [CrossRef]
- Becker, R.C.; Owens, A.P.; Sadayappan, S. Tissue-level inflammation and ventricular remodeling in hypertrophic cardiomyopathy. J. Thromb Thrombolysis 2020, 49, 177–183. [Google Scholar] [CrossRef] [PubMed]
- Melnikov, I.S.; Kozlov, S.G.; Saburova, O.S.; Avtaeva, N.Y.; Prokofieva, L.V.; Gabbasov, Z.A. Current position on the role of monomeric C-reactive protein in vascular pathology and atherothrombosis. CPD 2019, 25. [Google Scholar] [CrossRef]
- Chiu, Y.-J.; Hsieh, Y.-H.; Lin, T.-H.; Lee, G.-C.; Hsieh-Li, H.M.; Sun, Y.-C.; Chen, C.-M.; Chang, K.-H.; Lee-Chen, G.-J. Novel compound VB-037 inhibits Aβ aggregation and promotes neurite outgrowth through enhancement of HSP27 and reduction of P38 and JNK-mediated inflammation in cell models for Alzheimer’s disease. Neurochem. Int. 2019, 125, 175–186. [Google Scholar] [CrossRef] [PubMed]
- Vogel, S.; Thein, S.L. Platelets at the crossroads of thrombosis, inflammation and haemolysis. Br. J. Haematol 2018, 180, 761–767. [Google Scholar] [CrossRef] [PubMed]
- Mkhize, N.V.P.; Qulu, L.; Mabandla, M.V. The Effect of Quercetin on Pro- and Anti-Inflammatory Cytokines in a Prenatally Stressed Rat Model of Febrile Seizures. J. Exp. Neurosci. 2017, 11, 117906951770466. [Google Scholar] [CrossRef] [PubMed]
- Ortega, M.A.; Asúnsolo, Á.; Romero, B.; Álvarez-Rocha, M.J.; Sainz, F.; Leal, J.; Álvarez-Mon, M.; Buján, J.; García-Honduvilla, N. Unravelling the Role of MAPKs (ERK1/2) in Venous Reflux in Patients with Chronic Venous Disorder. Cells Tissues Organs 2018, 206, 272–282. [Google Scholar] [CrossRef]
- Ortega, M.A.; Asúnsolo, Á.; Leal, J.; Romero, B.; Alvarez-Rocha, M.J.; Sainz, F.; Álvarez-Mon, M.; Buján, J.; García-Honduvilla, N. Implication of the PI3K/Akt/mTOR Pathway in the Process of Incompetent Valves in Patients with Chronic Venous Insufficiency and the Relationship with Aging. Oxidative Med. Cell. Longev. 2018, 2018, 1–14. [Google Scholar] [CrossRef]
- Colmorten, K.B.; Nexoe, A.B.; Sorensen, G.L. The Dual Role of Surfactant Protein-D in Vascular Inflammation and Development of Cardiovascular Disease. Front. Immunol. 2019, 10, 2264. [Google Scholar] [CrossRef]
- Kuznetsova, T.; Prange, K.H.M.; Glass, C.K.; de Winther, M.P.J. Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Nat. Rev. Cardiol 2019. [Google Scholar] [CrossRef]
- Alvarez-Mon, M.A.; Gómez, A.M.; Orozco, A.; Lahera, G.; Sosa, M.D.; Diaz, D.; Auba, E.; Albillos, A.; Monserrat, J.; Alvarez-Mon, M. Abnormal Distribution and Function of Circulating Monocytes and Enhanced Bacterial Translocation in Major Depressive Disorder. Front. Psychiatry 2019, 10, 812. [Google Scholar] [CrossRef] [PubMed]
- Jayashree, B.; Bibin, Y.S.; Prabhu, D.; Shanthirani, C.S.; Gokulakrishnan, K.; Lakshmi, B.S.; Mohan, V.; Balasubramanyam, M. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol. Cell. Biochem. 2014, 388, 203–210. [Google Scholar] [CrossRef] [PubMed]
- Sieve, I.; Ricke-Hoch, M.; Kasten, M.; Battmer, K.; Stapel, B.; Falk, C.S.; Leisegang, M.S.; Haverich, A.; Scherr, M.; Hilfiker-Kleiner, D. A positive feedback loop between IL-1β, LPS and NEU1 may promote atherosclerosis by enhancing a pro-inflammatory state in monocytes and macrophages. Vasc. Pharmacol. 2018, 103–105, 16–28. [Google Scholar] [CrossRef] [PubMed]
