Table 2.

Cardio-cerebrovascular functional modulation of phthalides.

Cardio-cerebr-ovascular functions	Phthalides	Possible mechanisms	Reference
Angiogenesis or neovascularization	Ligustilide	Increase cerebral vessels number, VEGF and eNOS activation	[17]
	Butylphthalide	Alter Ang-1/Ang-2/Tie-2 signaling axis	[88]
	Butylphthalide	Promote VEFG and Ang-1, and upregulate sonic hedgehog expression	[89]
	Butylidenephthalide	Enhance VEGF and BDNF expressions via activation of AKT/mTOR signal pathway	[90]
Protection on endothelial cells	Ligustilide	Stimulate NRF2/ARE pathway	[91]
	Butylphthalide	Maintain the endothelial PGC-1α expression via regulating eNOS activity	[92]
	Butylidenephthalide	Elevate the pool of PI species, and inhibit the phosphorylation of PLCλ and ERK1/2	[93]
	Levistilide A	Suppress NLRP3 gene expression by blocking the Syk–p38/JNK pathway	[94]
	Z,Z′-3a.7a′,7a.3a′-dihydroxyligustilide	Increase the viability and proliferation of HUVECs, and reduce the apoptosis	[95]
Smooth muscle relaxation, inhibition of VSMCs abnormal proliferation and migration	Ligustilide	Downregulate c-Myc/MMP2 signaling pathway and ROCK-JNK signaling pathway	[96]
	Butylphthalide	Inhibit the β-catenin signaling pathway	[97]
	Butylidenephthalide	Phosphorylate JNK and p38 MAPK, and upregulate Nur77 gene	[98]
Vasodilatation or vasorelaxation activities	Ligustilide	Inhibit [Ca2+] influx and cold-sensing protein TRPM8 and TRPA1	[99]
	Butylphthalide	Increase the regional blood flow by preventing vasoconstriction of the artery and maintaining its diameter at normal level	[100]
	Senkyunolide A	Inhibit RYRs and VDCCs	[101]
Anti-arthrosclerosis effects	Ligustilide and Senkyunolide A	Inhibit CD137 expression through suppressing AP-1 and AKT/NF-κB signaling pathway	[102]
	Ligustilide	Activate Nrf2/HO-1 induction and NO synthesis	[103]
	Ligustilide	Activate Nrf2 and ARE-driven genes	[91]
Anti-thrombotic effects	Butylphthalide	Inhibit human platelet activation via inhibition of cPLA2-mediated TXA2 synthesis and PDE	[104]
	(S)-ZJM-289, a nitric oxide-releasing derivative of 3-n-butylphthalide	Maintain mitochondrial integrity and function, and block mitochondria-mediated cell death possibly by upregulation of Hsp70	[105]
	3-Butyl-2-benzothiophen-1(3H)-one (5d)	Decrease NADPH oxidase activity by promoting Nrf2 nuclear localization through PI3K/Akt signaling pathway	[106]
Anti-myocardial ischemia effects	Ligustilide and Cnidilide	Reduce serum lactic acid and free fatty acid	[107]
	Butylphthalide	Inhibit inflammatory and oxidative stress responses by regulating the Akt/Nrf2 signaling pathway	[108]
	Butylidenephthalide	Target the PI3K/STAT3 axis	[12]