Phytochemistry and Pharmacological Aspects of Apigenin: A Review

Hemlata      Bhardawaj; Neeru      Vasudeva; Sunil      Sharma
Abstract

Background: A bioactive flavone, apigenin, is plentifully present in common vegetables and fruits, including spinach, parsley, celery stalks, peas, black olives, olive oil, grapefruit, kumquat, honey etc. It is a low-toxic flavonoid. Flavonoids are currently considered an important component in a huge range of cosmetic, pharmacological, and medical formulations. According to epidemiological research, flavone-rich diets have been related to a lower risk of cancer, notably, lung, skin, prostate, breast cancers and certain hematological disorders. It has been proposed as a preventive agent in other disorders such as oxidative stress, inflammation, and cardiovascular and neurological issues. Apigenin-enriched medications are more effective for some chronic conditions, but if consumed regularly, they can harm animal and human health such as stomach discomfort, skin irritation, numbness and prolonged sedation etc. Apigenin's bioavailability limitations need the development of innovative carriers to increase bioavailability. Flavonoid’s data is gathered from the major public databank in order to emphasize apigenin's important role in the treatment and prevention of numerous illnesses, as well as to explore its health consequences.
Methods: The literature review of the apigenin was collected from various databases viz. Web of Science, PubMed, Google Scholar, Google and Science Direct, etc.
Results: The compiled data on the therapeutic efficacy of apigenin and its derivatives provides a platform for future researchers.
Conclusion: The data revealed the pharmacological effects viz. anti-microbial, anti-cancer, antioxidant, anti-viral, anti-inflammatory, anti-diabetic, ischemic stroke and anti-arthritic activities of apigenin isolated by using different solvents and analytical methods that can be useful in the utilization for the development and formulation of herbal preparation by future researchers.
Keywords: Apigenin, pharmacological activities, sources, bioavailability, patents, apigenin derivatives.
[1]
El-Saber Batiha, G.; Beshbishy, A.M.; Ikram, M.; Mulla, Z.S.; Abd El-Hack, M.E.; Taha, A.E.; Algammal, A.M.; Ali Elewa, Y.H. The pharmacological activity, biochemical properties and pharmacokinetics of the major natural polyphenolic flavonoid: Quercetin. Foods,  2020, 9(3), 374.
 [http://dx.doi.org/10.3390/foods9030374]

[2]
Figueira, I.; Garcia, G.; Pimpão, R.C.; Terrasso, A.P.; Costa, I.; Almeida, A.F.; Tavares, L.; Pais, T.F.; Pinto, P.; Ventura, M.R.; Filipe, A.; McDougall, G.J.; Stewart, D.; Kim, K.S.; Palmela, I.; Brites, D.; Brito, M.A.; Brito, C.; Santos, C.N. Polyphenols journey through blood-brain barrier towards neuronal protection. Sci. Rep.,  2017, 7(1), 11456.
 [http://dx.doi.org/10.1038/s41598-017-11512-6] [PMID: 28904352]

[3]
Ali, F. Health functionality of apigenin: A review. Inter. J. Food Propert.,  2017, , 1197-1238.
 [http://dx.doi.org/10.1155/2019/7010467]

[4]
Al-Snafi, A.E. Phenolics and flavonoids contents of medicinal plants, as natural ingredients for many therapeutic purposes-A review. IOSR
J. Pharm. (IOSRPHR),  2020, 10(7), 42-81.

[5]
Wang, M.; Firrman, J.; Liu, L.S.; Yam, K. A review on flavonoid apigenin: Dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. BioMed Res. Inter.,  2019, 2019, 1-18.

[6]
Sharma, A.; Ghani, A.; Sak, K.; Tuli, H.S.; Sharma, A.K.; Setzer, W.N.; Sharma, S.; Das, A.K. Probing into therapeutic anti-cancer potential of apigenin: Recent trends and future directions. Recent Pat. Inflamm. Allergy Drug Discov.,  2019, 13(2), 124-133.
 [http://dx.doi.org/10.2174/1872213X13666190816160240] [PMID: 31418666]

[7]
Huang, S.; Xue, Q.; Xu, J.; Ruan, S.; Cai, T. Simultaneously improving the physicochemical properties, dissolution performance, and bioavailability of apigenin and daidzein by co-crystallization with theophylline. J. Pharm. Sci.,  2019, 108(9), 2982-2993.
 [http://dx.doi.org/10.1016/j.xphs.2019.04.017] [PMID: 31029571]

[8]
Javed, Z.; Sadia, H.; Iqbal, M.J.; Shamas, S.; Malik, K.; Ahmed, R.; Raza, S.; Butnariu, M.; Cruz-Martins, N.; Sharifi-Rad, J. Apigenin role as cell-signaling pathways modulator: Implications in cancer prevention and treatment. Cancer Cell Inter. BioMed Central Ltd,  2021, 2(89), 1.

[9]
Lin, C.M.; Chen, H.H.; Lin, C.A.; Wu, H.C.; Sheu, J.J.C.; Chen, H.J. Apigenin-induced lysosomal degradation of β-catenin in Wnt/β-catenin signaling. Sci. Rep.,  2017, 7(1), 372.
 [http://dx.doi.org/10.1038/s41598-017-00409-z] [PMID: 28337019]

[10]
Bao, Y.Y.; Zhou, S.H.; Fan, J.; Wang, Q.Y. Anticancer mechanism of apigenin and the implications of GLUT-1 expression in head and neck cancers. Future Oncol.,  2013, 9(9), 1353-1364.
 [http://dx.doi.org/10.2217/fon.13.84] [PMID: 23980682]

[11]
Nabavi, S.F.; Khan, H.; D’onofrio, G.; Šamec, D.; Shirooie, S.; Dehpour, A.R.; Argüelles, S.; Habtemariam, S.; Sobarzo-Sanchez, E. Apigenin as neuroprotective agent: Of mice and men. Pharmacol. Res.,  2018, 359-365.
 [http://dx.doi.org/10.1016/j.phrs.2017.10.008]

[12]
Shukla, S.; Gupta, S. Apigenin and Cancer Chemoprevention. Bioactive Foods in Promoting Health; Elsevier Inc., 2010, pp. 663-689.
 [http://dx.doi.org/10.1016/B978-0-12-374628-3.00041-4]

[13]
Leopoldini, M.; Prieto Pitarch, I.; Russo, N.; Toscano, M. Structure, conformation, and electronic properties of apigenin, luteolin, and taxifolin antioxidants. A first principle theoretical study. J. Phys. Chem. A,  2004, 108(1), 92-96.
 [http://dx.doi.org/10.1021/jp035901j]

