Salvianolic Acid B and Ginsenoside Re Synergistically Protect Against Ox-LDL-Induced Endothelial Apoptosis Through the Antioxidative and Antiinflammatory Mechanisms

Abstract

Salvianolic acid B (SalB) and ginsenoside Re (Re) protect endotheliocytes against apoptosis through different mechanisms. However, whether both compounds could synergistically protect endothelial cells against oxidized low-density lipoprotein (Ox-LDL)-induced apoptosis is unclear. This study aimed to assess the protective effect of combined SalB and Re (SR) treatment on Ox-LDL-induced endothelial apoptosis and to explore the mechanism underlying this effect. Results showed that SalB, Re, or SR could protect against Ox-LDL-induced endothelial apoptosis. Furthermore, the composition of SR was optimized through central composite design with response surface methodology. SR with a composition of 60 μg/mL of SalB and 120 μg/mL of Re exerted the optimal protective effect. Network pharmacology research revealed that SalB and Re in SR synergistically protect against Ox-LDL-induced endothelial apoptosis by regulating oxidative stress and phlogistic pathways. In vitro experiments confirmed these results. Compared with the same dose of SalB or Re alone, SR significantly decreased the contents of inflammatory mediators and increased the activities of antioxidant enzymes. SR could synergistically restore the balanced redox state of the cells and inhibit the activation of nuclear transcription factor kappa B and the caspase cascade by activating the phosphatidylinositol 3 kinase/protein kinase B pathway and inhibiting the phosphorylation of p38 mitogen-activated protein kinase. These pathways are regulated by down-regulating the expression of lectin-like Ox-LDL receptor-1 and NADPH oxidase and up-regulating the expression of estrogen receptor alpha. Therefore, SR effectively prevents Ox-LDL-induced endothelial apoptosis through antioxidative and antiinflammatory mechanisms.

Hormesis and Ginseng: Ginseng Mixtures and Individual Constituents Commonly Display Hormesis Dose Responses, Especially for Neuroprotective Effects

“…The Yang et al [119] study did not address the issue of a direct low dose stimulation but demonstrated an hormetic dose response in a preconditioning protocol using a broader dose range which had a 3.5-fold higher maximum dose tested than in the Huang et al [118] study. This study also used Ox-LDL as the stressor rather than hydrogen peroxide.…”

“…The ginsenoside Re has been reported to display hormetic dose responses, but to a more limited extent than Rg1, Rb1, and Rd. Amongst these hormetic publications were two papers using HUVEC to assess whether Re may reduce oxidative stress and its potential value in diminishing the risk of developing atherosclerosis [118,119]. The remaining three hormetic papers dealt with (1) the capacity of Re to promote nerve cell regeneration by enhancing the proliferation, differentiation, and migration of Schwann cells in the Sprague-Dawley rat model of sciatic nerve crush injury [120], (2) the capacity of Re to prevent toxicity induced by beta amyloid in SH-SY5Y cells [121], and (3) whether Re could block I/R toxicity using PC 12 cells [52].…”

Pharmacokinetics of Active Ingredients of Salvia miltiorrhiza and Carthamus tinctorius in Compatibility in Normal and Cerebral Ischemia Rats: A Comparative Study

“…It is often used for the treatment of cardio-cerebral-vascular disease caused by blood stasis [30,44,45]. Existing studies have shown that DSS, SAA, SAB, and HSYA have the ability to scavenge free oxygen radicals, inhibit apoptosis, and prevent inflammation [5][6][7][8][9][10][11][12][13][14][15][16][17][18][25][26][27][28], thereby protecting against cerebral ischemic injury. Over the past few years, the Dan-Hong injection and its ingredients have been widely studied in clinical and basic research [30,[46][47][48].…”

“…SAA can scavenge free oxygen radicals [5,6] and has a protective effect on cell damage caused by oxidative stress [7,8]. SAB not only has strong antioxidant effects [9][10][11][12][13], but it can also inhibit apoptosis [14][15][16][17][18]. DSS is an important water-soluble ingredient, which has been pharmacologically shown to improve blood circulation [19] and eliminate blood stasis [20,21], and can also protect against cerebral ischemia reperfusion injury [22].…”

CD137 Signaling Promotes Endothelial Apoptosis by Inhibiting Nrf2 Pathway, and Upregulating NF-κB Pathway

“…Activation of Nrf2 activates a variety of downstream proteins such as HO-1, MnSOD, and NQO1, which are involved in promoting cell oxidation resistance and enhancing the levels of intracellular antioxidant GPx [3]. Recent studies have revealed that activation of the Nrf2 pathway can reduce cardiac toxicity and improve endothelial dysfunction in the context of oxidative stress [4,5]. Oxidative stress can abnormally activate NF-κB, which is a ubiquitous transcription factor that plays a critical role in cell proliferation, differentiation, and apoptosis.…”