1 Mechanisms of herbal compounds
1.1 Alkaloids
Coptisine inhibits the activation of the MAPK signaling pathway and the nuclear translocation of NF-kB to have an anti-inflammatory action(Feng et al., 2017). Leonine can balance NO generation driven by ox-LDL in human umbilical vein endothelial cells are and block NF-κB/P65 nuclear translocation(Peng et al., 2020), thereby reducing atherosclerosis related inflammation. 13-Methylberberine exerts a cytoprotective effect by inhibiting the activation of NLRP3 inflammasome via autophagy induction in an H2O2-induced HUVEC cell injury model(Ding et al., 2021). Activating autophagy through the AMPK/mTOR signaling pathway, Berberine suppresses inflammatory responses(Fan et al., 2015; Ke et al., 2020; Ma et al., 2020d; Tan et al., 2020). Dendrobium suppresses inflammation, oxidative stress, apoptosis, and aging utilizing ox-LDL autophagy mediated by FKBP1A(Ning et al., 2020; Lou et al., 2022; Wen et al., 2022).
1.2 Terpenoids
Terpenoids are a class of naturally occurring organic chemicals. Most of them are polycyclic structures containing oxygen-containing functional groups and have a wide range of pharmacological effects. Previous studies have shown that natural terpenoids can significantly reduce atherosclerotic lesion area.
MAPK pathway. The iridoid glycoside geniposide reduces the ox-LDL-dependent increase in CD36 expression by decreasing the phosphorylation of p38 MAPK, ERK, JNK, and NF-κB p65, inhibiting foam cell production and inflammation. Ginsenoside compound K (CK) inhibited ox-LDL-induced inflammation and apoptosis in HUVEC cells by suppressing the NF-κB, p38, and JNK-MAPK signaling pathways. CK also reduced macrophage inflammation and foam cell production.
AMPK pathway. Alisitol A can successfully block arterial plaque formation in ApoE-/- mice fed a high-fat diet, prevent the progression of atherosclerosis, and drastically diminish the expression of inflammatory cytokines in the aorta, including ICAM-1, IL-6, and MMP. Alisitol B 23-acetate enhances cholesterol efflux from dendritic cells, enhancing immune-inflammatory responses and reducing dyslipidemia and inflammation in mice with advanced atherosclerosis. Geniposide coupled with notoginsenoside R1 can improve blood lipid levels and plaque formation in high-fat diet fed ApoE-/- mice, as well as suppress the release of serum inflammatory markers and oxidative stress factors. The combination of geniposide and Panax notoginsenoside R1 reduces the expression of pyrin domain-containing protein 3 (NLRP3) inflammasome-related proteins and Bax/Bcl2/caspase-3 pathway-related proteins. It inhibits H2O2-induced human umbilical vein endothelial cells (HUVECs) inflammatory response and apoptosis, primarily related to Nrf2/HO-1 signal activation. The information presented above suggests that geniposide and notoginsenoside R1 can inhibit the NLRP3 inflammasome and the Bax/Bcl2/caspase-3 pathway by activating the AMPK/mTOR/Nrf2 signaling pathway, hence decreasing inflammation and apoptosis in atherosclerosis efficiently.
PI3K/Akt pathway. Ilexgenin A inhibits the expression of active inflammatory cytokines generated by oxidized LDL in THP-1 cells, including IL-6, IL-1, and tumor necrosis factor-α (TNF-α). Moreover, Ilexgenin A reduced ox-LDL induced phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), IKK, and NF-κB activity. Gynostemma saponin XVII can effectively decrease the lipid content of apolipoprotein E, boost the expression of antioxidant enzymes, reduce the size of atherosclerotic lesions, and prevent ox-LDL induced endothelial damage. By restoring the normal redox state, upregulating the ratio of Bcl-2 to Bax, and suppressing the expression of cleaved caspase-3, gynoside XVII exerts its effects. Notably, treatment with Gypenoside XVII primarily elevated ERα expression, but not ERβ. Due to its antioxidant characteristics, these findings imply that Gypenoside XVII can mitigate atherosclerosis via the ERα mediated PI3K/Akt pathway. Additionally, Gypenosides can reduce blood cholesterol levels, atherosclerotic plaque formation, and aortic intimal thickening. This impact may result in the ability of Gypenosides to activate the PI3K/Akt/Bad signaling pathway and regulate apoptosis in the aorta.
