Table 1.
The Role of various natural products and the derivatives in atherosclerosis through Inhibiting IKKβ-mediated Inflammation
| Classification/Name | major ingredient | Drug Class | Drug Source | Effective Dose of Drug | Animal/Cell Model Induction | Effect | Target | Pathway | Ref | |
|---|---|---|---|---|---|---|---|---|---|---|
| Natural products-based derivatives | ||||||||||
| Vinpocetine | Vinpocetine | Vincamine alkaloid | Vinca minor | 5 mg/kg (i.p.) | high cholesterol diet (16.6% fat, 10.6% sucrose and 1.3% cholesterol) for 12 weeks + apoE−/− mice-induced atherosclerosis model | anti-inflammatory, anti-oxidant stress, inhibit monocyte adhesion to ECs | TNF-α, IL-6, MCP-1, MCP-1, MMP-2, MMP-9↓ | p-Akt, p-IKKα, p-IKKβ, p-IκBα ↓ | Akt/NF-κB | [80] |
| 30, 50 µM | 20 μg/ml ox-LDL + PMA-induced macrophages for 12 h | |||||||||
| 20 μg/ml ox-LDL + (HUVECs + THP-1 cells) to induce monocyte-endothelial cell adhesion | ||||||||||
| Metformin | guanidine | hypoglycemic agents | Galega officinalis | 200 mg/kg/day (p.o.) | atherogenic diet (0.8% cholesterol and 3% soybean oil) for 10 weeks + new zealand white rabbits to induce atherosclerosis model | anti-inflammatory, inhibit monocyte adhesion to ECs | MCP-1, CRP, TNF-α, IL-6, IL-4, IL-10, IL-8, IL-1, VCAM-1, ICAM-1, LOX-1 ↓ | p65 ↓, IκBα ↑ | - | [86] |
| 100, 200, 300 µM/ml | 10 ng/ml TNF-α + rabbit endothelial cells + rabbit monocytes | |||||||||
| 100, 500,1000 µM | 10 ng/ml TNF-α + HUVECs-induced inflammation | anti-inflammatory | IL-6 ↓ | P-IKKα/β↓, IκBα, P-AMPK, αAMPK ↑ | PI3K/AMPK/IKKα/β | [88] | ||||
| 10−3 mol/L | (10−4 mmol/L Insulin + 30 mM glucose + 1 µM dexamethasone) + HUVECs-induced Insulin resistance of endothelial cells model | enhance endothelial function | NO, eNOS, ET-1 ↑ | - | - | [84] | ||||
| Naringin | Naringin | flavonoid | grape, citrus species, fractus aurantii | 50, 100, 200 μg/ml | 10 ng/ml TNF-α stuimilated-HUVECs + THP-1- induced inflammation and monocyte adhesion | anti-inflammatory, inhibit monocyte adhesion to ECs | ICAM-1,VCAM-1, MCP-1, E-selectin, RANTES↓ | p-p65, p-IκBα, p-IKKα/β ↓, IκBα ↑ | IKK/NF-κB | [92] |
| Emodin | Emodin | anthraquonoid compound | dried root of Rhei Rizoma | 10 µM | 100 ng/ml Light + monocyte-like cell line (THP-1) to induce monocytes migration | anti-inflammatory, inhibit migration | CCR1, CCR2, ICAM-1, IL-8, MCP-1, TNF-α, IL-6 ↓ | p38, p-p38, p-IκBα | p38/NF-κB | [94] |
| 10 µM | 10 ng/ml TNF-α inducing rat aortic VSMCs migration | anti-inflammatory | MMP-2, MMP-9, MCP-1, IL-1β, IL-6, ICAM-1, VCAM-1↓ | - | NF-κB pathway | [95] | ||||
| Green tea polyphenols | Epigallocatechin gallate | polyphenols | green tea | 0.1, 0.2, 0.4 mg/ml | 50 mg/ml ox-LDL + HUVECs-induced inflammation model | anti-inflammatory, improve endothelial dysfunction | TNF-α↓ | p65↓ | IKK/NF-κB | [99] |