- Murray, P.J. Immune regulation by monocytes. Semin. Immunol. 2018, 35, 12–18. [Google Scholar] [CrossRef]
- Swirski, F.K.; Nahrendorf, M. Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure. Science 2013, 339, 161–166. [Google Scholar] [CrossRef]
- Umamaheswari, S. Anti-Inflammatory Effect of Selected Dihydroxyflavones. JCDR 2015, 9, FF05. [Google Scholar] [CrossRef]
- González, R.; Ballester, I.; López-Posadas, R.; Suárez, M.D.; Zarzuelo, A.; Martínez-Augustin, O.; Medina, F.S.D. Effects of Flavonoids and other Polyphenols on Inflammation. Crit. Rev. Food Sci. Nutr. 2011, 51, 331–362. [Google Scholar] [CrossRef]
- Dymarska, M.; Janeczko, T.; Kostrzewa-Susłow, E. Glycosylation of Methoxylated Flavonoids in the Cultures of Isaria fumosorosea KCH J2. Molecules 2018, 23, 2578. [Google Scholar] [CrossRef]
- Justino, A.B.; Costa, M.S.; Saraiva, A.L.; Silva, P.H.; Vieira, T.N.; Dias, P.; Linhares, C.R.B.; Dechichi, P.; de Melo Rodrigues Avila, V.; Espindola, F.S.; et al. Protective effects of a polyphenol-enriched fraction of the fruit peel of Annona crassiflora Mart. on acute and persistent inflammatory pain. Inflammopharmacology 2019. [Google Scholar] [CrossRef]
- Domingos, O.D.S.; Alcântara, B.G.V.; Santos, M.F.C.; Maiolini, T.C.S.; Dias, D.F.; Baldim, J.L.; Lago, J.H.G.; Soares, M.G.; Chagas-Paula, D.A. Anti-Inflammatory Derivatives with Dual Mechanism of Action from the Metabolomic Screening of Poincianella pluviosa. Molecules 2019, 24, 4375. [Google Scholar] [CrossRef]
- Saha, S.; Panieri, E.; Suzen, S.; Saso, L. The Interaction of Flavonols with Membrane Components: Potential Effect on Antioxidant Activity. J. Membr. Biol 2020, 253, 57–71. [Google Scholar] [CrossRef] [PubMed]
- Boligon, A.A.; de Freitas, R.B.; de Brum, T.F.; Waczuk, E.P.; Klimaczewski, C.V.; de Ávila, D.S.; Athayde, M.L.; de Freitas Bauermann, L. Antiulcerogenic activity of Scutia buxifolia on gastric ulcers induced by ethanol in rats. Acta Pharm. Sin. B 2014, 4, 358–367. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Sdiri, M.; Peng, J.; Xie, Y.; Yang, B.B. Identification and characterization of chemical components in the bioactive fractions of Cynomorium coccineum that possess anticancer activity. Int. J. Biol. Sci. 2020, 16, 61–73. [Google Scholar] [CrossRef] [PubMed]
- Mendes, L.F.; Gaspar, V.M.; Conde, T.A.; Mano, J.F.; Duarte, I.F. Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways. Sci Rep. 2019, 9, 14906. [Google Scholar] [CrossRef]
- Magne Nde, C.B.; Zingue, S.; Winter, E.; Creczynski-Pasa, T.B.; Michel, T.; Fernandez, X.; Njamen, D.; Clyne, C. Flavonoids, Breast Cancer Chemopreventive and/or Chemotherapeutic Agents. Curr. Med. Chem. 2015, 22, 3434–3446. [Google Scholar]
- Zaragozá, C.; Monserrat, J.; Mantecón, C.; Villaescusa, L.; Zaragozá, F.; Álvarez-Mon, M. Antiplatelet activity of flavonoid and coumarin drugs. Vasc. Pharmacol. 2016, 87, 139–149. [Google Scholar] [CrossRef]
- Khalilpourfarshbafi, M.; Gholami, K.; Murugan, D.D.; Abdul Sattar, M.Z.; Abdullah, N.A. Differential effects of dietary flavonoids on adipogenesis. Eur J. Nutr 2019, 58, 5–25. [Google Scholar] [CrossRef]
