Therapeutical properties of apigenin: a review on the experimental evidence and basic mechanisms

Figures & data

Figure 1. Chemical structure of apigenin (4,’5,7-trihydroxyflavone).

Figure 2. Natural sources and potential health benefits of apigenin.

Figure 3. Pharmacokinetics: Absorption, distribution, metabolism and excretion of apigenin.

Figure 4. Anticancer activity of apigenin.

Table 1. Health perspectives and basic mechanisms of action of apigenin.

Disorders	Mechanisms of action	References
Anticancer	Prostate: Down regulated the Snail, matrix metallopeptidases-2, −9, and Slug, Decreased p105/p50, NF-κB Akt, PI3K, and the phosphorylation of p-Akt and pluripotency marker Oct3/4 protein expression Lowered the phosphorylation of p-Akt	^[Citation12]
	Prostate: Lowered effect on cell viability, migration and invasion Induced apoptotic cell death, and exhibited the cell cycle arrest	^[Citation16]
	Hepatic: Exhibited cell cycle arrest at the G1 phase Up regulated the cyclinD1, down regulate CDK4 expressions	^[Citation15,Citation96]
	Oesophagus: Increased activated M1 profile marker OX-42 and iNOS Modulated IL-10 and tumor necrosis factor release Lowered cell viability, tumor migration and M2 profile marker CD206 expressions	^[Citation14,Citation41]
	Breast: Suppressed the cell growth, pSTAT3, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), pERK, IL-6, N-cadherin and pAkt expressions Lowered the phosphorylated extracellular signal-regulated kinase, snail, vimentin expressions	^[Citation43]
	Colon colorectal: Reduced signaling from the MAP kinase, activation of the p53 response pathway and PARP cleavage	^[Citation39]
	Oesophagus: Suppressed cell proliferation, VEGF levels, tumor-induced angiogenesis	^[Citation40]
	Colorectal: Induce apoptotic cell death	^[Citation42]
Diabetes prevention	Facilitated the accumulation of Nrf2 nuclear translocation Enhanced HO-1 and NQO1 protein expressions	^[Citation54]
	Inhibition of α-glucosidase	^[Citation56]
	Reduced fibrosis, oxidative stress, and renal dysfunction (lower transforming growth factor-1, fibronectin, and type IV collagen) Stop MAPK from activating Reduced expression of TNF, IL-6, and NF-B, increased expression of Bcl-2, and reduced expression of Bax and caspase-3.	^[Citation55]
Anti-obesity	Body weight loss and visceral adipose tissue reduction Decreased phosphorylation of STAT3 and transcriptional activity PPAR expression were lowered.	^[Citation61]
	Repressed inflammatory markers and NF-κB activation Induced cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) expression	^[Citation62]
	Enhanced energy export and activated lipolysis (ATGL/FOXO1/SIRT1) Lowered adipose tissue metabolic inflammation (NF-кB, MAPK)	^[Citation145]
	Increased mRNA levels of ATG Lowered FASN expression	^[Citation63]
	Boosted the skeletal muscle weight Reduced expression of atrophic genes, such as Atrogin-1 and MuRF1, mitochondrial biogenesis and function were improved Suppressed mitochondrial dysfunction and muscle atrophy caused by palmitic acid	^[Citation64]
Hepatoprotective	Promoted APAP-induced autophagy Inhibited the transcriptional activation of nuclear p65	^[Citation79]
	lower serum aspartate and alanine aminotransferase activity Decreased signal transducer and activator of transcription 3 expression and interleukin-1 levels Reduced levels of malondialdehyde, nitrite/nitrate, and superoxide dismutase activity were achieved in the liver. Caspase-3 expression is negatively regulated.	^[Citation71]
	Reduced alanine aminotransferase and aspartate aminotransferase Increased level of superoxide dismutase, reduced glutathione, glutathione peroxidases and catalase Down-regulated tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) Upregulated IL-10 expression Enhancing the activity of TNF receptor-associated factor (TRAF) 2/3 and cellular inhibitor of apoptosis protein (c-IAP) 1 Ameliorated NF-κB-inducing kinase (NIK), which mediates translocation of NF-κB2	^[Citation68]
	Enhanced insulin sensitivity and markedly reduce lipid accumulation Reduced inflammatory cytokines IL-1β and IL-18 release Inhibited xanthine oxidase (XO) activity Lowered uric acid and reactive oxygen species	^[Citation66,Citation67]