NF-κB signaling pathway. Artesunate can block LPS induced elevation of HIF-1 expression and activate the NF-κB signaling pathway, reducing atherosclerotic plaque. Catalpol suppressed NF-κB transcriptional activity and reduced the overexpression of Nox4, ICAM-1, VCAM-1, and MCP-1 proteins. Catalpol raised the expression of Bcl-2 protein, decreased the expression of Bax, caspase-3, and caspase-9 protein, and inhibited endoplasmic reticulum stress-related sensor activation. Catalpol ameliorates blood cell oxidation, apoptosis, and inflammation by decreasing Nox4/NF-κB and endoplasmic reticulum stress and is correlated with enhanced ERα expression and macrophage polarization inhibition.
In addition, the following may be included in the mechanism of action of terpenoids on atherosclerosis: Paeoniflorin can inhibit the HMGB1-RAGE/TLR-2/TLR-4-NF-κB pathway; Ginsenoside Rb1 can regulate miR-33 and its target genes PEDF; Ginkgolide B can inhibit PCSK-9, block the NF-κB signaling pathway, and inhibit the generation of ROS; Diosgenin can regulate the PGC-1α/ERα pathway; Triptolide can activate liver X receptor α (LXRα )expression.
1.3 Flavonoids
Flavonoids have previously been proposed to affect the development of atherosclerosis through a variety of mechanisms, including improved lipid profiles, reduced LDL-oxidation, and reduction of many inflammatory cells and mediators.
PPAR-γ signaling. Total flavonoids of Psoralea corylifoliainhibits adhesion molecules’ mRNA and protein expression (VCAM-1, ICAM-1, and E-selectin) to prevent leukocyte and endothelial cell adhesion; inhibits the NF-κB pathway to avoid oxidative hypodensity(Wang et al., 2018; Ma et al., 2022). Inflammation of HUVEC induced by lipoprotein stimulation(Zhuo et al., 2019); activation of cholesterol efflux via PPARγ-ABCA1/ABCG1 significantly ameliorated macrophage-directed foam cell production generated by ox-LDL and reduced atherosclerotic lesion size and intraplaque macrophage proliferation(Xue et al., 2017; Zhang et al., 2021). Anti-atherosclerosis activity of formononetin involves 14 hub genes intimately associated with inflammation, oxidative stress, and apoptosis(Ma et al., 2020a; Duan et al., 2022; Liu et al., 2022). It reduces ox-LDL-induced endothelium damage in HUVECs via activating the PPAR-γ signaling pathway(Sun et al., 2017; Meng et al., 2022).
Nrf2 pathway. By upregulating Wnt/β-catenin and Nrf2 signaling pathways, vitexin rescued HUVECs from damage caused by high hyperglycemia(Yang et al., 2020). G protein-coupled estrogen receptor (GPER) mediated activation of the PI3K/AKT/Nrf pathway is responsible for the therapeutic effects of kaempferol on atherosclerosis(Luo et al., 2017; Feng et al., 2021). Homoplantaginin, and dihydrohomoplantagin prevent enhanced ROS production, ERK phosphorylation, and nuclear translocation of NF-κB(Mo et al., 2018), promote nuclear translocation of Nrf2 and boost the antioxidant downstream HO-1 protein in HUVECs and plaque endothelial cells, thereby decreasing atherosclerosis(Zhang et al., 2022a).
MAPK signaling pathway. Puerarin can considerably decrease the mRNA expression levels of IL-6 and TNF- in oxidized low-density lipoprotein (ox-LDL) stimulated vascular smooth muscle cells (VSMC), reduce MDA generation, boost SOD activity, and inhibit p38 and JNK activation(Hu et al., 2016; Chang et al., 2021). Myricetin can suppress early plaque development in atherosclerosis, prevent and ameliorate H2O2 induced endothelial damage related to dramatically decreasing p53 gene expression(Cao et al., 2019), activating caspase-3 and MAPK signaling pathways, and altering pro-apoptotic and anti-apoptotic gene expression patterns(Sun et al., 2013; Hu et al., 2020). Icariin can significantly inhibit blood lipid levels, serum IL-6 and TNF-α concentrations, tissue mRNA concentrations, and p-p38 MAPK expression(Ma et al., 2020b; Li et al., 2021a).
NF-κB pathway. Total flavonoids of Astragalus membranaceussuppressed the activity of ABCA1/G1 and reduced inflammation by inhibiting the miR-33 and NFB pathways(Meng et al., 2021). Morin hydrate can enhance vascular endothelial autophagy, lower tumor necrosis TNF-α and IL-6 expression, and increase vascular endothelial autophagy to treat atherosclerosis(Bo and Zhishan, 2017). By expanding the LXRα-ABCA1/ABCG1 pathway and decreasing NF-κB activation, Kuwanon G dramatically reduced fat accumulation and cytokine mRNA levels in macrophages(Liu et al., 2018a).