[14]
Ashrafizadeh, M.; Bakhoda, M.R.; Bahmanpour, Z.; Ilkhani, K.; Zarrabi, A.; Makvandi, P.; Khan, H.; Mazaheri, S.; Darvish, M.; Mirzaei, H. Apigenin as tumor suppressor in cancers: Biotherapeutic activity, nanodelivery, and mechanisms with emphasis on pancreatic cancer. Front Chem.,  2020, 8, 829.
 [http://dx.doi.org/10.3389/fchem.2020.00829]

[15]
Kazi, M.; Alhajri, A.; Alshehri, S.M.; Elzayat, E.M.; Al Meanazel, O.T.; Shakeel, F.; Noman, O.; Altamimi, M.A.; Alanazi, F.K. Enhancing oral bioavailability of apigenin using a bioactive selfnanoemulsifying drug delivery system (bio-SNEDDS): In vitro, in vivo and stability evaluations. Pharmaceutics,  2020, 12(8), 1-22.
 [http://dx.doi.org/10.3390/pharmaceutics12080749] [PMID: 32785007]

[16]
Meyer, H.; Bolarinwa, A.; Wolfram, G.; Linseisen, J. Bioavailability of apigenin from apiin-rich parsley in humans. Ann. Nutr. Metab.,  2006, 50(3), 167-172.
 [http://dx.doi.org/10.1159/000090736] [PMID: 16407641]

[17]
Alshehri, S.M.; Shakeel, F.; Ibrahim, M.A.; Elzayat, E.M.; Altamimi, M.; Mohsin, K.; Almeanazel, O.T.; Alkholief, M.; Alshetaili, A.; Alsulays, B.; Alanazi, F.K.; Alsarra, I.A. Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques. Saudi Pharm. J.,  2019, 27(2), 264-273.
 [http://dx.doi.org/10.1016/j.jsps.2018.11.008] [PMID: 30766439]

[18]
Hanske, L.; Loh, G.; Sczesny, S.; Blaut, M.; Braune, A. The bioavailability of apigenin-7-glucoside is influenced by human intestinal microbiota in rats. J. Nutr.,  2009, 139(6), 1095-1102.
 [http://dx.doi.org/10.3945/jn.108.102814] [PMID: 19403720]

[19]
Ding, S.M.; Zhang, Z.H.; Song, J.; Cheng, X.D.; Jiang, J.; Jia, X.B. Enhanced bioavailability of apigenin via preparation of a carbon nanopowder solid dispersion. Int. J. Nanomed.,  2014, 9(1), 2327-2333.
 [http://dx.doi.org/10.2147/IJN.S60938] [PMID: 24872695]

[20]
Kashyap, D.; Sharma, A.; Tuli, H.S.; Sak, K.; Garg, V.K.; Buttar, H.S.; Setzer, W.N.; Sethi, G. A natural bioactive flavone-type molecule with promising therapeutic function. J. Funct. Foods,  2018, 457-471.
 [http://dx.doi.org/10.1016/j.jff.2018.07.037]

[21]
Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr.,  2017, 423-435.
 [http://dx.doi.org/10.3945/an.116.012948]

[22]
Shankar, E.; Goel, A.; Gupta, K.; Gupta, S. Plant flavone apigenin: An emerging anticancer agent. Curr. Pharmacol. Reports,  2017, 423-446.
 [http://dx.doi.org/10.1007/s40495-017-0113-2]

[23]
Ginwala, R.; Bhavsar, R.; Chigbu, D.G.I.; Jain, P.; Khan, Z.K. Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin. Antioxidants,  2019, 8(2), 35.
 [http://dx.doi.org/10.3390/antiox8020035]

[24]
Mara de Menezes Epifanio, N.; Rykiel Iglesias Cavalcanti, L.; Falcão Dos Santos, K.; Soares Coutinho Duarte, P.; Kachlicki, P.; Ożarowski, M.; Jorge Riger, C.; Siqueira de Almeida Chaves, D. Chemical characterization and in vivo antioxidant activity of parsley (Petroselinum crispum) aqueous extract. Food Funct.,  2020, 11(6), 5346-5356.
 [http://dx.doi.org/10.1039/D0FO00484G] [PMID: 32462155]

[25]
Eddouks, M.; Lemhadri, A.; Zeggwagh, N.A.; Michel, J.B. Potent hypoglycaemic activity of the aqueous extract of Chamaemelum nobile in normal and streptozotocin-induced diabetic rats. Diabetes Res. Clin. Pract.,  2005, 67(3), 189-195.
 [http://dx.doi.org/10.1016/j.diabres.2004.07.015] [PMID: 15713350]

[26]
Johnston, G.A.R.; Chebib, M.; Duke, R.K.; Fernandez, S.P.; Hanrahan, J.R.; Hinton, T.; Mewett, K.N. Herbal products and gaba receptors; Elsevier Ltd: Amsterdam, 2009, 4, pp. 1095-1101.

[27]
Martínez, C.A.; Mosquera, O.M.; Niño, J. Apigenin glycoside: An antioxidant isolated from Alchornea coelophylla Pax & k. Hoffm. (Euphorbiaceae) leaf extract. Univ. Sci. (Bogota),  2016, 21(3), 245-257.
 [http://dx.doi.org/10.11144/Javeriana.SC21-3.agaa]

[28]
Zanoli, U.; Avallone, R.; Baraldi, M. Behavioral Characterisation of the Flavonoids Apigenin and Chrysin; Elsevier, Amsterdam. 2000, (51), 5117-5123.
 [http://dx.doi.org/10.1016/S0367-326X(00)00186-6]

[29]
Kumar, S.; Sharma, A. Apigenin: The anxiolytic constituent of Turnera aphrodisiaca. Pharm. Biol.,  2006, 44(2), 84-90.
 [http://dx.doi.org/10.1080/13880200600591758]

[30]
Al-Rawi, M.I.; Kahtan Almzaien, A.; Almzaien, K.A. Hypolipidemic and antioxidant efficacy of apigenin in hydrogen peroxide induced oxidative stress in adult male rats. Med.-Leg. Update,  2021, 21, 1473-1480.

[31]
Coté, H.; Boucher, M-A.; Pichette, A.; Legault, J. Anti-inflammatory, antioxidant, antibiotic, and cytotoxic activities of Tanacetum vulgare L. Essential oil and its constituents. Medicines (Basel),  2017, 4(2), 34.
 [http://dx.doi.org/10.3390/medicines4020034] [PMID: 28930249]

[32]
Andrade, J.M.; Faustino, C.; Garcia, C.; Ladeiras, D.; Reis, C.P.; Rijo, P. Rosmarinus officinalis L.: An update review of its phytochemistry and biological activity. Future Sci. OA,  2018, 4(4), FSO283.
 [http://dx.doi.org/10.4155/fsoa-2017-0124] [PMID: 29682318]

[33]
Ahmed, H.M. Ethnomedicinal, Phytochemical and pharmacological investigations of Perilla frutescens (L.) Britt. Molecules. MDPI AG.,  2019, 24(1), 102.

