Table 1.

Apigenin for disease management: revealing its multifaceted mechanisms of action.

Activity	Study Type	Dose	Mechanism	Outcome	Refs.
Anti-inflammatory	In vitro	10, 20, 40 Μm	TNF-α ↓, IL-1ß ↓, and IL-6 ↓	Apigenin suppressed these inflammatory markers	[52]
	In vivo	20 and 40 mg/kg	TNF α ↓, IL-1-ß ↓, and IL-6 ↓	The levels of pro-inflammatory cytokines were reduced by apigenin	[55]
	In vitro	30 μM	IL-10 ↓ and TNF-α ↓	Apigenin decreases the expression of IL-10 and TNF-α and secretion	[56]
	In vitro	10, 50 μM	ICAM-1 ↓, COX-2 ↓, VCAM-1 ↓ NO ↓	Apigenin exhibits anti-inflammatory properties by inhibiting the expression of COX-2 facilitated by NO	[61]
Anti-diabetic	In vivo	20 mg/kg	Fibrosis ↓, oxidative stress ↓	Apigenin treatment reduced renal dysfunction as well as oxidative stress It also decreased fibrosis	[69]
	In vivo	0.78 mg/kg	Insulin ↑, glucose ↓	This compound increased the levels of thyroid hormones and serum insulin Decrease in hepatic G-6-Pase and glucose concentration activity This compound decreased LOP and increased antioxidant enzymes	[71]
Hepatoprotective	In vivo	50, 100, 200 mg/kg	Liver function enzyme ↓, oxidative stress ↓, inflammation ↓	Apigenin decrease enzyme function, caused by CCl4 Alleviated the lipid peroxidation as malondialdehyde decreased	[75]
	In vitro	10, 20, and 40 μM	OxidativesStress ↓, inflammation ↓	Apigenin ameliorated oxidative stress Apigenin alleviated H2O2-induced upregulated expression of pro-inflammatory cytokines	[75]
	In vivo	25 mg/kg	Oxidative stress ↓, fibrosis ↓, inflammation ↓	Apigenin pretreatment prevented oxidative stress, fibrosis, and inflammation	[76]
	In vivo	150–300 mg/kg	Lipid peroxidation ↓ and oxidative stress ↓	Apigenin treatment has been proven to reduce NF-kappa B proteins c and malondialdehyde significantly The levels of hepatic reduced antioxidant enzymes were increased An important change in hepatic steatosis was seen	[78]
Reno protective	In vivo	10, 15, and 20 mg/kg	Lipid hydroperoxides ↓, antioxidant level ↑	Lipid hydroperoxides were reduced and total antioxidant levels were enhanced by apigenin Simultaneous apigenin treatment caused a reduction in the histopathological changes	[82]
	In vivo	20, 40 mg/kg	Infarct size ↓, LDH ↓, CPK ↓	Reducing renal function markers This compound played a role in the upregulation of expressions of ATP6 and ATP8 and relieving the rise in the Bax/Bcl2 ratio	[83]
Cardioprotective	In vivo	50 and 100 mg/kg	Inflammation ↓, nuclear translocation of NF-κB ↓	Myocardial infarct size was reduced by this compound It decreases myocardial injury enzymes and pro-inflammatory cytokines	[86]
	In vitro	1, 6, and 25 μM	Pyroptosis and apoptosis ↓	Pyroptosis and apoptosis stimulated by I/H injury was suppressed by apigenin	[87]
	In vivo	5 mg/kg	LDH activity, intracellular reactive oxygen species generation ↓, improved the loss of mitochondrial membrane potential, antioxidant enzymes ↑	Apigenin protects the myocardium against SI/R injury	[88]
	In vitro	20 μM	LDH activity, intracellular reactive oxygen species generation ↓, Hes1 expression ↑	SI/R injury-induced expression of Hes1 in the cardiomyocytes, which was enhanced in the apigenin plus SI/R cardiomyocytes and decreased by cotreatment of GSI This compound pretreatment maintained mitochondrial function	[88]
Neuroprotective	In vivo	20 and 40 mg/kg	Lucigenin and luminol ↓ and IL-10 levels ↑	Apigenin treatment showed neuroprotective effects via increasing the IL-10 levels and diminishing the level of lucigenin and luminol	[94]
	In vivo	10 and 20 mg/kg	Inflammation and pxidative stress ↓, apoptosis ↓	Apigenin plays a role in promoting the recovery of rat neuronal function	[95]
Role in the respiratory system	In vivo	10, 15, and 20 mg/kg	Fibrosis ↓, antioxidant enzymes ↑, tumor necrosis factor (TNF)-α, and transforming growth factor ↓	Apigenin prevents the fibrotic process The treatment was found to suppress the increases in (TNF)-α levels Attenuated the reduction in superoxide dismutase activity	[101]
	In vivo	20 mg/kg	Expression of NF-κB ↓	This compound showed anti-allergic as well as anti-neutrophil-related inflammatory activity	[102]
Role in the reproductive system	In vivo	25 mg/kg	Sperm density ↓, seminiferous epithelium cells ↑	Sperm density was reduced by apigenin treatment The % of seminiferous epithelium cells was increased	[107]
	In vivo	20 or 40 mg/kg	Testosterone levels and sperm ↑, antioxidant enzymes ↑, and inflammation ↓	The administration of apigenin attenuated testosterone levels as well as sperm measurements This compound administration reduced the CP-induced testicular damage via increasing antioxidants, suppressing the pro-inflammatory cytokines, and decreasing apoptosis	[110]
Role in skin health	In vitro	5, 10, and 20 µM	Cellular senescence ↓ MMP-1 ↓	The number of senescent cells decreased in a dose-dependent manner UVA-induced induction of MMP-1 expression was inhibited by this compound	[111]
