1,629
Views
7
CrossRef citations to date
0
Altmetric
Review

Recent efforts in drug discovery on vascular inflammation and consequent atherosclerosis

ORCID Icon, &
Pages 411-427 | Received 29 Jul 2020, Accepted 09 Nov 2020, Published online: 15 Dec 2020

References

  • Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 2015;209(1):13–22.
  • Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol. 2009;27:165–197.
  • Marchio P, Guerra-Ojeda S, Vila JM, et al. Targeting early atherosclerosis: a focus on oxidative stress and inflammation. Oxid Med Cell Longev. 2019;8563845. doi: 10.1155/2019/8563845
  • Leopold JA, Loscalzo J. Oxidative mechanisms and atherothrombotic cardiovascular disease. Drug Discov Today Ther Strateg. 2008;5(1):5–13.
  • Muller WA. Getting leukocytes to the site of inflammation. Vet Pathol. 2013;50(1):7–22.
  • Ley K, Miller YI, Hedrick CC. Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol. 2011;31(7):1506–1516.
  • Chistiakov DA, Bobryshev YV, Orekhov AN. Macrophage-mediated cholesterol handling in atherosclerosis. J Cell Mol Med. 2016;20(1):17–28.
  • Ramel D, Gayral S, Sarthou MK, et al. Immune and smooth muscle cells interactions in atherosclerosis: how to target a breaking bad dialogue? Front Pharmacol. 2019;10:1276.
  • Fatkhullina AR, Peshkova IO, Koltsova EK. The role of cytokines in the development of atherosclerosis. Biochemistry (Mosc). 2016;81(11):1358–1370.
  • Sardu C, Gambardella J, Morelli MB, et al., Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J Clin Med. 2020;9(5): 1417.
  • Henry BM, de Oliveira MHS, Benoit S, et al. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7):1021–1028.
  • Meftahi GH, Jangravi Z, Sahraei H, et al. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”. Inflamm Res. 2020;69(9):825–839.
  • Gustafson D, Raju S, Wu R. et al. Overcoming barriers: the endothelium as a linchpin of coronavirus disease 2019 pathogenesis? Arterioscler Thromb Vasc Biol. ATVBAH. 2020;2020;40(8):1818–1829.
  • Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e21.
  • Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-angiotensin-aldosterone system inhibitors and risk of covid-19. N Engl J Med. 2020;382(25):2441–2448.
  • Rossi GP, Sanga V, Barton M. Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients. Elife. 2020;9:e57278.
  • Liberale L, Carbone F, Montecucco F, et al. Statins reduce vascular inflammation in atherogenesis: a review of underlying molecular mechanisms. Int J Biochem Cell Biol. 2020;122:105735.
  • Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97(12):1129–1135.
  • Ortego M, Bustos C, Hernandez-Presa MA, et al. Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis. 1999;147(2):253–261.
  • Marchesi S, Lupattelli G, Siepi D, et al. Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J Cardiovasc Pharmacol. 2000;36(5):617–621.
  • Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol. 2007;28(2):88–98.
  • Kunal S, Gupta K, Gupta S. Statins in COVID-19: A new ray of hope. Heart Lung. 2020;49:887–889.
  • Liberale L, Montecucco F, Camici GG, et al. Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce cardiovascular inflammation and outcomes. Curr Med Chem. 2017;24(14):1403–1416.
  • Filippatos TD, Christopoulou EC, Elisaf MS. Pleiotropic effects of proprotein convertase subtilisin/kexin type 9 inhibitors? Curr Opin Lipidol. 2018;29(4):333–339.
  • Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220(2):381–386.
  • Zhang Y, Zhu CG, Xu RX, et al. Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J Clin Lipidol. 2014;8(5):494–500.
  • Landlinger C, Pouwer MG, Juno C, et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden. CETP mice Eur Heart J. 2017;38(32):2499–2507.
  • Bernelot Moens SJ, Neele AE, Kroon J, et al. PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia. Eur Heart J. 2017;38(20):1584–1593.
  • Sahebkar A, Di Giosia P, Stamerra CA, et al. Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms. Br J Clin Pharmacol. 2016;81(6):1175–1190.
  • Baruch A, Mosesova S, Davis JD, et al. Effects of RG7652, a monoclonal antibody against PCSK9, on LDL-C, LDL-C subfractions, and inflammatory biomarkers in patients at high risk of or with established coronary heart disease (from the phase 2 EQUATOR study). Am J Cardiol. 2017;119(10):1576–1583.