[34]
Das, S.; Das, J.; Samadder, A.; Boujedaini, N.; Khuda-Bukhsh, A.R. Apigenin-induced apoptosis in A375 and A549 cells through selective action and dysfunction of mitochondria. Exp. Biol. Med. (Maywood),  2012, 237(12), 1433-1448.
 [http://dx.doi.org/10.1258/ebm.2012.012148] [PMID: 23354402]

[35]
Aslam Bhatti, H.; Noor, R. Isolation of apigenin by solute-solvent extraction from Symphotrichum novea anglea. Integr. Food. Nutr. Metab.,  2019, 6(6)
 [http://dx.doi.org/10.15761/IFNM.1000268]

[36]
Tang, D.; Chen, K.; Huang, L.; Li, J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opinion Drug
Metabol. Toxicol.,  2017, 13(3), 323-330.
 [http://dx.doi.org/10.1080/17425255.2017.1251903]

[37]
Gradolatto, A.; Basly, J.P.; Berges, R.; Teyssier, C.; Chagnon, M.C.; Siess, M.H.; Canivenc-Lavier, M.C. Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug Metab. Dispos.,  2005, 33(1), 49-54.
 [http://dx.doi.org/10.1124/dmd.104.000893] [PMID: 15466493]

[38]
Gazolaa, A.C.; Costaa, G.M.; Castellanos, L.; Ramos, F.A.; Reginatto, F.H.; de Lima, T.C.M.; Schenkel, E.P. Involvement of GABAergic pathway in the sedative activity of apigenin, the main flavonoid from Passiflora quadrangularis Pericarp. Rev. Bras. Farmacogn.,  2015, 25(2), 158-163.
 [http://dx.doi.org/10.1016/j.bjp.2015.03.009]

[39]
Saeidnia, S.; Gohari, A.; Mokhber-Dezfuli, N.; Kiuchi, F. A review on phytochemistry and medicinal properties of the genus Achillea. Daru,  2011, 19(3), 173-186.
 [PMID: 22615655]

[40]
Wang, J.; Fernández, A.E.; Tiano, S.; Huang, J.; Floyd, E.; Poulev, A.; Ribnicky, D.; Pasinetti, G.M. An extract of Artemisia dracunculus L. promotes psychological resilience in a mouse model of depression. Oxid. Med. Cell. Longev.,  2018, 2018, 7418681.
 [http://dx.doi.org/10.1155/2018/7418681] [PMID: 29861834]

[41]
Malar, D.S.; Prasanth, M.I.; Brimson, J.M.; Sharika, R.; Sivamaruthi, B.S.; Chaiyasut, C.; Tencomnao, T. Neuroprotective properties of green tea (Camellia sinensis) in Parkinson’s disease: A review. Molecules. Molecules,  2020, 25(17), 3926.
 [http://dx.doi.org/10.3390/molecules25173926]

[42]
Jung, W.W. Protective effect of apigenin against oxidative stressinduced damage in osteoblastic cells. Int. J. Mol. Med.,  2014, 33(5), 1327-1334.
 [http://dx.doi.org/10.3892/ijmm.2014.1666] [PMID: 24573323]

[43]
Banerjee, K.; Mandal, M. Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells. Redox Biol.,  2015, 5, 153-162.
 [http://dx.doi.org/10.1016/j.redox.2015.04.009] [PMID: 25965143]

[44]
Salehi, B.; Venditti, A.; Sharifi-Rad, M.; Kręgiel, D.; Sharifi-Rad, J.; Durazzo, A.; Lucarini, M.; Santini, A.; Souto, E.B.; Novellino, E.; Antolak, H.; Azzini, E.; Setzer, W.N.; Martins, N. The therapeutic potential of apigenin. Inter. J. Mol. Sci.,  2019, 20(6), 1305.

[45]
Qian, S.; Fan, W.; Qian, P.; Zhang, D.; Wei, Y.; Chen, H.; Li, X. Apigenin restricts FMDV infection and inhibits viral IRES driven translational activity. Viruses,  2015, 7(4), 1613-1626.
 [http://dx.doi.org/10.3390/v7041613] [PMID: 25835532]

[46]
Wang, L.; Song, J.; Liu, A.; Xiao, B.; Li, S.; Wen, Z.; Lu, Y.; Du, G. Research Progress of the Antiviral Bioactivities of Natural Flavonoids. Natural Products and Bioprospecting; Springer, 2020, pp. 271-283.

[47]
Khandelwal, N.; Chander, Y.; Kumar, R.; Riyesh, T.; Dedar, R.K.; Kumar, M.; Gulati, B.R.; Sharma, S.; Tripathi, B.N.; Barua, S.; Kumar, N. Antiviral activity of Apigenin against buffalopox: Novel mechanistic insights and drug-resistance considerations. Antiviral Res.,  2020, 181, 104870.
 [http://dx.doi.org/10.1016/j.antiviral.2020.104870] [PMID: 32707051]

[48]
Zhang, W.; Qiao, H.; Lv, Y.; Wang, J.; Chen, X.; Hou, Y.; Tan, R.; Li, E. Apigenin inhibits enterovirus-71 infection by disrupting viral RNA association with trans-acting factors. PLoS One,  2014, 9(10), e110429.
 [http://dx.doi.org/10.1371/journal.pone.0110429] [PMID: 25330384]

[49]
Hakobyan, A.; Arabyan, E.; Avetisyan, A.; Abroyan, L.; Hakobyan, L.; Zakaryan, H. Apigenin inhibits African swine fever virus infection in vitro. Arch. Virol.,  2016, 161(12), 3445-3453.
 [http://dx.doi.org/10.1007/s00705-016-3061-y] [PMID: 27638776]

[50]
Shin, G.C.; Kim, C.; Lee, J.M.; Cho, W.S.; Lee, S.G.; Jeong, M.; Cho, J.; Lee, K. Apigenin-induced apoptosis is mediated by reactive oxygen species and activation of ERK1/2 in rheumatoid fibroblastlike synoviocytes. Chem. Biol. Interact.,  2009, 182(1), 29-36.
 [http://dx.doi.org/10.1016/j.cbi.2009.07.016] [PMID: 19647729]

[51]
Li, Y.; Yang, B.; Bai, J.Y.; Xia, S.; Mao, M.; Li, X.; Li, N.; Chen, L. The roles of synovial hyperplasia, angiogenesis and osteoclastogenesis in the protective effect of apigenin on collagen-induced arthritis. Int. Immunopharmacol.,  2019, 73, 362-369.
 [http://dx.doi.org/10.1016/j.intimp.2019.05.024] [PMID: 31132731]

[52]
Maslikah, S.I.; Amalia, A.; Afifah, S. Red betel apigenin compound
(Piper crocatum ruiz & Pav.) as an anti-inflammatory rheumatoid arthritis
agent through virtual screening. In: AIP Conference Proceedings; American Institute of Physics Inc, 2019; p. 2120.