	In vivo	Cream containing 1% apigenin	Dermal thickness and skin texture ↑	Topical application of this compound enhances dermal thickness Skin elasticity and hydration were improved	[111]
	In vivo	0.1% apigenin	Transepidermal water loss ↓, skin surface pH ↓, and hydration increased ↑	Application of apigenin topically showed important reductions in transepidermal water loss and skin surface pH, while skin hydration increased	[114]
Anti-obesity	In vivo	0.005% (w/w) apigenin	Free fatty acid ↓, apolipoprotein B ↓, total cholesterol C ↓	Apigenin has been found to reduce the levels of apolipoprotein B, free fatty acid, and total cholesterol in mice that were fed a high-fat diet	[117]
Anti-depression	In vivo	12.5–25 mg/kg	Antioxidant enzymes ↑, corticosterone and lipid peroxidation ↑	Treatment with apigenin reduced anxiety and immobility time and reversed anhedonia Apigenin increased levels of glutathione and superoxide dismutase and reduced corticosterone and malondialdehyde levels	[121]
	In vivo	20 and 40 mg/kg	Hippocampal brain-derived neurotrophic factor ↑ and corticosterone levels ↓	Apigenin showed the upregulation of brain-derived neurotrophic factor levels	[124]
Anti-cancer	In vitro	0, 50, and 100 µM	Bax, p53 ↑ Bcl2 ↓	The levels of pro-apoptotic proteins and cleaved PARP expression were increased by apigenin This compound downregulated the expression of Bcl-2	[134]
	In vitro	0, 10, 20, and 40 μM	Apoptosis and autophagy ↑, PI3K/Akt/mTOR ↓	Apigenin induced apoptosis, inhibited cell growth, and triggered autophagy Apigenin-induced autophagy as well as apoptosis	[136]
		10, 20, and 40 μM	G2/M phase cell-cycle arrest, Bax, caspases 9 and 3 ↑	Apigenin causes DNA damage and G2/M phase cell-cycle arrest Pro-apoptotic protein and cleaved caspases 9 and 3 increased	[137]
	In vitro	0, 10, 20, and 30 μg/mL	BCL2 and NF-κB/MMP-9 ↓ miR-16 ↑	Apigenin promotes miR-16 expression and induces apoptotic cell death Apigenin inhibits cancer cell growth via suppression of BCL2 as well as NF-κB/MMP-9 and promoting miR-16	[140]
Anti-arthritis	In vivo	20 mg/kg	Pro-inflammatory cytokines ↓, Langerhans cells and Maturation and migration of dendritic cell ↓	Apigenin treatment delayed the onset as well as reduced the severity of arthritis Synovial hyperplasia was suppressed by apigenin treatment	[142]
	In vivo	20 and 40 mg/kg	Inflammation ↓ P2X7/NF-κB signal-related proteins ↓	This compound protects against synovial inflammatory cell infiltration, synovial tissue edema, and epithelial cell degeneration Apigenin treatment caused mild degeneration of epithelial cells as well as tissue congestion	[143]
Role in eye-associated pathogenesis	In vivo and in vitro	20 mg/kg and 20 and 40 μM	Inflammatory cytokines ↓, BRB disruption ↓, microglial M1 polarization inhibited	Apigenin treatment ameliorated the manifestations of disruption of the BRB Inflammatory cytokines protein were levels decreased by this compound Microglial M1 polarization via TLR4/MyD88 signaling was inhibited by apigenin	[144]
	In vivo	10, 20, and 50 mg/kg	Inflammation ↓	Apigenin treatment in dry-eye disease decreased the levels of TNF-α, IL-1β, and IL-6	[145]
Role in dental-associated pathogenesis	In vitro and in vivo	5 μM and 50 μM	Bone morphogenetic protein and osteogenesis-related signaling molecules ↑, TNF-α ↓	The highest ALP activity was noticed with apigenin treatment Bone morphogenetic protein-related as well as osteogenesis-related signaling molecules are enhanced by apigenin-treatment The localization of TNF-α is diminished in apigenin-treatment	[148]
Radioprotective	In vitro	2.5, 5, 10, and 25 µg/mL	Cytokinesis-block proliferation index ↓, cell proliferation ↓	The cytokinesis-block proliferation index was decreased after the apigenin concentration increased A severe decrease in cell proliferation was seen in cells treated with this compound	[152]
Anti-colitis	In vivo	3 mg/kg/day	MDA and NOx contents ↓, MPO activity ↓, mucosal addressin cell adhesion molecule-1 ↓, IL-1β content ↓	Apigenin improved the acetic acid-induced biochemical and pathological changes This compound maintained the colon contents of the studied biomarkers	[159]
	In vivo	10, 20, and 40 mg/kg	MPO activity ↓ inflammation ↓	This compound acts as an anti-inflammatory potential	[161]
Wound healing	In vivo	Apigenin cream 2%	wound size ↓ and wound contraction ↑	Superior wound healing capacity, wound contraction ratio, and wound size were noted in the animal treated with apigenin	[164]
Immunomodulatory	In vitro	1–20 μM	mRNA and protein levels of RelB ↓, pro-inflammatory cytokine production ↓	Apigenin showed a role in the reduction of soluble TNF-α release Apigenin impairs dendritic cells’ phenotypic as well as functional maturation	[166]