Drug Res (Stuttg) 2018; 68(03): 132-138
DOI: 10.1055/s-0043-120662
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Anti-degenerative effect of Apigenin, Luteolin and Quercetin on human keratinocyte and chondrocyte cultures: SAR evaluation

Lucia Crascì
1   Department of Drug Sciences, University of Catania, Viale A. Doria, Catania, Italy
Venera Cardile
2   Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
Giusy Longhitano
1   Department of Drug Sciences, University of Catania, Viale A. Doria, Catania, Italy
Francesco Nanfitò
3   Department of Medical and Surgery Specialties, Section of Plastic Surgery, Cannizzaro Hospital, Catania, Italy
Annamaria Panico
1   Department of Drug Sciences, University of Catania, Viale A. Doria, Catania, Italy
› Author Affiliations
Further Information

Publication History

received 27 July 2017

accepted 02 October 2017

Publication Date:
06 November 2017 (online)


Background Inflammation is a dynamic process that occur on vascularized tissue in response to different stimuli causing cell injury and tissue degeneration. Reactive oxygen and nitrogen species (ROS and RNS) and advanced glycation end products (AGEs) have a key mediatory role in the development and progression of degenerative tissue process. The bioflavonoids possess a broad-spectrum of pharmacological activities. Their capability is related to their chemical structure.

Methods In this study we evaluated and compare antioxidant, anti-glycative and anti-degenerative actions of two flavones apigenin and luteolin and a flavonol quercetin, in function of their hydroxyl groups arrangement. Moreover we assay, on NCTC 2544 and chondrocytes cultures, the flavonoids capacity to modulate NO and glycosamminoglycans levels, index of antidegenerative capacity.

Results All tested flavonoids act as free radicals scavengers (ROO and NO) and advanced glycation end products inhibitors, in agreement with their BDE, IP and molecular planarity. Quercetin showed a high ORAC value (2.70±0.12 ORAC Units), according to a low BDE (74.54 Kcal/mol) and IP (174.44 Kcal/mol) values. Luteolin is the most active compound in the NO (48.19±0.18%) and AGEs (60.06±0.52%) inhibition, in function of a low torsion angle (16.3°) between the 3-OH moiety and C’6 carbon atom.

Conclusion All tested flavonoids posses a protective role on degenerative tissue events. They acts in different manner depending on the functional groups, the biological substrate and the concentration used. In any case, it can be considered a suitable product preventing a degenerative processes.