  • Xu J, Zou MH. Molecular insights and therapeutic targets for diabetic endothelial dysfunction. Circulation. 2009;120(13):1266–1286.
  • Man AWC, Li H, Xia N. The role of sirtuin1 in regulating endothelial function, arterial remodeling and vascular aging. Front Physiol. 2019;10:1173.
  • Huang NL, Chiang SH, Hsueh CH, et al. Metformin inhibits TNF-alpha-induced IkappaB kinase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int J Cardiol. 2009;134(2):169–175.
  • Hattori Y, Suzuki K, Hattori S, et al. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 2006;47(6):1183–1188.
  • Chen Z, Yu J, Fu M, et al. Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway. Biochem Pharmacol. 2020;177:113951.
  • Rao X, Deiuliis JA, Mihai G, et al. Monocyte DPP4 expression in human atherosclerosis is associated with obesity and dyslipidemia. Diabetes Care. 2018;41(1):e1–e3.
  • Shah Z, Kampfrath T, Deiuliis JA, et al., Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation. 2011;124(21): 2338–2349.
  • Wicinski M, Gorski K, Wodkiewicz E, et al. Vasculoprotective effects of vildagliptin focus on atherogenesis. Int J Mol Sci. 2020;21(7):2275.
  • Birkeland KI, Jorgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol. 2017;5(9):709–717.
  • Verma S, Mazer CD, Al-Omran M, et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation. 2018;137(4):405–407.
  • Doggrell SA. Cardiovascular outcomes with canagliflozin - is it on the CANVAS? Expert Opin Pharmacother. 2018;19(2):163–166.
  • Nasiri-Ansari N, Dimitriadis GK, Agrogiannis G, et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol. 2018;17(1):106.
  • Leng W, Ouyang X, Lei X, et al. The SGLT-2 inhibitor dapagliflozin has a therapeutic effect on atherosclerosis in diabetic apoE(-/-) Mice. Mediators Inflamm. 2016;6305735. doi: 10.1155/2016/6305735.
  • Bosch A, Ott C, Jung S, et al. How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial. Cardiovasc Diabetol. 2019;18(1):44.
  • Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol. 2008;4(1):34–42.
  • Ridker PM, Everett BM, Thuren T, et al., Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12): 1119–1131.
  • Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391(10118):319–328.
  • Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS). Eur Heart J. 2018;39(38):3499–3507.
  • Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. 2001;104(14):1598–1603.
  • Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med. 2002;195(2):245–257.
  • Ridker PM, MacFadyen JG, Thuren T, et al. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1beta inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J. 2020;41(23):2153–2163.
  • Tremoulet AH, Jain S, Kim S, et al. Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial). Contemp Clin Trials. 2016;48:70–75.
  • Nowak KL, Chonchol M, Ikizler TA, et al. IL-1 inhibition and vascular function in CKD. J Am Soc Nephrol. 2017;28(3):971–980.
  • Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–420.
  • Chen S, Wang Y, Pan Y, et al. Novel role for tranilast in regulating NLRP3 ubiquitination, vascular inflammation, and atherosclerosis. J Am Heart Assoc. 2020;9(12):e015513.
  • Tsujikawa LM, Fu L, Das S, et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenetics. 2019;11(1):102.
  • Nicholls SJ, Ray KK, Johansson JO, et al. Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease. Am J Cardiovasc Drugs. 2018;18(2):109–115.
  • Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–2505.
  • Bucci M, Papapetropoulos A, Vellecco V, et al. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler Thromb Vasc Biol. 2010;30(10):1998–2004.
  • Martelli A, Testai L, Breschi MC, et al. Vasorelaxation by hydrogen sulphide involves activation of Kv7 potassium channels. Pharmacol Res. 2013;70(1):27–34.
  • Martelli A, Testai L, Citi V, et al. Pharmacological characterization of the vascular effects of aryl isothiocyanates: is hydrogen sulfide the real player? Vascul Pharmacol. 2014;60(1):32–41.
  • Barresi E, Nesi G, Citi V, et al. Iminothioethers as hydrogen sulfide donors: from the gasotransmitter release to the vascular effects. J Med Chem. 2017;60(17):7512–7523.
  • Martelli A, Citi V, Calderone V. Vascular effects of H2S-donors: fluorimetric detection of H2S generation and ion channel activation in human aortic smooth muscle cells. Methods Mol Biol. 2019;79–87.