| Stybenpropol A | Stybenpropol A | phenylpropane derivative | Benzoinum | 50, 200 μmol/ L | 12.5 ng/ml TNF-α + HUVECs-induced inflammation | anti-inflammatory, anti-apoptotic | sVCAM-1, sICAM-1, IL-1β, IL-8, Caspase-9, Bax↓, Bcl-2 ↑ | IKKβ, IκBα ↑ | IKK/NF-κB | [100] |
| Methyl-β-cyclodextrin | Methyl-β-cyclodextrin | cyclic oligosaccharide | starch hydrolysis enzymatic | 5 nM | (1 μg/ml LPS / 50 μg/ml ox-LDL) + (HUVECs + THP-1)-induced monocyte-endothelial adhesion | inhibit monocyte adhesion to ECs | ICAM-1, VCAM-1↓ | p-p65, p65, IKK, Akt↓, IκB, p-Akt↑ | LPS/IKK/NF-κB, oxLDL/Akt/NF-κB | [51] |
| Natural extracts | ||||||||||
| Tanshinone IIA | Tanshinone IIA | Diterpene | Salvia miltiorrhiza bunge | 90, 30 10 mg/kg/day (p.o.) | high-fat diet (fat: 21% (wt/wt), cholesterol: 0.15% (wt/wt)) for 13 weeks + ApoE−/− mice-induced atherosclerosis model | anti-inflammatory | MC-1, TNF-α ↓ | TLR4, MyD88, NF-κB ↓ | TLR4/MyD88/NF-κB | [104] |
| 5, 10, 20 µg/ml | 10 ng/ml TNF-α + (HUVECs + THP-1)-induced inflammation | anti-inflammatory | ICAM-1,VCAM-1, TNF-α, E-selectin ↓ | IKKα/β, p-IKKα/β, p65, p-IκBα, p-p65↓, IκBα↑ | IKK/NF-κB | [105] | ||||
| Quercetin | Quercetin | Flavonoid subclass | fruits and vegetables | 0.1%, w/w in diet | human CRP transgenic mice + IL-1β 100 L/mouse (i.p.); ApoE*3 leiden transgenic mice + high cholesterol diet (15% (w/w) cacao butter, 1% (w/w) palm oil, 40.5% sucrose, 20% acid casein, 10% corn starch and 6.2% cellulose, supplemented with or without 1% cholesterol (all w/w) for 15 weeeks-induced AS model | anti-inflammatory, anti-proliferation | CRP, SAA, E-selectin, VCAM-1 ↓ | p65 | - | [109] |
| 10, 30 µmol/L | 0.2 mmol/L H2O2/10 U/ml TNF-α/IL-1β 5 ng/ml- stimulated HUVECs/human HuH7 hepatoma cells | |||||||||
| Myricetin | myricetin | flavonoid | fruits, vegetables, medicinal herbs | - | TNF-α + ECV304 cells-induced inflammation | inhibit monocyte adhesion to ECs | - | IKK, p65, IκB ↓ | IKK/NF-κB/IκB | [115] |
| 10 µgl/ml | 10 ng/ ml LPS + dendritic cells-induced cells inflammation model | anti-inflammatory | TNF-α, IL-6, IL-12p70 ↓ | P65, p-IKKα/β, p-IκBα ↓, IκBα ↑ | IKK/NF-κB | [178] | ||||
| Clematichinenoside | Clematichinenoside | triterpene saponin | Clematis chinensis osbeck root | 1, 3, 10 µM | 10 ng/ml TNF-α + HUVECs-induced inflammation | anti-oxidant stress, suppress monocyte- HUVECs adhesion | ICAM-1,VCAM-1, ROS, O2(∙-), H2O2, NOX4, p47↓ | p-IκBα, IKKβ, p65↓, IκBα ↑ | IKK/NF-κB | [118] |
| Andrographolide | Andrographolide | diterpene lactone | leaves | 10 μM | 1 ng/ml TNF-α + EA.hy926 cells -induced inflammation | anti-inflammatory | ICAM-1 ↓ | p-IKKβ/IKKβ, p-IκBα, p-IKKα/IKKα, p65↓, IκBα ↑ | IKK/NF-κB | [179] |
| Avenanthramide-c | CH3-Avenanthramide-c | polyphenol | Avena sativa | 50, 100 μM | 100 ng/ml TNF-α + human aortic SMCs to induce proliferation and migration | anti-inflammatory, anti-proliferation | MMP-2, MMP-9, TNF-α, IL-1β, IL-6 ↓ | p65, p-IκB, p-ERK1/2, p-JNK, p-p38↓, IκB ↑ | MAPK/NF- κB | [123] |