- Meng, H.; Shao, D.; Li, H.; Huang, X.; Yang, G.; Xu, B.; Niu, H. Resveratrol improves neurological outcome and neuroinflammation following spinal cord injury through enhancing autophagy involving the AMPK/mTOR pathway. Mol Med. Rep. 2018, 18, 2237–2244. [Google Scholar] [CrossRef]
- Tanaka, T.; Takahashi, R. Flavonoids and Asthma. Nutrients 2013, 5, 2128–2143. [Google Scholar] [CrossRef]
- Che, C.-T.; Wong, M.; Lam, C. Natural Products from Chinese Medicines with Potential Benefits to Bone Health. Molecules 2016, 21, 239. [Google Scholar] [CrossRef]
- Gómez-Guzmán, M.; Rodríguez-Nogales, A.; Algieri, F.; Gálvez, J. Potential Role of Seaweed Polyphenols in Cardiovascular-Associated Disorders. Mar. Drugs 2018, 16, 250. [Google Scholar] [CrossRef] [PubMed]
- Gonçalves, C.; de Freitas, M.; Ferreira, A. Flavonoids, Thyroid Iodide Uptake and Thyroid Cancer—A Review. IJMS 2017, 18, 1247. [Google Scholar] [CrossRef] [PubMed]
- Kumar, S.; Pandey, A.K. Chemistry and Biological Activities of Flavonoids: An Overview. Sci. World J. 2013, 2013, 1–16. [Google Scholar] [CrossRef] [PubMed]
- Tripoli, E.; Guardia, M.L.; Giammanco, S.; Majo, D.D.; Giammanco, M. Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review. Food Chem. 2007, 104, 466–479. [Google Scholar] [CrossRef]
- Khan, H.; Ullah, H.; Aschner, M.; Cheang, W.S.; Akkol, E.K. Neuroprotective Effects of Quercetin in Alzheimer’s Disease. Biomolecules 2019, 10, 59. [Google Scholar] [CrossRef]
- Heim, K.E.; Tagliaferro, A.R.; Bobilya, D.J. Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 2002, 13, 572–584. [Google Scholar] [CrossRef]
- Doostdar, H.; Burke, M.D.; Mayer, R.T. Bioflavonoids: Selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology 2000, 144, 31–38. [Google Scholar] [CrossRef]
- Murota, K.; Nakamura, Y.; Uehara, M. Flavonoid metabolism: The interaction of metabolites and gut microbiota. Biosci. Biotechnol. Biochem. 2018, 82, 600–610. [Google Scholar] [CrossRef]
- De Isla, N.G.; Yang, J.W.; Huselstein, C.; Muller, S.; Stoltz, J.F. IL-1beta synthesis by chondrocyte analyzed by 3D microscopy and flow cytometry: Effect of Rhein. Biorheology 2006, 43, 595–601. [Google Scholar]
- Pescetelli, I.; Zimarino, M.; Ghirarduzzi, A.; De Caterina, R. Localizing factors in atherosclerosis. J. Cardiovasc. Med. 2015, 16, 824–830. [Google Scholar] [CrossRef]
- Sun, B.; Zhao, H.; Li, X.; Yao, H.; Liu, X.; Lu, Q.; Wan, J.; Xu, J. Angiotensin II-accelerated vulnerability of carotid plaque in a cholesterol-fed rabbit model-assessed with magnetic resonance imaging comparing to histopathology. Saudi J. Biol. Sci. 2017, 24, 495–503. [Google Scholar] [CrossRef] [PubMed]
- Dholakiya, S.L.; Benzeroual, K.E. Protective effect of diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF-α expression. Toxicology in Vitro 2011, 25, 1039–1044. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.-B.; Lee, W.S.; Shin, J.-S.; Jang, D.S.; Lee, K.T. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int. Immunopharmacol. 2017, 49, 21–29. [Google Scholar] [CrossRef] [PubMed]