  • Martelli A, Piragine E, Citi V, et al. Erucin exhibits vasorelaxing effects and antihypertensive activity by H2 S-releasing properties. Br J Pharmacol. 2020;177(4):824–835.
  • Citi V, Martelli A, Bucci M, et al. Searching for novel hydrogen sulfide donors: the vascular effects of two thiourea derivatives. Pharmacol Res. 2020;159:105039.
  • Roviezzo F, Bertolino A, Sorrentino R, et al. Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation. Pharmacol Res. 2015;100:85–92.
  • Marino A, Martelli A, Citi V, et al. The novel H2 S donor 4-carboxy-phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium. Br J Pharmacol. 2016;173(22):3222–3234.
  • Hashmp SF, Sattar MZA, Rathore HA, et al. A critical review on pharmacological significance of hydrogen sulfide (h(2)s) on nf-kappab concentration and icam-1 expression in renal ischemia reperfusion injury. Acta Pol Pharm. 2017;74(3):747–752.
  • Wilinski B, Wilinski J, Somogyi E, et al. Atorvastatin affects the tissue concentration of hydrogen sulfide in mouse kidneys and other organs. Pharmacol Rep. 2011;63(1):184–188.
  • Martelli A, Testai L, Citi V, et al. Arylthioamides as H2S donors: l-cysteine-activated releasing properties and vascular effects in vitro and in vivo. ACS Med Chem Lett. 2013;4(10):904–908.
  • Mitidieri E, Tramontano T, Gurgone D, et al. Mercaptopyruvate acts as endogenous vasodilator independently of 3-mercaptopyruvate sulfurtransferase activity. Nitric Oxide. 2018;75:53–59.
  • Severino B, Corvino A, Fiorino F, et al. 1,2,4-Thiadiazolidin-3,5-diones as novel hydrogen sulfide donors. Eur J Med Chem. 2018;143:1677–1686.
  • Citi V, Piragine E, Testai L, et al. The role of hydrogen sulfide and H2S-donors in myocardial protection against ischemia/reperfusion injury. Curr Med Chem. 2018;25(34):4380–4401.
  • Testai L, Marino A, Piano I, et al. The novel H2S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoKATP channels and reduction of oxidative stress. Pharmacol Res. 2016;113(Pt A):290–299.
  • Citi V, Corvino A, Fiorino F, et al. Structure-activity relationships study of isothiocyanates for H2S releasing properties: 3-Pyridyl-isothiocyanate as a new promising cardioprotective agent. J Adv Res. 2020; DOI:10.1016/j.jare.2020.02.017.
  • Testai L, D’Antongiovanni V, Piano I, et al. Different patterns of H2S/NO activity and cross-talk in the control of the coronary vascular bed under normotensive or hypertensive conditions. Nitric Oxide. 2015;47:25–33.
  • Calderone V, Martelli A, Testai L, et al. Using hydrogen sulfide to design and develop drugs. Expert Opin Drug Discov. 2016;11(2):163–175.
  • Citi V, Martelli A, Gorica E, et al. Role of hydrogen sulfide in endothelial dysfunction: pathophysiology and therapeutic approaches. J Adv Res. 2020;in press. doi: 10.1016/j.jare.2020.05.015
  • Brancaleone V, Esposito I, Gargiulo A, et al. D-Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-gamma-lyase. Br J Pharmacol. 2016;173(9):1556–1565.
  • Zheng Q, Pan L, Ji Y. H 2S protects against diabetes-accelerated atherosclerosis by preventing the activation of NLRP3 inflammasome. J Biomed Res. 2019;34(2):94–102.
  • Gojon G, Morales GA. SG1002 and catenated divalent organic sulfur compounds as promising hydrogen sulfide prodrugs. Antioxid Redox Signal. 2020;33:1010–1045.
  • Bibli SI, Hu J, Sigala F, et al. Cystathionine gamma lyase sulfhydrates the RNA binding protein human antigen r to preserve endothelial cell function and delay atherogenesis. Circulation. 2019;139(1):101–114.
  • Martelli A, Rapposelli S, Calderone V. NO-releasing hybrids of cardiovascular drugs. Curr Med Chem. 2006;13(6):609–625.
  • Martelli A, Testai L, Anzini M, et al. The novel anti-inflammatory agent VA694, endowed with both NO-releasing and COX2-selective inhibiting properties, exhibits NO-mediated positive effects on blood pressure, coronary flow and endothelium in an experimental model of hypertension and endothelial dysfunction. Pharmacol Res. 2013;78:1–9.