| 20, 40, 100 μM | 5 ng/ml hrIL-1β + HAECs / 20 ng/ml TNF-α + HUVECs-induced inflammation | anti-inflammatory | IL-6, IL-8, MCP-1↓ | p65, p-IKKα, p-IKKβ, p-IκB↓, IκBα↑ | IKK/NF-κB | [124] | ||||
| Digitoxin | digitoxin | steroid glycoside | Digitalis | 3, 10, 30 nmol/l | 10 ng/ml IL-1β + HUVECs-induced inflammation | anti-inflammatory | MCP-1, Caspase-3, eNOS↓ | p65, p-TAK1, p-IKK, p-IκBα ↓, IκBα↑ | TAK-1/IKK/NF-κB | [126] |
| Kansuinine A | Kansuinine A | Terpenoid | Euphorbia kansui L | 20, 60 μg/ kg (i.p.) | A high fat-diet + ApoE−/− mice + -induced atherosclerosis model | anti-oxidant stress, anti-apoptotic, anti-inflammatory | ROS, GPx, MDA, Bax, Bcl-2, CC3 ↓ | p-p65, p65, p-IKKβ, IKKβ, p-IκBα↓, IκBα ↑ | IKKβ/IκBα/NF-κB | [128] |
| 0.1, 0.3, 1.0 μM | 200 μM H2O2 + HAECs-induced endothelial injury | |||||||||
| Honokiol | Honokiol | pleiotropic lignan | Magnolia grandiflora | 10 μM | 0.5 mM Palmitic acid (PA) + HUVECs-induced endothelial cell injury model | anti-inflammatory | IL-6, IL-8, MCP-1, NO, iNOS, eNOS ↓ | p-IKKβ, p-IκB, p50, p65↓ | IKK/IκB/NF-κB | [131] |
| Longxuetongluo capsule | Dragon's Blood | totaenolic extract | Croton, Dracaen, Daemonorops, Pterocarpus | 100, 200, and 300 mg/kg/d (p.o.) | A high-fat diet (0.2% cholesterol,15% fat added) for 7 weeks + ApoE−/− mice-induced atherosclerosis model | anti-inflammatory, inhibit the adhesion of monocytes to HUVECs | eNOS ↑, VCAM-1, MCP-1, COX-2 ↓ | p-ErK/ErK, p-IKKα/β, p-IκBα, IKKβ, IKKα, p-p38/p38↓, IκBα ↑ | p38/IKK/IκB/NF-κB | [180] |
| 20, 40 µg/ml | 20 µg/ml ox-LDL + (HUVECs + THP-1)-induced inflammation | |||||||||
| Pulvones A/C | pulvones A/C | isoflavonoids | Millettia pulchra | 3, 10 µM | 1 µg/ml LPS + RAW264.7 macrophage cells to induce inflammation | anti-inflammatory | iNOS, COX-2, IL-6, IL-1β↓ | p65, IKK, p-IκBα↓, IκBα↑ | IKKβ/NF-κB | [133] |
| Acetyl-11-Keto-β-Boswellic Acid | Acetyl-11-Keto-β-Boswellic Acid | γ-cyclodextrin complex | oleogum resin | 100 mol/kg (i.p.) | 50 μg LPS-injected apoE−/− mices-induced atherosclerotic model |
Anti-inflammatory anti-atherogenic |
MCP-1, MCP-3, IL-1α, MIP-2, VEGF, TF ↓ | IKK, p-IκBα, p65↓, IκBα↑ | NF-κB signaling | [135] |
| 10 μmol/L | 100 ng/ml LPS + human macrophages / mouse mononuclear and macrophages-induced inflammation model | |||||||||
| Ginsenoside Re | Ginsenoside Re | - | Ginseng | 10 µM | 50 ng/ml LPS + peritoneal macrophages to induce inflammation model | anti-inflammatory | IL-1β, TNF-α, COX-2, iNOS, IRAK-4, IRAK-1↓ | p-IKKβ, p65, p-p65, TLR4, MyD88 ↓, IκBα ↑ | - | [137] |
| Corosolic acid | Corosolic acid | Pentacyclic triterpenoid | - | 50 μM | 1 μg/ml LPS + RAW 264.7 macrophage cells -induced inflammation model | anti-inflammatory | IFN-γ ↓ | Akt, NF-κB, c-JUN, IKKα, p-IKKα, p-IKKβ ↓ | Akt/IKK/NF-κB | [139] |
| Ursolic acid | Ursolic acid | 100 μM | ||||||||
| Pipernigramides | compounds 42/43/44 | amide alkaloids | Piper nigrum L | 2, 4, 8 μM | 1 μg/ml LPS + RAW 264.7 macrophage cells -induced inflammation model | anti-inflammatory | IL-1β, IL-6, TNF-α, PGE2, iNOS, COX-1, COX-2 ↓ | IKKα/β, P-IKKα/β, p-IκBα, p65, p-p65 ↓, IκBα ↑ | NF-κB signaling | [141] |