Cardioprotective	Induced mitochondria-dependent apoptosis Reversed hypoxia-induced inhibition of KV1.5 expression both in vivo and in vitro. The KV1.5 inhibitor diphenyl phosphine oxide-1 (DPO-1) abrogated apigenin-induced mitochondria-dependent apoptosis	^[Citation90–92]
	Attenuated the pyroptosis and apoptosis of myoblastic H9c2 cells Lowered the IL-1β and IL-18 levels	^[Citation96]
	Downregulated miR-15b expression Increased the expression of JAK2 and the activity of JAK2-STAT3 pathway Lowered myocardial apoptosis and ROS production Downregulated the expression of miR-15b Upregulated the expression of JAK2 and the activity of the JAK2-STAT3 pathway	^[Citation89]
	Increased ABCA1 expression through miR-33 repression Lowered the expression levels of TLR-4, MyD88 and p-IκB-α as well as nuclear NF-κB p65 Markedly decreased secretion levels of several pro-inflammatory cytokines Decreased the contents of macrophages and smooth muscle cells Reduced miR-33, TLR-4, and NF-κB p65 levels	^[Citation82,Citation83]
	Increased the MMP level of MI/Rinduced H9C2 cells Modulated apoptosis associated protein expression and phosphatidylinositol 3’-kinase (PI3K)/RACα serine/threonine protein kinase (Akt) signaling	^[Citation84]
	Momentous reduction in MDA levels, apoptotic proteins	^[Citation80]
Antimicrobial	Inhibition of synthesis of nucleic acid Suppression of cytoplasmic membrane function	^[Citation99]
	Showed antibacterial activity against Pseudomonas aeruginosa, Salmonella typhimurium, Proteus mirabilis, Klebsiella pneumoniae and Enterobacter aerogenes	^[Citation135]
	Caused destabilization of the membrane structure by disordering and disorientation of the membrane lipids	^[Citation98]
Neuroprotective	Down regulated the cytokine and nitric oxide Lowered the frequency of spontaneous Ca^2+ signals Decreased caspase-3/7 mediated apoptosis	^[Citation104,Citation105]
	Reduced microglial activation, characterized by inhibition of proliferation (BrdU+ cells) and modulation of microglia morphology (Iba-1 + cells) Lowered the expression of the M1 inflammatory marker CD68. Reduced expression of OX42, IL-6 and gp130 Enhanced the expression of brain-derived neurotrophic factor	^[Citation109]
	Exhibited neuroprotective effects against axonal degradation, myelin fragmentation, trans-dedifferentiation, and proliferation of Schwann cells via Krox20- and extracellular signal-regulated kinase-independent processes	^[Citation106]
	Downregulated the expression of NF-κB genes Prevented the neuroinflammation in substantia nigra pars compacta (SNpc) Prevented from the reduction of neurotrophic factors BDNF and GDNF mRNA expression Downregulated α-synuclein aggregation Upregulated the TH protein expression as well as dopamine D2 receptor (D2R) expression	^[Citation112]
	Downregulated the TLR4/NF-κB signaling pathway Lowered the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) Inhibited the mitochondria-mediated neuron apoptosis	^[Citation107]
Anti-inflammatory	Decreased HO-1 protein expression and activity mediated by nicotine and LPS Inhibited the synthesis of nitric oxide, prostaglandin E2 (PGE2), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-12 in response to nicotine and LPS. Increased activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS)	^[Citation117]
	Pro-inflammatory cytokines IL-6, IL-1β, and TNF-α were inhibited Caspase-1 activity suppressed by NLRP3 inflammasome assembly disruption Decreased mRNA stability through ERK1/2 activation inhibition	^[Citation118]
Reproductive role	Improved the frozen-thawed boar sperm quality	^[Citation124]
Respiratory role	Prevented from aggravation airway hyper-responsiveness (AHR) Decreased neutrophil infiltration and eosinophils concentration Decreased concentrations of total serum immunoglobulin IgE, cytokines associated to T helper type 2 (Th2), including IL-4 and IL-13, as well as Th17, including IL-17 Decreased the expression of (NF-κB) p65, an enhancer of nuclear factor kappa-light chain in activated B cells	^[Citation127]
Depression and insomnia	Lowered the rises in hydroxyproline concentration, MPO activity, TNF-α and TGF-β levels Inhibited excessive collagen deposition	^[Citation128]
	Reduced hippocampus levels of brain-derived neurotrophic factor (BDNF)	^[Citation134]
	Reduction in the mean arterial blood pressure Reduced symptoms of moderate to severe GAD	^[Citation146]

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