  • Anzini M, Di Capua A, Valenti S, et al. Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors. J Med Chem. 2013;56(8):3191–3206.
  • Sparatore A, Perrino E, Tazzari V, et al. Pharmacological profile of a novel H(2)S-releasing aspirin. Free Radic Biol Med. 2009;46(5):586–592.
  • Fortunato S, Lenzi C, Granchi C, et al. First examples of H2S-releasing glycoconjugates: stereoselective synthesis and anticancer activities. Bioconjug Chem. 2019;30(3):614–620.
  • Sestito S, Pruccoli L, Runfola M, et al. Design and synthesis of H2S-donor hybrids: a new treatment for alzheimer’s disease? Eur J Med Chem. 2019;184:111745.
  • Rapposelli S, Gambari L, Digiacomo M, et al. A Novel H2S-releasing Amino-Bisphosphonate which combines bone anti-catabolic and anabolic functions. Sci Rep. 2017;7(1):11940.
  • Sestito S, Daniele S, Pietrobono D, et al. Memantine prodrug as a new agent for Alzheimer’s Disease. Sci Rep. 2019;9(1):4612.
  • Zhao AS, Zou D, Wang HH, et al. Hydrogen sulphide-releasing aspirin enhances cell capabilities of anti-oxidative lesions and anti-inflammation. Med Gas Res. 2019;9(3):145–152.
  • Zhang H, Guo C, Zhang A, et al. Effect of S-aspirin, a novel hydrogen-sulfide-releasing aspirin (ACS14), on atherosclerosis in apoE-deficient mice. Eur J Pharmacol. 2012;697(1–3):106–116.
  • Xu Y, Jiang W, Zhong L, et al. miR-195–5p alleviates acute kidney injury through repression of inflammation and oxidative stress by targeting vascular endothelial growth factor A. Aging (Albany NY). 2020;12(11):10235–10245.
  • Canfran-Duque A, Rotllan N, Zhang X, et al. Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol Med. 2017;9(9):1244–1262.
  • Chu M, Qin S, Wu R, et al. Role of MiR-126a-3p in Endothelial Injury in Endotoxic Mice. Crit Care Med. 2016;44(8):e639–e650.
  • Sun P, Li L, Liu YZ, et al. MiR-181b regulates atherosclerotic inflammation and vascular endothelial function through Notch1 signaling pathway. Eur Rev Med Pharmacol Sci. 2019;23(7):3051–3057.
  • Gao C, Huang Q, Liu C, et al. Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines. Nat Commun. 2020;11(1):2622.
  • Zhang XQ, Even-Or O, Xu X, et al. Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis. Adv Healthc Mater. 2015;4(2):228–236.
  • Tang J, Baxter S, Menon A, et al. Immune cell screening of a nanoparticle library improves atherosclerosis therapy. Proc Natl Acad Sci U S A. 2016;113(44):E6731–E6740.
  • Tao W, Yurdagul A Jr., Kong N, et al. siRNA nanoparticles targeting CaMKIIgamma in lesional macrophages improve atherosclerotic plaque stability in mice. Sci Transl Med. 2020;12(553). DOI:10.1126/scitranslmed.aay1063.
  • Prasad K. Natural products in regression and slowing of progression of atherosclerosis. Curr Pharm Biotechnol. 2010;11(8):794–800.
  • Wicinski M, Socha M, Walczak M, et al. Beneficial effects of resveratrol administration-focus on potential biochemical mechanisms in cardiovascular conditions. Nutrients. 2018;10(11):1813.
  • Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res. 2019;124(2):315–327.
  • Schwager J, Richard N, Widmer F, et al. Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells. BMC Complement Altern Med. 2017;17(1):309.
  • Rivera L, Moron R, Zarzuelo A, et al. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol. 2009;77(6):1053–1063.
  • Yar AS, Menevse S, Alp E, et al. The effects of resveratrol on cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein levels in diabetic rat kidneys. Mol Biol Rep. 2010;37(5):2323–2331.
  • Xu L, Botchway BOA, Zhang S, et al. Inhibition of NF-kappaB signaling pathway by resveratrol improves spinal cord injury. Front Neurosci. 2018;12:690.
  • Tome-Carneiro J, Larrosa M, Yanez-Gascon MJ, et al. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res. 2013;72:69–82.
  • Sawda C, Moussa C, Turner RS. Resveratrol for Alzheimer’s disease. Ann N Y Acad Sci. 2017;1403(1):142–149.
