Table 3.

The toxicological effects and mechanisms of AN extract, other mixture compounds and arecoline resulting in several diseases.

Diseases	Toxicological Effects	AN Components	Mechanism	Biological Materials	References
Oral	dysregulating proinflammatory cytokines	AN	↓ TGF-β	human	[89]
	low prevalence of oral submucous fibrosis			human	[90]
	deteriorate prognosis of oral cancer	AN		human	[91]
	oral carcinogenesis	0.35% AN extract	↑ AP-1, apoptotic gnes, ↓ cell cycle regulators	KB cells	[92]
	initiate oral submucous fibrosis process	Arecoline		human	[93]
	reactive oxygen species ↑, cell cycle arrest, apoptosis ↓, DNA damage	800 μg/mL Arecoline		OSCC cells	[94]
	induce oral pathologies mechanisms	Arecoline	↑ MAPK, PI3K Akt, NF-κB, PKC pathways		[95]
	promote metastasis of oral cancer	160 μg/mL Arecoline	cytokines for EMT	CAL33 and UM2 cells	[96]
	promoted buccal mucosal fibroblasts	20 and 50 µg/mL Arecoline	↑ TGF-β	buccal mucosal fibroblasts	[98]
	increased oxidative stress	AN	↓ reductase, superoxide and dismutase, ↑ micronuclei in buccal exfoliated cells	human	[99]
	carcinogenesis not found in animal models	Arecoline			[100]
Liver	risk factor for various liver diseases	AN		human	[4]
	promoting migration and proliferation of human HepG2 cells	2.5 µM Arecoline	↑ PI3K-AKT pathway	HepG2 cells	[101]
	associated with liver fibrosis	AN		human	[102]
	high risk of liver fibrosis	AN		human	[103]
Behavior and Addiction	behavioral alterations	0.001, 0.01, 0.1, or 1 ppm four alkaloid		zebrafish	[19]
	increase sense of well-being, stamina, and euphoria	AN		human	[104]
	antidepressant	10 mg/kg Dichloromethane fraction	↓ monoamine oxidase-A	rat brain	[105]
	addiction of AN	AN		human	[106]
	methods for AN cessation	AN		human	[104]
	emerging pharmacological cessation therapies	AN		human	[11]
Cardiac	cardiac apoptosis	5 and 50 mg/kg/day arecoline	↑ Fas/Fas ligand pathway	rats	[108]
	cardiotoxicity and heart damage	5 and 50 mg/kg/day arecoline	↑ JAK2/STAT3, MEK5/ERK5, MAPK pathways	rats	[109]
	cardiac fibrosis	5 and 50 mg/kg/day arecoline	↑ TGF-β)/Smad pathways	rats	[110]
Gastric and intestinal	developed gastric cancer	1 mg raw areca nutt	↑ histone H3 epigenetic modifications and Rb/E2F1 pathway	mice	[111]
	decreases intestinal epithelial cell lining functions	AN extract	↓ membrane constituents	rats	[112]
Genotoxicity	genetic toxicology	Arecoline	↑ gene mutations, DNA damage and repair, cytogenetic effects	in vitro, in vivo	[17]
Reproduction and development	risk factor for preterm birth	AN	↑ oxidative stress	human	[113]
	low birth weight	AN		human	[114]
	inducing oocyte apoptosis	160, 180 and 200 μg/mL arecoline	↑ oxidative stress	mouse oocytes	[115]
	Inhibiting myogenesis	0.04 and 0.08 mM arecoline	↓ pStat3	C2C12 cells	[116]
	defective effects of myogenesis	0.04 and 0.08 mM arecoline	↓ myosin heavy chain, myogenin	C2C12 cells	[117]
Kidney	high risk of kidney stone disease	>30 AN quids		human	[118]
	promoting the progression of chronic kidney disease	10, 20, or 40 μg/mL arecoline	↑ EMT genes, fibrogenesis markers	HK2 cells	[119]
Neuron activation	nicotine addiction	100 µM four areca alkaloid	↑ nAChR	Xenopus oocytes	[120]
Abortifacient	may have abortifacient effects	AN		human	[121]

↑: Activated, ↓: Inhibited, AN: partial or whole AN chewing.