- Serreli, G.; Deiana, M. In vivo formed metabolites of polyphenols and their biological efficacy. Food Funct. 2019, 10, 6999–7021. [Google Scholar] [CrossRef]
- Olivares-Vicente, M.; Barrajon-Catalan, E.; Herranz-Lopez, M.; Segura-Carretero, A.; Joven, J.; Encinar, J.A.; Micol, V. Plant-Derived Polyphenols in Human Health: Biological Activity, Metabolites and Putative Molecular Targets. Curr. Drug Metab. 2018, 19, 351–369. [Google Scholar] [CrossRef]
- Cassidy, A.; Minihane, A.-M. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am. J. Clin. Nutr. 2017, 105, 10–22. [Google Scholar] [CrossRef]
- Heřmánková, E.; Zatloukalová, M.; Biler, M.; Sokolová, R.; Bancířová, M.; Tzakos, A.G.; Křen, V.; Kuzma, M.; Trouillas, P.; Vacek, J. Redox properties of individual quercetin moieties. Free Radic. Biol. Med. 2019, 143, 240–251. [Google Scholar] [CrossRef]
- Martel, C.; Cointe, S.; Maurice, P.; Matar, S.; Ghitescu, M.; Théroux, P.; Bonnefoy, A. Requirements for membrane attack complex formation and anaphylatoxins binding to collagen-activated platelets. PLoS ONE 2011, 6, e18812. [Google Scholar] [CrossRef]
- Staniewska, A. Safety of use of micronized diosmin at daily doses up to 2000 mg per day. Pol. Merkur. Lek. 2016, 41, 188–191. [Google Scholar]
- Russo, R.; Chandradhara, D.; De Tommasi, N. Comparative Bioavailability of Two Diosmin Formulations after Oral Administration to Healthy Volunteers. Molecules 2018, 23, 2174. [Google Scholar] [CrossRef]
- Ratnam, D.V.; Ankola, D.D.; Bhardwaj, V.; Sahana, D.K.; Kumar, M.N.V.R. Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. J. Control. Release 2006, 113, 189–207. [Google Scholar] [CrossRef] [PubMed]
- Najmanová, I.; Vopršalová, M.; Saso, L.; Mladěnka, P. The pharmacokinetics of flavones. Crit Rev. Food Sci Nutr 2019, 1–17. [Google Scholar] [CrossRef] [PubMed]
- Bogucka-Kocka, A.; Woźniak, M.; Feldo, M.; Kockic, J.; Szewczyk, K. Diosmin--isolation techniques, determination in plant material and pharmaceutical formulations, and clinical use. Nat. Prod. Commun 2013, 8, 545–550. [Google Scholar] [CrossRef] [PubMed]
- Lima, T.S.; Gov, L.; Lodoen, M.B. Evasion of Human Neutrophil-Mediated Host Defense during Toxoplasma gondii Infection. mBio 2018, 9, 02027-17. [Google Scholar] [CrossRef] [PubMed]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zaragozá, C.; Villaescusa, L.; Monserrat, J.; Zaragozá, F.; Álvarez-Mon, M. Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols. Molecules 2020, 25, 1017. https://doi.org/10.3390/molecules25041017
Zaragozá C, Villaescusa L, Monserrat J, Zaragozá F, Álvarez-Mon M. Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols. Molecules. 2020; 25(4):1017. https://doi.org/10.3390/molecules25041017
Chicago/Turabian StyleZaragozá, Cristina, Lucinda Villaescusa, Jorge Monserrat, Francisco Zaragozá, and Melchor Álvarez-Mon. 2020. "Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols" Molecules 25, no. 4: 1017. https://doi.org/10.3390/molecules25041017
APA StyleZaragozá, C., Villaescusa, L., Monserrat, J., Zaragozá, F., & Álvarez-Mon, M. (2020). Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols. Molecules, 25(4), 1017. https://doi.org/10.3390/molecules25041017