| Synthetic drugs | ||||||||||
| Sulforaphane | Sulforaphane | isothiocyanate | Isothiocyanate, broccoli | 0.25 mg/kg/day (p.o.) | A high cholesterol die (1% cholesterol-enriched chow) for 4 weeks + new zealand white rabbits to induce atherosclerosis model | anti-oxidant stress | MDA, SOD ↓, GSH ↑ | p65 | - | [143] |
| 2.5, 5 μM | 5 ng/ml TNF-α + Human endothelial cells ECV-304-induced inflammation | anti-inflammatory | IL-1β, IL-6, IL-8, ICAM-1, VCAM-1, E-select ↓ | p65, p-IκBα, p-IKKβ, IKKβ, p-RhoA, RhoA, p-ROCK, ROCK↓, IκBα↓ | RhoA/ROCK/NF-κB | [146] | ||||
| 10 μmol/L | 4 ng/mL TNF-α + HUVECs to induce inflammation model | anti-inflammatory | EL ↓ | p50, p65, p-IKK1/IKK1, p-IKK2/IKK2, p-IκB/IκB↓, IκBα ↑ | NF-κB/EL | [91] | ||||
| Vitamin C | Vitamin C | Vitamin | 10, 20, 40 mM | 10 ng/ml IL-1/100 ng/ml PMA / 0.2 mM H2O2 / 10 ng/ml TNF / 200 U/ml IFN-γ + ECV304 / HUVECs-induced inflammation model | anti-inflammatory anti-oxidant stress | IL-8 ↓ | p65, p-IκBα, IKKα, IKKβ ↓, IκBα ↑ | - | [149] | |
| Zinc | Zinc | - | - | 1, 15 μM | 10 μg/ml LPS + HUVECs-induced inflammation model | anti-inflammatory | TNF-α, IL-1β, MCP-1, NO, VCAM-1 ↓ | IKKα, p65↓ | IKKα/NF-κB | [152] |
| 1-Deoxynojirimycin | 1-Deoxynojirimycin | Polyhydroxy alkaloid | Mulberry Leaves | 10 mg/d (p.o.) | A total of 144 patients with stable angina pectoris and blood stasis syndrome |
anti-oxidant anti-inflammatory |
hs-CRP, IL-6, TNF-α, SOD, MDA ↓ | IKK, p65↓, IκBα ↑ | - | [153] |
| Ebselen | 2-phenyl-1,2-benzisoselenazol-3[2H]-one] | organoselen-ium compound | Synthetic compound | 20 mg/kg/d | C57Bl/J6 apoE−/− mice + streptozotocin-induced diabetic apoE−/− mouse model | anti-atherosclerosis | VEGF, RAGE, NOX2, SOD-1, GPx1, catalase, TNF-α ↓ | p-IKK, p-JNK↓ | - | [42] |
| 0.03 μmol/L | 100 μmol/L H2O2 + HAECs-induced inflammation model | |||||||||
| Polyethylene glycol-superoxide dismutase | - | superoxide anion scavenger | - | 300 U/mL | 100 μmol/L homocysteine + HUVECs / HAECs to induce endothelial injury | anti-oxidant stress, anti-inflammatory | SOD ↓ | p-IκBα, IKKα, IKKβ, p65↓, IκBα ↑ | - | [156] |
| Prostaglandin A1 | - | - | 30 μmol/L | |||||||
| FABP 4/5 inhibitors | Compound A16/B8 | FABP 4/5 inhibitor | - | 30, 60 µM | 100 ng/ml LPS + RAW 264.7 macrophage cells -induced inflammation model | anti-inflammatory | MCP-1, TNF-α, IL-6, COX-2↓ | IKK, p-IKK, p65, p-p65 ↓ | IKK/NF-κB | [181] |
| BAY11-7082 analogs | 8-tosylamino quinoline | IKK inhibitor | - | 20 μmol/L | 1 μg/ml LPS + RAW264.7 macrophage cells and peritoneal macrophages-induced inflammation model | anti-inflammatory | NO, PGE2, TNF-α, IL-12p40, iNOS, COX-2 ↓ | p65, IKK, p-IKK, Akt, p-Akt, p-IκBα ↓, IκBα ↑ | Akt/NF-κB | [159] |
| Losartan | Losartan | Ang II type 1 receptor antagonist | - | 30 mg/kg | male apoE−/− mice + 5/6 nephrectomy to induce experimental mild uremia |