  • References

  • 1 Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov 2009; 3: 73-80
  • 2 Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: Implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63: 582-592
  • 3 Percik R, Stumvoll M. Obesity and cancer. EXP Clin Endocr Diab 2009; 117: 563-566
  • 4 Dickinson PJ, Carrington AL, Frost GS. et al. Neurovascular disease, antioxidants and glycation in diabetes. Diabetes Metab Res 2002; 18: 260-272
  • 5 Crascì L, Lauro MR, Puglisi G et al. Natural antioxidant polyphenols on inflammation management: Anti-glycation activity vs metalloproteinases inhibition. Crit Rev Food Sci 2016 [Epub ahead of print]
  • 6 Sparvero LJ, Asafu-Adjei D, Kang R. et al. RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med 2009; 7: 1-17
  • 7 Goldring MB, Berenbaum F. The regulation of chondrocyte function by proinflammatory mediators: Prostaglandins and nitric oxide. Clin Orthop Relat R 2004; 427: S37-S46
  • 8 Vicini P, Crascì L, Incerti M. et al. Benzisothiazolyliminothiazolidin-4-ones with Chondroprotective Properties: Searching for Potent and Selective Inhibitors of MMP-13. ChemMedChem 2011; 6: 1199-1202
  • 9 Panico AM, Vicini P, Geronikaki A. et al. Heteroarylimino-4-thiazolidinones as inhibitors of cartilage degradation. Bioorgan Chem 2011; 39: 48-52
  • 10 Crascì L, Panico A. Protective effects of many citrus flavonoids on cartilage degradation process. J Biomater Nanobiotechnol 2013; 4: 279-283
  • 11 Panico A, Cardile V, Santagati NA. et al. Antioxidant and protective effects of sumac leaves on chondrocytes. J Med Plants Res 2009; 3: 855-861
  • 12 Puglia C, Lauro MR, Offerta A. et al. Nanostructured Lipid Carriers (NLC) as vehicles for topical administration of sesamol: In vitro percutaneous absorption study and evaluation of antioxidant activity. Planta Med 2017; 83: 398-404
  • 13 Lauro MR, Crascì L, Carbone C. et al. Encapsulation of a citrus by-product extract: Development, characterization and stability studies of a nutraceutical with antioxidant and metalloproteinases inhibitory activity. LWT-Food Sci Technol 2015; 62: 169-176
  • 14 Pietta PG. Flavonoids as antioxidants. J Nat Prod 2000; 63: 1035-1042
  • 15 Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002; 13: 572-584
  • 16 Galano A. Free radicals induced oxidative stress at a molecular level: the current status, challenges and perspectives of computational chemistry based protocols. J Mex Chem Soc 2015; 59: 231-262
  • 17 Trouillas P, Marsal P, Siri D. et al. A DFT study of the reactivity of OH groups in quercetin and taxifolin antioxidants: The specificity of the 3-OH site. Food Chem 2006; 97: 679-688
  • 18 Leopoldini M, Marino T, Russo N. et al. Antioxidant properties of phenolic compounds: H-atom versus electron transfer mechanism. J Phys Chem A 2004; 108: 4916-4922
  • 19 Leopoldini M, Pitarch IP, Russo N. et al. Structure, conformation, and electronic properties of apigenin, luteolin, and taxifolin antioxidants. A first principle theoretical study. J Phys Chem A 2004; 108: 92-96
  • 20 Leopoldini M, Chiodo SG, Russo N. et al. Detailed investigation of the OH radical quenching by natural antioxidant caffeic acid studied by quantum mechanical models. J Chem Theory Comput 2011; 7: 4218-4233
  • 21 Moalin M, Van Strijdonck GP, Beckers M. et al. A planar conformation and the hydroxyl groups in the B and C rings play a pivotal role in the antioxidant capacity of quercetin and quercetin derivatives. Molecules 2011; 16: 9636-9650
  • 22 Crascì L, Vicini P, Incerti M. et al. 2-Benzisothiazolylimino-5-benzylidene-4-thiazolidinones as protective agents against cartilage destruction. Bioorg Med Chem 2015; 23: 1551-1556
  • 23 Marcocci L, Maguire JJ, Droylefaix MT. et al. The nitric oxide-scavenging properties of Ginkgo biloba extract EGb 761. Biochem Bioph Res Co 1994; 201: 748-755
  • 24 Chaudhuri D, Ghate NB, Sarkar R. et al. Phytochemical analysis and evaluation of antioxidant and free radical scavenging activity of Withania somnifera root. Asian J Pharm Clin Res 2012; 5: 193-199
  • 25 Derbré S, Gatto J, Pelleray A. et al. Automating a 96-well microtiter plate assay for identification of AGEs inhibitors or inducers: application to the screening of a small natural compounds library. Anal Bioanal Chem 2010; 398: 1747-1758
  • 26 Maccari R, Vitale RM, Ottanà R. et al. Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents. Eur J Med Chem 2014; 81: 1-14
  • 27 Panico A, Maccari R, Cardile V. et al. 5-Arylidene-4-thiazolidinone derivatives active as antidegenerative agents on human chondrocyte cultures. Med Chem 2013; 9: 84-90
  • 28 Graziano ACE, Parenti R, Avola R. et al. Krabbe disease: involvement of connexin 43 in the apoptotic effects of sphingolipid psychosine on mouse oligodendrocyte precursors. Apoptosis 2016; 21: 25-35
  • 29 Panico A, Maccari R, Cardile V. et al. Evaluation of the anti-inflammatory/chondroprotective activity of aldose reductase inhibitors in human chondrocyte cultures. Med Chem Comm 2015; 6: 823-830
  • 30 Halliwell B, Rafter J, Jenner A. Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not?. Am J Clin Nutr 2005; 81: 268S-276S
  • 31 Yanm SF, Ramasamym R, Schmidtm AM. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Rev Endocrinol 2008; 4: 285-293
  • 32 Komosinska-Vassev K, Olczyk P, Winsz-Szczotka K. et al. Plasma biomarkers of oxidative and AGE-mediated damage of proteins and glycosaminoglycans during healthy ageing: A possible association with ECM metabolism. Mech Ageing Dev 2012; 133: 538-548
  • 33 Cardile V, Panico AM, Geronikaki A. et al. In vitro evaluation of thiazolyl and benzothiazolyl Schiff bases on pig cartilage. Il Farmaco 2002; 57: 1009-1013
  • 34 Nagai R, Murray DB, Metz TO. et al. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes 2012; 61: 549-559
  • 35 Federici M, Giustizieri ML, Scarponi C. et al. Impaired IFN-γ-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. J Immunol 2002; 169: 434-442
  • 36 Yamaoka J, Kabashima K, Kawanishi M. et al. Cytotoxicity of IFN-γ and TNF-α for vascular endothelial cell is mediated by nitric oxide. Biochem Bioph Res Co 2002; 291: 780-786
  • 37 Gasser P, Lati E, Peno-Mazzarino L. et al. Cocoa polyphenols and their influence on parameters involved in ex vivo skin restructuring. Int J Cosmetic Sci 2008; 30: 339-345
  • 38 Ikeda M, Naitoh M, Kubota H. et al. Elastic fiber assembly is disrupted by excessive accumulation of chondroitin sulfate in the human dermal fibrotic disease, keloid. Biochem Bioph Res Co 2009; 390: 1221-1228
  • 39 Panico AM, Cardile V, Garufi F. et al. Effect of hyaluronic acid and polysaccharides from Opuntia ficus indica (L.) cladodes on the metabolism of human chondrocyte cultures. J Ethnopharmacol 2007; 111: 315-321
  • 40 Clouet J, Vinatier C, Merceron C. et al. From osteoarthritis treatments to future regenerative therapies for cartilage. Drug Discov Today 2009; 14: 913-925