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