[53]
Sun, Q.W.; Jiang, S.M.; Yang, K.; Zheng, J.M.; Zhang, L.; Xu, W.D. Apigenin enhances the cytotoxic effects of tumor necrosis factorrelated apoptosis-inducing ligand in human rheumatoid arthritis fibroblast-like synoviocytes. Mol. Biol. Rep.,  2012, 39(5), 5529-5535.
 [http://dx.doi.org/10.1007/s11033-011-1356-3] [PMID: 22189539]

[54]
Chang, X.; He, H.; Zhu, L.; Gao, J.; Wei, T.; Ma, Z.; Yan, T. Protective effect of apigenin on Freund’s complete adjuvant-induced arthritis in rats via inhibiting P2X7/NF-κB pathway. Chem. Biol. Interact.,  2015, 236, 41-46.
 [http://dx.doi.org/10.1016/j.cbi.2015.04.021] [PMID: 25935278]

[55]
Li, X.; Han, Y.; Zhou, Q.; Jie, H.; He, Y.; Han, J.; He, J.; Jiang, Y.; Sun, E. Apigenin, a potent suppressor of dendritic cell maturation and migration, protects against collagen-induced arthritis. J. Cell. Mol. Med.,  2016, 20(1), 170-180.
 [http://dx.doi.org/10.1111/jcmm.12717] [PMID: 26515512]

[56]
Khan, H.; Sureda, A.; Belwal, T.; Çetinkaya, S.; Süntar, İ.; Tejada, S.; Devkota, H.P.; Ullah, H.; Aschner, M. Polyphenols in the Treatment of Autoimmune Diseases. MOI. Pharmacol. Elsevier B.V.,  2019, 18(7), 647-657.

[57]
Kasiri, N.; Rahmati, M.; Ahmadi, L.; Eskandari, N. The significant impact of apigenin on different aspects of autoimmune disease. In: Inflammopharmacology,  2018, 26(6), 1359-1373.

[58]
Zhang, S.; Liu, X.; Sun, C.; Yang, J.; Wang, L.; Liu, J.; Gong, L.; Jing, Y. Apigenin attenuates experimental autoimmune myocarditis by modulating Th1/Th2 cytokine balance in mice. Inflammation,  2016, 39(2), 678-686.
 [http://dx.doi.org/10.1007/s10753-015-0294-y] [PMID: 26658748]

[59]
Ginwala, R.; McTish, E.; Raman, C.; Singh, N.; Nagarkatti, M.; Nagarkatti, P.; Sagar, D.; Jain, P.; Khan, Z.K. Apigenin, a natural flavonoid, attenuates EAE severity through the modulation of dendritic cell and other immune cell functions. J. Neuroimmune Pharmacol.,  2016, 11(1), 36-47.
 [http://dx.doi.org/10.1007/s11481-015-9617-x] [PMID: 26040501]

[60]
Yan, X.; Qi, M.; Li, P.; Zhan, Y.; Shao, H. Apigenin in Cancer Therapy: Anti-Cancer Effects and Mechanisms of Action. Cell and Bioscience; BioMed Central Ltd.,  2017, 79-50.

[61]
Salmani, J.M.M.; Zhang, X.P.; Jacob, J.A.; Chen, B.A. Apigenin’s anticancer properties and molecular mechanisms of action: Recent advances and future prospectives. Chin. J. Nat. Med.,  2017, 15(5), 321-329.
 [http://dx.doi.org/10.1016/S1875-5364(17)30052-3] [PMID: 28558867]

[62]
Rajendran, I.; Dhandapani, H.; Anantanarayanan, R.; Rajaram, R. Apigenin mediated gold nanoparticle synthesis and their anti-cancer effect on human epidermoid carcinoma (A431) cells. RSC Adv.,  2015, 5(63), 51055-51066.
 [http://dx.doi.org/10.1039/C5RA04303D]

[63]
Yang, J.; Fa, J.; Li, B. Apigenin exerts anticancer effects on human cervical cancer cells via induction of apoptosis and regulation of Raf/MEK/ERK signalling pathway. Trop. J. Pharm. Res.,  2018, 17(8), 1615-1619.
 [http://dx.doi.org/10.4314/tjpr.v17i8.21]

[64]
Shields, M. Chemotherapeutics. In: Pharmacognosy: Fundamentals, Applications and Strategy; Elsevier Inc.: Washington, DC, 2017; pp. 295-313.
 [http://dx.doi.org/10.1016/B978-0-12-802104-0.00014-7]

[65]
Adamczak, A.; Ożarowski, M.; Karpiński, T.M. Antibacterial activity of some flavonoids and organic acids widely distributed in plants. J. Clin. Med.,  2019, 9(1), 109.
 [http://dx.doi.org/10.3390/jcm9010109] [PMID: 31906141]

[66]
Osonga, F.J.; Akgul, A.; Miller, R.M.; Eshun, G.B.; Yazgan, I.; Akgul, A.; Sadik, O.A. Antimicrobial activity of a new class of phosphorylated and modified flavonoids. ACS Omega,  2019, 4(7), 12865-12871.
 [http://dx.doi.org/10.1021/acsomega.9b00077] [PMID: 31460413]

[67]
Nayaka, H.B.; Londonkar, R.L.; Umesh, M.K.; Tukappa, A. Antibacterial attributes of apigenin, isolated from Portulaca oleracea L. Int. J. Bacteriol.,  2014, 2014, 175851.
 [http://dx.doi.org/10.1155/2014/175851] [PMID: 26904730]

[68]
Gutiérrez-Venegas, G.; Gómez-Mora, J.A.; Meraz-Rodríguez, M.A.; Flores-Sánchez, M.A.; Ortiz-Miranda, L.F. Effect of flavonoids on antimicrobial activity of microorganisms present in dental plaque. Heliyon,  2019, 5(12), e03013.
 [http://dx.doi.org/10.1016/j.heliyon.2019.e03013] [PMID: 31886429]

[69]
Malik, S.; Suchal, K.; Irfan Khan, S.; Bhatia, J.; Kishore, K.; Kumar Dinda, A.; Singh Arya, D. Apigenin ameliorates streptozotocininduced diabetic nephropathy in rats via MAPK-NF-B-TNF-and TGF-1-MAPK-fibronectin pathways. Am. J. Physiol. Renal Physiol.,  2017, 313(2), 414-422.
 [http://dx.doi.org/10.1152/ajprenal.00393.2016]