  • Yang X, Li Y, Li Y, et al. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol. 2017;8:600.
  • Chow SE, Hshu YC, Wang JS, et al. Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages. J Appl Physiol. 2007;102(4):1520–1527.
  • Kuhn G, Pallauf K, Schulz C, et al. Resveratrol modulates desaturase expression and fatty acid composition of cultured hepatocytes. Front Nutr. 2018;5:106.
  • Xia N, Daiber A, Forstermann U, et al. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2017;174(12):1633–1646.
  • Sandoo A, van Zanten JJ, Metsios GS, et al. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J. 2010;4:302–312.
  • Xia N, Forstermann U, Li H. Resveratrol and endothelial nitric oxide. Molecules. 2014;19(10):16102–16121.
  • Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016;17(11):679–690.
  • El-Mowafy AM, Alkhalaf M, Nassar NN. Resveratrol reverses ET-1-evoked mitogenic effects in human coronary arterial cells by activating the kinase-G to inhibit ERK-enzymes. Int J Cardiol. 2009;136(3):263–269.
  • Dyck GJB, Raj P, Zieroth S, et al., The effects of resveratrol in patients with cardiovascular disease and heart failure: a narrative review. Int J Mol Sci. 2019;20(4): 63–71.
  • Aguirre L, Portillo MP, Hijona E, et al. Effects of resveratrol and other polyphenols in hepatic steatosis. World J Gastroenterol. 2014;20(23):7366–7380.
  • Pal S, Ho N, Santos C, et al. Red wine polyphenolics increase LDL receptor expression and activity and suppress the secretion of ApoB100 from human HepG2 cells. J Nutr. 2003;133(3):700–706.
  • Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14(5):612–622.
  • Martelli A, Citi V, Testai L, et al. Organic Isothiocyanates as Hydrogen Sulfide Donors. Antioxid Redox Signal. 2020;32(2):110–144.
  • Citi V, Martelli A, Testai L, et al. Hydrogen sulfide releasing capacity of natural isothiocyanates: is it a reliable explanation for the multiple biological effects of Brassicaceae? Planta Med. 2014;80(8–9):610–613.
  • Lucarini E, Micheli L, Trallori E, et al. Effect of glucoraphanin and sulforaphane against chemotherapy-induced neuropathic pain: kv7 potassium channels modulation by H2 S release in vivo. Phytother Res. 2018;32(11):2226–2234.
  • Citi V, Piragine E, Pagnotta E, et al. Anticancer properties of erucin, an H2 S-releasing isothiocyanate, on human pancreatic adenocarcinoma cells (AsPC-1). Phytother Res. 2019;33(3):845–855.
  • Ercolano G, De Cicco P, Frecentese F, et al. Anti-metastatic properties of naproxen-HBTA in a murine model of cutaneous melanoma. Front Pharmacol. 2019;10:66.
  • Benavides GA, Squadrito GL, Mills RW, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U S A. 2007;104(46):17977–17982.
  • Wang ZJ, Wu J, Guo W, et al. Atherosclerosis and the hydrogen sulfide signaling pathway - therapeutic approaches to disease prevention. Cell Physiol Biochem. 2017;42(3):859–875.
  • Asdaq SM. Antioxidant and hypolipidemic potential of aged garlic extract and its constituent, s-allyl cysteine, in rats. Evid Based Complement Alternat Med. 2015;328545. doi: 10.1155/2015/328545.
  • Reddy GD, Reddy AG, Rao GS, et al. Interaction study on garlic and atorvastatin with reference to nephrotoxicity in dyslipidaemic rats. Toxicol Int. 2010;17(2):90–93.
  • Morihara N, Ide N, Weiss N. Aged garlic extract inhibits CD36 expression in human macrophages via modulation of the PPARgamma pathway. Phytother Res. 2010;24(4):602–608.
  • Brito VB, Rocha JB, Folmer V, et al. Diphenyl diselenide and diphenyl ditelluride increase the latency for 4-aminopyridine-induced chemical seizure and prevent death in mice. Acta Biochim Pol. 2009;56(1):125–134.
  • Arreola R, Quintero-Fabian S, Lopez-Roa RI, et al. Immunomodulation and anti-inflammatory effects of garlic compounds. J Immunol Res. 2015;401630. doi: 10.1155/2015/401630.
  • Kimura S, Tung YC, Pan MH, et al. Black garlic: a critical review of its production, bioactivity, and application. J Food Drug Anal. 2017;25(1):62–70.