1.4 Glycosides
Through MAPKs, AP-1, and NF-κB p65 signaling pathways, amygdalin can relieve atherosclerosis and exert anti-inflammatory actions(Wang et al., 2020a). Ganoderma lucidum triterpenes and Ganoderma lucidum polysaccharides can reduce ROS and malondialdehyde (MDA) by preventing the up-regulation of NF-κB p65 and associated receptor LOX-1; inhibit the inflammatory polarization of macrophages and reduce TNF-α via modulating Notch1 and DLL4 pathways(Ku et al., 2021; Wei et al., 2021). Crocin lowers adipogenesis and decreases inflammation by boosting M2 macrophage polarization and potentially reducing NF-κB p65 nuclear translocation(Li et al., 2018; Lin et al., 2021). 2,3,5,4’-Tetrahydroxy-stilbene-2-O-β-D-glucoside can suppress inflammation by lowering blood levels of IL-6, TNF-α, VCAM-1, and MCP-1. It also significantly reduced the production of atherosclerosis plaques.Dendrobium huoshanensis polysaccharide increased superoxide dismutase (SOD) activity, decreased plaque formation, decreased neutrophil recruitment, and decreased total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), and ROS levels in parallel flow chambers, ameliorating low-shear stress-induced oxidative stress and endothelial cell dysfunction(Fan et al., 2020). Gastrodin and Gastrodia extract can lower TC and LDL-C levels in atherosclerosis mice’s peripheral blood while rescuing gut bacteria(Li et al., 2020; Liu et al., 2021). Poria cocos polysaccharides block TLR4/NF-κB pathway activation in the aorta, lower serum inflammatory mediators (,TNF-α, IL-6 and NO) and lipids (low-density lipoprotein cholesterol, triglycerides, and TC)(Huang et al., 2018; Sun et al., 2020; Li et al., 2021b).
1.5 Phenylpropanoids
Curcumin can turn down LCN2, interfere with the ERK1/2 signaling pathway for ROS(Yuan et al., 2019a), stop aldosterone from making vascular smooth muscle cells make C-reactive protein, control the AMPK/mTOR/p70S6K signaling pathway to reduce endothelial lipotoxicity and control autophagy(Pai et al., 2021; Ji et al., 2022), and improve the hardening of the arteries caused by atherosclerosis(Wan et al., 2016; Zhang et al., 2020; Xiang et al., 2021; Zhao et al., 2021a). Paeonol stops the activation of the downstream NLRP3 inflammasome and NF-κB pathway by increasing the exosomal miR-223(Liu et al., 2018b; Shi et al., 2020), promoting the expression of miR126(Yuan et al., 2016), up-regulating the expression of caveolin-1, and decreasing the expression of STAT3 and p-STAT3(Tang et al., 2020). Block PI3K/Akt/NF-κB signaling pathway(Lei et al., 2019; Li et al., 2019; Liu et al., 2020b). Salvianolic acid A can increase the activity of antioxidant enzymes, up-regulate the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway, down-regulate the expression of p47phox and p22phox, reduce oxidative stress by a lot, and block the toll-like receptor 4/nuclear factor erythroid 2-related factor 2 pathway(Song et al., 2019). The factor kappaB pathway decreases pro-inflammatory mediators, lowers serum levels of hs-CRP, and stops the NLRP3 inflammasome and NF-κB signaling pathways from turning on(Ma et al., 2020c). Salvianolic acid B can reduce inflammation through the MAPKs/NF-κB signaling pathway(Zhang et al., 2022b).
1.6 Quinones
The main mechanisms of action of Tanshinone IIA in the treatment of atherosclerosis include: interfering with RAGE and NFB and down-regulating downstream inflammatory factors, including ICAM1, VCAM, and MMP2, 3, and 9(Zhao et al., 2016a); activating NRF2 to inhibit ferroptosis(He et al., 2021); mediating miR-130b and WNT5A(Yuan et al., 2020); inhibiting miR-375 to reduce atherosclerosis, activate KLF4(Chen et al., 2019), and promote autophagy and M2 polarization in macrophages(Zhao et al., 2021b). By decreasing CLIC1 expression and membrane translocation, Tanshinone IIA Sodium sulfonate exhibits antioxidant and anti-inflammatory actions(Zhu et al., 2017); Dihydrotanshinone I stabilizes susceptible plaques by inhibiting rip3-mediated macrophage necrosis and suppressing NOX4/NF-κB signaling pathway directed by LOX-1(Zhao et al., 2016b). Shikonin can significantly ameliorate atherosclerosis in HHcy ApoE-/- mice due to its ability to prevent the inflammatory activation of CD4+ T cells via PKM2 dependent metabolic inhibition(Lü et al., 2020).
TABLE 1 | Mechanisms of Herbal medicines