[70]
Jung, U.J.; Cho, Y.Y.; Choi, M.S. Apigenin ameliorates dyslipidemia, hepatic steatosis and insulin resistance by modulating metabolic and transcriptional profiles in the liver of high-fat diet-induced obese mice. Nutrients,  2016, 8(5), E305.
 [http://dx.doi.org/10.3390/nu8050305] [PMID: 27213439]

[71]
Sik Suh, K.; Oh, S.; Woo, J-T.; Kim, S-W.; Kim, J-W.; Seol Kim, Y.; Chon, S. Apigenin attenuates 2-deoxy-D-ribose-induced oxidative cell damage in HIT-T15 pancreatic β-cells. Biol. Pharm. Bull.,  2012, 35, 121-126.
 [http://dx.doi.org/10.1248/bpb.35.121]

[72]
Wang, N.; Yi, W.J.; Tan, L.; Zhang, J.H.; Xu, J.; Chen, Y.; Qin, M.; Yu, S.; Guan, J.; Zhang, R. Apigenin attenuates streptozotocininduced pancreatic β cell damage by its protective effects on cellular antioxidant defense. In Vitro Cell. Dev. Biol. Anim.,  2017, 53(6), 554-563.
 [http://dx.doi.org/10.1007/s11626-017-0135-4] [PMID: 28181104]

[73]
Lee, J-H.; Zhou, Y.; Yean Cho, S.; Shik Kim, Y.; Soo Lee, Y.; Sik Jeong, C. Anti-inflammatory mechanisms of apigenin: Inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules. Arch. Pharm. Res.,  2007, 30, 1318-1327.

[74]
Deb, S.; Mazumder, M.K.; Dutta, A.; Phukan, B.C.; Bhattacharya, P.; Paul, R.; Borah, A. Therapeutic Implications of Anti-Inflammatory Natural Products in Alzheimer’s disease. Discovery and Development of Anti-inflammatory Agents from Natural Products; Elsevier, 2019, pp. 241-258.
 [http://dx.doi.org/10.1016/B978-0-12-816992-6.00008-5]

[75]
Funakoshi-Tago, M.; Nakamura, K.; Tago, K.; Mashino, T.; Kasahara, T. Anti-inflammatory activity of structurally related flavonoids, Apigenin, Luteolin and Fisetin. Int. Immunopharmacol.,  2011, 11(9), 1150-1159.
 [http://dx.doi.org/10.1016/j.intimp.2011.03.012] [PMID: 21443976]

[76]
Martínez-Castillo, M.; Pacheco-Yepez, J.; Flores-Huerta, N.; Guzmán-Téllez, P.; Jarillo-Luna, R.A.; Cárdenas-Jaramillo, L.M.; Campos-Rodríguez, R.; Shibayama, M. Flavonoids as a natural treatment against Entamoeba histolytica. Front. Cell. Infect. Microbiol.,  2018, 8, 209.
 [http://dx.doi.org/10.3389/fcimb.2018.00209]

[77]
Fonseca-Silva, F.; Inacio, J.D.F.; Canto-Cavalheiro, M.M.; Menna-Barreto, R.F.S.; Almeida-Amaral, E.E. Oral efficacy of apigenin against cutaneous Leishmaniasis: Involvement of reactive oxygen species and autophagy as a mechanism of action. PLoS Negl. Trop. Dis.,  2016, 10(2), e0004442.
 [http://dx.doi.org/10.1371/journal.pntd.0004442] [PMID: 26862901]

[78]
Emiliano, Y.S.S.; Almeida-Amaral, E.E. Efficacy of apigenin and miltefosine combination therapy against experimental cutaneous leishmaniasis. J. Nat. Prod.,  2018, 81(8), 1910-1913.
 [http://dx.doi.org/10.1021/acs.jnatprod.8b00356] [PMID: 30095915]

[79]
Amiri, M.; Nourian, A.; Khoshkam, M.; Ramazani, A. Apigenin inhibits growth of the Plasmodium berghei and disrupts some metabolic pathways in mice. Phytother. Res.,  2018, 32(9), 1795-1802.
 [http://dx.doi.org/10.1002/ptr.6113] [PMID: 29748995]

[80]
Singh, G.; Kumar, P.; Joshi, S.C. Treatment of dermatophytosis by a new antifungal agent ‘apigenin’. Mycoses,  2014, 57(8), 497-506.
 [http://dx.doi.org/10.1111/myc.12188] [PMID: 24708558]

[81]
Lee, H.; Woo, E-R.; Lee, D.G. Apigenin induces cell shrinkage in Candida albicans by membrane perturbation. FEMS Yeast Res.,  2018, 18(1), 1-9.

[82]
Wei, X.; Gao, P.; Pu, Y.; Li, Q.; Yang, T.; Zhang, H.; Xiong, S.; Cui, Y.; Li, L.; Ma, X.; Liu, D.; Zhu, Z. Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Clin. Sci. (Lond.),  2017, 131(7), 567-581.
 [http://dx.doi.org/10.1042/CS20160780] [PMID: 28143892]

[83]
Ji, J.; Yu, Q.; Dai, W.; Wu, L.; Feng, J.; Zheng, Y.; Li, Y.; Guo, C. Apigenin alleviates liver fibrosis by inhibiting hepatic stellate cell activation
and autophagy via TGF-β 1/Smad3 and P38/PPAR α pathways. PPAR Res.,  2021, 2021
 [http://dx.doi.org/10.1155/2021/6651839]

[84]
Rašković, A.; Gigov, S.; Čapo, I.; Paut Kusturica, M.; Milijašević, B.; Kojić-Damjanov, S.; Martić, N. Antioxidative and protective actions of apigenin in a paracetamol-induced hepatotoxicity rat model. Eur. J. Drug Metab. Pharmacokinet.,  2017, 42(5), 849-856.
 [http://dx.doi.org/10.1007/s13318-017-0407-0] [PMID: 28255865]

[85]
Je, H.D.; Kim, H.D.; La, H.O. The inhibitory effect of apigenin on the agonist-induced regulation of vascular contractility via calcium desensitization-related pathways. Biomol. Ther. (Seoul),  2014, 22(2), 100-105.
 [http://dx.doi.org/10.4062/biomolther.2014.012] [PMID: 24753814]

[86]
Yue, S.; Xue, N.; Li, H.; Huang, B.; Chen, Z.; Wang, X. Hepatoprotective effect of apigenin against liver injury via the non-canonical NF-κB pathway in vivo and in vitro. Inflammation,  2020, 43(5), 1634-1648.
 [http://dx.doi.org/10.1007/s10753-020-01238-5] [PMID: 32458347]

[87]
Oaarowski, M.; Kujawski, R.; Mikoajczak, P.A.; Wielgus, K.; Klejewski, A.; Wolski, H.; Seremak-Mrozikiewicz, A. In vitro and in vivo activities of flavonoids - apigenin, baicalin, chrysin, scutellarin - in regulation of hypertension - a review for their possible effects in pregnancy-induced hypertension. In: Herba Polonica; Sciendo, 2019; pp. 55-70.