antiinflammatory anti-atherosclerosis |
BUN, CRE, CCL2/MCP-1, CX3CL1, TNF-α, IL-6↓ | IRE1α, p-IRE1α, GRP78, p-IKK, IKKα, IKKβ, p65 ↓, IκBα ↑ | IRE1α/IKK/NF-κB | [70] |
| 10 μmol/L | 1 μg/ml Ang II + RAW264.7 murine macrophages to induce inflammation model | |||||||||
| TMP195 | TMP195 | class IIa histone deacetylase inhibitor | 50 mg/kg/d, i.p | ApoE–/– mice + Western-type diet (21% fat) to induce atherosclerosis model | alleviate vascular inflammation | CXCL-1, CCL-2, TNF-α, IL-1β, IL-6, IL-8, VCAM-1 ↓ | IKKβ, p-p65 ↓ | IKKβ/NF-κB | [68] | |
| 3, 5 µmol/L | 50 ng/mL mouse recombinant + Human Peripheral Blood Mononuclear Cells (PBMCs) to induce inflammation model | |||||||||
| LCY-2-CHO | LCY-2-CHO | carbazole analogue | - | 3, 10 μM | 50 nM TNF-α/10 ng/ml IL-1β + Rat aortic VSMCs to induce inflammation model | anti-inflammatory | HO-1, Nrf2, Lamin B, iNOS, COX-2, IL-8, GRO-α, eNOS, p-eNOS, MBP ↓ | IKK, p-IKK ↓, IκBα ↑ | IKK/NF-κB | [160] |
| other drugs | ||||||||||
| β-defensins 3 | β-defensins 3 | Antimicrobial peptide | mucosa and epithelial cells | 15, 10, 5 μg/ml | 40 ng/ml TNF-α + (HUVECs + TPH-1)-induced inflammation and monocyte adhesion | anti-inflammatory, reduce monocyte adhesion | IL-6, IL-8, MCP-1, MIF, ICAM-1, VCAM-1, Bax, E-selectin, ROS, cleaved caspase-3/caspase-3↓, Bcl-2 ↑ | p-IKK, p-IκBα, p-p65↓, IκBα ↑ | NF-κB, MAPK | [162] |
| Glucagon-like peptide 1 | Liraglutide | incretin hormone | gut enteroendocrine cells | 30 nM | 5 ng/ml TNF-α + HUVECs-induced oxidative damage and inflammation | anti-oxidant stress, anti-inflammatory | SOD, catalase, GPx ↑ | PKC-α, P-IKKα/β, IKKα, IKKβ ↓, IκBα ↑ | - | [165] |
| s.c and tail i.v 0.2 mg/kg | 2.5 mg/kg adriamycin (i.p.) + GK rats for 6 weeks- induced diabetic cardiomyopathy model | anti-oxidant stress, alleviate myocardial fibrosis | MDA↓, SOD, GPx ↑ | PPARγ↑, p65 ↓ | - | [164] | ||||
| Mediterranean diet + CoQ | - | - | - | Med diet + CoQ | Clinical inclusion criteria: age 65 years or older, body mass index 20 ~ 40 kg/m2, total cholesterol concentration ≤ 8.0 mmol/L, and nonsmokers | anti-inflammatory | IL-1β, JNK-1, MMP-9, sXBP-1, CRT, BiP/Grp78 ↓ | p65, IKKβ ↓, IκBα ↑ | - | [182] |
| Jianpi huazhuo tiaozhi granules | - | chinese herbal medicine | - | 2.5%, 5%, 10% concentrations | 100 mg/L ox-LDL + RAW264.7 macrophage cells- induced oxidative stress injury model |
anti-oxidant stress anti-apoptosis |
MDA, SOD, ROS, NOX4, p22phox ↓ | IKKα, IKKβ, p65↓ | NOX/ROS/NF-κB | [62] |
| Fufang-Zhenzhu-Tiaozhi Capsule | - | Chinese herbal medicine | - | 0.66 mg/kg/d | male new zealand rabbits + balloon rubbing the endothelium of the abdominal aorta + a high fat diet (1.5% cholesterol, 0.5% sodium cholate, 8% lard, and 10% egg yolk powder)-induced atherosclerosis model |
lipid-lowering anti-inflammatory |
TC, TG, LDL-C, VLDL-C, IL-1, IL-6, IL-8, IL-12, TNF-α, MCP-1, ICAM-1 ↓ | p65, p-IκBα, IKK-α, p-IKKα/β↓, IκBα ↑ | IKK/NF-κB | [169] |
i.p. Intraperitoneally, p.o. Persral oral