  • Ha AW, Kim WK. Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway. Nutr Res Pract. 2017;11(3):206–213.
  • Onasanwo SA, Velagapudi R, El-Bakoush A, et al. Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism. Mol Cell Biochem. 2016;414(1–2):23–36.
  • Bai Y, Wang X, Zhao S, et al. Sulforaphane protects against cardiovascular disease via Nrf2 activation. Oxid Med Cell Longev. 2015;407580. doi: 10.1155/2015/407580.
  • Hung CN, Huang HP, Wang CJ, et al. Sulforaphane inhibits TNF-alpha-induced adhesion molecule expression through the Rho A/ROCK/NF-kappaB signaling pathway. J Med Food. 2014;17(10):1095–1102.
  • Shan Y, Zhao R, Geng W, et al. Protective effect of sulforaphane on human vascular endothelial cells against lipopolysaccharide-induced inflammatory damage. Cardiovasc Toxicol. 2010;10(2):139–145.
  • Youn HS, Kim YS, Park ZY, et al. Sulforaphane suppresses oligomerization of TLR4 in a thiol-dependent manner. J Immunol. 2010;184(1):411–419.
  • Nallasamy P, Si H, Babu PV, et al. Sulforaphane reduces vascular inflammation in mice and prevents TNF-alpha-induced monocyte adhesion to primary endothelial cells through interfering with the NF-kappaB pathway. J Nutr Biochem. 2014;25(8):824–833.
  • Cook-Mills JM, Marchese ME, Abdala-Valencia H. Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants. Antioxid Redox Signal. 2011;15(6):1607–1638.
  • Belinky PA, Aviram M, Fuhrman B, et al. The antioxidative effects of the isoflavan glabridin on endogenous constituents of LDL during its oxidation. Atherosclerosis. 1998;137(1):49–61.
  • Wang G, Sun G, Wang Y, et al. Glabridin attenuates endothelial dysfunction and permeability, possibly via the MLCK/p-MLC signaling pathway. Exp Ther Med. 2019;17(1):107–114.
  • Hu Q, Zhang T, Yi L, et al. Dihydromyricetin inhibits NLRP3 inflammasome-dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells. Biofactors. 2018;44(2):123–136.
  • Liu TT, Zeng Y, Tang K, et al. Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice. Atherosclerosis. 2017;262:39–50.
  • Pang H, Wu L, Tang Y, et al. Chemical analysis of the herbal medicine salviae miltiorrhizae radix et rhizoma (danshen). Molecules. 2016;21(1):51.
  • Zhu H, Chen Z, Ma Z, et al. Tanshinone IIA protects endothelial cells from H(2)O(2)-induced injuries via PXR activation. Biomol Ther (Seoul). 2017;25(6):599–608.
  • Cheng Q, Zhao Y, Li J. Sodium tanshinone IIA sulfonate suppresses heat stress-induced endothelial cell apoptosis by promoting NO production through upregulating the PI3K/AKT/eNOS pathway. Mol Med Rep. 2017;16(2):1612–1618.
  • Li ZM, Xu SW, Liu PQ. Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin. 2018;39(5):802–824.
  • Liu Z, Wang J, Huang E, et al. Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1. J Lipid Res. 2014;55(2):201–213.
  • Shahidi F, Ambigaipalan P. Omega-3 polyunsaturated fatty acids and their health benefits. Annu Rev Food Sci Technol. 2018;9:345–381.
  • Chang CL, Deckelbaum RJ. Omega-3 fatty acids: mechanisms underlying ‘protective eff.ects’ in atherosclerosis. Curr Opin Lipidol. 2013;24(4):345–350.
  • Sato T, Horikawa M, Takei S, et al. Preferential Incorporation of Administered Eicosapentaenoic Acid Into Thin-Cap Atherosclerotic Plaques. Arterioscler Thromb Vasc Biol. 2019;39(9):1802–1816.
  • Wu MY, Li CJ, Hou MF, et al. New insights into the role of inflammation in the pathogenesis of atherosclerosis. Int J Mol Sci. 2017;18(10):2034.
  • Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 2008;13:1813–1826.
  • Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–1098.
  • Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22.
  • Budoff MJ, Muhlestein JB, Bhatt DL, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results. Cardiovasc Res. 2020. DOI:10.1093/cvr/cvaa184.
  • Chatterjee S, Bandyopadhyay D, Ghosh RK, et al. SGLT-2 inhibitors and peripheral artery disease: a statistical hoax or reality? Curr Probl Cardiol. 2019;44(7):207–222.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.