[88]
Zhu, Z.Y.; Gao, T.; Huang, Y.; Xue, J.; Xie, M.L. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats. Food Funct.,  2016, 7(4), 1992-1998.
 [http://dx.doi.org/10.1039/C5FO01464F] [PMID: 26987380]

[89]
Anusha, C.; Sumathi, T.; Joseph, L.D. Protective role of apigenin on rotenone induced rat model of Parkinson’s disease: Suppression of neuroinflammation and oxidative stress mediated apoptosis. Chem. Biol. Interact.,  2017, 269, 67-79.
 [http://dx.doi.org/10.1016/j.cbi.2017.03.016] [PMID: 28389404]

[90]
Hussain, G.; Zhang, L.; Rasul, A.; Anwar, H.; Sohail, M.U.; Razzaq, A.; Aziz, N.; Shabbir, A.; Ali, M.; Sun, T. Role of plant-derived flavonoids and their mechanism in attenuation of Alzheimer’s and Parkinson’s diseases: An update of recent data. Molecules,  2018, 23(4), 814.
 [http://dx.doi.org/10.3390/molecules23040814]

[91]
Patil, S.P.; Jain, P.D.; Sancheti, J.S.; Ghumatkar, P.J.; Tambe, R.; Sathaye, S. RETRACTED: Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice. Neuropharmacology,  2014, 86, 192-202.
 [http://dx.doi.org/10.1016/j.neuropharm.2014.07.012] [PMID: 25087727]

[92]
Jung, U.J.; Kim, S.R. Beneficial effects of flavonoids against Parkinson’s disease. J. Med. Food,  2018, 421-432.
 [http://dx.doi.org/10.1089/jmf.2017.4078]

[93]
Siddique, Y.H.; Jyoti, S. Alteration in biochemical parameters in the brain of transgenic Drosophila melanogaster model of Parkinson’s disease exposed to apigenin. Integr. Med. Res.,  2017, 6(3), 245-253.
 [http://dx.doi.org/10.1016/j.imr.2017.04.003] [PMID: 28951838]

[94]
Dourado, N.S.; Souza, C. dos S.; de Almeida, M.M.A.; Bispo da Silva, A.; dos Santos, B.L.; Silva, V.D.A.; De Assis, A.M.; da Silva, J.S.; Souza, D.O.; Costa, M. de. F.D.; Butt, A.M.; Costa, S.L. Neuroimmunomodulatory and neuroprotective effects of the flavonoid apigenin in in vitro models of neuroinflammation associated with Alzheimer’s disease. Front. Aging Neurosci.,  2020, 12, 119.

[95]
Balez, R.; Steiner, N.; Engel, M.; Muñoz, S.S.; Lum, J.S.; Wu, Y.; Wang, D.; Vallotton, P.; Sachdev, P.; O’Connor, M.; Sidhu, K.; Münch, G.; Ooi, L. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease. Sci. Rep.,  2016, 6(1), 31450.
 [http://dx.doi.org/10.1038/srep31450] [PMID: 27514990]

[96]
Olajide, O.A.; Sarker, S.D. Alzheimer’s Disease: Natural Products as Inhibitors of Neuroinflammation. Inflammopharmacology. Springer Science and Business Media Deutschland GmbH,  2020, 28(6), 1439-1455.

[97]
Yi, L.T.; Li, J.M.; Li, Y.C.; Pan, Y.; Xu, Q.; Kong, L.D. Antidepressant-like behavioral and neurochemical effects of the citrusassociated chemical apigenin. Life Sci.,  2008, 13(14), 741-751.
 [http://dx.doi.org/10.1016/j.lfs.2008.01.007]

[98]
Küpeli Akkol, E.; Gürağaç Dereli, F.T.; Ilhan, M. Assessment of antidepressant effect of the aerial parts of Micromeria myrtifolia Boiss. & Hohen on mice. Molecules,  2019, 24(10), E1869.
 [http://dx.doi.org/10.3390/molecules24101869] [PMID: 31096603]

[99]
Zhang, X.; Bu, H.; Jiang, Y.; Sun, G.; Jiang, R.; Huang, X.; Duan, H.; Huang, Z.; Wu, Q. The antidepressant effects of apigenin are associated with the promotion of autophagy via the mTOR/AMPK/ULK1 pathway. Mol. Med. Rep.,  2019, 20(3), 2867-2874.
 [http://dx.doi.org/10.3892/mmr.2019.10491] [PMID: 31322238]

[100]
Li, R.; Wang, X.; Qin, T.; Qu, R.; Ma, S. Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain. Behav. Brain Res.,  2016, 296, 318-325.
 [http://dx.doi.org/10.1016/j.bbr.2015.09.031] [PMID: 26416673]

[101]
Zhou, X.; Wang, F.; Zhou, R.; Song, X.; Xie, M. Apigenin: A current review on its beneficial biological activities. J. Food Biochem.,  2017, 41(4), e12376.
 [http://dx.doi.org/10.1111/jfbc.12376]

[102]
Dong, X.; Zhou, H.; Zhang, Y.; Xu, M.; Hao, Y. Apigenin inhibits pressure overload-induced cardiac hypertrophy. Int. J. Clin. Exp. Med.,  2018, 11(4), 3772-3778.

[103]
Zare, M.F.R.; Rakhshan, K.; Aboutaleb, N.; Nikbakht, F.; Naderi, N.; Bakhshesh, M.; Azizi, Y. Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats. Life Sci.,  2019, 232, 116623.
 [http://dx.doi.org/10.1016/j.lfs.2019.116623] [PMID: 31279781]

[104]
Ling, C.; Lei, C.; Zou, M.; Cai, X.; Xiang, Y.; Xie, Y.; Li, X.; Huang, D.; Wang, Y. Neuroprotective effect of apigenin against cerebral ischemia/reperfusion injury. J. Int. Med. Res.,  2020, 48(9), 300060520945859.
 [http://dx.doi.org/10.1177/0300060520945859] [PMID: 32993408]

[105]
Ha, S.K.; Lee, P.; Park, J.A.; Oh, H.R.; Lee, S.Y.; Park, J.H.; Lee, E.H.; Ryu, J.H.; Lee, K.R.; Kim, S.Y. Apigenin inhibits the production of NO and PGE2 in microglia and inhibits neuronal cell death in a middle cerebral artery occlusion-induced focal ischemia mice model. Neurochem. Int.,  2008, 52(4-5), 878-886.
 [http://dx.doi.org/10.1016/j.neuint.2007.10.005] [PMID: 18037535]

[106]
Pang, Q.; Zhao, Y.; Chen, X.; Zhao, K.; Zhai, Q.; Tu, F. Apigenin
protects the brain against ischemia/reperfusion injury via caveolin-
1/VEGF in vitro and in vivo. Oxid. Med. Cell. Longev,  2018, 2018
 [http://dx.doi.org/10.1155/2018/7017204]

[107]
Choi, E.J.; Kim, G.H. Apigenin induces apoptosis through a mitochondria/caspase-pathway in human breast cancer MDA-MB-453 cells. J. Clin. Biochem. Nutr.,  2009, 44(3), 260-265.
 [http://dx.doi.org/10.3164/jcbn.08-230] [PMID: 19430615]

[108]
Shukla, S.; Fu, P.; Gupta, S. Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and Ku70-Bax interaction in prostate cancer. Apoptosis,  2014, 19(5), 883-894.
 [http://dx.doi.org/10.1007/s10495-014-0971-6] [PMID: 24563225]

[109]
Shukla, S.; Gupta, S. Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol. Carcinog.,  2004, 39(2), 114-126.
 [http://dx.doi.org/10.1002/mc.10168] [PMID: 14750216]

[110]
Weng, L.; Guo, X.; Li, Y.; Yang, X.; Han, Y. Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice. Eur. J. Pharmacol.,  2016, 774, 50-54.
 [http://dx.doi.org/10.1016/j.ejphar.2016.01.015] [PMID: 26826594]

[111]
Li, F.; Lang, F.; Zhang, H.; Xu, L.; Wang, Y.; Zhai, C.; Hao, E. Apigenin alleviates endotoxin-induced myocardial toxicity by modulating
inflammation, oxidative stress, and autophagy. Oxid. Med.
Cell. Longev.,  2017, 2017
 [http://dx.doi.org/10.1155/2017/2302896]

[112]
Liaudanskas, M.; Žvikas, V.; Petrikaitė, V. The potential of dietary antioxidants from a series of plant extracts as anticancer agents against melanoma, glioblastoma, and breast cancer. Antioxidants,  2021, 10(7), 1115.
 [http://dx.doi.org/10.3390/antiox10071115] [PMID: 34356348]

[113]
Rabbani, M.; Sajjadi, S.E.; Karimi-Firouzjaei, M.; Ghanadian, M. Bioactivity guided isolation of apigenin from stachys lavandulifolia vahl. in mice with anxiolytic effects. J. HerbMed Pharmacol.,  2018, 7(2), 74-78.
 [http://dx.doi.org/10.15171/jhp.2018.13]

[114]
Yarmolinsky, L.; Zaccai, M.; Ben-Shabat, S.; Mills, D.; Huleihel, M. Antiviral activity of ethanol extracts of Ficus binjamina and Lilium candidum in vitro. N. Biotechnol.,  2009, 26(6), 307-313.
 [http://dx.doi.org/10.1016/j.nbt.2009.08.005] [PMID: 19703599]

[115]
Aloke, C.; Ibiam, U.A.; Orji, O.U.; Ugwuja, E.I.; Ezeani, N.N.; Aja, P.M.; Obasi, N.A. Anti-arthritic potential of ethanol and aqueous extracts of stem bark of Cleistopholis patens on complete Freund’s adjuvant-induced rheumatoid arthritis in rats. J. Ayurveda Integr. Med.,  2021, 12(1), 28-34.
 [http://dx.doi.org/10.1016/j.jaim.2018.12.009] [PMID: 31606270]

[116]
Eteraf-Oskouei, T.; Allahyari, S.; Akbarzadeh-Atashkhosrow, A.; Delazar, A.; Pashaii, M.; Gan, S.H.; Najafi, M. Methanolic extract of ficus carica linn. leaves exerts antiangiogenesis effects based on the rat air pouch model of inflammation. evidence-based complement. Altern. Med,  2015, 2015, 1-9.

[117]
Aiyalu, R.; Subramaniam, I.; Govindarajan, A.; Ramasamy, A. Evaluation of synergistic effect of methanol leaf extract of cardiospermum halicacabum and vitex negundo on inflammation and arthritis. J. Herbs Spices Med. Plants,  2014, 20(4), 372-385.
 [http://dx.doi.org/10.1080/10496475.2013.879757]

[118]
Rani, N.Z.A.; Husain, K.; Kumolosasi, E. Moringa genus: A review of phytochemistry and pharmacology. Front. Pharmacol.,  2018, 9, 108.
 [http://dx.doi.org/10.3389/fphar.2018.00108]

[119]
Ghițu, A.; Schwiebs, A.; Radeke, H.H.; Avram, S.; Zupko, I.; Bor, A.; Pavel, I.Z.; Dehelean, C.A.; Oprean, C.; Bojin, F.; Farcas, C.; Soica, C.; Duicu, O.; Danciu, C. A Comprehensive assessment of apigenin as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. Nutrients,  2019, 11(4), E858.
 [http://dx.doi.org/10.3390/nu11040858] [PMID: 30995771]

[120]
Akinyede, K.A.; Cupido, C.N.; Hughes, G.D.; Oguntibeju, O.O.; Ekpo, O.E. Medicinal properties and in vitro biological activities of selected helichrysum species from South Africa: A review. Plants,  2021, 10(8), 1566.
 [http://dx.doi.org/10.3390/plants10081566] [PMID: 34451611]

[121]
Saravanan, S.; Arunachalam, K.; Parimelazhagan, T. Antioxidant, analgesic, anti-inflammatory and antipyretic effects of polyphenols from passiflora subpeltata leaves - a promising species of Passiflora. Ind. Crops Prod.,  2014, 54, 272-280.
 [http://dx.doi.org/10.1016/j.indcrop.2014.01.038]

[122]
Kma, L. Roles of plant extracts and constituents in cervical cancer therapy. Asian Pacific J. Cancer Prevention,  2013, 3429-3436.
 [http://dx.doi.org/10.7314/APJCP.2013.14.6.3429]

[123]
Dirar, A.I.; Wada, M.; Watanabe, T.; Devkota, H.P. Phenolic compounds from the aerial parts of Blepharis linariifolia Pers. and their free radical scavenging and enzyme inhibitory activities. Medicines (Basel),  2019, 6(4), 113.
 [http://dx.doi.org/10.3390/medicines6040113] [PMID: 31766752]

[124]
Peng, H.; Xing, Y.; Gao, L.; Zhang, L.; Zhang, G. Simultaneous separation of apigenin, luteolin and rosmarinic acid from the aerial parts of the copper-tolerant plant Elsholtzia splendens. Environ. Sci. Pollut. Res. Int.,  2014, 21(13), 8124-8132.
 [http://dx.doi.org/10.1007/s11356-014-2747-5] [PMID: 24671394]

[125]
Liu, W.; Zhang, S.; Zu, Y.G.; Fu, Y.J.; Ma, W.; Zhang, D.Y.; Kong, Y.; Li, X.J. Preliminary enrichment and separation of genistein and apigenin from extracts of pigeon pea roots by macroporous resins. Bioresour. Technol.,  2010, 101(12), 4667-4675.
 [http://dx.doi.org/10.1016/j.biortech.2010.01.058] [PMID: 20153169]

[126]
El-Beltagi, H.S.; Mohamed, H.I.; Megahed, B.M.H.; Gamal, M.; Safwat, G. Cite This Paper evaluation of some chemical constituents, antioxidant, antibacterial and anticancer activities of beta vulgaris l. root. Fresenius Environ. Bull.,  2018, 27(9), 6369-6378.

[127]
Srivastava, J.K.; Gupta, S. Extraction, characterization, stability and biological activity of flavonoids isolated from chamomile flowers. Mol. Cell. Pharmacol.,  2009, 1(3), 138-147.
 [http://dx.doi.org/10.4255/mcpharmacol.09.18] [PMID: 20098626]

[128]
World Intellectual Property Organization.  Available from: https://www.wipo.int/publications/en/

[129]
Huang, C.; Wei, Y.X.; Shen, M.C.; Tu, Y.H.; Wang, C.C.; Huang, H.C. Chrysin, abundant in morinda citrifolia fruit water-etoac extracts, combined with apigenin synergistically induced apoptosis and inhibited migration in human breast and liver cancer cells. J. Agric. Food Chem.,  2016, 64(21), 4235-4245.
 [http://dx.doi.org/10.1021/acs.jafc.6b00766] [PMID: 27137679]

[130]
Xia, F.; Li, X.; Wang, B.; Gong, P.; Xiao, F.; Yang, M.; Zhang, L.; Song, J.; Hu, L.; Cheng, M.; Sun, C.; Feng, X.; Lei, L.; Ouyang, S.; Liu, Z.J.; Li, X.; Gu, J.; Han, W. Combination therapy of LysGH15 and apigenin as a new strategy for treating pneumonia caused by Staphylococcus aureus. Appl. Environ. Microbiol.,  2015, 82(1), 87-94.
 [http://dx.doi.org/10.1128/AEM.02581-15] [PMID: 26475103]

[131]
Wang, Y.; Xu, Y.S.; Yin, L.H.; Xu, L.N.; Peng, J.Y.; Zhou, H.; Kang, W. Synergistic anti-glioma effect of Hydroxygenkwanin and Apigenin in vitro. Chem. Biol. Interact.,  2013, 206(2), 346-355.
 [http://dx.doi.org/10.1016/j.cbi.2013.10.009] [PMID: 24144774]

[132]
Li, K.; Li, M.; Luo, Z.; Mao, Y.; Yu, Y.; He, Y.; Zhou, J.; Fei, Y.; Pei, Y.; Cai, K. Overcoming the hypoxia-induced drug resistance in liver tumor by the concurrent use of apigenin and paclitaxel. Biochem. Biophys. Res. Commun.,  2020, 526(2), 321-327.
 [http://dx.doi.org/10.1016/j.bbrc.2020.03.010] [PMID: 32220496]

[133]
Guo, X.; Liu, J.; Cai, S.; Wang, O.; Ji, B. Synergistic interactions of apigenin, naringin, quercetin and emodin on inhibition of 3T3-L1 preadipocyte differentiation and pancreas lipase activity. Obes. Res. Clin. Pract.,  2016, 10(3), 327-339.
 [http://dx.doi.org/10.1016/j.orcp.2015.08.004] [PMID: 26314502]

[134]
Şirin, N.; Elmas, L.; Seçme, M.; Dodurga, Y. Investigation of possible effects of apigenin, sorafenib and combined applications on apoptosis and cell cycle in hepatocellular cancer cells. Gene,  2020, 737, 144428.
 [http://dx.doi.org/10.1016/j.gene.2020.144428] [PMID: 32045658]

[135]
Karim, R.; Palazzo, C.; Laloy, J.; Delvigne, A.S.; Vanslambrouck, S.; Jerome, C.; Lepeltier, E.; Orange, F.; Dogne, J.M.; Evrard, B.; Passirani, C.; Piel, G. Development and evaluation of injectable nanosized drug delivery systems for apigenin. Int. J. Pharm.,  2017, 532(2), 757-768.
 [http://dx.doi.org/10.1016/j.ijpharm.2017.04.064] [PMID: 28456651]

[136]
Pápay, Z.E.; Kósa, A.; Böddi, B.; Merchant, Z.; Saleem, I.Y.; Zariwala, M.G.; Klebovich, I.; Somavarapu, S.; Antal, I. Study on the pulmonary delivery system of apigenin-loaded albumin nanocarriers with antioxidant activity. J. Aerosol Med. Pulm. Drug Deliv.,  2017, 30(4), 274-288.
 [http://dx.doi.org/10.1089/jamp.2016.1316] [PMID: 28282259]

[137]
Al Shaal, L.; Shegokar, R.; Müller, R.H. Production and characterization of antioxidant apigenin nanocrystals as a novel UV skin protective formulation. Int. J. Pharm.,  2011, 420(1), 133-140.
 [http://dx.doi.org/10.1016/j.ijpharm.2011.08.018] [PMID: 21871547]

[138]
Jangdey, M.S.; Gupta, A.; Saraf, S.; Saraf, S. Development and optimization of apigenin-loaded transfersomal system for skin cancer delivery: In vitro evaluation. Artif. Cells Nanomed. Biotechnol.,  2017, 45(7), 1452-1462.
 [http://dx.doi.org/10.1080/21691401.2016.1247850] [PMID: 28050929]

[139]
Zhao, L.; Zhang, L.; Meng, L.; Wang, J.; Zhai, G. Design and evaluation of a self-microemulsifying drug delivery system for apigenin. Drug Dev. Ind. Pharm.,  2013, 39(5), 662-669.
 [http://dx.doi.org/10.3109/03639045.2012.687378] [PMID: 22607130]

[140]
Zhang, Z.; Cui, C.; Wei, F.; Lv, H. Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system. Drug Dev. Ind. Pharm.,  2017, 43(8), 1276-1282.
 [http://dx.doi.org/10.1080/03639045.2017.1313857] [PMID: 28358225]
Cite As
The Natural Products Journal

Phytochemistry and Pharmacological Aspects of Apigenin: A Review

Abstract
